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Overview of the initial evaluation, diagnosis, and staging of patients with suspected

lung cancer
Authors:
Karl W Thomas, MD
Michael K Gould, MD, MS
Section Editor:
David E Midthun, MD
Deputy Editor:
Geraldine Finlay, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Dec 2016. | This topic last updated: Jul 14, 2016.

INTRODUCTION — Lung cancer is the leading cause of cancer deaths worldwide in both
men and women [1]. Non-small cell lung cancer (NSCLC) accounts for the majority
(approximately 85 percent) of lung cancers with the remainder as mostly small cell lung
cancer (SCLC). Most patients present for diagnostic evaluation because of symptoms
suspicious for lung cancer or an incidental finding on chest imaging. The goal of the initial
evaluation is to obtain sufficient clinical and radiologic information to guide diagnostic
tissue biopsy, staging, and treatment.

This review will provide a general overview of the initial evaluation, diagnosis, and staging
of patients with suspected lung cancer. Typically, the approach for those with suspected
NSCLC is the same for those with suspected SCLC, although most of the data is derived
from patients with suspected NSCLC. Thus, throughout the text of this topic the term
NSCLC is frequently cited. The approach to a patient and modalities used for tissue biopsy
and treatment of patients with NSCLC are reviewed elsewhere. (See "Selection of modality
for diagnosis and staging of patients with suspected non-small cell lung
cancer" and "Procedures for tissue biopsy in patients with suspected non-small cell lung
cancer" and "Management of stage I and stage II non-small cell lung
cancer" and "Management of stage III non-small cell lung cancer" and "Overview of the
treatment of advanced non-small cell lung cancer" and "Personalized, genotype-directed
therapy for advanced non-small cell lung cancer".)

GENERAL GOALS AND TIMING OF EVALUATION — For each patient with suspected
lung cancer the overall goal is a timely diagnosis and accurate staging so appropriate
therapy can be administered. The general approach should be tailored to the individual
values and preferences of the patient, the clinical presentation, as well as the technical
expertise at the practicing institution. Our approach to the initial evaluation and radiologic
staging of patients with suspected lung cancer is concordant with the guidelines issued by
the American College of Chest Physicians (ACCP) and the National Comprehensive
Cancer Network (NCCN) [2-4]. The role of multidisciplinary teams in the timely evaluation
of patients with suspected lung cancer is discussed in detail separately. (See "Selection of
modality for diagnosis and staging of patients with suspected non-small cell lung cancer",
section on 'Role of multidisciplinary teams'.)

Goals — The major goals of the initial evaluation of a patient with suspected lung cancer
are to assess the following (figure 1):

●Clinical extent and stage of disease


●Optimal target site and modality for the first tissue biopsy
●Specific histological subtype
●Presence of comorbidities, secondary complications, and paraneoplastic syndromes
that influence treatment options and outcome
●Patient values and preferences that influence diagnostic and therapeutic choices

The preferred approach uses imaging as a road map and invasive biopsy as a tool to
confirm both the histopathological diagnosis and the stage of disease. When feasible,
diagnosis and staging should be established concurrently by targeting for invasive biopsy
the abnormality that would yield the most advanced stage. However, some patients will
require multiple imaging studies and/or invasive procedures for tissue sampling. Although
imaging and sampling procedures are often described separately, in practice, the
pathways to diagnosis and staging are often synchronous. As an example, thoracentesis
with cytology examination of fluid or transbronchial needle aspiration biopsy of mediastinal
lymphadenopathy may provide both diagnosis and staging data.

No single diagnostic algorithm sufficiently addresses the complexity and variation in


disease patterns of lung cancer. The local expertise and resources, as well as institution
and health system factors, may influence the approach taken. Multi-disciplinary teams may
help facilitate an investigative plan so that therapy can be implemented in a timely fashion.
The selection of a biopsy modality, the role of multidisciplinary teams, and the procedures
used to obtain tissue are discussed in detail separately. (See "Selection of modality for
diagnosis and staging of patients with suspected non-small cell lung
cancer" and "Selection of modality for diagnosis and staging of patients with suspected
non-small cell lung cancer", section on 'Role of multidisciplinary teams' and "Procedures
for tissue biopsy in patients with suspected non-small cell lung cancer".)

Timeliness of the evaluation — Despite conflicting data, there is consensus that the
initial evaluation of patients with suspected lung cancer be performed in a timely and
efficient manner [4]. Most patients can be investigated in an outpatient setting. However,
patient factors including comorbidities (eg, respiratory failure, hemoptysis, debilitating
metastases to the brain or bone) may lead clinicians to conduct the work-up in a hospital
setting. Expedient diagnosis is especially important when there is concern for small cell
carcinoma, such as in patients with large, central tumors or evidence of bulky mediastinal
disease. (See 'Differential diagnosis' below.)
While some observational series show improved time to therapy with system-driven
interventions (eg, multidisciplinary clinic and tumor board, healthcare and hospital
associated rapid investigation systems), few studies report improved patient-relevant
outcomes due to the intervention [5-7]. We prefer that patients with tolerable symptoms
and no evidence of complications complete the initial evaluation within six weeks [4]. While
most cases of non-small cell lung cancer (NSCLC) are slow growing with a typical
doubling time of 90 to 180 days, some cases are rapidly growing and can progress during
the evaluation period. One case series reported disease progression in 13, 31, and 46
percent of patients at 4, 8, and 16 weeks, respectively, with distant metastasis newly
evident in 3, 13, and 13 percent of cases [8]. These data suggest that it may be helpful to
reevaluate disease stage with imaging in some patients who have a delay in completion of
evaluation by eight weeks or more.

Patient values and preferences — It is critical that the initial evaluation of patients with
suspected lung cancer establish good communication that adequately assesses patient
goals [9]. Patient preferences vary significantly along a spectrum from aggressive
investigation aimed at cure to minimal or no investigation and symptom-directed treatment
only. Establishing patient preferences early facilitates shared decision-making for future
diagnostic and therapeutic choices.

CLINICAL MANIFESTATIONS

Signs and symptoms — The majority of patients who present with clinical signs or
symptoms due to lung cancer have advanced disease [10]. The most common presenting
manifestations are the following [11-14]:

●Cough – 50 to 75 percent
●Hemoptysis – 25 to 50 percent
●Dyspnea – 25 percent
●Chest pain – 20 percent

Less common manifestations include the signs and symptoms or laboratory abnormalities
of distant metastases or paraneoplastic syndromes. When any of these manifestations are
present in a patient with suspected lung cancer, they should prompt additional testing.
(See 'Laboratory' below and 'Radiographic staging' below.)

Lung cancer should always be suspected in a current or former smoker with new onset of
cough or hemoptysis. Both non-small cell lung cancer (NSCLC) and small cell lung cancer
(SCLC) can present with similar symptoms, and few clinical features reliably distinguish
them from each other. Features that suggest SCLC include rapidly progressive symptoms
and the presence of paraneoplastic syndromes (eg, syndrome of inappropriate antidiuretic
hormone), bulky multi-station mediastinal metastasis, superior vena cava syndrome, and
bone and brain metastases. In contrast, Pancoast’s syndrome and hypercalcemia are
more frequently encountered in patients with NSCLC.
The spectrum of clinical signs and symptoms including paraneoplastic syndromes that can
be seen in patients with lung cancer are discussed in detail separately. (See "Overview of
the risk factors, pathology, and clinical manifestations of lung cancer", section on 'Clinical
manifestations'.)

Initial imaging — Asymptomatic patients may come to clinical attention during screening
or following the incidental detection of imaging abnormalities. Patients with symptoms
suggestive of primary or metastatic lung cancer should undergo initial imaging with chest
radiograph. Every attempt should be made to obtain and review any prior chest imaging
studies to determine the age and growth pattern of identified abnormalities. Solid-
appearing lesions on chest computed tomography (CT) that are stable in size for at least
two years are highly unlikely to represent lung carcinoma [15]. Malignant non-solid and
part-solid nodules often grow more slowly, so a longer period of stability is needed to
exclude malignancy. (See "Diagnostic evaluation and management of the solitary
pulmonary nodule".)

Findings suggestive of cancer or cancer-related complications on chest radiograph should


be further evaluated with contrast-enhanced CT chest. (See 'Radiographic
staging' below.)

The following features should prompt further evaluation for lung cancer, regardless of
symptoms:

●Chest radiograph demonstrating a new or enlarging focal lesion, a pleural effusion,


pleural nodularity, enlarged hilar or paratracheal nodes, endobronchial lesion, post-
obstructive pneumonia or segmental or lobar atelectasis. (See "Diagnostic evaluation
and management of the solitary pulmonary nodule", section on 'Computed
tomography' and "Imaging of non-small cell lung cancer", section on 'Chest
radiography'.)
●CT findings suggestive of malignancy in a patient with a solitary pulmonary nodule
include large lesion size (eg, >15 mm), irregular or spiculated borders, upper lobe
location, thick-walled cavitation, presence or development of a solid component within
a ground glass lesion, and detection of growth by follow-up imaging. The finding of
multiple nodules in a patient with a known or suspected extrathoracic malignancy
strongly suggests pulmonary metastasis. (See "Computed tomographic and positron
emission tomographic scanning of pulmonary nodules", section on 'Computed
tomography (CT)'.)

Estimation of cancer probability — The probability of lung cancer may be estimated by


using clinical data (eg, patient's age, sex, family history, and presence of emphysema) as
well as the radiographic features of the nodule (calculator 1). If lung cancer is suspected
based upon symptoms, CT findings, or probability calculations, formal CT staging focused
on the primary tumor (T-factor in Tumor Node Metastasis staging) and lymph nodes (N)
should be obtained, if not already performed. Estimating the probability of cancer for
solitary pulmonary nodules, the approach to initial radiographic staging, and modalities
used for imaging patients with suspected NSCLC are discussed in detail separately.
(See "Diagnostic evaluation and management of the solitary pulmonary nodule", section
on 'Assessing the risk of malignancy' and 'Radiographic staging' below and "Imaging of
non-small cell lung cancer".)

INITIAL EVALUATION

Clinical — Every patient with suspected lung cancer should undergo a thorough history
and physical exam. The presence of signs or symptoms typically indicates advanced
disease and portends a poor prognosis [10]. The clinical evaluation should be symptom-
directed with particular attention to non-pulmonary symptoms that might suggest
metastases (table 1). For example:

●Hip pain may prompt plain radiographs of the hip (M1b disease)
●Horner's syndrome (ipsilateral ptosis, anhidrosis, and miosis) may prompt an MRI of
the superior sulcus (T4 disease)
●Neurologic symptoms may prompt imaging of the brain or spinal cord (M1b disease)
●Hypotension with sinus tachycardia and pulsus paradoxus may prompt an
echocardiogram to evaluate for malignant pericardial effusion (M1a disease)
(see 'Imaging metastatic disease' below)

We prefer symptom-directed evaluation because it prompts appropriate imaging and


laboratory testing for the identification of nodal or metastatic disease and paraneoplastic
syndromes. A meta-analysis of 25 studies that examined the role of the clinical evaluation
for the detection of metastatic disease reported a high negative predictive value of an
expanded clinical exam for brain (95 percent), abdominal (94 percent), and bone (89
percent) metastases [16]. Symptoms can also be prognostic. In a cohort of 1266 patients
with lung cancer, asymptomatic patients or patients with symptoms due to the primary
tumor had a better prognosis than patients with signs and symptoms suggestive of
metastatic disease [10].

Laboratory — We perform the following laboratory studies when chest imaging is


suspicious for lung cancer [4,17]:

●Complete blood count


●Electrolytes
●Calcium
●Alkaline phosphatase
●Alanine aminotransferase (ALT) and aspartate aminotransferase (AST), total
bilirubin
●Creatinine
●Albumin and lactate dehydrogenase (not essential)
A detailed clinical exam together with laboratory testing can predict the likelihood of
metastases in patients with lung cancer, especially non-small cell lung cancer (NSCLC)
[16]. Abnormal testing in these circumstances can prompt additional imaging that guides
the clinician in their diagnostic and staging work-up. For example:

●Liver function test abnormalities possibly due to liver metastasis should prompt
evaluation of the liver with liver-directed imaging. (See 'Imaging metastatic
disease' below.)
●Calcium elevation should prompt additional imaging for bone metastasis and/or a
work up for a paraneoplastic manifestation of the primary tumor. (See "Hypercalcemia
of malignancy: Mechanisms".)
●Elevation of the alkaline phosphatase could be due to liver or bone metastases and
should prompt measurement of gamma glutamyl transpeptidase (GGT). When GGT
is normal an evaluation for bone metastasis is indicated; when abnormal, an
evaluation for liver metastases is indicated.

A prolonged diagnostic work-up can ultimately delay and complicate definitive cancer
therapy [4]. Thus, in patients that present with signs or symptoms of paraneoplastic
syndromes, an evaluation targeted at the paraneoplastic syndrome is warranted in parallel
with the evaluation of NSCLC. The evaluation of patients with possible paraneoplastic
syndromes is discussed in the following sections:

●Paraneoplastic syndromes of muscle, nerve, and bone (see "Overview of


paraneoplastic syndromes of the nervous system" and "Diagnosis and differential
diagnosis of dermatomyositis and polymyositis in adults")
●Endocrine paraneoplastic syndromes (see "Diagnostic evaluation of adults with
hyponatremia" and "Establishing the diagnosis of Cushing's
syndrome" and "Diagnostic approach to hypercalcemia")

Serum tumor markers have not been shown to have broad clinical utility in patients with
NSCLC and their routine use is not recommended. (See "Overview of the initial evaluation,
treatment and prognosis of lung cancer", section on 'Prognosis of NSCLC'.)

Radiographic staging

Overview — The clinical staging of patients with suspected lung cancer, in particular
NSCLC, starts with radiographic imaging [2-4]. Determining the highest radiographic stage
prior to biopsy facilitates the selection of a modality that optimizes tissue sampling for
diagnosis. We and others agree that every patient with suspected NSCLC should undergo
the following [2,18]:

●Imaging of the chest with contrast-enhanced computed tomography (CT) scan


●Imaging of the upper abdomen including liver and adrenal glands, usually by
extension of the chest CT through this region (see 'CT scan of the chest' below)
●Imaging directed at sites of potential metastasis when symptoms or focal findings
are present are present, or when chest CT shows evidence of stage III (eg, invasion
of vital structures by the primary tumor or enlarged subcarinal or contralateral
mediastinal lymph nodes) or stage IV disease. (see 'Imaging metastatic
disease' below)

There are conflicting data regarding the harms and benefits (improved survival or
reduction in futile thoracotomy) of routinely performing whole body positron emission
tomography (PET) or integrated PET/CT in every patient with suspected NSCLC [19-22].
Until large randomized trials provide more convincing data demonstrating improved
survival or a clear reduction in thoracotomies with routine PET or PET/CT, we prefer an
approach that is symptom and/or CT-directed. (See 'Whole body PET' below
and 'Integrated PET/CT' below.)

CT and (in some cases) PET provide a non-invasive assessment of tumor size (T),
mediastinal node enlargement (N), and potential intra- or extra-thoracic metastases (M)
[2,18]. Although confirmation by tissue biopsy must be pursued, these imaging tests
provide the basis for the initial assessment of the TNM stage of disease (table 2) and help
guide the clinician in choosing the optimal site(s) for tissue sampling. (See "Selection of
modality for diagnosis and staging of patients with suspected non-small cell lung cancer",
section on 'Approach to the patient'.)

There is no perfect threshold for what is considered metastatic lymphadenopathy by CT or


PET. Small lymph nodes can harbor occult malignancy and some lesions that are not
highly fluorodeoxyglucose (FDG)-avid are malignant. However, cut-offs worrisome for
metastasis to mediastinal lymph nodes are:

●Size >1 cm by short-axis diameter on transverse CT scan and/or


●FDG uptake greater than that of mediastinal blood pool on PET imaging [23]

The major limitation of CT and PET is that neither can stage NSCLC with a high degree of
accuracy. The prevalence of granulomatous disease such as tuberculosis or
histoplasmosis in the local patient population is an important factor in interpretation of PET
results [24]. Consequently, with the possible exception of bulky and confluent mediastinal
disease (group A (table 3)), the identification of suspicious mediastinal metastases by CT
or PET does not bypass the need for histologic assessment of mediastinal lymph nodes
for accurate staging and exclusion of alternative diagnoses [25]. (See 'CT scan of the
chest' below.)

The relatively low sensitivity and specificity of CT (55 and 81 percent) and PET (80 and 88
percent) can miss occult cancer (false negatives) and result in missed opportunities for
potentially curative thoracotomy (false positives) [2,20]. Thus, the major use of CT and
PET as staging tools is to facilitate the optimal approach to biopsy so that patients can be
accurately staged histologically and futile surgery avoided. The accuracy of CT and PET
and the approach to tissue biopsy are discussed separately. (See "Selection of modality
for diagnosis and staging of patients with suspected non-small cell lung cancer" and 'CT
scan of the chest' below and 'Whole body PET' below.)

Routine extrathoracic imaging aimed to detect metastases is not necessary in all patients
and should be directed at symptoms and abnormal physical exam findings. Specifically,
routine imaging of the brain is not necessary for all patients, but should be limited to
patients with symptoms or in those who are more likely to have metastatic disease such as
those with evidence of stage III or IV NSCLC [2]. Brain CT scan should be used when MRI
is not available. The poor sensitivity of PET for brain metastases limits this modality in the
detection of brain NSCLC. (See 'Imaging metastatic disease' below.)

CT scan of the chest — Every patient with suspected lung cancer should undergo CT
scan of the chest. Intravenous (IV) contrast enhancement is preferable as it may
distinguish mediastinal invasion of the primary tumor or metastatic lymph nodes from
vascular structures. Images of the liver and adrenal glands should also be included. In
most patients, CT scan assesses the anatomic location and size of the tumor (T), nodal
(N), and metastatic disease of the pleura, liver, and adrenal glands (M). With the possible
exception of those with bulky mediastinal tumor (group A, see below), most patients with
mediastinal node involvement by CT will need tissue biopsy of the mediastinum (ie,
mediastinal staging) to confirm suspected mediastinal nodal disease. The role of CT in the
evaluation and staging of patients suspected to have NSCLC is discussed here. The value
of CT in the evaluation of a solitary pulmonary nodule is discussed separately.
(See "Diagnostic evaluation and management of the solitary pulmonary nodule", section
on 'Computed tomography' and "Computed tomographic and positron emission
tomographic scanning of pulmonary nodules", section on 'Computed tomography (CT)'.)

The major advantage of CT is that it provides accurate anatomic definition of the tumor
within the thorax, which consequently directs tissue biopsy for histopathologic diagnosis
and staging. For example, CT frequently permits the accurate identification of T3 or T4
lesions (ie, larger tumors that invade surrounding bony or mediastinal structures) and
identifies high-yield targets for biopsy including N1-3 lymph nodes (table 2). CT also
identifies tumor-related atelectasis or post-obstructive pneumonitis (T2 disease) and intra-
thoracic and extra-thoracic metastatic disease that can prompt additional testing (eg, MRI
for brachial plexus involvement), as well as co-existing lung disease (eg, emphysema) that
may affect biopsy choice or operability. (See "Selection of modality for diagnosis and
staging of patients with suspected non-small cell lung cancer", section on 'Assessing
patient risk'.)

Four major radiographic stages have been suggested to facilitate further diagnostic work-
up and staging [2]. These groups include patients with the following findings on CT scan
(table 3):
●A – Patients with bulky tumor encircling/invading mediastinal structures such that
isolated lymph nodes cannot be distinguished from primary tumor (image 1)
●B – Patients with discrete lymph node involvement such that an isolated lymph node
can be distinguished from the primary tumor (image 2 and image 3)
●C – Patients with central tumor and elevated risk of nodal disease despite normal
sized nodes (ie, high risk N2/3 disease) (image 4)
●D – Patients with low risk of N2/3 involvement or distant metastatic disease (ie,
peripheral T1 tumors) (image 5 and image 6)

The allocation of patients to these categories helps guide the clinician in the selection of a
targeted site for tissue biopsy. As an example, patients in group A are not candidates for
surgical treatment. The focus of biopsy in this setting is on diagnosis of the tumor by the
safest method and imaging may be used as the staging modality. In contrast, for all
patients with discrete suspicious lymphadenopathy (group B), invasive sampling of the
mediastinum and in particular, the targeted node, is critical for accurate staging. The
selection of modality based upon the radiographic findings described above (A through D)
and disease stage is discussed in detail separately. (See "Selection of modality for
diagnosis and staging of patients with suspected non-small cell lung cancer", section on
'Approach to the patient'.)

The major limitation of CT is its low accuracy in the identification of mediastinal


metastases [2,26]. A 2013 systematic review of 43 studies reported the accuracy of CT as
a mediastinal staging tool in 7368 patients with suspected NSCLC, where a positive scan
was defined as lymph nodes measuring >1 cm in short scanning diameter (prevalence of
mediastinal metastasis was 30 percent) [2]. CT predicted mediastinal lymph node
involvement with a sensitivity, specificity, positive predictive value and negative predictive
value of 55, 81, 58, and 83 percent, respectively. Thus, due to its low sensitivity and
specificity, CT scanning is not a reliable modality for accurately staging the mediastinum in
patients with NSCLC. With the exception of bulky mediastinal disease, this necessitates
tissue sampling in most cases to confirm suspected regional lymph node involvement.
(See "Procedures for tissue biopsy in patients with suspected non-small cell lung
cancer" and "Selection of modality for diagnosis and staging of patients with suspected
non-small cell lung cancer", section on 'Approach to the patient'.)

Whole body PET — Despite the widespread use of whole-body PET as a routine staging
tool, there is no consensus regarding the value of this practice. [19-21]. Although whole-
body PET is more accurate than CT in detecting occult disease, its use has not been
shown to improve survival, and the evidence is conflicting on whether PET can reduce the
risk of futile thoracotomy. Thus, the use of PET as a staging modality should be
considered in the context of the risk of missing occult disease, patient preferences, and
local expertise. We prefer the targeted use of PET in potentially resectable patients with
CT stage IB to IIIA disease, ie, those with a high risk for minimal or occult N2 lymph node
involvement. When a PET scan is positive, with the exception of those with bulky
mediastinal tumor (group A), it does not obviate the need for tissue biopsy to confirm
suspected disease. The value of PET in mediastinal staging is discussed here. The role of
PET in the evaluation of a solitary pulmonary nodule and in the evaluation of distant
metastases associated with NSCLC is discussed separately. (See 'Modality' below
and "Diagnostic evaluation and management of the solitary pulmonary nodule", section on
'Functional imaging' and "Computed tomographic and positron emission tomographic
scanning of pulmonary nodules", section on 'Positron emission tomography (PET)'.)

PET scanning has limited anatomic resolution but does provide information on the
metabolic activity of the primary tumor, mediastinal involvement, and potential distant
metastases. There are no standardized criteria defining what constitutes a positive PET
result and no ideal cut-off point for the standardized uptake value (SUV). However, lymph
nodes with FDG uptake greater than that observed in the mediastinal blood pool are highly
suspicious for metastatic disease [23].

PET is more accurate in the evaluation of mediastinal disease (N) when compared to
contrast-enhanced chest CT and sometimes detects occult disease (eg, liver, adrenal,
bone, and pleural metastases) outside the thoracic cavity (M) that is not radiologically
evident by CT scanning. With respect to mediastinal staging by PET, one systematic
review of 45 studies which included 4105 patients reported sensitivity, specificity, positive
predictive value and negative predictive values of 80, 88, 75, and 91 percent, respectively
[2]. Another meta-analysis of 39 studies reported increased sensitivity of PET (100
percent) when lymph nodes were also enlarged (>1 cm) on CT [26].

The rationale for the use of PET in operable patients with potentially resectable cancers is
derived from randomized trials that included patients with radiographic (CT) stage I, II,
and IIIA NSCLC that suggest a reduction in futile thoracotomy when PET is performed.
However, trials evaluating the association between PET scanning and therapeutic
outcome in this population have had conflicting results [20-22,27,28]. While two studies
suggest a reduction in the rate of futile thoracotomies with the use of PET as a staging
modality in this population [20,22], three studies suggest no difference in the same
population [21,27,28]. This conflict may be explained by the heterogeneity in scanning
modality and population studied (high risk versus low risk metastatic disease). Our
approach prioritizes the avoidance of unnecessary surgery.

The value of PET in radiographic stage IA (T1N0M0) NSCLC is controversial. In this


population, the estimated prevalence of metastatic disease is very low (approximately 4
percent) [29]. Some argue that PET is unnecessary in this situation and proceed directly to
either cervical mediastinoscopy or surgical resection of the primary tumor with mediastinal
sampling at the time of surgery, while others believe that when used in this context, PET
can further reduce the risk of unnecessary surgery [26,29-33]. While we favor surgical
resection with mediastinal sampling, it is also reasonable to perform PET scanning pre-
operatively in those at high surgical risk. Importantly, patients and clinicians must be aware
that limiting preoperative staging to imaging alone without biopsy of radiographically
positive lymph nodes sampling carries a risk of a false positive result that may result in a
missed opportunity for surgical cure.

When staging the mediastinum, errors associated with PET that should be considered are
the following (see "Thoracic positron emission tomography", section on 'Sources of error'):

●False positives can occur with benign FDG-avid lesions such as infections,
inflammation, and granulomatous disease [34].
●False negatives typically occur when there are microscopic foci of metastasis, and in
non-enlarged lymph nodes (<10 mm) [35-37]. As an example, although PET can be
positive in small lesions, the detection of occult malignancy in normal sized lymph
nodes for early stage cancer is lower than for enlarged nodes.
(See "Bronchioloalveolar carcinoma, including adenocarcinoma in situ".)

Integrated PET/CT — Despite its widespread use, there is no consensus regarding the
routine use of integrated PET/CT as a staging modality for patients with suspected NSCLC
[38]. Although randomized trials suggest that the use of integrated PET/CT reduced futile
thoracotomies, and is probably superior to either modality alone, it has not been shown to
improve survival. We prefer the routine use of CT together with the targeted use of
dedicated PET OR PET/CT in patients with suspected NSCLC. In general, the indications
for PET/CT are the same as for dedicated PET. In many centers, only PET/CT is available,
in which case it is the de facto test of choice. As is true for dedicated PET, a suspicious
finding for metastases on PET/CT should always prompt biopsy for histologic confirmation.
The value of integrated PET/CT in mediastinal staging is discussed here. The role of
integrated PET/CT in the evaluation of solitary pulmonary nodules is discussed separately.
(See "Computed tomographic and positron emission tomographic scanning of pulmonary
nodules", section on 'PET/CT'.)

One of the major limitations of whole-body PET alone is the poor anatomic definition of
suspicious lesions. For example if metabolic activity is seen in the region of the
mediastinum, its relation to vascular, hilar or endobronchial structures is unknown. The
addition of coregistered CT to PET scanning adds correlative anatomic information,
thereby combining the advantages of both imaging modalities [39,40]. However, one meta-
analysis of 19 studies (2014 patients) of integrated PET/CT in patients suspected of
having NSCLC reported a sensitivity, specificity, positive predictive value, and negative
predictive value of 62, 90, 63, and 90 percent, respectively [2]. Although the sensitivity was
lower than that reported in meta-analyses of CT or PET alone, it is not plausible that
addition of information obtained from either modality would reduce sensitivity. The reasons
for this lower sensitivity are unclear. Differences in methodology between the included
studies may be responsible.

Two randomized trials showed that, by appropriately altering the disease stage,
integrated PET/CT prevents unnecessary thoracotomies [20,22]. In a total of 526 patients
suspected to have potentially resectable NSCLC, compared to conventional staging,
integrated PET/CT prevented unnecessary thoracotomy in 7 to 17 percent of patients.
Additionally, integrated PET/CT has been shown to detect unanticipated stage IV disease
[39,41-47]

Imaging metastatic disease

Indications — Although most clinicians agree that routine imaging for distant metastases
is not required for every case of suspected NSCLC, the practice varies widely among
clinicians. Regardless of the imaging modality used, tissue confirmation of suspected
metastases is indicated. We prefer imaging that is symptom-focused or CT-directed and
typically image the following groups:

●Patients with focal symptoms, signs, or laboratory tests suggestive of metastatic


disease. The modality used depends on the site of suspected metastases.
(See "Procedures for tissue biopsy in patients with suspected non-small cell lung
cancer", section on 'Sampling metastatic disease'.)
●Patients with clinical stage III or IV disease should undergo routine imaging of the
brain with magnetic resonance imaging (MRI) or CT if MRI is not available. The
rationale for routine imaging is the high risk of distant disease in this population,
especially metastases to the brain. In this setting, an MRI of the brain may be
performed for the early detection of brain metastases so that early treatment can be
administered before development of neurologic deficits or seizures.

In patients with clinical stage I/II disease who are candidates for curative resection, there is
consensus that routine brain imaging with MRI is not indicated. In contrast, some experts
believe that PET or PET/CT is indicated to identify occult metastasis in patients with
clinical stage IB/II disease. Both modalities have been shown in small prospective
observational studies to result in the avoidance of unnecessary thoracotomy in patients
with solid tumors [41,48-50]. It is less clear whether PET is useful to identify occult
metastasis among patients with clinical stage IA NSCLC in whom the risk of occult
metastasis is very low or among patients with clinical stage IIIA/B disease in whom the risk
of occult stage IV disease may be high but of uncertain benefit to detect.

Patients may require repeat imaging during staging and evaluation when new symptoms
arise or if there is a significant delay in initiation of therapy. The optimal timing for repeat
imaging is not standardized and should be tailored to the individual patient. For example,
patients with clinical stage I or II who develop new onset headache or bone pain do require
modification of the original evaluation plan to investigate those symptoms. A critical
objective in the staging evaluation is timeliness. However, re-imaging is reasonable in
select circumstances prior to biopsy when unavoidable, prolonged delays occur (eg,
rapidly progressive disease or new symptoms) if there is a delay by eight weeks or more
[2,4]. (See 'Timeliness of the evaluation' above.)
Modality — With the exception of brain metastases, whole body PET or PET/CT scanning
is more accurate than conventional scanning (abdominal CT, bone scan) for the detection
of unsuspected pleural and extrathoracic metastases [39,41-47]. When evaluating patients
for brain metastases, gadolinium-enhanced MRI of the brain is usually preferred because it
is more sensitive than non-enhanced MRI or CT. When PET, PET/CT or MRI is not
available, conventional staging with abdominal CT, bone scintigraphy, and CT scan of the
brain should be performed when indicated. The detection of occult metastases by any of
these modalities is not associated with a proven survival benefit, although it is desirable to
prevent an unnecessary surgical procedure. With the exception of brain, histologic
confirmation of suspected metastatic disease by any of these modalities is indicated,
unless there is convincing evidence of widespread metastasis by noninvasive imaging.
Imaging directed at specific sites suspected to be involved with metastases is discussed
separately. (See 'Site-specific imaging' below.)

Small randomized studies and case series of PET or PET/CT suggest that, when used as
staging modalities for NSCLC, unsuspected metastases are discovered between 6 and 36
percent of cases [51-54]. Additionally, their discovery can result in stage migration (up-
stage or down-stage) and changes in management in 19 to 22 percent of patients [41,46-
48,53,55,56]. However, improved survival due to the discovery of occult metastases has
not been reported, and most cases of upstaging by PET should be confirmed by tissue
sampling so as not to result in a missed opportunity for surgical cure.

Brain metastases can be hyper- or hypo-metabolic, thereby limiting the utility of PET for
the detection of NSCLC in the brain [57]. Gadolinium-enhanced MRI of the brain is more
sensitive than non-enhanced MRI or CT due to the increased detection of small cerebral
lesions [58,59]. In addition, MRI improves detection when added to PET-CT and can be
used in conjunction with this modality for the evaluation of suspected brain metastases
[60,61].

Site-specific imaging — When imaging is indicated and PET or PET/CT is not available
or is inconclusive, other modalities should be used to evaluate patients with suspected
NSCLC for distant disease. The choice of imaging modality is determined by the anatomic
location or suspected organ involved by metastatic disease. Organs that are frequently
involved by metastatic NSCLC that may require imaging include the following:

●Brain, spine, and nerve – Gadolinium-enhanced MRI detects spinal bone lesions
and brain lesions and differentiates metastases from other central nervous system
lesions with greater sensitivity than nonenhanced MRI [2,62]. (See "Magnetic
resonance imaging of the thorax" and "Epidemiology, clinical manifestations, and
diagnosis of brain metastases", section on 'Imaging studies'.)
●Adrenal gland – Adrenal gland nodules or masses may be found by CT in 3 to 4
percent of patients during the initial work-up [63-65]. In patients with NSCLC, most
adrenal nodules are benign. However, all adrenal anomalies in patients with
suspected NSCLC require directed evaluation to distinguish benign lesions from
malignant metastases. Those with imaging characteristics suggestive of malignancy
should be considered for biopsy. (See "The adrenal incidentaloma", section on
'Imaging characteristics' and "The adrenal incidentaloma", section on 'Adrenal
metastases'.)
PET scanning is a sensitive modality for the detection of adrenal metastases in
patients with NSCLC. In a series of 94 patients with 113 adrenal masses, the
sensitivity, specificity, and accuracy of PET imaging for detection of metastatic
disease was 93, 90, and 92 percent, respectively [66]. Although PET scans are
accurate for the detection of adrenal metastases, small lesions may be missed (<1.5
cm) [67-71]. Positive findings should be confirmed histologically.
Conventional CT lacks a high sensitivity or specificity for the diagnosis of adrenal
metastases [72]. CT scans that use specific adrenal imaging protocols significantly
improve the sensitivity and specificity of CT for characterizing adrenal lesions. As an
example, in two studies of 363 patients with 279 adrenal masses, CT identified
adrenal adenomas with a high sensitivity (98 to 100 percent) and specificity (92 to 95
percent) [73,74].
MRI also lacks sensitivity but may be helpful in distinguishing benign, fat-containing
adrenal adenomas from adrenal metastases [75,76].
Percutaneous biopsy and, rarely, adrenalectomy are considered for isolated lesions
involving the adrenal gland. In the setting of overwhelming metastatic disease tissue,
confirmation may not be necessary. (See "The adrenal incidentaloma", section on
'Fine-needle aspiration biopsy' and "The adrenal incidentaloma", section on
'Adrenalectomy'.)
●Liver – The liver is rarely (3 percent) the sole site of metastases and most liver
lesions in patients with NSCLC are benign cysts or hemangiomas [77]. However, all
liver abnormalities in patients with suspected NSCLC require directed evaluation to
distinguish benign lesions from malignant metastases. Those with imaging (usually on
CT, ultrasound, and/or radionuclide imaging) characteristics suggestive of malignancy
should be considered for biopsy particularly if this is the only suspected metastatic
site. (See "Solid liver lesions: Differential diagnosis and evaluation", section on
'Imaging test findings' and "Solid liver lesions: Differential diagnosis and evaluation",
section on 'Metastatic disease'.)
Limited data suggest that PET scanning can detect liver metastases with an accuracy
of 92 to 100 percent [67,78,79]. Although subgroup analysis in observational case
series suggest that PET may be superior to CT for the detection of liver metastases,
false positive and false negative findings were also reported [67,80]. In the absence
of overwhelming evidence of systemic metastasis such as multiple other sites with
imaging consistent with tumor metastasis, isolated hepatic lesions require careful
evaluation and biopsy to achieve accurate staging. Isolated PET-positive liver lesions
in an otherwise early-stage patient should not be used as the basis for determination
of metastatic tumor stage without confirmatory biopsy. (See "Percutaneous, fine-
needle aspiration, and laparoscopic liver biopsy".)
●Bone – Although data are limited in NSCLC, PET scanning appears to be superior
to radionuclide bone scintigraphy for the detection of bony metastases [67,81-85].
Two studies of 158 patients with biopsy-proven bony metastases from NSCLC
reported that, compared to bone scintigraphy, PET scanning had similar sensitivity
(93 percent) but greater specificity (93 to 96 versus 66 to 73 percent) for the detection
of metastases [81,82]. However false positive and false negative findings on PET
scan have been reported [67,71,86].
Bone scintigraphy can be used when PET or PET/CT is not available or is
inconclusive. The known caveat of bone scintigraphy is that the false positive rate is
high due to the common prevalence of degenerative and traumatic skeletal disease in
the general population. One meta-analysis of eight studies suggested that, compared
to PET, bone scintigraphy has a comparable negative predictive value of >90 percent
[2].
MRI has comparable accuracy to bone scintigraphy for the diagnosis of bony
metastases. In practice it can be used as a supplementary tool, especially when a
suspected lesion crosses tissue planes to involve multiple structures [85,87,88]. For
example, apical lesions that invade through the chest wall can involve the shoulder as
well as the brachial plexus, and lesions of the posterior mediastinum can involve the
vertebra and spinal canal. In these settings, MRI can be used in conjunction with
other imaging modalities to distinguish true bony metastases from T3 lesions that are
potentially resectable [89].
●Pleura – Two common clinical presentations of pleural disease are: metastases
associated with pleural effusion or multiple pleural-based nodules, and direct
extension of the primary tumor to the pleura or chest wall. Complete evaluation of
pleural disease may require multiple imaging modalities (PET, CT,
ultrasound, and/or MRI) as well as invasive testing (thoracentesis, thoracoscopy, or
pleural biopsy). While imaging is important in the detection of suspected pleural
metastases, it should not obviate the need to sample the pleural space for histological
confirmation. (See "Procedures for tissue biopsy in patients with suspected non-small
cell lung cancer", section on 'Suspected pleural metastases'and "Imaging of pleural
plaques, thickening, and tumors".)
Imaging (usually CT) is particularly important in the evaluation of tumors with direct
extension into extrapleural fat, visceral pleura, or parietal pleura. Such lesions
are T2/3 tumors that are operable and need to be distinguished from metastatic
disease of the pleural space (M1a) which is inoperable (table 2) [90]. When imaging is
insufficient to make this distinction, direct vision at the time of thoracotomy may be
required.
Retrospective studies have shown PET to be an accurate modality in the detection of
pleural metastases from NSCLC [91,92]. In one retrospective study of patients with
an established diagnosis of NSCLC, the sensitivity, negative predictive value, and
accuracy of PET for detecting pleural metastases was 95, 67, and 92 percent.
However, the prevalence of pleural metastases in this study may have falsely lowered
the negative predictive value [91]. PET imaging, in another study, correctly detected
the presence of malignant pleural involvement in 16 of 18 patients with NSCLC and
more importantly excluded a malignant effusion in 16 of 17 patients with a sensitivity
and accuracy of 88 and 91 percent, respectively [92]. PET is not useful in examining
the extent of invasion across tissues planes.
CT is important for the anatomic delineation of tumor involvement of all components
of the pleural space, extrapleural fat, visceral and parietal pleura. Apart from obvious
pleural masses, thickening and effusions, subtle beading, and pleural puckering
visible on CT are also highly suspicious for pleural metastases. The detection of
metastatic pleural involvement by CT has been shown to have important implications
for prognosis of patients with NSCLC. As an example, in one retrospective study of
98 patients with NSCLC, compared to wet pleural dissemination (pleural fluid), dry
pleural dissemination (nodularity without pleural fluid) was associated with better
median survival (38 versus 13 months) [93].
Ultrasound can also be used to evaluate the pleural space. In a small prospective
case series, when distinguishing benign from malignant disease, the sensitivity of
ultrasound was comparable to CT at 79 percent [94]. Pleural thickening >1 cm,
pleural nodularity, and diaphragmatic thickening >7 mm were highly suggestive of
malignant metastases [94].
MRI may be useful when evaluating the extent of tumor invasion through muscle,
nerve, and bone but has not been formally studied as a staging tool pleural
involvement in NSCLC.

DIAGNOSIS — A diagnosis of lung cancer should not be made without definitive


pathology. At a minimum, this involves selecting a biopsy site and obtaining an adequate
sample for microscopic examination. Additional consideration needs to be given to
obtaining a large enough sample for supplemental immunohistochemical and genetic
analysis.

Tissue biopsy — Acquiring tissue for microscopic examination is necessary for the
diagnosis and staging of patients with suspected lung cancer. Most data are derived from
studies of patients with non-small cell lung cancer (NSCLC). Although not absolute, for
patients with higher disease stage, minimally invasive modalities (eg, endoscopic
procedures) are typically preferred over more invasive modalities (eg, video-assisted
thoracic surgery and mediastinoscopy) for the initial biopsy. Conversely, for patients with
peripheral stage IA disease, surgical biopsy is sometimes preferred because diagnosis
and curative resection may be achieved simultaneously. (See "Selection of modality for
diagnosis and staging of patients with suspected non-small cell lung
cancer" and "Diagnostic evaluation and management of the solitary pulmonary nodule",
section on 'Surgical biopsy'.)

Modality — The selection of a biopsy modality must take into consideration its yield for a
target lesion in the context of safety and expediency, as well as the patient's preferences
and values. Bronchoscopy with endobronchial ultrasound (EBUS)-directed biopsy has
emerged as the most common modality used for diagnosis and staging of suspected
NSCLC due to its high diagnostic accuracy for accessing central primary tumors and most
mediastinal lymph nodes. Furthermore, EBUS-directed biopsy in patients with mediastinal
adenopathy on computed tomography (CT) scan may be performed quickly and reduce
the time to establishing of treatment decisions [95]. If initial tissue sampling provides
inconclusive results or is insufficient for essential immunohistochemical or molecular
characterization, a second biopsy procedure is required. The selection of a second biopsy
procedure should favor modalities with a higher diagnostic yield (eg, surgical sampling).
The selection of modality and procedures used for tissue biopsy of NSCLC are discussed
separately. Although genetic and molecular microarray techniques of both tissue and
peripheral blood have been studied as potential diagnostic tools designed to enhance the
sensitivity of bronchoscopy for the diagnosis of lung cancer, further study is required
before they can be recommended for routine use [96,97]. (See "Selection of modality for
diagnosis and staging of patients with suspected non-small cell lung
cancer" and "Procedures for tissue biopsy in patients with suspected non-small cell lung
cancer".)

Specimen type — A pathologic diagnosis can be made on cytopathologic or


histopathologic (tissue biopsy) samples. In general, if both types of specimens can be
obtained with similar feasibility and risks, a tissue biopsy is preferable to a cytologic
specimen. This preference is based upon the ability to differentiate with greater accuracy
adenocarcinoma features from squamous cell carcinoma as well as the importance of
obtaining sufficient material for immunohistochemical and genetic analysis of the tumor.
(See "Pathology of lung malignancies" and "Personalized, genotype-directed therapy for
advanced non-small cell lung cancer".)

Cytologic specimens can be obtained from the following sites:

●Lung – Sputum, transthoracic needle aspirates, and bronchoscopic washings,


brushings, or needle aspirates (see "Procedures for tissue biopsy in patients with
suspected non-small cell lung cancer", section on 'Sputum cytology' and "Procedures
for tissue biopsy in patients with suspected non-small cell lung cancer", section on
'Minimally invasive procedures')
●Lymph node – Transthoracic, transbronchial, and transesophageal aspirates
(see "Procedures for tissue biopsy in patients with suspected non-small cell lung
cancer", section on 'Minimally invasive procedures')
●Distant metastasis – Pleural fluid, needle aspirates of metastatic tissue (eg, liver)
(see "Procedures for tissue biopsy in patients with suspected non-small cell lung
cancer", section on 'Sampling metastatic disease')

Core or biopsy tissue can be obtained from the following:


●Lung – Endobronchial biopsy (forceps), transbronchial biopsy (forceps or needle),
transthoracic (needle) biopsy, surgical biopsy (see "Procedures for tissue biopsy in
patients with suspected non-small cell lung cancer", section on 'Minimally invasive
procedures' and "Procedures for tissue biopsy in patients with suspected non-small
cell lung cancer", section on 'Video-assisted thoracic surgery')
●Lymph node – Bronchoscopic and transthoracic needle core biopsy, surgical biopsy
(see "Procedures for tissue biopsy in patients with suspected non-small cell lung
cancer", section on 'Minimally invasive procedures' and "Procedures for tissue biopsy
in patients with suspected non-small cell lung cancer", section on 'Surgical staging
procedures')
●Distant metastasis – Core needle aspirates of metastatic tissue (eg liver, bone,
adrenal) (see "Procedures for tissue biopsy in patients with suspected non-small cell
lung cancer", section on 'Sampling metastatic disease')

The modalities used to obtain tissue in patients with suspected NSCLC are discussed in
detail separately. (See "Procedures for tissue biopsy in patients with suspected non-small
cell lung cancer".)

Histopathology — Distinguishing among the different histologic subtypes of NSCLC is


increasingly important to guide subsequent testing for specific mutations and to guide
treatment selection, including the identification of patients who are more likely to respond
to newer targeted therapies. Adenocarcinoma, squamous carcinoma, adenosquamous
carcinoma, and large cell carcinoma are the four major histological subtypes of NSCLC.
The four subtypes of NSCLC are histologically characterized by the absence of the
pathologic features of small cell lung cancer (SCLC; eg, small cell size, nuclear molding,
“salt and pepper” chromatin pattern, and nuclear crush artifact) together with the following:

●Adenocarcinoma – Neoplastic gland formation or intracytoplasmic mucin (picture


1 and picture 2) (see "Pathology of lung malignancies", section on 'Adenocarcinoma')
●Squamous cell carcinoma – The presence of keratin production by tumor
cells and/or intercellular desmosomes ("intercellular bridges") (picture 3 and picture 4)
(see "Pathology of lung malignancies", section on 'Squamous cell carcinoma')
●Adenosquamous carcinoma – Greater than 10 percent malignant glandular and
squamous components (see "Pathology of lung malignancies", section on
'Adenosquamous carcinoma')
●Large cell carcinoma – The absence of glandular or squamous differentiation
features (ie, poorly differentiated NSCLC)

Panels of immunohistochemical (IHC) stains are typically used to classify NSCLC (eg,
adenocarcinoma, squamous cell carcinoma) and to distinguish NSCLC from other cancers
involving the lung (eg, primary lung cancer from secondary metastases). The major IHC
stains that are commonly used are the following:
●Adenocarcinoma is typically positive for thyroid transcription factor (TTF-1), mucin,
napsin-A, surf-A, surf-B.
●Squamous cell carcinoma is typically positive for p63, cytokeratin 5/6 (CK5/6), and
CK 7.
●Adenosquamous or large cell carcinoma may have a combination of IHC staining
patterns characteristic of both adenocarcinoma and squamous cell carcinoma.
●Poorly differentiated cancers and metastases from distant sites may need to be
distinguished from primary NSCLC. As examples, stains that are classically negative
in NSCLC are CK 20 (typically positive in adenocarcinoma of the colon) and estrogen
and progesterone receptor (typically positive in adenocarcinoma of the breast),
thereby distinguishing the tissue of origin for adenocarcinoma found in the lung. Other
common staining patterns used to determine the tissue of origin for poorly
differentiated neoplasms are described in the table (table 4). The stains (eg,
chromogranin) that are used to distinguish NSCLC from SCLC are described
separately. (See 'Differential diagnosis' below.)

The common genetic mutations with known targeted therapies include mutations in
epithelial growth factor receptor (EGFR) and rearrangements of the anaplastic lymphoma
kinase (ALK) gene. These and other driver mutations involved in the pathogenesis of
NSCLC are discussed in detail separately. (See "Personalized, genotype-directed therapy
for advanced non-small cell lung cancer".)

The pathology, immunohistochemistry, and genetic mutations associated with lung


malignancies are discussed in detail separately. (See "Pathology of lung
malignancies" and "Personalized, genotype-directed therapy for advanced non-small cell
lung cancer", section on 'NSCLC genotypes'.)

Differential diagnosis — The differential diagnosis of NSCLC depends on the presenting


symptoms and imaging findings. Biopsy is required to distinguish NSCLC from other
cancers or benign lesions of the lung. Among the malignant etiologies, the major entity that
needs to be distinguished from NSCLC is SCLC. This distinction is critical because the
prognosis and treatment for NSCLC and SCLC are different. Although not always present,
there are a number of clinical, radiologic, and pathologic features that can help the
clinician make this distinction.

The clinical, radiologic, and pathologic manifestations that may help to distinguish NSCLC
from SCLC are the following:

●Rapid presentation – Although the common symptoms of lung cancer, cough,


dyspnea, hemoptysis, and chest pain, can be encountered in both NSCLC and SCLC,
a more rapid presentation over weeks favors SCLC. This may be due to the higher
doubling time associated with SCLC. As an example, a rapidly growing lesion on
chest imaging (eg, a mass that grows over three to six weeks) is more suggestive of
SCLC rather than NSCLC.
●Pancoast’s syndrome – Benign and malignant lesions of the superior sulcus (ie,
the thoracic inlet at the apex of the lung) can cause Pancoast’s syndrome. Pancoast’s
syndrome is a constellation of one or more clinical signs (eg, weakness and atrophy
of the muscles of the hand and/or ipsilateral ptosis, anhidrosis, and miosis [Horner’s
syndrome]) that are due to compression or involvement of the brachial plexus (nerves
and vessel) and the cervical sympathetic nerves. Unlike superior vena cava (SVC)
syndrome, Pancoast's syndrome is overwhelmingly more common in NSCLC and
rarely due to SCLC or a benign lesion. Imaging findings of apical masses that have
malignant features should always prompt additional evaluation and biopsy for NSCLC
involvement of the thoracic outlet. (See "Superior pulmonary sulcus (Pancoast)
tumors".)
●Paraneoplastic syndromes – Paraneoplastic manifestations are more commonly
observed in SCLC. They are discussed separately in the following sections:
•Paraneoplastic syndromes of muscle, nerve, and bone (see "Paraneoplastic
syndromes affecting peripheral nerve and muscle" and "Clinical manifestations
of dermatomyositis and polymyositis in adults")
•Endocrine paraneoplastic syndromes (see "Pathophysiology and etiology of the
syndrome of inappropriate antidiuretic hormone secretion (SIADH)", section on
'Etiology' and "Etiology of hypercalcemia" and "Epidemiology and clinical
manifestations of Cushing's syndrome", section on 'Clinical manifestations')
●Pathology - The major histologic feature that distinguishes NSCLC from SCLC is
cell size. Typically, the cells in SCLC are roughly twice the size of lymphocytes when
subjectively assessed on light microscopy. Additional features that distinguish SCLC
from NSCLC include hyperchromatic appearance, small amounts of cytoplasm (ie,
high nuclear to cytoplasmic ratio), cohesive sheets of small “blue” cells with rosette
formation, crush artifact with necrosis, and cell fragility. When classic features of
SCLC are present, morphologic criteria alone are often diagnostic and support high
interobserver reliability [98]. In contrast, the classic features of epithelial differentiation
(eg, keratin pearls [squamous], gland formation [adenocarcinoma]) do not support the
diagnosis of small cell carcinoma but are highly suggestive for non-small cell
carcinoma. (See "Pathology of lung malignancies", section on 'Small cell
carcinoma' and "Pathology of lung malignancies", section on
'Adenocarcinoma' and 'Histopathology' above.)
●Immunohistochemical staining – Select patterns of immunohistochemical staining
are typically used to confirm the tissue of origin in NSCLC (eg, TTF-1, CK5/6, p63)
(table 4). SCLC can be positive for TTF-1. However, as a neuroendocrine tumor,
SCLC should have no other shared IHC staining patterns with NSCLC and is typically
positive for synaptophysin, CD56, chromogranin, or neuron specific enolase (NSE),
while NSCLC is negative for these stains. The immunohistochemical characteristics
of NSCLC are discussed separately. (See 'Histopathology' above.)
●Other – Superior vena cava syndrome and metastatic disease were originally
thought to be more common in SCLC but due to the higher prevalence of NSCLC,
they are commonly encountered in both entities.
•Superior vena cava syndrome – SVC syndrome is a manifestation of benign
or malignant disease of the mediastinum. The three most common malignancies
associated with SVC syndrome are NSCLC, SCLC, and lymphoma. Unilateral
disease may favor SCLC and NSCLC over lymphoma which is more likely to
involve the mediastinum symmetrically. Biopsy is required to distinguish all three
entities. (See "Malignancy-related superior vena cava syndrome".)
•Metastatic disease – Clinical manifestations of metastatic disease, particularly
bone metastases, are commonly seen in both SCLC and NSCLC. (See "Solid
liver lesions: Differential diagnosis and evaluation" and "The adrenal
incidentaloma" and "Epidemiology, clinical manifestations, and diagnosis of brain
metastases" and "Bone tumors: Diagnosis and biopsy techniques".)

Importantly, if biopsy demonstrates NSCLC but the clinical presentation or course is more
consistent with SCLC (eg, rapid growth, multiple metastases, paraneoplastic syndromes),
a second pathologic opinion and, rarely, a repeat biopsy is indicated due to a concern for
misdiagnosis.

STAGING — The 7th edition of the Tumor Node Metastasis (TNM) system is used for
staging non-small cell lung cancer (NSCLC) (table 2). Staging NSCLC determines the
appropriate therapy and, when combined with the patient’s unique features, provides
valuable prognostic information. Four types of staging can be designated in patients with
NSCLC:

●The clinical-diagnostic stage is based upon all investigations (clinical, laboratory,


radiologic, and pathologic) that are undertaken prior to surgical resection. It is
assigned the prefix c (eg, cT3N2M0). A limitation of clinical-diagnostic staging is that
the stage is related to the intensity of the preoperative evaluation. Thus, a less
aggressively staged patient may be inaccurately down-staged or up-staged.
●The surgical-pathologic stage is based on the clinical-diagnostic stage plus
histopathologic data from the resected tumor and lymph nodes. It provides
confirmation of the T descriptor, N descriptor, and histologic type. In addition, it takes
into account the histologic grade, resection margins, and presence or absence of
lymphovascular invasion. The surgical-pathologic stage is assigned the prefix p (eg,
pT3N2M0).
●A retreatment stage is assigned if there is recurrence of disease, new staging
evaluations have been completed and a new treatment program is planned.
●An autopsy stage is based on a complete postmortem examination.

The 7th edition of the TNM system for staging NSCLC and the selection of modality for
clinical-diagnostic staging are discussed separately. (See "Tumor, node, metastasis (TNM)
staging system for non-small cell lung cancer" and "Selection of modality for diagnosis and
staging of patients with suspected non-small cell lung cancer" and "Procedures for tissue
biopsy in patients with suspected non-small cell lung cancer".)

The staging for small cell lung cancer (limited versus extensive and TNM) is also
discussed separately. (See "Pathobiology and staging of small cell carcinoma of the lung",
section on 'Staging'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education


materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient education: Non-small cell lung cancer (The Basics)")
●Beyond the Basics topics (see "Patient education: Non-small cell lung cancer
treatment; stage I to III cancer (Beyond the Basics)" and "Patient education: Non-
small cell lung cancer treatment; stage IV cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●The initial approach to patients with suspected lung cancer is based largely upon
data derived from patients with non-small cell lung cancer (NSCLC). NSCLC is a
heterogeneous group of tumors (eg, adenocarcinoma, squamous cell carcinoma,
adenosquamous carcinoma, large cell carcinoma) that together account for the
majority of lung cancers. The goal of the initial evaluation of a patient with suspected
NSCLC is to obtain sufficient clinical and radiologic information to proceed with
diagnostic tissue biopsy, staging, and treatment in a timely fashion. A second major
goal of the initial evaluation is to identify patient values and preferences that will
determine the context and choices for care. (See 'General goals and timing of
evaluation' above.)
●The most common clinical manifestations of NSCLC at presentation are cough,
hemoptysis, and dyspnea. Asymptomatic patients may come to clinical attention
during screening or following the incidental detection of imaging abnormalities.
Symptoms, when present, often represent advanced disease. (See 'Signs and
symptoms' above and 'Initial imaging'above.)
●The clinical evaluation should be symptom-directed. This approach relies upon the
clinician maintaining a high index of suspicion for nodal or metastatic disease, which
in turn allows appropriate imaging and invasive testing to confirm nodal or metastatic
disease. (See 'Clinical' above and 'Laboratory' above.)
●Every patient with suspected NSCLC should undergo computed tomography (CT)
scan of the chest and upper abdomen (usually contrast-enhanced) to evaluate the
extent of the primary tumor and potential spread to the mediastinum, liver, and
adrenal glands. Radiographic staging does not obviate the need for tissue biopsy.
(See 'CT scan of the chest'above.)
●We reserve positron emission tomographic scanning (PET) or integrated PET/CT for
use in potentially resectable patients with CT stage IB to IIIA disease, ie, those at high
risk for minimal or occult N2 lymph node involvement. PET imaging in patients with
clinical stage IA (T1N0M0) disease prior to curative surgery is controversial; while we
favor surgical resection with mediastinal sampling in this population, preoperative
PET scanning in those at high surgical risk is appropriate. (See 'Whole body
PET' above and 'Integrated PET/CT' above.)
●Routine imaging to screen for distant metastases is not required for every case of
suspected NSCLC. Imaging for metastatic disease should be symptom-focused or
CT-directed. Gadolinium-enhanced magnetic resonance imaging (MRI) of the brain is
used to evaluate symptomatic patients for brain metastases and to assess
asymptomatic patients with clinical stage III or IV NSCLC. (See 'Imaging metastatic
disease' above.)
●A diagnosis of NSCLC is made based upon the pathologic evaluation of cytologic
(eg, pleural fluid) or histopathologic (eg, tissue biopsy) specimens. The initial
radiographic staging optimizes the selection of a biopsy site and preferred modality to
obtain a pathologic sample. Consideration should be given to obtaining a large
enough sample to allow supplemental immunohistochemical and genetic analysis.
(See 'Diagnosis' above and "Selection of modality for diagnosis and staging of
patients with suspected non-small cell lung cancer".)
●Adenocarcinoma, squamous carcinoma, adenosquamous carcinoma, and large cell
carcinoma are the four major histological subtypes of NSCLC. The main entity on the
differential diagnosis of NSCLC is small cell lung cancer (SCLC). While clinical and
imaging features can help the clinician distinguish NSCLC from SCLC, pathologic
review of adequate biopsy specimens is required to make this distinction.
(See 'Histopathology' above and 'Differential diagnosis' above.)
●The 7th edition of the Tumor Node Metastasis (TNM) system is used for staging
NSCLC (table 2). The clinical-diagnostic stage is based upon investigations (clinical,
laboratory, radiologic, and pathologic) that are undertaken prior to primary therapy. It
is assigned the prefix c (eg, cT3N2M0). (See 'Staging' above.)
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Overview of the initial evaluation, treatment and prognosis of lung cancer
Author:
David E Midthun, MD
Section Editors:
Rogerio C Lilenbaum, MD, FACP
Steven E Schild, MD
Deputy Editor:
Sadhna R Vora, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Dec 2016. | This topic last updated: Nov 21, 2016.

INTRODUCTION — Worldwide, lung cancer occurred in approximately 1.8 million patients


in 2012 and caused an estimated 1.6 million deaths [1]. In the United States, there will be
approximately 225,000 new cases of lung cancer and over 160,000 deaths annually [2].

Both the absolute and relative frequencies of lung cancer have risen dramatically. Around
1953, lung cancer became the most common cause of cancer deaths in men. In 1985 it
became the leading cause of cancer deaths in women, and now causes approximately
twice as many deaths as breast cancer. Lung cancer deaths are declining in men, and the
death rate in women has plateaued secondary to decreases in smoking. Now however,
almost one-half of all lung cancer deaths occur in women. (See "Women and lung
cancer".)

The term lung cancer, or bronchogenic carcinoma, refers to malignancies that originate in
the airways or pulmonary parenchyma. Approximately 95 percent of all lung cancers are
classified as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC).
This distinction is required for proper staging, treatment, and prognosis. Other cell types
comprise about 5 percent of malignancies arising in the lung.

This discussion will present an overview of the initial diagnosis, treatment, and prognosis
of patients with both NSCLC and SCLC. An overview of the risk factors, pathology, and
clinical manifestations of lung cancer is presented separately, as is an overview of the
management of patients with advanced NSCLC, and a discussion of issues concerning
lung cancer survivors. (See "Overview of the risk factors, pathology, and clinical
manifestations of lung cancer" and "Overview of the treatment of advanced non-small cell
lung cancer" and "Overview of approach to lung cancer survivors".)

INITIAL EVALUATION — The main issues to assess in a patient with a suspected lung
cancer are to confirm that the lesion is malignant, determine whether the cell type non-
small cell lung cancer (NSCLC) or small cell lung cancer (SCLC), assess the stage of
disease, and the functional status of the patient. These parameters are essential for
appropriate patient management. The initial evaluation of a patient with suspected lung
cancer is discussed in detail separately. (See "Overview of the initial evaluation, diagnosis,
and staging of patients with suspected lung cancer".)

●A tissue diagnosis is necessary to determine whether a lung cancer is a NSCLC or


an SCLC, as well as to rule out the possibility that disease represents a nonmalignant
process or lung metastasis from a primary tumor at another site. This information is
critical for treatment planning. (See "Procedures for tissue biopsy in patients with
suspected non-small cell lung cancer" and "Diagnostic evaluation and management
of the solitary pulmonary nodule".)
●Staging for NSCLC is critical in determining the appropriate treatment for a patient
with resectable disease and avoiding unnecessary and unhelpful surgery in advanced
disease [3]. Staging of NSCLC utilizes the tumor node metastasis (TNM) system
(table 1). (See "Overview of the initial evaluation, diagnosis, and staging of patients
with suspected lung cancer" and "Tumor, node, metastasis (TNM) staging system for
non-small cell lung cancer".)
●Staging of SCLC usually uses the Veterans Administration Lung Study Group
designations of limited (confined to one hemithorax) or extensive (beyond one
hemithorax) disease [4], although the TNM system is sometimes also used (table 1).
This distinction is important since treatment algorithms differ for patients with limited
versus extensive stage disease. (See "Pathobiology and staging of small cell
carcinoma of the lung".)
●Treatment of lung cancer, whether with surgery, chemotherapy, radiation therapy
(RT) or a combination of these, can be associated with substantial toxicity. Patients
with significant impairment due to their lung cancer or comorbid conditions may not
be able to withstand resection or alternatively aggressive chemoradiotherapy.
Performance status can be assessed by a variety of methods including the Karnofsky
Performance Status (KPS) and the Eastern Cooperative Oncology Group
Performance Scale (ECOG PS) (table 2 and table 3). The KPS was introduced in the
1940s and uses a 100-point scale and 11 measures to describe patient's abilities to
pursue activities and perform work [5]. The ECOG PS uses a five-point scale and has
been shown in a comparative study to be a better predictor of prognosis [6].

Diagnostic procedures and staging should be carried out simultaneously, even though it
may be tempting to simply pursue a diagnosis when an obvious abnormality is present on
imaging. As an example, in a patient with a 4 cm lung mass and mediastinal adenopathy
on CT, a mediastinal node biopsy may provide a diagnosis and confirm N2 (IIIA) disease
(image 1 and picture 1). In contrast, a transthoracic needle aspirate of the mass may
provide a tissue diagnosis but does not stage the mediastinum. This can lead to the
inappropriate assumption that mediastinal lymph nodes are involved or necessitate a
second procedure. (See "Tumor, node, metastasis (TNM) staging system for non-small
cell lung cancer".)
NSCLC — Rapid advances in understanding the molecular pathogenesis of NSCLC have
demonstrated that NSCLC is a heterogeneous group of diseases. Although the initial
treatment of localized disease is the same, the molecular characterization of tumor tissue
in patients with NSCLC serves as a guide to treatment both in those who present with
metastatic disease and in those who relapse after primary therapy. (See "Personalized,
genotype-directed therapy for advanced non-small cell lung cancer".)

Currently defined NSCLC subsets for which specific targeted therapies have been
standard therapy include those with mutations in the epidermal growth factor receptor
(EGFR), those with the EML4-ALK fusion oncogene, and ROS1 fusions. Other driver
mutations, such as BRAF, have also been identified and specific treatments are being
developed. (See "Personalized, genotype-directed therapy for advanced non-small cell
lung cancer" and "Systemic therapy for advanced non-small cell lung cancer with an
activating mutation in the epidermal growth factor receptor" and "Anaplastic lymphoma
kinase (ALK) fusion oncogene positive non-small cell lung cancer".)

For those without driver mutations, in whom a high level of programmed death ligand 1
(PD-L1) expression is observed (staining on least 50 percent of tumor cells, regardless of
intensity), immunotherapy is available as first-line treatment. (See "Immunotherapy of non-
small cell lung cancer with immune checkpoint inhibition", section on 'First-line setting'.)

Treatment — Surgical resection offers the best opportunity for long-term survival and cure
in patients with resectable NSCLC (algorithm 1). The appropriateness of surgical resection
of candidates with known or suspected NSCLC includes preoperative staging and an
assessment of performance status with concurrent comorbidities and pulmonary function
to allow prediction of postoperative function.

A patient with lung cancer may be “resectable” by virtue of having a surgically removable
NSCLC, but may not be "operable" due to poor pulmonary function or comorbidities.
Advances in surgical technique, the role of limited resection, and postoperative care may
provide the opportunity for surgical resection in patients who previously might not have
been considered candidates for aggressive treatment. (See "Preoperative evaluation for
lung resection".)

●Patients with stage I or II NSCLC should be treated with complete surgical resection
whenever possible (picture 2). Postoperative adjuvant chemotherapy improves
survival in patients with pathologic stage II disease and may have a role for patients
with stage IB disease (table 1). (See "Management of stage I and stage II non-small
cell lung cancer"and "Adjuvant systemic therapy in resectable non-small cell lung
cancer".)
●Patients with stage I or II disease who are not candidates for surgical resection or
who refuse surgery may be candidates for nonsurgical local therapy. Radiation may
be applied by stereotactic techniques or conventional methods. Radiofrequency
ablation (RFA) and cryoablation are alternatives to radiation. Photodynamic therapy
may also be useful as a primary treatment modality in carefully selected patients with
superficial airway lesions (picture 2). (See "Management of stage I and stage II non-
small cell lung cancer", section on 'Nonsurgical candidates' and "Endobronchial
photodynamic therapy in the management of airway disease in adults".)
●For patients with pathologically proven stage III disease prior to definitive therapy, a
combined modality approach using concurrent chemoradiotherapy is generally
preferred. The role of surgery following chemoradiotherapy is an area of active
investigation. Surgery may also retain a role for carefully selected patients with T3 or
T4 lesions and negative mediastinal lymph nodes. (See "Management of stage III
non-small cell lung cancer".)
●In patients with clinical stage I or II disease, in whom tumor involvement of
mediastinal lymph nodes (pathologic stage IIIA) is documented in the histologic
evaluation of the surgical resection specimen, adjuvant chemotherapy has been
shown to improve survival. (See "Adjuvant systemic therapy in resectable non-small
cell lung cancer".)
●Patients with stage IV disease are generally treated with systemic therapy or a
symptom-based palliative approach. In appropriately selected patients,
chemotherapy, molecularly targeted therapy, and/or immunotherapy may prolong
survival without sacrificing quality of life. Therapy in this situation should be guided by
the mutation status of the tumor whenever possible. RT and surgery may also be
useful for symptom palliation in some patients. (See "Overview of the treatment of
advanced non-small cell lung cancer" and "Personalized, genotype-directed therapy
for advanced non-small cell lung cancer" and "Immunotherapy of non-small cell lung
cancer with immune checkpoint inhibition".)
●Patients with stage IV disease based upon the presence of an isolated metastasis
(eg, brain, adrenal) may benefit from resection of the metastasis as well as
aggressive treatment of the primary tumor [7]. (See "Overview of the treatment of
brain metastases".)
●Local palliative measures may be useful in patients with uncontrolled pulmonary
disease [8]. Dyspnea due to bulky central airway involvement may be palliated by
rigid or flexible bronchoscopic removal of tumor using laser for coagulation or
cryotherapy. Stenting may be necessary to maintain airway patency and allow
external beam radiation. Brachytherapy can be applied locally by a bronchoscopy-
directed catheter placement and may be helpful for recurrent or persistent disease in
the airway. This approach is usually pursued after maximal external beam radiation.
(See "Clinical presentation, diagnostic evaluation, and management of central airway
obstruction in adults".)

Prognosis of NSCLC

Stage of disease — The TNM stage at presentation in patients with NSCLC is the factor
that has the greatest impact on prognosis (table 1).
The most extensive data relating stage to prognosis come from a validation series of over
31,000 cases from the Surveillance, Epidemiology and End Results (SEER) database
used to validate the 7th TNM staging system [9]. Survival decreased progressively with
more advanced disease from a median of 59 months for patients with stage IA disease to
four months for those with stage IV disease (figure 1). (See "Overview of the initial
evaluation, diagnosis, and staging of patients with suspected lung cancer" and "Tumor,
node, metastasis (TNM) staging system for non-small cell lung cancer".)

Clinical parameters — Other clinical factors that exist at the time of diagnosis that can
predict survival independent of the disease stage. Most of these factors were identified in
studies that primarily included patients with advanced or inoperable NSCLC:

●Performance status – Poor performance status and weight loss have been
associated with shortened survival [10-15]. Reduced appetite, a precursor of weight
loss, also has negative prognostic implications [10].
●Ethnicity – African American ethnicity does not appear to be an independent
predictor of poorer survival. Although some studies suggested that African Americans
have a worse prognosis even after correcting for stage and treatment, a multivariate
analysis indicated that performance status and weight loss account for these results
[11].

Histopathology — Studies of patients with NSCLC have given conflicting results as to


whether the distinction between adenocarcinoma and squamous cell carcinoma affects
prognosis [16-20]. Other pathologic factors that have been linked to prognosis in some
studies include the degree of differentiation [21,22], lymphatic invasion [23-26], occult
lymph node metastases [27], and intense tumor lymphocytic infiltration [28].
(See "Pathology of lung malignancies".)

Each histologic subtype can vary in its degree of differentiation. The impact of tumor
differentiation on resectable NSCLC is uncertain. Some studies indicate that poorly
differentiated tumors have a worse prognosis than better differentiated tumors [21,22].
However, this finding has not been universal [18].

Lymphatic vessel invasion has a negative impact on outcome [23-25,29]. In one study of
244 patients who had resected stage I NSCLC, five-year cancer-free survival was higher
among patients without lymphatic vessel invasion (74 versus 54 percent) [24]. The
presence of microscopic vascular invasion (MVI) also has a negative impact on survival in
patients with resected T1/T2 N0 lesions (table 1) [30,31]. The importance of this finding
was illustrated by a single institution series of 746 patients, in which MVI was present in
257 (34 percent) [30]. On multivariate analysis, the five-year survival rate was significantly
increased in those without MVI (65 versus 55 percent).

Occult lymph node metastasis can be detected by immunohistochemistry, and one large
study has correlated the presence of such micrometastases with a poorer long-term
outcome in patients with stage I disease [27] (see "Adjuvant systemic therapy in resectable
non-small cell lung cancer"). The reverse transcriptase polymerase chain reaction (RT-
PCR) has also been used to detect tumor markers in lymph nodes from patients with
NSCLC [32]. However, such studies are limited by lack of laboratory standardization and
reproducibility, although the clinical significance of this finding based upon RT-PCR will
remain uncertain until long-term studies are reported.

In a study including almost 1000 patients with resected NSCLC treated with platinum-
based adjuvant chemotherapy, intense lymphocytic infiltration was observed in 6 percent
of tumors and was associated with improved overall survival (hazard ratio [HR] 0.45, 95%
CI 0.23-0.85) and disease-free survival (HR 0.44, 95% CI 0.24-0.78) at a median follow-up
of six years [28].

Molecular characterization — Contemporary studies have identified various molecular


abnormalities that allow the characterization of particular subsets of patients with NSCLC.
This subclassification has important implications for personalizing patient care and may
define patient categories with differing prognoses. (See "Personalized, genotype-directed
therapy for advanced non-small cell lung cancer".)

Specific targeted therapies are widely used for patients with advanced disease with
specific molecular features:

●Activating mutations in the epidermal growth factor receptor (EGFR) define a subset
of patients with adenocarcinoma that more frequently affect patients who are never
smokers, women, and/or of Asian ethnicity. These patients are generally highly
responsive to EGFR tyrosine kinase inhibitors (erlotinib, gefitinib, afatinib) and have a
significantly better prognosis than those without EGFR mutations [33]. (See "Systemic
therapy for advanced non-small cell lung cancer with an activating mutation in the
epidermal growth factor receptor".)
●The presence of the ROS1 or EML4-anaplastic lymphoma kinase (ALK) fusion
oncogene defines other NSCLC subsets that are more frequent in nonsmokers or
former smokers and occurs at a younger age. These patients are highly responsive
to crizotinib, an inhibitor of the ALK. (See "Anaplastic lymphoma kinase (ALK) fusion
oncogene positive non-small cell lung cancer".)
●Other less frequent driver mutations in non-small cell lung cancer have been
identified, including BRAF, HER2, β-catenin, DDR2, and MEK1. Their potential role in
therapy is being defined. Multiplexed and whole genome testing may identify
presence of these potential targets. Improved results from therapy targeted to the
molecular abnormality are propelling the development of highly specific treatment.
●Expression of tumor PD-L1 predicts response to certain immunotherapies and can
guide choice of treatment in both the first-line and subsequent-line treatment settings.
(See "Immunotherapy of non-small cell lung cancer with immune checkpoint
inhibition", section on 'Antibodies to PD-1 and PD-L1'.)
PET and PET-CT — Positron emission tomography (PET), alone or integrated with
computed tomography (CT), is useful in the initial staging to identify sites of tumor
involvement. Integrated PET-CT has been shown to improve staging over PET scanning
alone [34]. (See "Imaging of non-small cell lung cancer", section on 'Positron emission
tomography'.)

A tumor's metabolic activity can be measured using the standardized uptake value (SUV)
to assess the tumor uptake of fluorodeoxyglucose (FDG). A meta-analysis, based upon 21
retrospective studies that included 2637 patients with stages I to IV NSCLC, found that a
high SUV was associated with a poor prognosis [35]. Subsequent multivariate analysis
including 1500 patients suggested that SUV was an independent prognostic feature in
patients with stage I to III disease, although not for patients with stage IV disease [36]. A
second independent meta-analysis, limited to patients with stage I NSCLC, also found that
a lower FDG uptake was associated with a better prognosis [37]. PET (or PET-CT) may
also be useful in predicting response to chemotherapy [38-40].

Additional studies are needed to establish the role of SUV as a prognostic tool or in
predicting the response to treatment.

Recurrence after complete resection — Patients who undergo a complete resection for
NSCLC may develop recurrent and/or metastatic disease. Multiple factors influence
survival following disease recurrence.

In a series of 1073 patients who underwent a complete resection, recurrent NSCLC was
identified in 445 patients (41 percent) [41]. The median time to recurrence following
surgery was 11.5 months, and the median survival following recurrence was 8.1 months.
Multivariate analysis identified several factors that predicted shorter survival following
recurrence. These included poor performance status, disease-free interval of one year or
less, prior use of neoadjuvant chemotherapy or adjuvant RT, and distant metastases (as
opposed to intrathoracic recurrence alone).

SCLC

Treatment — SCLC is a disseminated disease in most patients at presentation and is very


responsive to chemotherapy. Thus systemic chemotherapy is an integral part of the initial
treatment.

●Patients with limited stage disease are primarily treated with a combination of
chemotherapy and radiation therapy, since the addition of radiation therapy has been
shown to prolong survival compared with chemotherapy therapy alone (See "Limited
stage small cell lung cancer: Initial management" and "Extensive stage small cell lung
cancer: Initial management".)
•Surgery is not used except in the rare patient who presents with a solitary
pulmonary nodule without distant metastases or regional lymph node
involvement. (See "Role of surgery in multimodality therapy for small cell lung
cancer".)
•Prophylactic cranial irradiation decreases the incidence of brain metastases and
prolongs survival in patients with limited stage SCLC who respond to their initial
treatment. (See "Prophylactic cranial irradiation for patients with small cell lung
cancer".)
●For patients with extensive stage SCLC, chemotherapy alone is used as the initial
therapy (algorithm 2). Radiation therapy, including both prophylactic cranial irradiation
and thoracic RT, may be beneficial in patients with a complete or partial response to
their initial chemotherapy. (See "Extensive stage small cell lung cancer: Initial
management".)

Prognosis — The most important prognostic factor in patients with SCLC is the extent of
disease (stage) at presentation. For patients with limited stage disease, median survivals
range from 15 to 20 months, and the reported five-year survival rate is 10 to 13 percent.
By contrast, for patients with extensive-stage disease, the median survival is 8 to 13
months, and the five-year survival rate is 1 to 2 percent. (See "Extensive stage small cell
lung cancer: Initial management", section on 'Extensive stage disease'.)

Clinical parameters also have prognostic importance in patients with SCLC [15]. Poor
performance status and/or weight loss have been associated with shortened survival.

SIDE EFFECTS OF TREATMENT — Both curative and palliative treatment of lung cancer
often involves multimodality approaches that may include surgery, RT, and systemic
therapy using cytotoxic chemotherapy or molecularly targeted agents.

The side effects of systemic therapy are often of particular concern, because of their
potential negative effects on quality of life both during and after treatment. Toxicities will
vary depending upon the therapeutic regimen.

Common toxicities observed in patients being treated for lung cancer include the following:

●Chemotherapy-induced nausea and vomiting of variable severity may be seen with


most chemotherapy regimens (table 4), but can usually be prevented or managed
effectively with aggressive therapy. (See "Pathophysiology and prediction of
chemotherapy-induced nausea and vomiting" and "Prevention and treatment of
chemotherapy-induced nausea and vomiting in adults".)
●Hematologic toxicity, including in particular anemia and neutropenia with an
increased risk of infection, is seen with most cytotoxic chemotherapy regimens.
(See "Risk assessment of adults with chemotherapy-induced
neutropenia" and "Hematologic complications of malignancy: Anemia and bleeding".)
●Nephrotoxicity, especially with chemotherapy regimens containing cisplatin, can be
severe. Intensive hydration is required to prevent this complication. (See "Cisplatin
nephrotoxicity".)
●Neurotoxicity, which is especially frequent with cisplatin and the taxanes
(paclitaxel, docetaxel), is usually at least partially reversible after therapy is
discontinued. (See "Overview of neurologic complications of non-platinum cancer
chemotherapy" and "Overview of neurologic complications of platinum-based
chemotherapy".)
●Fatigue is frequent and may be due to systemic chemotherapy, radiation therapy, or
the cancer itself. (See "Cancer-related fatigue: Prevalence, screening and clinical
assessment".)
●Cutaneous toxicity, manifested as an acneiform rash, is frequent
with erlotinib and gefitinib. Although this side effect is troublesome, the presence of a
rash is correlated with a response to therapy.
●Treatment with crizotinib is usually well tolerated; visual disturbances (photophobia,
flashes of light, decreased visual acuity, blurred vision) are the most common side
effects. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small
cell lung cancer", section on 'ALK inhibitors: Toxicity'.)
●Anorexia and weight loss are common in patients with lung cancer, and may be due
to the disease or its treatment. (See "Pathogenesis, clinical features, and assessment
of cancer cachexia" and "Pharmacologic management of cancer anorexia/cachexia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education


materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient education: Lung cancer (The Basics)")


●Beyond the Basics topics (see "Patient education: Lung cancer risks, symptoms,
and diagnosis (Beyond the Basics)")

SUMMARY — Lung cancer is the most common cause of cancer mortality worldwide for
both men and women.

●The initial stage in management is to confirm the diagnosis of a malignancy and to


assess whether the patient has a non-small cell lung cancer (NSCLC) or a small cell
lung cancer (SCLC), the stage of the disease, and the overall performance status of
the patient. (See 'Initial evaluation' above.)
●For patients with NSCLC, initial management is largely determined by the stage of
disease (algorithm 1). For patients with early stage disease, surgical resection offers
the best opportunity for cure, while concurrent chemoradiotherapy is preferred for
those with more extensive intrathoracic disease. In contrast, patients with advanced
disease are managed palliatively with systemic therapy and/or local palliative
modalities. (See 'NSCLC' above.)
●For patients with SCLC, systemic chemotherapy is an important component of
treatment, because SCLC is disseminated at presentation in almost all patients
(algorithm 2). For those with limited stage disease, thoracic radiation therapy is used
in combination with chemotherapy. Prophylactic cranial irradiation is often used to
decrease the incidence of brain metastases and prolong survival. Prophylactic cranial
irradiation and thoracic radiation may also be beneficial in those with a complete or
partial response to initial systemic chemotherapy. (See 'SCLC' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
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Overview of the risk factors, pathology, and clinical manifestations of lung cancer
Author:
David E Midthun, MD
Section Editor:
Rogerio C Lilenbaum, MD, FACP
Deputy Editor:
Sadhna R Vora, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Dec 2016. | This topic last updated: Feb 23, 2015.

INTRODUCTION — Worldwide, lung cancer occurred in approximately 1.8 million patients


in 2012 and caused an estimated 1.6 million deaths [1]. In the United States, lung cancer
occurs in about 225,000 patients and causes over 160,000 deaths annually [2].

Both the absolute and relative frequency of lung cancer has risen dramatically. Around
1953, lung cancer became the most common cause of cancer deaths in men, and in 1985,
it became the leading cause of cancer deaths in women. Lung cancer deaths have begun
to decline in both men and women, reflecting a decrease in smoking [3]. (See "Women
and lung cancer".)

The term lung cancer, or bronchogenic carcinoma, refers to malignancies that originate in
the airways or pulmonary parenchyma. Approximately 95 percent of all lung cancers are
classified as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC).
This distinction is essential for staging, treatment, and prognosis. Other cell types
comprise about 5 percent of malignancies arising in the lung.

This discussion will present an overview of the risk factors, pathology, and clinical
manifestations of NSCLC and SCLC. An overview of the initial evaluation, treatment, and
prognosis of lung cancer is presented separately. (See "Overview of the initial evaluation,
treatment and prognosis of lung cancer".)

RISK FACTORS — A number of environmental and lifestyle factors have been associated
with the subsequent development of lung cancer, of which cigarette smoking is the most
important. The risk factors associated with the development of lung cancer are discussed
in detail separately. (See "Cigarette smoking and other possible risk factors for lung
cancer".)

Smoking — The primary risk factor for the development of lung cancer is cigarette
smoking, which is estimated to account for approximately 90 percent of all lung cancers
[4]. The risk of developing lung cancer for a current smoker of one pack per day for 40
years is approximately 20 times that of someone who has never smoked. Factors that
increase the risk of developing lung cancer in smokers include the extent of smoking and
exposure to other carcinogenic factors, such as asbestos.

Thus, the most important aspects of lung cancer prevention are preventing people from
starting to smoke and inducing those who already smoke to stop. In individuals who do
quit smoking, the risk of developing lung cancer falls compared with those who continue to
smoke; the benefit is greatest in those who stop by age 30 [5]. Despite stopping smoking,
the risk for lung cancer continues to rise with age at a faster rate than those who never
smoked [6]. (See "Overview of smoking cessation management in adults".)

Other factors — A number of other factors may affect the risk of developing lung cancer:

●Radiation therapy (RT) can increase the risk of a second primary lung cancer in
patients who have been treated for other malignancies. This increased risk has been
demonstrated in patients with both Hodgkin lymphoma and breast cancer.
(See "Cigarette smoking and other possible risk factors for lung cancer", section on
'Radiation therapy'.)
●Environmental toxins – Environmental factors have been associated with an
increased risk for developing lung cancer. These include exposure to second-hand
smoke, asbestos, radon, metals (arsenic, chromium, and nickel), ionizing radiation,
and polycyclic aromatic hydrocarbons [4]. (See "Secondhand smoke exposure:
Effects in adults".)
●Pulmonary fibrosis – Several studies have shown that the risk for lung cancer is
increased about sevenfold in patients with pulmonary fibrosis [7]. This increased risk
appears to be independent of smoking. (See "Idiopathic interstitial pneumonias:
Clinical manifestations and pathology".)
●HIV infection – The incidence of lung cancer among individuals infected with HIV is
increased compared with that seen in uninfected controls. (See "HIV infection and
malignancy: Management considerations", section on 'Lung cancer'.)
●Genetic factors – Genetic factors can affect both the risk for and prognosis from lung
cancer. Although the genetic basis of lung cancer is still being elucidated, there is a
clearly established familial risk. (See "Cigarette smoking and other possible risk
factors for lung cancer", section on 'Genetic factors'.)
●Alcohol – The relationship between alcohol and lung cancer is discussed in further
detail elsewhere. (See "Overview of the risks and benefits of alcohol consumption",
section on 'Lung cancer'.)
●Dietary factors – Epidemiologic evidence has suggested that various dietary factors
(antioxidants, cruciferous vegetables, phytoestrogens) may reduce the risk of lung
cancer, but the role of these factors is not well established. Attempts to confirm these
epidemiologic findings and to decrease the incidence of lung cancer in high-risk
patients have not been successful. As an example, the Alpha-Tocopherol, Beta-
Carotene Cancer Prevention Study actually showed an increase in lung cancer
among smokers with dietary supplementation of beta-carotene.
(See "Chemoprevention of lung cancer".)

SCREENING — The diagnosis of lung cancer is primarily based upon evaluation of


individuals with symptoms. Screening for lung cancer was not widely used until recently
because chest radiography and sputum cytology had not been shown to reduce mortality
from lung cancer.

Prospective, single-arm observational studies have shown that a large percentage of lung
cancers detected by computed tomography (CT) screening are early stage tumors, which
have a favorable prognosis. These findings led to the randomized National Lung
Screening Trial that compared CT screening with chest x-ray [8]. This trial demonstrated a
20 percent decrease in lung cancer mortality in heavy smokers who were screened
annually for three years and is the only trial to show benefit in mortality reduction.

The US Preventative Services Task Force has given low-dose CT scanning a “B”
recommendation for those at high risk for lung cancer [9]. The Center for Medicare and
Medicaid Services (CMS) has agreed to cover the cost of CT screening in approved
programs for those age 55 to 77 who have no symptoms of lung cancer, have a 30 pack-
year smoking history, and if they have quit have done so within 15 years [10].
(See "Screening for lung cancer", section on 'National Lung Screening Trial'.)

PATHOLOGY — The 2015 World Health Organization classification for primary lung
cancer should be the foundation for lung cancer classification. It is discussed in detail
elsewhere. (See "Pathology of lung malignancies".)

The relative incidence of adenocarcinoma has risen dramatically, and there has been a
corresponding decrease in the incidence of other types of non-small cell lung cancer
(NSCLC) and small cell lung cancer (SCLC). The increased incidence of adenocarcinoma
is thought to be due to the introduction of low-tar filter cigarettes in the 1960s, although this
relationship is unproven.

Until recent years the simple pathologic separation of NSCLC from SCLC along with stage
was adequate to make treatment decisions for a new diagnosis of lung cancer. Since
2008, it has been shown that separation of adenocarcinoma and squamous cell carcinoma
is important in determining optimal therapy for stage IV disease. The development of
targeted therapy for specific gene mutations has resulted in the reality of individually
tailored therapy. Subtype analysis of NSCLC has come full circle now that epidermal
growth factor receptors (EGFR), anaplastic lymphoma kinase (ALK), and c-ROS oncogene
1 (ROS1) mutations are not only identifiable but their targeted treatment results in
responses better than that with standard chemotherapy [11]. (See "Personalized,
genotype-directed therapy for advanced non-small cell lung cancer".)

Approximately 15 to 30 percent of non-Asian patients and 30 to 60 percent of Asian


patients with adenocarcinoma have a mutation of the EGFR gene [12]. The ALK gene
mutations present in 2 to 7 percent of United States patients with NSCLC [12]. The
improved response to tyrosine kinase inhibitors specific to these mutations has led the
College of American Pathologists Guideline to recommend testing for EGFR and ALK
mutations in all advanced-stage adenocarcinomas, mixed cancers, and those with NSCLC
in whom an adenocarcinoma component cannot be excluded [12]. Using multiplexed
assays one group identified driver mutations in over 60 percent of more than 700 patients
with adenocarcinomas [13].

The potential for mutation identification and tailored treatment has implications at the initial
evaluation of suspected lung cancer as diagnostic sampling needs to be adequate to be
assessed for mutation if advanced stage adenocarcinoma is present. Over 90 percent of
samples from endobronchial ultrasound-guided needle aspirates, transthoracic needle
aspirates, and pleural fluid cytology specimens showing adenocarcinoma are adequate for
mutation analysis; however, adequacy rates are lower from bone biopsy aspirates that
require decalcification [14,15].

CLINICAL MANIFESTATIONS — The majority of patients with lung cancer have


advanced disease at clinical presentation (table 1). This may reflect the aggressive biology
of the disease and the frequent absence of symptoms until locally advanced or metastatic
disease is present. Many high-risk patients will be diagnosed while asymptomatic due to
an effective screening test. (See "Screening for lung cancer".)

Symptoms may result from local effects of the tumor, from regional or distant spread, or
from distant effects not related to metastases (paraneoplastic syndromes). Approximately
three-fourths of non-screened patients have one or more symptoms at the time of
diagnosis. A study of 2293 consecutive patients with non-small cell lung cancer (NSCLC)
noted that the mean age was 64 years and the most common symptoms at presentation
were cough (55 percent), dyspnea (45 percent), pain (38 percent), and weight loss (36
percent) [16].

Intrathoracic effects of the cancer — There are a wide range of symptoms due to the
intrathoracic effects of the cancer, the most common of which are cough, hemoptysis,
chest pain, and dyspnea.

Cough — Cough is present in 50 to 75 percent of lung cancer patients at presentation and


occurs most frequently in patients with squamous cell and small cell carcinomas because
of their tendency to involve central airways [16-18]. The new onset of cough in a smoker or
former smoker should raise suspicion that lung cancer is present. Bronchorrhea or cough
productive of large volumes of thin, mucoid secretions may be a feature of mucinous
adenocarcinoma and usually indicates advanced disease. Both NSCLC and SCLC may
cause a post-obstructive pneumonia. However, bronchiectasis from bronchial obstruction
is uncommon because lung cancer usually progresses too rapidly for bronchiectasis to
develop. In contrast, slow-growing neoplasms such as carcinoid tumor or hamartoma are
more likely to present with bronchiectasis. (See "Evaluation of subacute and chronic cough
in adults" and "Bronchioloalveolar carcinoma, including adenocarcinoma in
situ" and "Bronchial neuroendocrine (carcinoid) tumors: Epidemiology, risk factors,
classification, histology, diagnosis, and staging".)

Hemoptysis — Hemoptysis is reported by 20 to 50 percent of patients who are diagnosed


with lung cancer, although bronchitis is the most common cause of this symptom [16-18].
Any amount of hemoptysis can be alarming to the patient, and large volumes of
hemoptysis may cause asphyxia. In a patient with hemoptysis, the likelihood of lung
cancer varies from 3 to 34 percent in different series depending upon the patient's age and
smoking history [19]. In smokers with hemoptysis and a nonsuspicious or normal chest
radiograph, bronchoscopy will diagnose lung cancer in about 5 percent of cases [20].
(See "Etiology and evaluation of hemoptysis in adults" and "Massive hemoptysis: Initial
management".)

Chest pain — Chest pain is present in approximately 20 to 40 percent of patients


presenting with lung cancer [16,18,21]. It can be quite variable in character and is more
common in younger compared with older patients. Pain is typically present on the same
side of the chest as the primary tumor. Dull, aching, persistent pain may occur from
mediastinal, pleural, or chest wall extension, but the presence of pain does not necessarily
preclude resectability. Although pleuritic pain may be the result of direct pleural
involvement, obstructive pneumonitis or a pulmonary embolus related to a
hypercoagulable state may also cause chest pain.

Dyspnea — Shortness of breath is a common symptom in patients with lung cancer at the
time of diagnosis, occurring in approximately 25 to 40 percent of cases [16-18]. Dyspnea
may be due to extrinsic or intraluminal airway obstruction, obstructive pneumonitis or
atelectasis, lymphangitic tumor spread, tumor emboli, pneumothorax, pleural effusion, or
pericardial effusion with tamponade. Partial obstruction of a bronchus may cause a
localized wheeze, heard by the patient or by the clinician on auscultation, while stridor can
result from obstruction of larger airways.

Pulmonary function testing may be useful in a patient with dyspnea when due to lung
cancer, as it may show flattening of the expiratory and/or inspiratory flow-volume loop from
presence of tumor in the trachea itself (figure 1), from extrinsic compression, or from vocal
cord paralysis. (See "Overview of pulmonary function testing in adults".)

Unilateral paralysis of the diaphragm may be due to damage of the phrenic nerve (image
1). Patients may be asymptomatic or report shortness of breath. In one series, lung cancer
was the most common neoplasm affecting the phrenic nerve, although malignancy
accounted for only 4 percent of patients presenting with diaphragmatic paralysis [22].
(See "Causes and diagnosis of bilateral diaphragmatic paralysis".)

Hoarseness — The differential diagnosis of persistent hoarseness in a smoker includes


both laryngeal cancer and lung cancer. In patients with lung cancer, this is due to
malignancy involving the recurrent laryngeal nerve along its course under the arch of the
aorta and back to the larynx [23,24]. (See "Hoarseness in adults" and "Overview of the
diagnosis and staging of head and neck cancer".)

Pleural involvement — Extension of tumor into the visceral pleura is stage T2 and into
the parietal pleura is T3. The presence of carcinoma cells in the pleural fluid classifies the
lung cancer as M1a (stage IV) in the seventh edition TNM staging system (table 2). Pleural
involvement can manifest as pleural thickening without pleural effusion (image 2).
(See "Overview of the initial evaluation, diagnosis, and staging of patients with suspected
lung cancer" and "Tumor, node, metastasis (TNM) staging system for non-small cell lung
cancer".)

Patients with malignant effusions are considered incurable and managed palliatively.
Although malignant pleural effusions can cause dyspnea and cough, approximately one-
fourth of patients who have lung cancer and pleural metastases are asymptomatic [25].
Although a malignant pleural effusion precludes curative resection, not all pleural effusions
in patients with lung cancer are malignant. A benign pleural effusion may occur in a patient
with a resectable lung cancer due to lymphatic obstruction, post-obstructive pneumonitis,
or atelectasis. In a patient with a pleural effusion, the presence of tumor needs to be
confirmed or excluded so that a chance for curative resection is not missed. Series report
that 5 to 14 percent of patients with NSCLC and an ipsilateral pleural effusion have
resectable disease [26,27]. Surgical thoracoscopy or medical pleuroscopy should follow
two or three negative cytologies to further evaluate the pleural space prior to surgical
resection of a primary lesion.

Malignant effusions are typically exudates and may be serous, serosanguineous, or


grossly bloody. The yield of pleural fluid cytology after a single thoracentesis in patients
with documented pleural involvement is about 60 percent; the yield rises to about 75
percent with a second thoracentesis and there is little additional gain with additional
thoracentesis [28,29].Closed pleural biopsy adds little to the yield of cytologic examination.
In a patient with a suspected malignancy, repeat pleural fluid cytology with or without
pleural biopsy is appropriate if the initial study is negative. A prospective series evaluated
cytologic yield from pleural fluid aliquots of 10 mL, 60 mL, and ≥150 mL [30]. The
sensitivity for diagnosing malignancy in the pleural fluid was lower for volumes of 10 mL
compared with the higher volumes. Medical pleuroscopy has a sensitivity of >90 percent
for malignancy and may be considered for patients with pleural effusions and suspected
malignancy who are cytology negative (picture 1) [31]. (See "Diagnostic evaluation of a
pleural effusion in adults: Initial testing".)

During the course of their disease, approximately 10 to 15 percent of patients who have
lung cancer will have malignant pleural effusions (image 3A-B) [32]. The management of
patients with malignant pleural effusions is discussed separately. (See "Management of
malignant pleural effusions".)

Superior vena cava syndrome — Obstruction of the superior vena cava (SVC) causes
symptoms that commonly include a sensation of fullness in the head and dyspnea. Cough,
pain, and dysphagia are less frequent. Physical findings include dilated neck veins, a
prominent venous pattern on the chest, facial edema, and a plethoric appearance (picture
2). The chest radiograph typically shows widening of the mediastinum or a right hilar mass.
Computed tomography (CT) can often identify the cause, level of obstruction, and extent of
collateral venous drainage [33].

The SVC syndrome is more common in patients with SCLC than NSCLC. For most
patients who have SVC syndrome secondary to lung cancer, the symptoms resolve after
treatment of the mediastinal tumor. The pathophysiology and treatment options for the
management of patients with SVC syndrome are discussed separately. (See "Malignancy-
related superior vena cava syndrome".)

Pancoast syndrome — Lung cancers arising in the superior sulcus cause a characteristic
Pancoast syndrome manifested by pain (usually in the shoulder, and less commonly in the
forearm, scapula, and fingers), Horner's syndrome, bony destruction, and atrophy of hand
muscles. (See "Horner syndrome".)
Pancoast syndrome is most commonly caused by NSCLC (typically squamous cell) and
only rarely by small cell lung cancer (SCLC) (image 4A-B). The presentation, diagnosis,
and treatment of patients with Pancoast syndrome due to superior sulcus tumors is
discussed in detail elsewhere. (See "Superior pulmonary sulcus (Pancoast) tumors".)

Extrathoracic metastases — Lung cancer can spread to any part of the body tissue.
Metastatic spread may result in the presenting symptoms or may occur later in the course
of disease.

The staging at presentation of patients with known or suspected lung cancer is reviewed
elsewhere. (See "Overview of the initial evaluation, diagnosis, and staging of patients with
suspected lung cancer" and "Tumor, node, metastasis (TNM) staging system for non-small
cell lung cancer".)

The most frequent sites of distant metastasis are the liver, adrenal glands, bones, and
brain.

Liver — Symptomatic hepatic metastases are uncommon early in the course of disease.
Asymptomatic liver metastases may be detected at presentation by liver enzyme
abnormalities, CT (image 5), or positron emission tomography (PET) (image 6). Among
patients with otherwise resectable NSCLC in the chest, CT evidence of liver metastasis
has been identified in approximately 3 percent of cases [34]. PET or integrated PET-CT
identifies unsuspected metastases in the liver or adrenal glands in about 4 percent of
patients [35,36]. The incidence of liver metastases is much higher later in the course of the
disease. Autopsy studies have shown that hepatic metastases are present in more than 50
percent of patients with either NSCLC or SCLC [37,38]. (See "Imaging of non-small cell
lung cancer".)

Bone — Metastasis from lung cancer to bone is frequently symptomatic. Pain in the back,
chest, or extremity, and elevated levels of serum alkaline phosphatase are usually present
in patients who have bone metastasis. The serum calcium may be elevated due to
extensive bone disease. Approximately 20 percent of patients with NSCLC have bone
metastases on presentation [39]. An osteolytic radiographic appearance is more frequent
than an osteoblastic one, and the most common sites of involvement are the vertebral
bodies (image 7). Bone metastases are even more frequent in SCLC and can be found in
30 to 40 percent of patients (image 8) [40]. PET and PET-CT have improved the ability to
identify metastases to many organs, including bone, with greater sensitivity than CT or
bone scan [41]. (See "Imaging of non-small cell lung cancer".)

Adrenal — The adrenal glands are a frequent site of metastasis but such metastases are
only rarely symptomatic. Concern about adrenal metastasis usually occurs when a
unilateral mass is found by staging CT in a patient with a known or suspected lung cancer.
Only a fraction of adrenal masses detected on staging scans represent metastasis. This
was illustrated by a series of 330 patients with operable NSCLC, in which 32 (10 percent)
had an isolated adrenal mass [42]. Only 8 of these 32 (25 percent) were malignant while
the remainder had benign lesions (adenomas, nodular hyperplasia, hemorrhagic cysts).
Conversely, a negative imaging study does not exclude adrenal metastases. A study of
patients with SCLC found that 17 percent of adrenal biopsies showed metastatic
involvement despite having a normal CT scan [43].

The lack of specificity of an initial CT identifying an adrenal mass creates a special


problem in patients with an otherwise resectable lung cancer. In this situation, PET may be
particularly useful in distinguishing a benign from malignant adrenal mass (figure 2) [44].
Other procedures that may be useful in excluding a metastasis include magnetic
resonance imaging (MRI) consistent with a benign adenoma or a negative needle biopsy.
(See "Imaging of non-small cell lung cancer".)

Involvement of the adrenal glands is more frequent in patients with widely disseminated
disease. In autopsy series, adrenal gland metastases have been identified in about 40
percent of patients with lung cancer [37].

Brain — Neurologic manifestations of lung cancer include metastases and paraneoplastic


syndromes. (See 'Paraneoplastic phenomena' below.)

Symptoms from central nervous system metastasis are similar to those with other tumors
and include headache, vomiting, visual field loss, hemiparesis, cranial nerve deficit, and
seizures. (See "Epidemiology, clinical manifestations, and diagnosis of brain metastases".)

In patients with NSCLC, the frequency of brain metastasis is greatest with


adenocarcinoma and least with squamous cell carcinoma. The risk for brain metastasis
increases with larger primary tumor size and the presence of regional node involvement
(image 9) [45]. For carefully selected patients, sequential resection may be feasible in
cases that have operable NSCLC in the chest and a solitary brain metastasis.
(See "Overview of the treatment of brain metastases".)

In patients with SCLC, metastasis to brain is present in approximately 20 to 30 percent of


patients at presentation [46]. Without prophylactic irradiation, relapse in the brain occurs in
about one-half of patients within two years. Randomized trials have shown that the
frequency of brain metastases can be significantly reduced with prophylactic cranial
radiation. (See "Prophylactic cranial irradiation for patients with small cell lung cancer".)

Paraneoplastic phenomena — Paraneoplastic effects of tumor are remote effects that


are not related to the direct invasion, obstruction, or metastasis.

Hypercalcemia — Hypercalcemia in patients with lung cancer may arise from a bony
metastasis or less commonly tumor secretion of a parathyroid hormone-related protein
(PTHrP), calcitriol or other cytokines, including osteoclast activating factors.
In one study of 1149 consecutive lung cancers, 6 percent had hypercalcemia [47]. Among
those with hypercalcemia, squamous cell carcinoma, adenocarcinoma, and SCLC were
responsible in 51, 22, and 15 percent of cases, respectively. Most patients with
hypercalcemia have advanced disease (stage III or IV) and a median survival of a few
months [47]. (See "Hypercalcemia of malignancy: Mechanisms".)

Symptoms of hypercalcemia include anorexia, nausea, vomiting, constipation, lethargy,


polyuria, polydipsia, and dehydration. Confusion and coma are late manifestations, as are
renal failure and nephrocalcinosis. (See "Clinical manifestations of hypercalcemia".)

Symptomatic patients who have serum calcium of 12 mg/dL (3 mmol/L) or higher require
treatment that includes hydration and bisphosphonate [48]. The treatment of
hypercalcemia due to malignancy is discussed in detail separately. (See "Hypercalcemia
of malignancy: Mechanisms" and "Treatment of hypercalcemia".)

SIADH secretion — The syndrome of inappropriate antidiuretic hormone secretion


(SIADH) is frequently caused by SCLC and results in hyponatremia. Approximately 10
percent of patients who have SCLC exhibit SIADH [49,50]. SCLC accounts for
approximately 75 percent of all malignancy-related of SIADH. (See "Diagnostic evaluation
of adults with hyponatremia" and "Pathophysiology and etiology of the syndrome of
inappropriate antidiuretic hormone secretion (SIADH)".)

The severity of symptoms is related to the degree of hyponatremia and the rapidity of the
fall in serum sodium. Symptoms include anorexia, nausea, and vomiting. Cerebral edema
can occur when the onset of hyponatremia is rapid. Symptoms caused by cerebral edema
may include irritability, restlessness, personality changes, confusion, coma, seizures, and
respiratory arrest. (See "Manifestations of hyponatremia and hypernatremia in adults",
section on 'Hyponatremia'.)

The treatment of SIADH focuses on treating the malignancy. In the majority of patients
with SCLC, the hyponatremia will resolve within weeks of starting chemotherapy. Chronic
hyponatremia or that of unclear duration may be treated with normal saline infusion to
euvolemia, fluid restriction and demeclocycline, or a vasopressin-receptor antagonist.
Acute and severe hyponatremia may be carefully treated with hypertonic (3 percent) saline
infusion for a correction of 1 to 2 mmol per liter per hour with a correction of not more than
8 to 10 mmol per liter in 24 hours [51]. (See "Treatment of hyponatremia: Syndrome of
inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat".)

Neurologic — Lung cancer is the most common cancer associated with paraneoplastic
neurologic syndromes; typically these are associated with SCLC. Paraneoplastic
neurologic syndromes are thought to be immune-mediated, and autoantibodies have been
identified in a number of instances. The various neurologic paraneoplastic syndromes and
their pathophysiology are discussed elsewhere. (See "Paraneoplastic syndromes affecting
peripheral nerve and muscle" and "Paraneoplastic syndromes affecting the spinal cord and
dorsal root ganglia" and "Overview of paraneoplastic syndromes of the nervous
system" and "Paraneoplastic visual syndromes" and "Paraneoplastic cerebellar
degeneration" and "Paraneoplastic and autoimmune encephalitis" and "Opsoclonus
myoclonus syndrome".)

These diverse neurologic manifestations include, but are not limited to, Lambert-Eaton
myasthenic syndrome (LEMS), cerebellar ataxia, sensory neuropathy, limbic encephalitis,
encephalomyelitis, autonomic neuropathy, retinopathy, and opsomyoclonus [52].

The most common of these is LEMS, which may be seen in approximately 3 percent of
patients with SCLC (waveform 1) [53]. The neurologic symptoms of LEMS precede the
diagnosis of SCLC in more than 80 percent of cases, often by months to years.
(See "Clinical features and diagnosis of Lambert-Eaton myasthenic
syndrome" and "Treatment of Lambert-Eaton myasthenic syndrome", section on
'Evaluation for malignancy'.)

As many as 70 percent of patients who have SCLC and an associated paraneoplastic


neurologic syndrome have limited stage disease [54]. The finding of a paraneoplastic
autoantibody in patients presenting with a neurologic syndrome should lead to an
evaluation for malignancy. A CT of the chest is indicated in current or former smokers who
have a suspected paraneoplastic neurologic syndrome. If the CT chest is negative, then
PET may be useful in identifying the location of a neoplasm. Even subtle abnormalities of
the lungs or mediastinum require biopsy in this situation (image 10A-B) [55].

Paraneoplastic neurologic syndromes generally do not improve with immunosuppressive


treatment. However, symptoms may stabilize with response of the underlying neoplasm to
treatment.

Hematologic manifestations — A number of hematologic abnormalities are seen in


patients with lung cancer. These include the following:

●Anemia – Anemia is frequent in patients with lung cancer and can contribute to
fatigue and dyspnea. As an example, in one series 40 percent of untreated patients
had a hemoglobin ≤12 g/dL, while the incidence of anemia was 80 percent in those
on chemotherapy [56]. Anemia may be due to any of a number of causes, including
treatment. (See "Hematologic complications of malignancy: Anemia and
bleeding" and "Role of erythropoiesis-stimulating agents in the treatment of anemia in
patients with cancer".)
●Leukocytosis – In one series, tumor-associated leukocytosis was found in 15
percent of patients with lung cancer. Nearly all had NSCLC, and the leukocytosis was
thought to be due to overproduction of granulocyte-colony stimulating factor [57].
Leukocytosis in association with lung cancer is associated with a poor prognosis and
has also been associated with hypercalcemia [47,57]. (See "Causes of neutrophilia",
section on 'Secondary neutrophilia'.)
●Thrombocytosis – Thrombocytosis is common and maybe present in as many as 14
percent of patients with lung cancer at presentation [58]. Thrombocytosis at
presentation has been identified as an independent predictor of shortened survival
[59].
●Eosinophilia – Eosinophilia in tissue or blood is rare, but has been reported in
patients with large cell carcinoma. (See "Eosinophil biology and causes of
eosinophilia".)
●Hypercoagulable disorders – A variety of hypercoagulable disorders have been
associated with lung cancer and other malignancies. These hypercoagulable
disorders include:
•Trousseau's syndrome (migratory superficial thrombophlebitis)
•Deep venous thrombosis and thromboembolism
•Disseminated intravascular coagulopathy
•Thrombotic microangiopathy
•Nonthrombotic microangiopathy

These complications and their management are discussed separately. (See "Risk and
prevention of venous thromboembolism in adults with cancer".)

Hypertrophic osteoarthropathy — Hypertrophic pulmonary osteoarthropathy (HPO) is


defined by the presence of clubbing (picture 3) and periosteal proliferation of the tubular
bones associated with lung cancer or other lung disease. Clinically, HPO is characterized
by a symmetrical, painful arthropathy that usually involves the ankles, knees, wrists, and
elbows. The metacarpal, metatarsal, and phalangeal bones may also be involved.
(See "Malignancy and rheumatic disorders", section on 'Hypertrophic osteoarthropathy'.)

A radiograph of the long bones (ie, tibia and fibula) shows characteristic periosteal new
bone formation in patients with HPO. An isotope bone scan or PET typically demonstrates
diffuse uptake by the long bones (image 11A-B). The symptoms of HPO may resolve after
tumor resection. For patients who are not operable, the usual treatment is with
nonsteroidal antiinflammatory agents or a bisphosphonate [60].

Dermatomyositis and polymyositis — Dermatomyositis and polymyositis are two


distinct forms of inflammatory myopathy, both of which are manifested clinically by muscle
weakness. These inflammatory myopathies can be the presenting symptom in patients
with lung cancer or can develop later in the course of disease. In addition to lung cancer,
other frequent primary sites associated with these disorders include the ovary, cervix,
pancreas, bladder, and stomach. The incidence of malignancy and the role of screening
for cancer in patients with dermatomyositis or polymyositis is discussed elsewhere.
(See "Malignancy in dermatomyositis and polymyositis".)

Cushing's syndrome — Ectopic production of adrenal corticotropin (ACTH) can cause


Cushing's syndrome. Patients typically present with muscle weakness, weight loss,
hypertension, hirsutism, and osteoporosis. Hypokalemic alkalosis and hyperglycemia are
usually present. (See "Epidemiology and clinical manifestations of Cushing's syndrome".)

Cushing's syndrome is relatively common in patients with SCLC and with carcinoid tumors
of the lung, as well as extrathoracic malignancies [61]. Patients with Cushing's syndrome
and SCLC appear to have a worse prognosis than patients with SCLC without Cushing's
syndrome [61-63]. (See "Establishing the cause of Cushing's syndrome" and "Bronchial
neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology,
diagnosis, and staging", section on 'Cushing's syndrome'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education


materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient education: Lung cancer (The Basics)" and "Patient
education: Asbestos exposure (The Basics)")
●Beyond the Basics topics (see "Patient education: Lung cancer risks, symptoms,
and diagnosis (Beyond the Basics)")

SUMMARY — Lung cancer is the most common cause of cancer mortality worldwide for
both men and women.

●Cigarette smoking is responsible for approximately 90 percent of cases of lung


cancer. Thus prevention of smoking and cessation of smoking offer the most
important route to decreasing the morbidity and mortality associated with this disease.
(See "Cigarette smoking and other possible risk factors for lung cancer".)
●Lung cancer is divided into several histologic types. The most important distinction is
between non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).
Gene mutations in those with adenocarcinomas may allow for individualized
treatment with greater success compared with standard chemotherapy.
(See "Pathology of lung malignancies" and "Personalized, genotype-directed therapy
for advanced non-small cell lung cancer".)
●The clinical manifestations of lung cancer can be due to intrathoracic effects of the
tumor (eg, cough, hemoptysis, pleural disease), extrathoracic metastases (most
commonly, liver, bone, brain), or paraneoplastic phenomena (eg, hypercalcemia,
Cushing's syndrome, hypercoagulability disorders, various neurologic syndromes).
(See 'Clinical manifestations' above.)
●The initial evaluation, treatment, and prognosis of lung cancer are presented
separately. (See "Overview of the initial evaluation, treatment and prognosis of lung
cancer".)
Use of UpToDate is subject to the Subscription and License Agreement.
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Pathobiology and staging of small cell carcinoma of the lung


Authors:
Bonnie S Glisson, MD, FACP
Lauren A Byers, MD
Section Editors:
Rogerio C Lilenbaum, MD, FACP
Andrew Nicholson, MD
James R Jett, MD
Deputy Editor:
Sadhna R Vora, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Dec 2016. | This topic last updated: Nov 03, 2014.

INTRODUCTION — Small cell lung cancer (SCLC) is distinguished from non-small cell
lung cancer (NSCLC) by its rapid doubling time, high growth fraction, and the early
development of widespread metastases. Although the cancer is initially highly responsive
to chemotherapy and radiotherapy, the majority of patients will relapse with broadly
resistant disease within a few months to a year from initial therapy.

The epidemiology, pathology, clinical presentation, staging, and prognostic factors of


SCLC will be reviewed here. The treatment of SCLC is discussed separately.
(See "Extensive stage small cell lung cancer: Initial management" and "Limited stage small
cell lung cancer: Initial management" and "Prophylactic cranial irradiation for patients with
small cell lung cancer".)

EPIDEMIOLOGY — Small cell lung cancer (SCLC) occurs almost exclusively in smokers
and appears to be most common in heavy smokers [1]. Historically SCLC has been rare in
never smokers, representing just 2.9 percent of the lung cancer cases in women, and
none in men, from a case control series [2].

The proportion of lung cancer in the United States that is classified as SCLC has steadily
decreased. This was illustrated by an analysis of the Surveillance, Epidemiology, and End
Results (SEER) database, in which the proportion of SCLC declined from 17 percent in
1986 to 13 percent in 2002 [3]. This overall decrease in incidence was accompanied by an
increase in the percentage of cases of SCLC arising in women (28 percent in 1973 versus
50 percent in 2002).
These epidemiologic changes may be due to differences in smoking patterns (eg,
decreased in men) [3]. In addition, changes in the pathologic criteria for SCLC may have
led to some cases being classified as having large cell neuroendocrine carcinoma [1].
(See 'Classification of SCLC' below.)

PATHOLOGY

Classification of SCLC — The histologic classification of small cell lung cancer (SCLC)
has evolved over several decades. Initially, the World Health Organization (WHO)
classified SCLC into the three histologic subtypes (oat cell, intermediate cell type, and
combined [SCLC with non-small cell component (usually squamous cell or
adenocarcinoma)]) [4]. This classification system has undergone progressive revisions that
attempted to correlate histopathologic observations with clinical behavior. (See "Pathology
of lung malignancies" and "Pathology of lung malignancies", section on 'Small cell
carcinoma'.)

The 2004 World Health Organization (WHO) classification of lung tumors eliminated
intermediate cell carcinoma and added a new variant of large cell carcinoma (LCC)
designated large cell neuroendocrine carcinoma (LCNEC) [5], which shares biologic and
clinical features with SCLC [6]. In 2011, a multidisciplinary expert panel representing the
International Association for the Study of Lung Cancer (IASLC), the American Thoracic
Society (ATS), and the European Respiratory Society (ERS) proposed an updated
classification system for adenocarcinomas of the lung, which included modification in the
classification of large cell carcinomas (table 1) [7].

The WHO classification system recognizes the neuroendocrine origin of the following
primary lung malignancies (table 2) [8]:

●Small cell lung carcinoma (SCLC)


●Combined SCLC, consisting predominantly of SCLC with some areas of NSCLC
●LCNEC, a type of NSCLC that is distinct from SCLC
●Typical carcinoid
●Atypical carcinoid

SCLC and LCNEC are both high-grade neuroendocrine tumors, as compared with atypical
carcinoid and typical carcinoid which are intermediate-grade and low-grade tumors,
respectively. Large cell neuroendocrine cancer appears to have a biologic behavior that is
similar to SCLC, which is supported by their similar gene expression and proteomic
profiles [9-11]. (See "Pathology of lung malignancies", section on 'Large cell
neuroendocrine carcinoma'.)

A diagnosis of SCLC is based primarily upon light microscopy. Small cell carcinoma is
characterized by small "blue" malignant cells about twice the size of lymphocytes. The
cytoplasm is sparse, and nuclear features include finely dispersed chromatin without
distinct nucleoli. In contrast, the cells of LCNEC are distinguished by the presence of
prominent nucleoli, a more granular chromatin pattern, and variable amounts of cytoplasm.
Mitotic rates are high, and necrosis of individual tumor cells is common. Nuclear molding is
considered characteristic in well-preserved specimens, although a nondiagnostic "crush"
artifact is more frequently observed. The neoplastic cells are typically arranged in clusters,
sheets, or trabeculae, separated by a delicate fibrovascular stroma.

In the combined cell subtype, SCLC coexists with squamous cell carcinoma,
adenocarcinoma, LCC, or rarely spindle cell carcinoma. If SCLC coexists with large cell
components, at least 10 percent of each component should be present. For other non-
small cell elements, the presence of any amount indicates classification as "combined."
While coexistence with another cell type of carcinoma is rarely detected in untreated
specimens, up to 30 percent of autopsies with SCLC demonstrate areas of differentiation
into non-small cell carcinoma.

These findings have led to the hypothesis that pulmonary carcinogenesis occurs in a
pluripotent stem cell capable of differentiation along several pathways. Further supporting
this is the observation that approximately 14 percent of NSCLC tumors with EGFR
mutations acquire SCLC morphology and expression of neuroendocrine markers as
EGFR-inhibitor resistance evolves, and that these tumors are sensitive to standard SCLC
regimens [12].

In the combined cell subtype, metastatic disease usually contains predominantly SCLC
even if the SCLC element is low. Therefore treatment for patients with the combined
subtype is appropriate for SCLC.

The prognostic significance of the combined SCLC variant is unclear. In some reports, the
combined variant has been more resistant to treatment and had a short survival [13].
However, other reports suggest a more favorable prognosis [14,15].

Tumor markers — For SCLC and LCNEC, there are standard immunohistochemical
markers for lung origin and/or neuroendocrine features which are useful for establishing
the diagnosis. Additionally, some molecular biomarkers, especially those that are
potentially targetable, may be useful for guiding treatment in the future. However, unlike
NSCLC where biomarkers such as EGFR mutations have been incorporated into standard
clinical practice, there are currently no molecular markers that are recommended for
treatment selection for SCLC outside of clinical trials.

●Virtually all SCLCs are immunoreactive for keratin and epithelial membrane antigen
because of their epithelial cellular origin. A majority will also express thyroid
transcription factor-1 (TTF1), which can help distinguish SCLC from neuroendocrine
cancers originating in an organ other than the lung.
●One or more markers of neuroendocrine differentiation can be found in
approximately 75 percent of SCLCs [16]. In contrast to LCNEC, the
immunohistochemical demonstration of neuroendocrine differentiation is not a
prerequisite for the diagnosis of small cell carcinoma [17]. Markers reflecting
neuroendocrine and neural differentiation commonly used in the diagnostic setting
include synaptophysin, chromogranin, and CD56 (neural cell adhesion molecule
[NCAM]). Expression of neuron-specific enolase (NSE), dopa decarboxylase,
calcitonin, gastrin releasing peptide (GRP), and insulin-like growth factor-I (IGF-I) is
also commonly observed.

A subset of patients produce autoantibodies that crossreact with both SCLC cells and the
central nervous system or the neuromuscular junction. These autoantibodies can cause
cerebellar degenerative syndromes or the Lambert Eaton myasthenic syndrome. SCLC is
the most common malignancy associated with neurologic paraneoplastic syndromes.
(See "Overview of paraneoplastic syndromes of the nervous system" and "Clinical features
and diagnosis of Lambert-Eaton myasthenic syndrome", section on
'Pathophysiology' and "Treatment of Lambert-Eaton myasthenic syndrome", section on
'Evaluation for malignancy'.)

SCLC cells can also produce a number of polypeptide hormones, including ACTH and
vasopressin (antidiuretic hormone), resulting in various paraneoplastic endocrinologic
syndromes. (See "Pathophysiology and etiology of the syndrome of inappropriate
antidiuretic hormone secretion (SIADH)" and "Establishing the cause of Cushing's
syndrome".)

The growth factors IGF-I and GRP and their respective receptors constitute
autocrine and/or paracrine loops that enhance the growth of SCLC. In addition to
overexpression of these growth factors, the enzyme which inactivates these small
polypeptide hormones, neural endopeptidase (CALLA), is underexpressed in SCLC cells
and in bronchoalveolar lavage (BAL) fluid from smokers [18]. However, contemporary trials
targeting IGF-1R with antibodies in combination with chemotherapy have not shown
clinical benefit. (See "Experimental approaches to treatment for small cell lung cancer",
section on 'IGF-1R inhibitors'.)

Genetic abnormalities — The development of both SCLC and NSCLC occurs through
stimulation of proliferation and mutagenesis occurring over years, and resulting from
exposure to tobacco and other carcinogens. Multiple genetic defects have been detected;
some are characteristic and perhaps involved with oncogenesis, whereas others are
probably random or secondary events. A detailed discussion of the molecular genetic
changes associated with neuroendocrine tumors is beyond the scope of this review. The
most common characteristics of SCLC are summarized below and were recently reviewed
[19-21]:

●p53 mutations are detected in 75 to 90 percent of SCLCs [22-24].


●Loss of the retinoblastoma gene (RB1) function at 13q14 is nearly ubiquitous in
SCLC [25,26]. As an example, approximately 60 percent of SCLC cell lines have
undetectable transcripts, while the remaining 40 percent have an abnormal gene
product.
●Haploinsufficiency due to loss of material on chromosome 3p at multiple break sites
leads to absent or lower expression of many putative tumor-suppressor genes in the
majority of SCLCs [27]. The FHIT gene (for fragile histidine triad), which is involved in
the accumulation of diadenosine tetraphosphate, thereby leading to DNA synthesis
and proliferation, has been localized to 3p14.2 and is believed to be an important
tumor suppressor gene involved in the pathogenesis of lung cancer [28]. A second
postulated tumor suppressor gene located at 3p21.3 is RASSF1A, which is absent in
all SCLCs tested [29,30]. Deletion of a third gene, TGFBR2, located at 3p21.3.22 and
encoding the transforming growth factor beta type II receptor, has also been
described in SCLC [31]. TUSC1(FUS1), in the same region on 3p21.3, is also either
not expressed or expressed at very low levels in SCLC and has tumor suppressor
activity in preclinical studies [32].
●Telomerase is a ribonucleoprotein enzyme that compensates for telomere
shortening during cell division by synthesizing telomeric DNA, thereby maintaining
telomere length. In normal somatic cells, telomerase activity is usually undetectable,
with the exception of some cell types that possess the ability to divide indefinitely (eg,
hematopoietic cells, hair follicles, intestinal crypt cells, and basal cells of the
epidermis). Activation of telomerase is detected in approximately 90 percent of
SCLCs [33]. In cancer cells, telomerase activity correlates with the stabilization of
telomere length and cellular immortalization.
●Upregulation of wild type c-Kit and its ligand stem cell factor represents
another autocrine/paracrine growth factor loop that is detected in up to 80 to 90
percent of SCLCs [34,35]; however, cKit inhibitors such as imatinib have not
demonstrated activity in phase II trials.
●MYC family members (MYC, MYCL1, and MYCN) are amplified in approximately 20
percent of SCLCs and are mutually exclusive of each other [19]. MYC amplified
tumors may be more sensitive to targeted therapy with Aurora kinase inhibitors,
currently in clinical trials [36-38]. (See "Experimental approaches to treatment for
small cell lung cancer", section on 'Aurora A kinase inhibitor'.)
●Loss of PTEN is observed in only 2 to 4 percent of tumors [39-41], but rates
of PTEN/PI3K pathway alterations overall may be significantly higher and appear to
play a role in promoting SCLC tumorigenesis in animal models [42].
●Gene expression arrays and CGH analyses have shown upregulation of the islet-1
and the forkhead box protein G1B transcription factors in SCLCs [10,20,43]. Other
pathways have been shown to be abnormally regulated in SCLC, such as bcl-2,
although trials examining bcl-2 and bcl-2 family antagonists have not yielded
promising results. (See "Experimental approaches to treatment for small cell lung
cancer".)
●A study sequencing 53 SCLC tumors and cell lines identified a large number of DNA
alterations in each sample. Guanine (G) to thymidine (T) transversions (interchanges
of purines and pyrimidines) were especially common, consistent with the known
association between these types of mutations and smoking [44]. Among the observed
mutations, 22 genes were identified as being commonly altered in SCLC. In addition
to those previously established in SCLC (TP53, RB1), novel observations from this
study included SOX2 amplifications and RLF-MYCL1 fusions which represent
potential therapeutic targets [45].
●Proteomic profiling has identified major differences in protein expression between
SCLC or LCNEC and other NSCLC cancers. These include higher expression of
PARP1 and other DNA repair proteins and of EZH2. Clinical trials investigating the
use of PARP1 inhibitors in SCLC patients have been initiated.
●LCNECs frequently have genomic alterations similar to SCLC, including p53
mutations, loss of Rb, and strong expression of cKit, which distinguishes LCNEC and
SCLC from the lower grade, more differentiated carcinoid tumors [6].
●In contrast to NSCLC, mutations in the EGFR and KRAS oncogenes and p16
abnormalities are rare.

INITIAL EVALUATION — A tissue diagnosis is required to confirm the diagnosis of small


cell lung cancer (SCLC) and to distinguish this from NSCLC and from other
neuroendocrine cancers. The initial evaluation of a patient with suspected lung cancer is
discussed separately. (See "Overview of the initial evaluation, treatment and prognosis of
lung cancer".)

CLINICAL PRESENTATION — Small cell lung cancer (SCLC) typically arises in the
central airways, infiltrating the submucosa, and gradually narrowing the bronchial lumen
through extrinsic or endobronchial spread. The most common presentation is that of a
large hilar mass with bulky mediastinal adenopathy. Potential clinical consequences
include cough, dyspnea, weight loss, and debility. Hemoptysis and postobstructive
pneumonia are less common than with squamous cancers, for example, due to the diffuse
submucosal, as opposed to intraluminal, growth pattern. Approximately 70 percent of
patients present with overt metastatic disease; SCLC has a particular propensity to spread
to liver, adrenals, bone, bone marrow, and brain.

SCLC can occasionally present as a peripheral nodule without central adenopathy.


However, this presentation of SCLC is uncommon and a cytologic diagnosis alone (eg,
from a fine needle aspirate) cannot be trusted to differentiate SCLC from other
neuroendocrine cancers such as typical or atypical carcinoid, for which surgery should be
strongly considered. In this situation, mediastinal staging followed by surgical resection is
recommended. Histopathologic evaluation of the resected tumor frequently fails to confirm
SCLC. (See "Role of surgery in multimodality therapy for small cell lung cancer".)

Less commonly, SCLC can present with an endocrinologic or neurologic paraneoplastic


syndrome. (See "Overview of paraneoplastic syndromes of the nervous
system" and "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic
hormone secretion (SIADH)" and "Establishing the cause of Cushing's syndrome".)

STAGING

Limited versus extensive stage disease — A modification of the two-stage system


originally introduced by the Veterans' Affairs Lung Study Group (VALSG) for use in clinical
trials in the late 1950’s continues to be widely utilized in staging patients with small cell
lung cancer (SCLC) because of its simplicity and clinical utility:

●Limited disease – Tumor confined to the ipsilateral hemithorax and regional nodes
able to be included in a single tolerable radiotherapy port (corresponding to TNM
stages I through IIIB (table 3)).
●Extensive disease – Tumor beyond the boundaries of limited disease including
distant metastases, malignant pericardial, or pleural effusions, and contralateral
supraclavicular and contralateral hilar involvement.

Compared with TNM staging, which has historically depended upon pathologic staging
and, thus, surgical resection for confirmation, the simplified system above is quite
functional, given that approximately 90 percent of patients with SCLC present with either
locally advanced (35 to 40 percent) or metastatic disease (60 to 65 percent), and thus are
not amenable to resection. This simple two–stage system carries both prognostic
importance and implications for treatment that are similar to the value of TNM staging
since patients with limited stage disease are candidates for curative-intent chemoradiation
and chemotherapy while those with extensive stage disease are treated with
chemotherapy alone and palliative radiation as clinically indicated.

TNM staging system — In 2007, the International Association for the Study of Lung
Cancer (IASLC) proposed changes to the TNM non-small cell lung cancer (NSCLC)
staging system, mainly in T and M descriptors and subsequent stage groupings [46].
These changes in the lung cancer TNM system have been incorporated into the AJCC
7th edition (2010), which recommends TNM staging for SCLC as well as NSCLC (table 3).

The applicability of the proposed changes to SCLC was validated in a study comparing the
new system with the Union for International Cancer Control (UICC) 6th edition criteria using
8088 clinically staged cases in the IASLC database diagnosed between 1990 and 2000
[46]. This study demonstrated the applicability and improved prognostication of the
proposed system compared with the UICC 6th edition, with both T and N descriptors, and
overall stage groupings prognostic for survival with the exception of overlap in stage IA
and II A, and IB and IIB [46]. The prognostic import of the stage groupings was confirmed
in a separate cohort of 4884 patients in the Surveillance, Epidemiology, and End Results
(SEER) database. The two systems were further compared in 349 patients staged
surgically, confirming trends toward decreasing survival with increased T, N, and overall
stage classification [47].
The specific prognosis of patients with stage IV(M1a) (table 3) by virtue of pleural or
pericardial effusion or contralateral pulmonary metastasis was demonstrated in a cohort of
10,660 patients from the California Cancer Registry [48]. Patients with stage M1a disease
had outcomes for survival that were intermediate between stages I-IIIB and stage IV(M1b),
as is also the case for patients with NSCLC.

Currently, TNM staging does not alter clinical management frequently due to the
predominance of advanced stage at presentation, and it is less powerful in prognostication
for SCLC than for NSCLC. TNM staging is most useful in the identification of patients for
whom resection may be beneficial (ie, for patients that are thoroughly evaluated and have
clinical stage I [T1-2N0] disease). In these cases, resection followed by adjuvant
chemotherapy is recommended; however, this applies to fewer than 5 percent of patients.
(See "Role of surgery in multimodality therapy for small cell lung cancer".)

While recognizing the limitations of influence on current management, TNM staging should
be incorporated into clinical research and in cancer registries for future reference since
more precise stage classification could influence treatment approaches in the future.

Staging workup — Systemic therapy is required for all patients with tissue diagnosis of
SCLC, including those with stage I disease. Therefore, the major therapeutic significance
of staging is to guide the use of definitive chemoradiation and to lesser extent, surgery, as
discussed above.

Prompt treatment is of greater importance than the complete ascertainment of every


involved site of disease because of the rapid tempo of untreated SCLC. Most patients are
diagnosed within three months of symptom onset, reflecting a short tumor doubling time,
and may die quickly in the absence of effective therapy. Staging should not delay initiation
of treatment more than seven days. Patients who are very symptomatic should be treated
urgently with chemotherapy despite the absence of complete staging information. Staging
can continue during and immediately after initial treatment.

A complete staging workup includes physical examination, hematologic and chemical


laboratory profiles, chest radiography, computed tomography (CT) of chest and abdomen,
magnetic resonance imaging (MRI, preferred) or CT imaging of brain [49], and skeletal
imaging. Skeletal imaging historically was conducted with technetium, but now more
commonly uses 18-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET).
Other tests that may be clinically indicated in selected cases include bone marrow biopsy,
lumbar puncture, thoracentesis, and pericardiocentesis.

●Brain imaging is positive in about 15 percent of patients at diagnosis, including 5 to


8 percent of asymptomatic patients [50-52]. Early identification and treatment of brain
metastases is important, as it results in a lower rate of chronic neurologic morbidity.
(See "Epidemiology, clinical manifestations, and diagnosis of brain metastases".)
●Bone marrow is involved in 15 to 30 percent of patients at presentation, but it
represents a solitary site of metastatic disease in only 2 to 6 percent of cases [53-56];
bone marrow biopsy is thus no longer used routinely in staging but is indicated in the
evaluation of cytopenias.
●Radionuclide bone scans with technetium are positive in up to 30 percent of patients
without symptoms or an abnormal alkaline phosphatase [50,53,54].

Outside of the context of a clinical trial, an abbreviated staging algorithm could be directed
by symptoms and terminated as soon as extensive disease is documented. This latter
strategy, the rule for many European trials, may become more prevalent in the United
States in this time of health care parsimony and need for economic justification [57].

Utility of PET scanning — PET with FDG is a noninvasive method to assess for
mediastinal or distant metastases by detecting areas of high FDG uptake (ie, increased
metabolic activity) consistent with malignancy. Although PET has been widely studied as a
component of the staging evaluation for NSCLC, less data are available on its role in
patients with SCLC [58-62]. Most reports are retrospective and involve small numbers of
patients. Few have included pathologic documentation of PET findings that resulted in
either up- or down-staging or an alteration of treatment. (See "Thoracic positron emission
tomography".)

PET is associated with 100 percent sensitivity for SCLC, and its use in initial staging
results in stage shifting for 5 to 20 percent of patients, as illustrated by a retrospective
report of 51 patients who were studied with both PET and CT at diagnosis [60]. PET
detected the thoracic disease in all 51 (100 percent). In 18 cases, patients were classified
as having limited stage disease based upon results of CT; of these, two (11 percent) were
reclassified as having extensive stage disease based upon the results of PET. Of the 33
patients with extensive stage disease on CT scan, six (18 percent) were restaged as
having limited stage disease using PET. Similar findings were reported in a prospective
study of 120 patients [61]. It is important to pathologically assess lesions that will alter
patient management and are only identified by PET. This has been performed variably in
the available literature.

PET may alter initial treatment through change either in stage or more commonly in
refining thoracic radiation fields and doses. In a prospective study of 60 patients with
limited stage, there was discrepancy between baseline PET and CT scans in 30 percent of
patients, fairly equally distributed between extending or reducing involvement as indicated
by CT [63]. Although isolated nodal failure was observed in only 3 percent of patients, the
overall rate of nodal failure was 33 percent. Further investigation of PET in radiation
planning and influence on outcomes is required.

SUV values from PET scans have been investigated for their prognostic significance. In a
study of 76 patients, the mean SUV values from all FDG-avid lesions were calculated and
evaluated using a Cox proportional hazards model with other prognostic indicators
including stage, performance status, and lactate dehydrogenase. High mean values were
correlated with other poor prognostic features and predicted poor survival in multivariate
analysis for patients with both limited and extensive disease. (See "Computed tomographic
and positron emission tomographic scanning of pulmonary nodules", section on 'Metabolic
activity'.)

As is true for NSCLC, PET seems useful in combination with diagnostic CT in restaging
post thoracic radiation and distinguishing evolving radiation reaction in normal tissue from
progressive malignancy. However, rigorous prospective data regarding this issue and the
use of PET in restaging of extensive disease are not available.

PROGNOSTIC FACTORS — The median ranges of survival from the time of diagnosis for
limited and extensive disease are 15 to 20 months and 8 to 13 months, respectively.
Approximately 20 to 40 percent of limited stage and less than 5 percent of extensive stage
patients survive two years [64,65]. The respective values for five-year survival are 10 to
13, and 1 to 2 percent, respectively [66-68].

The most important adverse prognostic factors are:

●The host factors of poor performance status and weight loss [69]. Continuation of
smoking also contributes to chemoresistance [70].
●Tumor-related factors such as the extent of disease (limited versus extensive). In
limited disease, as discussed above, TNM staging is prognostic for improved
outcome with earlier stage, while an elevated LDH is unfavorable [67,71]. In extensive
disease, the number of organ sites involved is inversely related to prognosis [66].
Metastatic involvement of the central nervous system, the marrow, or the liver is
unfavorable compared with other sites, although these variables are confounded by
the number of sites of involvement.
●In most trials, women fare better than men, although the reasons for this are not
known.
●The presence of endocrinologic paraneoplastic syndromes is generally unfavorable.

With longer duration of follow-up, the prognostic importance of many of these variables
diminishes, largely as a result of the smaller numbers of long-term survivors [67,72].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education


materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient education: Small cell lung cancer (The Basics)")
●Beyond the Basics topics (see "Patient education: Small cell lung cancer treatment
(Beyond the Basics)")

SUMMARY

●Small cell lung cancer (SCLC) typically arises in the central airways of smokers, and
due to its short doubling time and biological aggressiveness, patients have only a
brief period of pre-diagnosis symptoms. Despite this, 60 to 70 percent of patients
present with overt metastatic disease.
●SCLC is distinguished from non-small cell lung cancer (NSCLC) by its rapid
doubling time, high growth fraction, and the early development of widespread
metastases. Although SCLC is highly responsive to chemotherapy and radiotherapy,
the disease usually relapses within two years despite treatment. Overall, only 10 to 15
percent of patients with limited stage SCLC and 1 to 2 percent of patients with
extensive stage SCLC survive beyond five years. (See 'Prognostic factors' above.)
●SCLC is generally diagnosed by light microscopy. On routine hematoxylin and eosin
staining, it is a small, blue, round cell tumor with cells two to three times the size of
mature lymphocytes. The cytoplasm is sparse, and nuclear features include finely
dispersed chromatin without distinct nucleoli. (See 'Clinical presentation' above
and 'Pathology' above.)
●In most clinical settings, patients are evaluated as having either limited stage
disease or extensive stage disease. This distinction has important therapeutic and
prognostic implications. The TNM staging system provides more detailed information
(table 3), which may be particularly important in identifying patients for whom
resection may be indicated. Furthermore, the TNM system should be adopted for
clinical trials and tumor registry information as precise staging information may inform
therapeutic advances in the future for identifying that small number of patients who
may be surgical candidates (T1-2N0). (See 'Staging' above.)
●The goal of the staging evaluation is to determine whether or not the patient has
extensive disease. In addition to a physical examination, hematology, and chemical
laboratory profiles, imaging of the chest, abdomen, skeleton, and brain is generally
indicated. However, prompt treatment is of greater importance than the complete
ascertainment of every involved site of disease because of the rapid tempo of
untreated disease. An abbreviated evaluation is often sufficient to begin treatment.
Completion of staging can proceed during and immediately following initial
chemotherapy. (See 'Staging workup' above.)
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Procedures for tissue biopsy in patients with suspected non-small cell lung cancer
Authors:
Karl W Thomas, MD
Michael K Gould, MD, MS
Section Editor:
James R Jett, MD
Deputy Editor:
Geraldine Finlay, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Dec 2016. | This topic last updated: Nov 02, 2016.
INTRODUCTION — Lung cancer is the most common cancer worldwide. Non-small cell
lung cancer (NSCLC) accounts for approximately 85 percent of all lung cancers, of which,
adenocarcinoma is the most common histologic subtype [1].

Traditionally, the histopathologic diagnosis of NSCLC has been made based upon
information obtained from small biopsies. There has been a shift towards the use of
therapies targeted at specific mutations, the identification of which can be challenging on
small biopsy samples. This, together with the rising incidence of adenocarcinoma and its
classification into subgroups, has led to greater emphasis on the importance of tissue
biopsy for the diagnosis of NSCLC. (See "Pathology of lung
malignancies" and "Personalized, genotype-directed therapy for advanced non-small cell
lung cancer".)

This topic will discuss the accuracy of procedures commonly used to obtain tissue for
diagnosis and staging in patients with suspected NSCLC. The clinical presentation, initial
evaluation and staging, and approach to the selection of modality for biopsy of patients
with suspected NSCLC are discussed separately. (See "Overview of the initial evaluation,
diagnosis, and staging of patients with suspected lung cancer" and "Selection of modality
for diagnosis and staging of patients with suspected non-small cell lung cancer".)

SELECTION OF MODALITY FOR TUMOR BIOPSY — Selection of the optimal biopsy


target and modality should be driven by evidence-based and institution-specific protocols
that preferably involve a lung cancer tumor board or multidisciplinary team. When an
institution is equipped with reliable expertise, one of the minimally invasive or more
invasive tools listed in the section below may be used to biopsy a target lesion.
Importantly, estimates of sensitivity and specificity for individual modalities are usually
based upon small studies with inadequate gold standard comparators that lead to bias and
significantly limit interpretation of the data. Furthermore, the post-test probability of
malignant disease particularly in metastatic locations will depend not only on patient risk
factors, but also the local prevalence of alternative diagnoses such as granulomatous
disease. The clinician should be aware of these clinically relevant limitations when
choosing among the modalities available for tissue acquisition. (See "Selection of modality
for diagnosis and staging of patients with suspected non-small cell lung
cancer" and 'Minimally invasive procedures' below and 'Surgical staging
procedures' below.)

Prior to biopsy the following should be in place:

●A thorough history and examination with routine laboratory studies. (See "Overview
of the initial evaluation, diagnosis, and staging of patients with suspected lung
cancer", section on 'Initial evaluation'.)
●Imaging with contrast-enhanced computed tomographic (CT) scan of the chest and
upper abdomen to assess suspected stage prior to biopsy. Some patients may
require additional imaging including positron emission tomography (PET), or
integrated PET/CT (eg, IB to IIIA non-small cell lung cancer [NSCLC] to detect occult
metastases) or imaging of sites suspected to be involved with metastases (eg, those
with symptoms or focal findings). (See "Overview of the initial evaluation, diagnosis,
and staging of patients with suspected lung cancer", section on 'Radiographic
staging'.)
●Good working knowledge of the Tumor Node Metastasis (TNM) staging of NSCLC
(table 1), the International Association for the Study of Lung Cancer (IASLC) lymph
node map (figure 1), and the therapeutic strategies for the suspected stage.
(See "Management of stage I and stage II non-small cell lung
cancer" and "Management of stage III non-small cell lung cancer" and "Overview of
the treatment of advanced non-small cell lung cancer".)

Guidelines issued by the American College of Chest Physicians (ACCP), European


Society of Thoracic Surgeons (ESTS), and International Association for the Study of Lung
cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) are
available to guide the physician with modality selection [2-5].

The evidence for the diagnostic and staging accuracy of each procedure for NSCLC is
discussed in this topic. General biopsy goals and a suggested diagnostic and staging
algorithm are discussed in detail separately. (See "Selection of modality for diagnosis and
staging of patients with suspected non-small cell lung cancer", section on 'Biopsy
goals' and "Selection of modality for diagnosis and staging of patients with suspected non-
small cell lung cancer", section on 'Approach to the patient'.)

MINIMALLY INVASIVE PROCEDURES

Overview — Commonly used minimally invasive approaches employ bronchoscopic and


percutaneous modalities. Bronchoscopic techniques include endobronchial ultrasound-
guided transbronchial needle aspiration (EBUS-TBNA), bronchial washings, brushings,
forceps transbronchial biopsy, navigational-guided transbronchial biopsy, and "blind"-
TBNA. Bronchoscopic techniques may be combined in a single procedure and this
provides a potential advantage of obtaining both the diagnosis and staging in a single
procedure. Percutaneous approaches include transthoracic needle aspiration (TTNA)
or needle/core biopsy (TTNB) of the primary tumor. A combination of bronchoscopic and
percutaneous modalities may be necessary to permit sampling from several lesions or
when the first modality is non diagnostic. Selecting one of these procedures or combining
several modalities to achieve the most accurate histologic classification and staging
information relies on knowledge of the technique’s diagnostic accuracy for the target
lesion(s). Critical considerations for procedure selection also include patient-specific
details like cardiovascular status and goals of care, as well as systems factors such as
available equipment, laboratory resources, and operator proficiency. (See "Selection of
modality for diagnosis and staging of patients with suspected non-small cell lung cancer",
section on 'Approach to the patient'.)
The evidence for each minimally invasive procedure pertinent to its diagnostic and staging
accuracy for NSCLC is discussed in this section. In general, the following applies:

●Bronchoscopy with EBUS-TBNA has gained wide acceptance as a first-choice


diagnostic and staging procedure for thoracic mass lesions and enlarged lymph
nodes that are accessible by this modality. This is due to its ability to establish both a
suspected diagnosis of lung cancer as well as its high diagnostic accuracy for
sampling central lesions and lymph nodes in the paratracheal, subcarinal and hilar
regions of the mediastinum [4,6-10]. Limitations of EBUS-TBNA include inability to
access retrotracheal, periaortic, paraesophageal and pulmonary ligament lymph node
stations (3a, 5, 6, 8, 9) and variable operator proficiency, which may influence the rate
of non-diagnostic findings. (See 'Endobronchial ultrasound' below.)
●Although transthoracic (percutaneous) needle aspiration/biopsy (TTNA/TTNB) has a
high accuracy for diagnosing NSCLC, the higher risk of complications (eg,
pneumothorax) is an important limitation, and it is rarely useful for mediastinal lymph
node staging [2,4,11-16]. TTNA may be used for peripheral nodules and masses,
especially when lesions appear to directly involve the chest wall or skeleton, or as an
alternate procedure when lesions cannot be safely or reliably accessed using another
modality. (See 'Transthoracic needle biopsy' below.)
●Conventional flexible bronchoscopy with forceps biopsy, brushing, or washing is
best utilized for accessing large, central lesions and those with suspected airway
involvement. These lesions may present with hemoptysis or postobstructive
pneumonia, and direct visualization reveals endobronchial involvement or obstruction
(see 'Conventional bronchoscopy' below). Conventional bronchoscopy with blind
transbronchial needle aspiration may be utilized for diagnosis and staging of
significantly enlarged subcarinal, paratracheal, and hilar nodes (figure 1). However,
without ultrasound guidance, TBNA alone has limited sensitivity for staging of the
mediastinum. The use of ultrasound guidance for tissue biopsy enhances the ability of
bronchoscopy to sample lymph nodes and tumors outside the airways, making EBUS
the preferred bronchoscopic modality for diagnosis and staging [7]
●Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) using a
transesophageal approach is a sensitive staging tool for suspected NSCLC in
subcarinal and paratracheal nodes. EUS-FNA can be combined with EBUS-TBNA to
enhance mediastinal staging. However, it requires special expertise.
(See 'Transesophageal endoscopic ultrasound' below and 'Combined
modalities' below.)
●Electromagnetic navigational bronchoscopy (EMN) is another modality for sampling
peripheral lung lesions that is increasingly available. Its use is best determined by the
expertise of practitioners within the institution. (See 'Electromagnetic navigational
bronchoscopy' below.)

Although obtaining samples of lavage fluid or tissue for genomic analysis has been studied
as a potential diagnostic tool designed to enhance the sensitivity of bronchoscopy for the
diagnosis of lung cancer, further study is required before it can be recommended for
routine use [17]. Histologic or cytologic classification of all lung cancers remains the gold
standard. Molecular and genetic profile sub-classification should be utilized within research
protocols and in limited circumstances for treatment and prognosis considerations.

Guidelines issued by the American College of Chest Physicians (ACCP), European


Society of Thoracic Surgeons (ESTS), International Association for the Study of Lung
cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS), and
the European Society of Gastrointestinal Endoscopy (ESGE)/ERS/ESTS have
incorporated the use of minimally invasive tools in the diagnostic work-up of NSCLC [18].
Evidence to support their use is largely derived from retrospective case series or from
smaller comparative studies, many of which have inherent bias favoring one modality over
another. The clinician should be aware of this bias prior to selecting a modality for tissue
biopsy. (See "Selection of modality for diagnosis and staging of patients with suspected
non-small cell lung cancer", section on 'Individualizing the approach'.)

Bronchoscopic approaches — Although different technical bronchoscopic approaches


have been studied as separate entities and are discussed individually in this section, in
practice, most experienced bronchoscopists can use multiple modalities and combine
them to increase the overall sensitivity for the diagnosis of NSCLC.

Conventional bronchoscopy — There are several ways to obtain tissue with


conventional, flexible, white light bronchoscopy (see "Flexible bronchoscopy in adults:
Preparation, procedural technique, and complications", section on 'Diagnostic and
therapeutic procedures' and "Flexible bronchoscopy in adults: Overview"):

●Washings, brushings, or endobronchial forceps biopsy for visually obvious lesions in


the main airways.
●Transbronchial forceps for biopsy of peripheral, parenchymal lesions that are not
directly visualized. Transbronchial biopsy is typically guided by fluoroscopy, but can
also be guided by electromagnetic navigation. (See 'Electromagnetic navigational
bronchoscopy' below.)
●TBNA, for biopsy of lesions and lymph nodes that are close to or encroaching upon
the airway. Bronchoscopic TBNA can be performed based on computed tomography
(CT) imaging and anatomic relationships or under real-time guidance by
endobronchial ultrasound. Endobronchial ultrasound requires a special bronchoscope
and image processors distinct from conventional flexible bronchoscopes.
(See 'Endobronchial ultrasound' below.)

For primary lesions that are large or central, or for lesions that obstruct airways, the
diagnostic sensitivity of conventional bronchoscopy with endobronchial or transbronchial
biopsy is 65 to 88 percent [2]. For similar, centrally located lesions, the use of needle
aspiration (bronchoscopic-TBNA) increases the diagnostic sensitivity (70 to 96 percent)
[2]. Bronchoscopy has a higher sensitivity for diagnosis of the primary tumor in this setting
because proximal lesions in or close to the airway are easily visualized and accessed by
this modality. However, for smaller peripheral lesions that are not visible endoscopically or
are located distal to sub-segmental bronchi, the sensitivity decreases significantly [2,19].
(See "Image-guided bronchoscopy for biopsy of peripheral pulmonary lesions".)

For patients with central lesions and CT evidence of bronchial, carinal, or tracheal
involvement, conventional bronchoscopy is essential for accurate determination of T-factor
staging (Tumor Node Metastasis staging). Conventional bronchoscopy with blind TBNA
may also be appropriate in some cases when there is bulky, central mediastinal disease.
However, conventional bronchoscopic TBNA without ultrasound guidance has a more
limited role in mediastinal staging in most patients with hilar, paratracheal and smaller
subcarinal lymph nodes because of its significantly lower sensitivity. Bronchoscopic-TBNA
without real-time ultrasound guidance is inferior to EBUS-TBNA for the diagnosis and
staging of NSCLC (sensitivity 36 versus 69 percent) [7-9,20,21]. The limited sensitivity
associated with bronchoscopic TBNA without real-time guidance for staging the
mediastinum often prompts additional mediastinal biopsy procedures when testing is
negative for cancer. (See 'Diagnostic and staging accuracy' below.)

Bronchoscopy (preferably with TBNA if CT and/or positron emission tomography (PET)


imaging demonstrate enlarged and/or hypermetabolic lymph nodes in accessible stations)
can be considered when EBUS-TBNA is not available or when it is the only diagnostic
modality that can be performed safely in patients in whom more invasive surgical
procedures or prolonged endoscopic procedures are contraindicated [20]. (See "Selection
of modality for diagnosis and staging of patients with suspected non-small cell lung
cancer", section on 'Approach to the patient'.)

The role of bronchoscopy pertinent to the diagnosis and staging of NSCLC is discussed
here. The general indications for flexible bronchoscopy, bronchoscopic-TBNA, and their
diagnostic role in the evaluation of a solitary pulmonary nodule are discussed separately.
(See "Flexible bronchoscopy in adults: Overview" and "Transbronchial needle
aspiration" and "Diagnostic evaluation and management of the solitary pulmonary
nodule" and "Diagnostic evaluation and management of the solitary pulmonary nodule",
section on 'Bronchoscopic techniques'.)

Diagnostic and staging accuracy — Major studies examining the diagnostic accuracy of
conventional, flexible, white light bronchoscopy and blind, bronchoscopic-TBNA for
NSCLC are summarized below.

●Diagnosis of primary tumor – Conventional bronchoscopy has moderately high


diagnostic accuracy for large, central or obstructive airway lesions that can be
biopsied under direct visualization using an endobronchial biopsy forceps (65 to 88
percent) [2]. Although bronchial lavage and brushings can be diagnostic, they
generally have a low sensitivity when used in isolation (43 and 54 percent,
respectively) [2]. Bronchoscopic-TBNA without real-time image guidance, which
involves aspirating tissue by passing a needle (19 to 21 gauge) through the working
channel of a conventional bronchoscope, can sample subcarinal, paratracheal, endo-
and peri-bronchial, as well as submucosal, lesions with sensitivity between 70 and 96
percent [22-24]. (See "Diagnostic evaluation and management of the solitary
pulmonary nodule", section on 'Bronchoscopic techniques'.)
Bronchoscopy is less useful for small or peripheral lesions (ie, not directly visible
bronchoscopically; sensitivity up to 65 percent), with higher sensitivity in lesions
greater than 2 cm [2]. Thus, when bronchoscopy is non-diagnostic, and clinical
suspicion remains high, further testing to pursue a diagnosis should be sought.
●Staging – Bronchoscopy is routinely performed pre-operatively to assess for
synchronous lesions and to delineate involvement of the central bronchi [2,25].
Specifically, bronchoscopy is necessary for assessing the proximal extent of central
or endobronchial tumors (ie, tumor size [T]). Tumors >2 cm from the carina are T2
lesions and tumors <2 cm are T3 lesions (table 1). Alteration of the stage from stage
1B (T2N0M0) to stage IIB (T3N0M0) can change the operative approach by the
surgeon, as well as the advisability of adjuvant chemotherapy.
Blind bronchoscopic-TBNA (ie, using only anatomic landmarks and previously
obtained CT images) can access paratracheal (4R, 4L), subcarinal (7), and less
commonly, hilar (10R, 10L) lymph nodes (figure 1). However, a meta-analysis
showed a pooled sensitivity of only 39 percent when limited to studies that enrolled
patients with potentially resectable NSCLC [26]. In a pooled analysis of a more
heterogeneous group of 2048 patients, including those with bulky adenopathy, the
sensitivity ranged from 14 to 100 percent (median 78 percent) with a negative
predictive value of 77 percent [2]. The sensitivity of conventional TBNA without image
guidance is likely related to the size of the target lymph node with greater sensitivity
for substantially enlarged nodes (eg, >2 cm) but markedly decreased sensitivity for
nodes 1 cm or less.
Three to four needle passes of selected lymph nodes for staging are often needed to
maximize the sensitivity. One study suggested that the diagnosis was established
with the first, second, third, and fourth needle pass at 64, 87, 95, and 98 percent of
targets, respectively [27]. Although the sensitivity varied widely with target site
features (eg, size, location), the stepwise increment to the maximum sensitivity
provided by serial passes was similar across target sites. In one study of 168 patients
with hilar and mediastinal adenopathy, the addition of rapid on-site cytologic
evaluation (ROSE) did not alter the sensitivity but did reduce the number of total
needle passes and lowered the rate of complications [28].

Endobronchial ultrasound — EBUS is an endoscopic imaging tool that utilizes real-time


ultrasonographic guidance to facilitate transbronchial needle aspiration as well as forceps,
needle, or brush biopsies of peripheral lesions. Although there are important technical
differences between conventional and EBUS-guided TBNA, such as the length of the
needle used, the main benefit of ultrasound guidance is related to the ability to visualize
anatomy and precisely localize suspicious lymph nodes or peripheral lung lesions. There
are two distinct ultrasound designs used in bronchoscopy: linear EBUS and radial probe
EBUS. Linear (ie, convex probe [CP]) EBUS is incorporated into the distal tip of a
dedicated bronchoscope that guides TBNA. Linear-EBUS TBNA is ideally suited for
sampling mediastinal lymph nodes or large, central masses. Radial probe (RP) ultrasound
is catheter-based and deployed through the working channel of a conventional flexible
bronchoscope and into subsegmental and distal airways to locate peripheral lesions and
then to guide forceps or brush biopsies. Radial EBUS is most commonly used for
diagnosis of parenchymal nodules or masses. (See "Endobronchial ultrasound: Technical
aspects" and "Image-guided bronchoscopy for biopsy of peripheral pulmonary lesions",
section on 'Radial probe endobronchial ultrasound (RP-EBUS)'.)

EBUS-TBNA is most sensitive when used to sample large, central primary lesions (84 to
85 percent) and suspicious or metastatic mediastinal lymph nodes (up to 96 percent) in the
paratracheal, posterior tracheal, subcarinal and hilar regions (2R, 2L, 3p, 4R, 4L, 7, 10R,
10L,) (figure 1) [7-9,29-33]. High operator proficiency and multiple passes with ROSE
enhance the overall sensitivity [5,34-38]. EBUS-TBNA has been shown to surpass the
sensitivity of conventional flexible bronchoscopy alone for the diagnosis and staging of
NSCLC [7-9]. Several studies suggest that EBUS-TBNA is at least comparable, and may
be superior to cervical mediastinoscopy but there are concerns regarding study design
[6,39-41]. The wide ranging and imperfect sensitivity associated with EBUS-TBNA
necessitate additional biopsy, usually mediastinoscopy, when testing is negative for
cancer. (See 'Diagnostic and staging accuracy' below and "Selection of modality for
diagnosis and staging of patients with suspected non-small cell lung cancer", section on
'Approach to the patient'.)

The value of EBUS-TBNA for the diagnosis and staging of NSCLC is discussed here. The
technical aspects of EBUS and other indications for its use are discussed separately.
(See "Endobronchial ultrasound: Indications, contraindications, and
complications" and "Endobronchial ultrasound: Technical aspects" and "Endoscopic
ultrasound-guided sampling of the mediastinum: Technique, indications, contraindications,
and complications".)

Diagnostic and staging accuracy — Major studies that have examined the diagnostic
accuracy of radial EBUS-TBNA for NSCLC are summarized below. (See "Endobronchial
ultrasound: Technical aspects" and "Endobronchial ultrasound: Technical aspects", section
on 'Types of EBUS'.)

●Diagnosis of primary tumor – EBUS has a sensitivity of 73 to 85 percent for large


symptomatic (eg, hemoptysis) or visible (eg, endobronchial) lesions that are centrally
located [7-9]. Its sensitivity declines for lesions <2 cm (71 percent), particularly those
that are peripherally located (56 percent) [8,9]. Although EBUS enhances the
accuracy of conventional transbronchial biopsy, CT-guided percutaneous
transthoracic needle aspiration or core needle biopsy has comparable results if not
superior accuracy for smaller lesions [8,9,13-15]. The sensitivity of EBUS-TBNA for
identifying mediastinal lesions other than NSCLC is discussed separately.
(See "Endobronchial ultrasound: Technical aspects" and "Endobronchial ultrasound:
Indications, contraindications, and complications".)
●Staging – EBUS-TBNA can access upper and lower paratracheal posterior tracheal,
subcarinal and hilar lymph node stations (2R, 2L, 3p, 4R, 4L, 7, 10R, 10L,) (figure 1).
However, it cannot access lymph nodes in the prevascular, para-aortic,
paraesophageal, or pulmonary ligament regions of the mediastinum (3a, 5, 8, 9).
•Early studies suggested that EBUS-TBNA detected malignant lymph node
involvement with sensitivity and negative predictive values of 95 and 90 percent,
respectively [29-32]. A subsequent 2013 meta-analysis that included 2756
patients reported that the sensitivity of EBUS-TBNA was lower than that
previously reported (median 89 percent, range 46 to 97 percent) [2].
•Similarly, the negative predictive value of EBUS-TBNA is probably lower than
originally thought and wide-ranging across studies [2,39,42]. While one
systematic review reported that the negative predictive value of EBUS-TBNA
was 91 percent (60 to 97 percent), some studies report higher rates of false
negative results and non-diagnostic findings [2,39,42].
•The variability in sensitivity and negative predictive value of EBUS-TBNA may
reflect variable expertise, uncertainty related to small sample sizes, and
differences in the prevalence or extent of adenopathy and in protocols for
sample processing. Nonetheless, the variable estimates of observed diagnostic
accuracy may also reflect natural variation in general practice.
•Most published studies have used systematic lymph node sampling that
samples representative lymph nodes from each station (figure 1). The approach
taken should depend upon factors including the clinical suspicion of nodal
metastasis based on CT and PET imaging, the expectation of definitive surgical
management of the primary lesion, the utilization of surgical mediastinal lymph
node dissection as well as the expertise and resources of the management
team.
Comparatively, EBUS is superior to unguided bronchoscopic TBNA for staging
NSCLC [7-9,29,32,43]. Several studies that have directly compared EBUS-TBNA with
the original “gold standard”, cervical mediastinoscopy, suggest that EBUS-TBNA is at
least comparable if not superior to mediastinoscopy [6,39,40]:
•One prospective, single center, cross over trial in 66 patients with suspected
NSCLC showed that EBUS had a superior sensitivity to cervical
mediastinoscopy (87 versus 68 percent) [6]. However, this study was performed
in a center with high level expertise in interventional bronchoscopy which may
not be generalizable to other centers where this level of expertise is not
available. In addition, this study included a high rate of EBUS-TBNA in the
subcarinal region, a region that cannot be as easily accessed by
mediastinoscopy.
•Another prospective study of 153 patients with suspected NSCLC compared
EBUS-TBNA to cervical mediastinoscopy in patients who were potentially
resectable and in whom both procedures were performed prior to surgery [40].
The sensitivity, negative predictive value, and diagnostic accuracy were
comparable for EBUS-TBNA and mediastinoscopy (81 versus 79 percent, 91
versus 90 percent, and 93 versus 93 percent).
•Another retrospective review of patients at high risk of N2 disease (table 1) who
had undergone both procedures, reported that, compared to mediastinoscopy,
EBUS-TBNA had a higher rate of non-diagnostic findings (20 percent) resulting
in a negative predictive value of 72 percent (95% CI, 56-89%) [39].
Large prospective trials comparing EBUS-TBNA with mediastinoscopy are in
progress to further define the procedure’s sensitivity in larger, less highly-selected
patients.
The airway wall is well visualized with RP-EBUS [44-46]. This allows more accurate
determination of the distance from the carina to the proximal portion of the tumor
when the right or left main bronchi are involved. This distance is an essential
component of the T component of the TNM staging system (table 1) and will partially
determine whether the lesion is T2 or T3, which can impact the disease stage.
Convex probe (CP)-EBUS does not visualize the airway wall as well as radial probe
(RP)-EBUS; therefore, it should not be used for this purpose. (See "Overview of the
initial evaluation, diagnosis, and staging of patients with suspected lung
cancer" and "Tumor, node, metastasis (TNM) staging system for non-small cell lung
cancer".)

Limitations — The practice rate of performing EBUS-TBNA as the first diagnostic


procedure in suspected thoracic malignancy and mediastinal adenopathy appears to be
growing [10,47]. The major limitations of EBUS-TBNA are that sampled specimens can be
small in size, rates of operator proficiency are variable, and availability is institution-
specific. In addition, EBUS cannot access periaortic and posterior lymph node stations.
These limitations of EBUS-TBNA among others are listed below:

●Small specimen size – Compared to surgical biopsy, the amount of tissue obtained
by a single needle pass on EBUS-TBNA is small and may be insufficient for
architectural and molecular assessment unless additional steps are taken.
To overcome small specimen size, multiple passes (three to eight per site) with
ROSE and well defined institutional procedural protocols for processing, improve the
clinical utility of EBUS-TBNA [5,34-37,48-53]. The use of ROSE has also been
associated with a lower need for additional procedures (eg, transbronchial biopsy)
and fewer punctures during bronchoscopy [54]. Blood core clot, often obtained during
EBUS-TBNA, has also been shown to contain cellular sample that can be additive
diagnostically [55]. In general, only 140 to 400 ng of DNA are extracted from needle
aspirations [56,57]. Estimates of amounts of total DNA extracted from EBUS-TBNA
samples are approximately 280 ng which is usually adequate for molecular testing
[58-61]. Thus, with the use of multiple needle passes and ROSE by proficient
endoscopists enough tissue (up to eight needle aspirates per cell block) can be
aspirated to obtain material suitable for both cytologic diagnosis as well as additional
immunohistochemical and molecular testing [5,34-38,53].
Small tissue samples are inherent to all needle aspiration techniques but may also be
partly due to variable rates of expertise and minor technical differences within or
between institutions [5,34-37,62]. Many interventional pulmonologists use larger
needles in an attempt to aspirate more tissue. However, larger needle size (eg, 21-
gauge versus 22-gauge) has been shown in three of four studies not to have an
impact on sensitivity of EBUS-TBNA [34,37,38,63].
●Availability and operator experience – Not every facility has the equipment and
fully trained team of operators to perform EBUS-TBNA. Low operator experience may
also contribute to low sensitivity and inaccurate staging of suspected NSCLC.
Conversely, training which includes simulation practice may improve procedure
performance [64].
●Lymph node access – EBUS cannot access all stations in the mediastinum. For
example, prevascular, periaortic, paraesophageal, or pulmonary ligament lymph node
stations (3a, 5, 6, 8, 9) cannot be sampled with this modality (figure 1). The access to
the posterior and inferior lymph node stations by endoscopic-guided fine needle
aspiration (EUS-FNA) has led to the combined use of EBUS and EUS for staging
patients with suspected NSCLC. (See 'Combined modalities' below.)
●Complications – Complications of EBUS-TBNA (eg, pneumothorax, hemorrhage)
are uncommon (<1.5 percent) and discussed separately. (See "Transbronchial needle
aspiration", section on 'Complications'.)

Electromagnetic navigational bronchoscopy — Electromagnetic navigational


bronchoscopy-guided biopsies are an emerging modality available in select centers.
Electromagnetic navigation functions like a global positioning system that utilizes
previously obtained CT chest images (the map), fused with real-time, 3-dimensional
instrument position location (the coordinates). A bronchoscopically placed steerable probe
enables the operator to navigate to lesions identified on reconstructed virtual images,
including to parenchymal lung lesions that are not endoscopically visible. Choosing to use
EMN-TBNA is best dictated by the expertise and experience in the institution as well as
the unique circumstance of each patient. Further details regarding EMN and other image-
guided techniques for peripheral pulmonary lesions are provided separately. (See "Image-
guided bronchoscopy for biopsy of peripheral pulmonary lesions".)

EMN-TBNA is best used for accessing peripheral lesions, but can also access lymph node
stations 12 to 14 that are difficult to access by linear EBUS (figure 1).

●The sensitivity of EMN-TBNA in the diagnosis of peripheral lung lesions ranges from
44 to 75 percent, the details of which are discussed separately. (See "Image-guided
bronchoscopy for biopsy of peripheral pulmonary lesions", section on
'Electromagnetic navigation bronchoscopy (ENB)'.)
●The performance of EMN-TBNA for mediastinal staging NSCLC has been studied in
one prospective pilot study of 60 patients that suggested a sensitivity per procedure
of 100 percent for malignant mediastinal lymph node involvement. However, further
studies are required to validate its accuracy in staging NSCLC [65].

Transthoracic needle biopsy — Transthoracic needle biopsy involves passing a needle


percutaneously, under image guidance (usually computed tomography), to either aspirate
(TTNA) or biopsy (TTNB) tissue. The needle frequently traverses pleura and lung to either
aspirate or biopsy target tissue (lung or lymph node). The term TTNB in this section refers
to both aspirate and biopsy samples because most studies examining sensitivity do not
distinguish between these entities.

TTNB has a sensitivity of 74 to 90 percent for lung and mediastinal lesions suspected to
be malignant [2,4,11,13-16,66,67]. It can access most intraparenchymal lesions and
almost all mediastinal lymph nodal stations (figure 1). However, traversing the pleural
space and lung tissue is frequently unavoidable resulting in high rates of pneumothorax
(on average 10 to 15 percent), limiting the use of TTNB as a diagnostic and staging tool
[12,15,16,66]. As with all minimally invasive procedures, the relatively high false negative
rates associated with needle aspiration necessitate additional biopsy procedures when the
pretest probability of cancer is high but TTNB is non-diagnostic. (See 'Diagnostic and
staging accuracy' below.)

TTNB is often considered for peripheral lesions or when another procedure (eg, EBUS- or
bronchoscopic-TBNA) has failed to obtain diagnostic tissue. It is also considered when the
patient is at high risk for complications of video-assisted thorascopic surgery or cervical
mediastinoscopy. The high diagnostic accuracy of TTNB should be weighed against the
risk of pneumothorax and bleeding while considering patient preference. The risk benefit
ratio is increased in patients with concomitant emphysema, bullous disease, or chronic
respiratory failure. (See "Selection of modality for diagnosis and staging of patients with
suspected non-small cell lung cancer", section on 'Approach to the patient'.)

The value of TTNB for the diagnosis and staging of NSCLC is discussed here. The
indications and use of TTNB in the work-up of the solitary pulmonary nodule is discussed
separately. (See "Diagnostic evaluation and management of the solitary pulmonary
nodule", section on 'Transthoracic needle biopsy'.)

Diagnostic and staging accuracy — Major studies that have examined the sensitivity of
TTNB for NSCLC are summarized below.

●Diagnosis of primary tumor – In one meta-analysis of 46 studies, TTNB detected


malignancy with a sensitivity of 90 percent [2]. The diagnostic accuracy of TTNB for
malignancy is lower for smaller lesions (<3 cm) with reported sensitivity and specificity
of 67 and 100 percent respectively, and non-diagnostic results occurring in 36 percent
of cases [11]. While some studies suggest that percutaneous biopsy is not more
sensitive than aspiration for the diagnosis of NSCLC, it has the advantage of
providing the pathologist with larger amounts of material to distinguish benign from
malignant pathologies and to perform molecular testing [2]. (See "Diagnostic
evaluation and management of the solitary pulmonary nodule", section on
'Transthoracic needle biopsy'.)
●Staging – In practice, TTNB of the mediastinum is rarely performed unless there is
bulky anterior lymphadenopathy. Stations 2, 4, 5, and 6 can be accessed by an
anterior parasternal approach, and stations 4, 7, 8, and 9 by a posterior approach
(figure 1) [3]. Although some reports suggest that the sensitivity of TTNB for
suspected NSCLC is over 90 percent, studies are often inherently biased because the
study populations frequently had enlarged or bulky mediastinal disease
(ie, N2/N3 disease) which may falsely inflate the sensitivity [3,4,68-71]. Thus, these
rates may not necessarily apply to patients with small or normal-sized lymph nodes.

Compared to bronchoscopic procedures, the prevalence of pneumothorax following TTNB


is high (10 to 15 versus <1 percent) [12]. The risk is greatest when the lung is traversed
[16]. Higher rates have also been noted in older patients with COPD, in whom a higher risk
of respiratory failure requiring mechanical ventilation has also been reported [12]. The risk
of hemorrhage is low (<1 percent) but may be higher if patients are taking anticoagulants
or the target for biopsy is close to a vascular structure. Complications of TTNB are
discussed separately. (See "Diagnostic evaluation and management of the solitary
pulmonary nodule", section on 'Transthoracic needle biopsy'.)

Transesophageal endoscopic ultrasound — EUS-FNA is similar to EBUS-TBNA but


may use either a larger gastrointestinal endoscope that is inserted into the esophagus or
the smaller ultrasound bronchoscope (EUS-B-FNA). EUS-FNA was originally developed
as a diagnostic and staging modality for gastric and esophageal cancers. However, it is a
potentially useful modality for the diagnosis and staging of lung cancer, particularly, in
those with mass lesions that appear to involve the posterior and inferior mediastinum as
well as the left paratracheal lymph nodes.

EUS-FNA is a sensitive staging tool for suspected NSCLC involvement in subcarinal (3, 7,
8, 9) and paratracheal nodes (2, 4) (figure 1 and figure 2) [4]. Case series also suggest a
potential role for EUS-FNA in suspected M1b disease (eg, adrenal gland or liver) [72-74]. It
has also been used to assess direct tumor invasion of the mediastinum (T4). EUS-FNA
can be used as an additive or alternative tool to other modalities (eg, EBUS-TBNA). EUS-
FNA requires experienced, skilled endoscopists. The imperfect sensitivity associated with
fine needle aspiration techniques necessitates additional biopsy, usually mediastinoscopy,
when testing is negative for cancer. (See 'Diagnostic and staging accuracy' below
and 'Sampling metastatic disease' below and "Selection of modality for diagnosis and
staging of patients with suspected non-small cell lung cancer", section on 'Approach to the
patient' and 'Combined modalities' below.)

The value of EUS-FNA for the diagnosis and staging of NSCLC is discussed here. The
general indications and use of EUS-FNA are discussed separately. (See "Endoscopic
ultrasound-guided sampling of the mediastinum: Technique, indications, contraindications,
and complications".)

Diagnostic and staging accuracy — Major studies that have examined the diagnostic
accuracy of EUS-FNA for NSCLC are summarized below.

●Diagnosis of primary tumor – EUS-FNA can access tumors that invade the
posterior and inferior, and occasionally, superior mediastinum that are close to the
esophagus. Studies demonstrating its efficacy diagnostically compared to other
modalities are lacking. In a series of 35 patients suspected of having lung cancer
where bronchoscopy was nondiagnostic, EUS-FNA detected lung cancer in 25 of 26
patients and correctly distinguished benign from malignant disease with sensitivity
and negative predictive values of 96 and 90 percent, respectively [75]. Other studies
have demonstrated similar results [76].
●Staging – The main use of EUS-FNA is to access paratracheal (2, 4) and posterior
subcarinal lymph nodes (3, 7, 8, and 9) (figure 1) [77]. Its ability to access station 5 is
dependent on specific anatomic relationships as well as the size of the target lymph
node.
A randomized trial of suspected lung cancer patients with 2L, 3, 4L, 7
lymphadenopathy or lung masses adjacent to the mediastinum compared the
diagnostic rate of EUS-FNA with EBUS-TBNA. EUS-FNA established a specific
diagnosis in 48/55 patients (87 percent) compared to 50/55 patients (91 percent) in
the EBUS-TBNA group, a difference that was not statistically significant. Procedure
time was shorter with EUS-FNA and additional equipment was not necessary since
both the EUS and EBUS procedures were performed using an ultrasound
bronchoscope [78].
One 2013 meta-analysis of 26 studies showed pooled sensitivity and negative
predictive values of 89 and 86 percent, respectively [4]. However, the wide range of
sensitivity (45 to 100 percent) and negative predictive values (68 to 100 percent)
suggest high variability among centers and/or heterogeneous patient samples. Three
to five passes per nodal site is suggested for adequate sampling [77].
Case series and observational studies also suggest that EUS-FNA can diagnose M1b
disease due to its unique ability to access retroperitoneal and celiac nodes, the left
lobe of the liver, and adrenal glands [72-75,79-85]. However, its diagnostic accuracy
in this context for staging NSCLC has not been formally evaluated.
T4 disease, which is for the most part inoperable, is defined as tumor of any size that
invades the mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve,
esophagus, vertebral body, and carina (table 1). The preoperative identification of T4
disease can potentially result in the avoidance of futile thoracotomies. Although many
case series of EUS-FNA have included patients with T4 level of disease, only one
study examined its performance for this indication [86]. The high false positive (30
percent) and low positive predictive value (70 percent) in that study suggested that it
was not sufficiently accurate to confirm the presence of T4 disease.

Additional trials are required to compare the performance of EUS-FNA to all staging tools,
including cervical mediastinoscopy. Smaller comparative studies are described below:

●One prospective, single center study of 104 patients reported that EUS-FNA
diagnosed metastatic NSCLC in posterior lymph nodes with a sensitivity and negative
predictive value of 93 and 94 percent, respectively [79].
●In a single-center trial of 60 patients with NSCLC, compared to cervical
mediastinoscopy, EUS-FNA was able to detect lymph node involvement with higher
sensitivity (96 versus 24 percent) [87].
●In a small study of 35 patients with NSCLC, EUS-FNA identified occult N2 or N3
disease, (not previously identified by cervical mediastinoscopy), in 37 percent of
cases [88]. Most of the occult disease that was identified by EUS-FNA and missed by
cervical mediastinoscopy was in the subcarinal region (7) [88].

The major limitation of EUS-FNA is its inability to simultaneously visualize the airway and
access the primary tumor mass, although it is often performed in tandem with
bronchoscopy and EBUS-FNA. As with most needle aspirative techniques, the imperfect
sensitivity often necessitates the use of a second staging procedure, usually
mediastinoscopy should the testing be negative for cancer. In addition, it requires a skilled
endoscopist experienced in its use.

Combined modalities — Combining modalities maximizes access to the mediastinum to


improve the sensitivity of staging. More sensitive staging identifies occult disease so that
multimodality treatment can be considered. The most common staging modalities that are
combined are endobronchial ultrasound-guided transbronchial needle aspiration plus
endoscopic ultrasound-guided fine needle aspiration (EBUS-TBNA plus EUS-FNA). This is
colloquially referred to as “medical mediastinoscopy” or combined ultrasound (CUS). Less
common are the combinations of EUS-FNA plus cervical mediastinoscopy and CUS plus
cervical mediastinoscopy.

●EBUS-TBNA plus EUS-FNA, can access almost all lymph node stations in the
mediastinum (2, 3, 4, 7, 8, 9, 10, 11, +/- 12) (figure 1). Both procedures overlap for
many mediastinal lymph nodal stations (2, 3, 4, and 7) but are complimentary for
stations 8, 9 (EUS), 10, 11, +/- 12 (EBUS).
●EUS-FNA plus cervical mediastinoscopy can access more mediastinal lymph
node stations than either procedure alone (1, 2, 3, 4, 7, 8, 9) (figure 1). Both
procedures overlap for reaching lymph nodal stations 2, 3, 4, and 7, but EUS-FNA
offers the additional ability to access stations 8 and 9. Combined modalities that
utilize EUS-FNA have the advantage of also accessing potential M1b disease in the
retroperitoneal, celiac lymph nodes as well as the liver and adrenal glands [72-
74,77].
●CUS plus cervical mediastinoscopy can access almost all lymph node stations in
the mediastinum (1, 2, 3, 4, 7, 8, 9, 10, 11, +/- 12) with overlap for stations 1, 2, 4,
and 7 (figure 1).

The combined approaches are promising but their clinical utility in general practice has not
been precisely defined. For most patients, the identification of nodal tumor metastasis in
N2 or N3 stations using a single technique makes the second procedure unnecessary. For
this reason combined modalities are not routinely used for staging NSCLC unless the
initial procedure is negative but the clinical probability of nodal metastasis remains
unacceptably elevated. Routine use of combined modality for staging should be reserved
for select cases, best dictated by the expertise and clinical protocols in specific institutions
where they are available.

The sensitivity of combined modalities pertinent to staging NSCLC is discussed here. The
value of individual techniques for the diagnosis and staging of NSCLC are discussed
separately. (See 'Endobronchial ultrasound' above and 'Transesophageal endoscopic
ultrasound' above.)

Diagnostic and staging accuracy — Major studies that have examined the diagnostic
accuracy of combined modalities for NSCLC are summarized below [21,80,89-95].

●EBUS-TBNA plus EUS-FNA – One multicenter randomized study of 241 patients


with suspected N2/N3 NSCLC reported that, compared with cervical mediastinoscopy
alone, CUS plus selective mediastinoscopy (when CUS results were negative) had a
higher sensitivity (94 versus 79 percent) and resulted in fewer unnecessary
thoracotomies (7 versus 18 percent) [89]. However, a post-hoc analysis of long-term
outcomes from this trial reported no survival advantage among those staged using
CUS plus selective surgical staging compared to those who underwent surgical
staging alone [96]. Another randomized trial of 160 of histologically confirmed or
strongly suspected potentially operable NSCLC found that adding EBUS-TBNA to
EUS-FNA increased the sensitivity (92 versus 60 percent) and diagnostic accuracy
(97 versus 87 percent) when compared to EUS-FNA alone [97].
Although these modalities are complimentary, the sensitivity appears to be reduced in
patients with normal-sized lymph nodes. Two prospective studies of CUS in patients
with enlarged (138 patients) and normal-sized (120 patients) lymph nodes,
respectively, reported that, compared with either procedure alone, CUS had higher
sensitivity for staging NSCLC (93 percent for enlarged nodes versus 68 percent for
normal-sized nodes) [21,91]. The negative predictive values were unaffected by node
size (97 and 91 percent respectively).
One retrospective study of patients with NSCLC compared the staging performance
of combined EBUS/EUS with an aggressive surgical staging modality, transcervical
extended mediastinal lymphadenectomy (TEMLA) [98]. Although CUS was not as
sensitive as TEMLA (96 versus 88 percent), it was a safer procedure. This study is
discussed in detail separately. (See 'Transcervical extended mediastinal
lymphadenectomy' below.)
Bronchoscopists and thoracic surgeons may introduce EBUS bronchoscopes into the
esophagus during the same procedure as bronchoscopic EBUS-TBNA and achieve
more accurate mediastinal node sampling and greater diagnostic success [78,92,93].
This approach has been termed EUS with bronchoscope-guided needle aspirate
(EBUS-B-NA or EUS-B-FNA). EBUS-B-NA was reported to have sensitivity and
negative predictive values of 96 and 96 percent, respectively [93].
●EUS-FNA plus cervical mediastinoscopy – There is a paucity of data regarding
the staging accuracy of this combination. In one multicenter study of 107 patients with
suspected NSCLC, cervical mediastinoscopy plus EUS-FNA detected more
metastatic disease than either mediastinoscopy or EUS-FNA alone (36 versus 20 and
28 percent) and resulted in the avoidance of unnecessary thoracotomies in 16
percent of cases [80].
●EBUS-TBNA plus EUS-FNA plus cervical mediastinoscopy – One multicenter
prospective study that primarily examined the diagnostic accuracy of CUS, reported a
sensitivity of 94 percent for CUS plus cervical mediastinoscopy [89].

Together, these and other studies suggest that combined approaches have a high
sensitivity for staging mediastinal NSCLC, especially when disease is suspected by CT
scan or PET. However, other clinical priorities and objectives such as reducing the number
of subsequent required surgical staging procedures (see 'Surgical staging
procedures' below) have less supporting evidence. Based on available evidence, clinical
practice guidelines from the European Society of Gastrointestinal Endoscopy endorse an
approach of combined EBUS-TBNA and EUS-FNA or EUS-B-FNA over either test alone
[18]. Larger randomized studies are required to determine which cases are most likely to
benefit from a combined approach and to specify which combination is preferred for
staging patients with NSCLC.

The limitations of EBUS-TBNA, EUS-FNA, and the complications of cervical


mediastinoscopy are discussed separately. (See 'Limitations' above and 'Endobronchial
ultrasound' above and "Surgical evaluation of mediastinal lymphadenopathy", section on
'Complications of mediastinoscopy'.)

SURGICAL STAGING PROCEDURES

Overview — Standard cervical mediastinoscopy (SCM), video-assisted thoracoscopic


surgery (VATS) and anterior mediastinotomy (Chamberlain procedure) are the three most
common surgical modalities used for staging non-small cell lung cancer (NSCLC). Other
surgical procedures (extended cervical mediastinoscopy [ECM], video-assisted
mediastinal lymphadenectomy [VAMLA], transcervical extended mediastinal
lymphadenectomy [TEMLA]) are not as well validated and experience is more limited.
Selecting one of these surgical procedures relies on physician judgment and knowledge of
their diagnostic accuracy for the target lesion(s), in the context of operator proficiency,
patient safety and eventual goals for treatment. (See "Selection of modality for diagnosis
and staging of patients with suspected non-small cell lung cancer", section on 'Approach to
the patient'.)

Guidelines issued by the American College of Chest Physicians (ACCP), European


Society of Thoracic Surgeons (ESTS), and International Association for the Study of Lung
cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) have
incorporated the use of invasive procedures in the diagnostic work-up of NSCLC.
Evidence for these surgical procedures is largely derived from older retrospective case
series and small studies that do not compare performance with thoracotomy.
(See "Selection of modality for diagnosis and staging of patients with suspected non-small
cell lung cancer", section on 'Approach to the patient'.)

In general, the following applies:

●SCM is a sensitive staging procedure when sampling nodal stations easily accessed
by this approach (1, 2, 3, 4, anterior 7, 10) (figure 1) [99-101]. Use of a video
mediastinoscope and systematic lymph node sampling may enhance sensitivity.
Although it is the historical gold standard for staging the mediastinum, disease will not
be detected in lymph nodes stations that are not accessed by this modality: subaortic
(5), para-aortic (6), inferior (8, 9), lobar/interlobar (11 to 14), and, occasionally, the
posterior subcarinal (7) stations. SCM can be used as a staging tool for NSCLC when
other staging modalities do not identify cancer, or are not available (eg, endobronchial
ultrasound). (See "Selection of modality for diagnosis and staging of patients with
suspected non-small cell lung cancer", section on 'Approach to the
patient' and 'Standard cervical mediastinoscopy' below.)
●VATS is an accurate modality for evaluating the extent of invasion (chest wall,
mediastinal) by the primary tumor (T). VATS can also sample mediastinal lymph
nodes (4, 5, 6, 7, 8, 9, 10 to 14) but only those on the affected side (N), unless a
bilateral thoracotomy is performed (figure 1). Bilateral thoracotomy is not typically
performed due to the increased mortality and morbidity associated with this
procedure. VATS is also useful for detecting pleural involvement (M1a) (table 1).
VATS is typically used for tissue diagnosis when there is a suspicious peripheral
lesion that is amenable to wedge resection and there is no computed tomographic
(CT) and/or positron emission (PET) evidence for extrathoracic or mediastinal nodal
metastasis. VATS may also be used when percutaneous or endoscopic procedures
cannot access the primary tumor or are non-diagnostic [102-105]. (See "Selection of
modality for diagnosis and staging of patients with suspected non-small cell lung
cancer", section on 'Approach to the patient' and 'Video-assisted thoracic
surgery'below.)
●Left anterior mediastinotomy (Chamberlain procedure) is often the only option for
sampling the subaortic (aortopulmonary window) (5) and para-aortic (6) lymph node
stations (although some endoscopic ultrasound techniques can reach the AP
window). (See "Selection of modality for diagnosis and staging of patients with
suspected non-small cell lung cancer", section on 'Approach to the
patient' and 'Anterior mediastinotomy (Chamberlain procedure)' below.)
●ECM [106-108], VAMLA [109,110], and TEMLA [98,111-113], are surgical
procedures that allow more extensive mediastinal sampling. Although they are
sensitive procedures for detecting occult mediastinal disease, their use is limited
because they are not widely available and are associated with increased morbidity
when compared with SCM (eg, recurrent laryngeal nerve paralysis). (See "Selection
of modality for diagnosis and staging of patients with suspected non-small cell lung
cancer", section on 'Approach to the patient' and 'Extended cervical
mediastinoscopy' below and 'Video-assisted mediastinal lymphadenectomy' below
and 'Transcervical extended mediastinal lymphadenectomy'below.)

The evidence for each invasive procedure pertinent to its diagnostic and staging accuracy
for NSCLC is discussed in this section. The surgical management of mediastinal
lymphadenopathy and procedural aspects of VATS are discussed separately.
(See "Surgical evaluation of mediastinal lymphadenopathy" and "Overview of minimally
invasive thoracic surgery".)

Standard cervical mediastinoscopy — SCM is a surgical procedure that accesses the


mediastinum and as such is primarily a mediastinal staging tool. Its major advantage,
compared to minimally invasive tools (eg, endobronchial ultrasound), is direct visualization
of nodes for sampling and/or dissection. In addition, use of biopsy forceps provides
sufficient amounts of material for diagnosis and immunohistochemical and molecular
analysis.

SCM is the historical gold standard for mediastinal lymph node staging of NSCLC with
reported sensitivities of 78 to 90 percent [4,99-101]. Traditionally, this procedure has not
used video-assistance for sampling lymph nodes and has sampled nodes by biopsy
forceps. Much of the evidence describing its performance as a staging modality relates to
this particular approach. However, there has been a paradigm shift in the use of a video-
assisted mediastinoscope to access the mediastinum. Videomediastinoscopy improves
operator visualization, so that systematic lymph node sampling (by biopsy forceps) can be
performed. When a video mediastinoscope is used to dissect and remove an entire lymph
node, this is known as VAMLA which is discussed below. (See 'Video-assisted mediastinal
lymphadenectomy' below.)

SCM can easily access pretracheal (1, 3), paratracheal (2R, 2L, 4R, 4L), anterior
subcarinal (7) and occasionally hilar (10) nodes (figure 1). It is not able to sample subaortic
(5) or para-aortic (6), inferior (8, 9), posterior subcarinal (7), or lobar/interlobar (11 to 14)
stations. Use of the video mediastinoscope can extend access to the posterior subcarinal
nodes (station 7). SCM is best used to sample lymph nodes in these selected stations,
particularly when other staging modalities have failed or are not available.

Evidence supporting the role of SCM in staging the mediastinum in patients with
suspected NSCLC is reviewed here. The technical aspects, complications of
mediastinoscopy, and comparative studies with other staging modalities are discussed
separately. (See "Surgical evaluation of mediastinal lymphadenopathy", section on
'Complications of mediastinoscopy'and 'Diagnostic and staging accuracy' above
and 'Endobronchial ultrasound' above and 'Diagnostic and staging accuracy' above
and 'Diagnostic and staging accuracy' above.)

Staging accuracy — The largest meta-analysis evaluating the accuracy of SCM pooled
data from 9267 patients with suspected NSCLC who underwent SCM for staging the
mediastinum [4]. This analysis reported that SCM had a median sensitivity and negative
predictive value of 78 and 91 percent, respectively. However, the sensitivity is wide
ranging (32 to 92 percent). Additional techniques that may enhance the accuracy of SCM
include:

●Extensive sampling and complete lymph node dissection may increase the accuracy
of staging with a reported sensitivity of 90 percent [100].
●Systematic lymph node sampling is when the operator systematically samples at
least one node from each accessible lymph node station (typically up to five stations).
Compared to selective node sampling where lymph nodes are randomly selected by
the operator, systematic lymph node sampling may result in increased sensitivity (up
to 89 percent) [3,4,100,101,114,115].

There are relatively few comparative studies of endobronchial ultrasound-guided


transbronchial needle aspiration or transesophageal endoscopic ultrasound-guided fine
needle aspiration, with surgical modalities. (See 'Diagnostic and staging accuracy' above
and 'Endobronchial ultrasound' above and 'Combined modalities' above.)

●A comparative study of 127 patients who completed both endobronchial ultrasound-


transbronchial needle aspiration (EBUS-TBNA) followed by mediastinoscopy followed
by open surgical resection and complete lymph node dissection for all patients with
negative initial results demonstrated a sensitivity, specificity, and accuracy of EBUS-
TBNA of 88, 100, and 92.9 percent compared to 81, 100, and 89.0 percent for
mediastinoscopy respectively [41].
●In a highly selected group of 159 patients who underwent EBUS-TBNA and cervical
mediastinoscopy, the sensitivity of both procedures was comparable (81 versus 79
percent) and there were no significant differences between the negative predictive
value and overall diagnostic accuracy of the procedures (93 versus 93 percent) [40].
One limitation of many of these studies is that they are small. In addition, up to half of
cases that are reported as falsely negative are due to the inability of SCM to access
certain lymph node stations [116-121]. The variable sensitivity may also be due to poor
adherence to guidelines for the performance of SCM [122,123]. One study of four hospitals
showed that guidelines for the use of mediastinoscopy in patients with suspected lung
cancer, between the years of 1993 and 1999, were adequately followed in only two-thirds
of cases [123]. Approximately, 17 percent of patients appeared to have
unforeseen N2/3 disease, resulting in 18 percent of cases in whom thoracotomy could
have been prevented had guidelines been followed [123]. However, whether this is
reflective of practice in most institutions is not known.

Cervical mediastinoscopy is a surgical procedure. Potential complications include


hemorrhage and viscus perforation. The complications of cervical mediastinoscopy are
discussed separately. (See "Surgical evaluation of mediastinal lymphadenopathy", section
on 'Complications of mediastinoscopy'.)

Video-assisted thoracic surgery — VATS is typically used in the diagnosis and staging
of suspected NSCLC when alternative procedures cannot access the tumor or are
nondiagnostic. Alternatively, VATS can be used as a primary diagnostic modality when the
probability of cancer is high and the tumor is easily accessible to wedge resection.

The main advantage of VATS is the direct visualization of and extensive access to the
lung, thoracic cavity, and all mediastinal structures (eg, lymph nodes, vessels, and
esophagus). This allows concurrent access to both the primary tumor and to almost all
lymph nodes in the ipsilateral mediastinum (4, 5, 6, 7, 8, 9, 10 to 14) (figure 1). Thus,
VATS can easily evaluate the extent of invasion by the primary tumor (T), especially that of
the chest wall and mediastinal structures (T), malignant mediastinal lymph node
involvement (N), and pleural involvement (M1a) (table 1) [102,103]. This approach permits
rapid intraoperative diagnosis, staging and occasionally therapy, thereby shortening the
time needed to diagnose and stage NSCLC.

VATS is a major surgical procedure requiring general anesthesia. Reaching the right side
of the mediastinum with VATS is technically easier than reaching the left, particularly, the
left paratracheal nodes (4L). In addition, although access to mediastinal node stations is
extensive, typically only one side can be sampled. Occult disease on the contralateral side
can be missed unless bilateral VATS is performed. However, bilateral VATS is not
routinely performed for this indication because it greatly increases the morbidity and
mortality of the surgery. The complications and procedural aspects of VATS and surgical
management of mediastinal lymphadenopathy are discussed separately. (See "Surgical
evaluation of mediastinal lymphadenopathy" and "Overview of minimally invasive thoracic
surgery".)

Staging accuracy — One 2013 meta-analysis of four small studies reported a median
sensitivity of 99 percent (range 58 to 100 percent) and negative predictive value of 96
percent (range 88 to 100 percent) [4]. However, of the four studies included in this meta-
analysis, the study that reported the lowest sensitivity (58 percent) was a multicenter
study. The variability of results and low sensitivity seen in the multicenter study suggest
wide differences in the accuracy of VATS for staging NSCLC or heterogeneity of patient
populations. There are no studies that directly compare the diagnostic or staging accuracy
of VATS to other staging modalities.

VATS has been shown to have value in the evaluation of T4 lesions (eg, large bulky
tumors infiltrating the mediastinum) [104,124,125]. T4 lesions for the most part represent
stage III disease that is inoperable. Further staging by VATS in this setting may either
downstage the disease such that the patient may become a candidate for surgery or
upstage it when unexpected metastatic disease of the pleura is found [103,104,125-128].
The best evidence to support this comes from one prospective study of 64 patients with
NSCLC [104]. All patients were thought be ineligible for surgery based on their computed
tomography (CT) scan characteristics (eg, pleural fluid, T4 lesions). Among the 30 patients
with mediastinal infiltration on CT scan (T4 disease), nine (30 percent) were down-staged
to stage IIIA (potentially operable) and two (7 percent) to stage II (operable disease). In
addition, this study and others have reported that VATS can upstage the disease to stage
IV by the identification of unsuspected pleural disease in 6 to 60 percent of cases
[103,104].

VATS is frequently used to perform lobectomies in patients with peripheral nodules and
suspected N0 or N1 disease. For accurate staging, these patients are routinely subjected
to mediastinal lymph node sampling intraoperatively. Two controversial issues arise
intraoperatively:

●Unexpected occult N2 disease (ie, stage IIIA) – Typically, surgery is not offered as
first line therapy to patients with known stage IIIA NSCLC. However, if occult N2
disease is discovered intraoperatively, most surgeons will proceed with resection if
the diseased node can be fully resected and adjuvant chemotherapy is subsequently
offered [129]. (See "Management of stage I and stage II non-small cell lung cancer",
section on 'Video-assisted thoracoscopic surgery'.)
●Extent of lymph node dissection – It is unknown whether lymph nodes should be
sampled systematically or fully dissected intraoperatively. One randomized study of
1111 patients with NSCLC who had negative preoperative sampling of lymph nodes
who also underwent VATS suggested that, compared with lymph node sampling,
lymph node dissection discovered more occult N2 disease (4 versus 1 percent) [130].
However, dissection was not associated with a survival advantage (median survival
8.5 years in both groups) or decrease in local or regional recurrence.
(See "Management of stage I and stage II non-small cell lung cancer", section on
'Mediastinal lymph node dissection'.)

Anterior mediastinotomy (Chamberlain procedure) — A left anterior mediastinotomy


(Chamberlain procedure) is a surgical procedure that requires general anesthesia. The
incision is made over the left second or third intercostal space to access lymph nodes in
stations 5 and 6 (figure 1). Due to lymphatic drainage patterns, cancers of the left upper
lobe preferentially drain to these regions (figure 1). However, these regions are
traditionally difficult to access and cannot be reached by minimally invasive techniques or
by standard cervical mediastinoscopy.

A left anterior mediastinotomy is the traditional surgical procedure used to stage left-sided
cancer when suspected nodes are located in stations 5 and 6. It has the added advantage
of accessing left upper lobe tumors for concurrent resection, if there is no evidence of
nodal or distant disease.

Because it is often the only option when suspicious lymph nodes are identified in this
region, there is a paucity of data regarding its diagnostic accuracy. Nonetheless, one
meta-analysis of four small studies reported a sensitivity and negative predictive value of
71 and 91 percent respectively [131]. No studies have directly compared its performance
to ECM, VATS), or to endoscopic ultrasound-guided fine needle aspiration which can
occasionally reach this region. (See 'Extended cervical mediastinoscopy' below
and 'Video-assisted mediastinal lymphadenectomy' below.)

Extended cervical mediastinoscopy — ECM accesses the mediastinum and as such is


primarily a mediastinal staging tool. It extends the sampling territory of standard cervical
mediastinoscopy (1, 2, 3, 4, 7, 10) to the subaortic (5) and para-aortic (6) lymph node
stations (figure 1). Stations 5 and 6 cannot be reached using standard cervical
mediastinoscopy. Traditionally, accessing nodes in these stations requires surgical
dissection via a left anterior mediastinotomy (Chamberlain procedure). Thus, the main
advantage of ECM is that when access to stations 5 and 6 is desired to stage tumors of
the left upper lobe, it avoids the surgical risk associated with a left anterior
mediastinoscopy. The main disadvantage of ECM is that its performance is limited to the
few centers with expertise for it as a staging modality.

Two case series of 377 patients with suspected cancer of the left lung compared the
staging accuracy of routine and selective ECM [106,108]. ECM was considered routine
when it was performed in every patient with suspected NSCLC, and considered selective
when biopsy was only performed in patients with suspicious nodes identified by CT or
positron emission tomography (PET). Compared to routine ECM, selective ECM had
higher sensitivity (65 to 75 versus 44 to 45 percent) but a similar negative predictive value
(95 versus 94 percent), although these results may be explained by spectrum bias (eg,
lymph nodes were larger and/or more likely to be involved in the ECM group). The
complication rate was 2 percent and included mediastinitis, ventricular fibrillation, and
wound infection.

Another retrospective analysis of 55 patients with NSCLC reported that, compared


with PET/CT, ECM had a higher sensitivity (69 versus 53 percent), and negative predictive
value (89 versus 83 percent) [107]. ECM is not widely available and requires further study.
Video-assisted mediastinal lymphadenectomy — Video-assisted mediastinoscopes
offer improved visualization and extensive sampling of mediastinal lymph nodes for
complete removal (lymphadenectomy) (figure 1). VAMLA can sample the same lymph
node stations as standard cervical mediastinoscopy (1, 2, 3, 4, anterior 7, and 8). In
addition, they provide better access to the posterior region of the subcarinal lymph node
station (7).

●One single-center study of 144 patients reported a sensitivity for VAMLA of 100
percent [109].
●A case series of 156 patients reported that, compared to standard mediastinoscopy,
VAMLA was superior with higher sensitivity (94 versus 64 percent) and negative
predictive value (96 versus 84 percent) [110].

In both studies, the complication rate was high (3 to 6 percent) with a higher than usual
rate of recurrent laryngeal nerve injury (4 to 5 percent) [109,110].

VAMLA is not widely available and requires further study.

Transcervical extended mediastinal lymphadenectomy — TEMLA uses a sternal


retractor to widen surgical access to the mediastinum for open (not endoscopic or video-
assisted) dissection. This open access approach allows sampling of stations 1, 2, 3, 4, 5,
6, 7, and 8 (figure 1).

One prospective study of 81 patients showed sensitivity and negative predictive values of
90 and 95 percent, respectively [111]. Compared to standard cervical mediastinoscopy, a
prospective randomized study of 41 patients reported that TEMLA had higher sensitivity
(100 versus 38 percent) and negative predictive values (100 versus 67 percent) [112].
However, a major caveat of this study was its early termination due to the unusually high
false negative rate in the cervical mediastinoscopy group. The recurrent laryngeal nerve
palsy rate appears lower than for VAMLA, at 2 percent with less than 1 percent having
permanent damage [113].

One retrospective study of patients with NSCLC compared the staging performance of
endoscopic modalities (EBUS-TBNA, EUS-FNA, and combined EBUS/EUS) with TEMLA
[98]. In the 276 patients where TEMLA was preceded by negative endoscopic sampling for
primary staging, TEMLA discovered occult disease in 50 patients and deferred surgery in
three patients. Compared to endoscopic modalities, TEMLA had higher sensitivity (96
versus 88 percent) and negative predictive values (99 and 83 percent, respectively).
However, the increased sensitivity of TEMLA occurred at the expense of increased
morbidity (7.2 versus 6.4 percent), mostly recurrent laryngeal nerve palsy (3 versus 0
percent), and mortality (0.4 versus 0 percent). (See 'Combined modalities' above.)

Additional large randomized multicenter trials will be needed to validate TEMLA further
before it can be routinely used as a staging procedure for NSCLC.
SAMPLING METASTATIC DISEASE — Sites of distant metastases in NSCLC are
classified into intrathoracic and extrathoracic metastases. Common intrathoracic sites are
the pleura, contralateral lung, and pericardium (stage IV; M1a). Common extrathoracic
sites are the liver, adrenal gland, brain and bone (stage IV; M1b) (table 1). An important
exception is that NSCLC in a supraclavicular node is considered to be N3 (stage IIIB)
disease despite the fact that it is not a mediastinal node. Tissue confirmation of suspected
disease at any of these sites indicates NSCLC that is inoperable.

Discovery of sites involved with metastatic NSCLC are often prompted by clinical
assessment and/or imaging. The imaging modalities should direct site selection for tissue
confirmation of metastatic NSCLC. Typically, consideration is given to sampling metastatic
sites first rather than sampling the suspected primary lesion. This is especially important
for solitary metastases when tissue diagnosis is essential to establish clear evidence of
inoperable NSCLC. When there is evidence on imaging to support a high probability of
multiple metastases, the site of tissue biopsy is selected based upon the ease of access
and risks of the procedure.

The accuracy of specific procedures used to biopsy suspected metastases from NSCLC is
discussed here. Imaging and approach to tissue biopsy of potential metastatic disease are
discussed separately. (See "Overview of the initial evaluation, diagnosis, and staging of
patients with suspected lung cancer", section on 'Imaging metastatic
disease' and "Selection of modality for diagnosis and staging of patients with suspected
non-small cell lung cancer", section on 'Suspected stage IV or supraclavicular node
disease'.)

Intrathoracic — Metastatic NSCLC in the pleura, contralateral lung, or pericardium


constitutes stage M1a disease, which is inoperable (table 1).

●Pleura – Two common clinical presentations of pleural disease are: metastases


associated with pleural effusion or multiple pleural-based nodules, and direct
extension of the primary tumor to the pleura or chest wall. Direct extension of the
primary tumor into the visceral or parietal pleura needs to be distinguished from
metastatic NSCLC of the pleural space that is separate from the primary tumor.
Primary tumor that infiltrates visceral or parietal pleura is staged as a T2 or T3 lesion,
respectively (table 1). T2/3 lesions are potentially operable. In contrast, metastatic
NSCLC discovered as separate solid lesion(s) in the visceral or parietal pleura or as
malignant cells in an effusion represent M1a disease that is inoperable. The
diagnostic accuracy of sampling pleural lesions is discussed below. (See 'Suspected
pleural metastases' below.)
●Lung – Solitary nodules or masses in the contralateral lung require histologic
evaluation to distinguish metastasis from a synchronous primary malignant tumor or
an unrelated non-malignant diagnosis. NSCLC with a histologically similar
contralateral solitary lesion is classified as M1a disease. The diagnostic accuracy for
sampling nodules or masses suspicious for metastatic disease in the contralateral
lung is the same as sampling a primary tumor or a solitary pulmonary nodule, which
are discussed separately. (See 'Minimally invasive procedures' above and 'Video-
assisted thoracic surgery' above and "Diagnostic evaluation and management of the
solitary pulmonary nodule", section on 'Nonsurgical biopsy' and "Diagnostic
evaluation and management of the solitary pulmonary nodule", section on 'Surgical
biopsy'.)
●Pericardium – Direct extension of the tumor to the pericardium constitutes a T4
lesion (table 1). A pericardial effusion due to NSCLC is M1a disease. Most cases of
T4 pericardial NSCLC and all cases of pericardial effusions due to NSCLC are
considered inoperable. Sampling pericardial fluid or tissue is discussed separately.
(See "Pericardial disease associated with malignancy".)

Suspected pleural metastases — Pleural effusions or pleural abnormalities


(solid masses/nodule/thickening) suspicious for metastatic disease are present on imaging
in up to one-third of patients with NSCLC at the time of presentation [132]. Although some
effusions may be benign (eg, due to post-obstructive pneumonitis or atelectasis), the
majority are malignant and establish a diagnosis of M1a disease (table 1). Sampling the
pleural space (effusions or solid lesions) is essential in all patients with suspected pleural
involvement. Thoracentesis is typically performed first for evaluation of pleural effusions.
Pleural biopsy (image-guided or thoracoscopic) is often performed when pleural fluid
cytology is negative or to obtain tissue from a solid pleural lesion.

The diagnostic accuracy of thoracentesis and pleural biopsy techniques for NSCLC are
discussed here. The imaging modalities (ultrasound, computed tomography [CT], positron
emission tomography [PET]) and approach to suspected pleural disease in patients with
NSCLC are discussed separately. (See "Selection of modality for diagnosis and staging of
patients with suspected non-small cell lung cancer", section on 'Suspected stage IV or
supraclavicular node disease' and "Overview of the initial evaluation, diagnosis, and
staging of patients with suspected lung cancer", section on 'Radiographic
staging' and "Imaging of pleural effusions in adults" and "Imaging of pleural plaques,
thickening, and tumors".)

Thoracentesis — Thoracentesis removes fluid from the pleural space for cytologic
analysis. The diagnostic accuracy of pleural fluid cytology is derived from older, poorly
controlled, small studies. In addition, many of these studies report the diagnostic yield in
the setting of benign and malignant disease of varied histologic types [133-139].
Nonetheless, one meta-analysis from seven studies reported a mean sensitivity for the
diagnosis of malignancy of 72 percent (49 to 71 percent) [2]. It is the imperfect sensitivity
of thoracentesis that necessitates pleural biopsy when fluid cytology is negative.
(See "Diagnostic thoracentesis" and "Diagnostic evaluation of a pleural effusion in adults:
Initial testing" and "Overview of the risk factors, pathology, and clinical manifestations of
lung cancer", section on 'Pleural involvement' and "Selection of modality for diagnosis and
staging of patients with suspected non-small cell lung cancer", section on 'Suspected
stage IV or supraclavicular node disease'.)

The sensitivity of pleural fluid cytology increases with recurrent sampling. Up to 30 percent
of second thoracenteses are positive for cancer when the results of the initial thoracentesis
are falsely negative [136,137,140]. Other studies report variable increases in the rates of
cancer diagnoses from 5 to 25 percent after the third thoracentesis [133,136].

There is conflicting data regarding the optimal volume required for the identification of
malignant cells in pleural fluid. Studies are hampered by varied definitions of what is
considered large volume versus small volume and lack comparators. While one study
suggested higher sensitivity from samples >60 mL, particularly those >150 mL, another
study suggested that 50 mL specimens are adequate [141,142]. Two studies also reported
higher sensitivity when enough material was collected for the preparation of a cell block
[137,141]. Typically, for cell block preparation, higher volumes are needed. Although
undetermined, it has been suggested that the variability in optimal volume required for
diagnosis may simply relate to the total number of malignant cells in the sample pleural
fluid, a variable which is unknown at the time of thoracentesis. Thus, the optimal volume
varies among institutions and interventional clinicians. In general, when feasible, volumes
of at least 50 to 60 mL processed by cell block preparation are recommended.
(See "Diagnostic thoracentesis", section on 'Technique' and "Diagnostic thoracentesis",
section on 'Complications' and "Large volume thoracentesis" and "Measurement of pleural
pressure".)

There has been a paradigm shift with the increased use of bedside thoracic ultrasound
(TUS) to guide the operator in performing thoracentesis safely. TUS decreases the
incidence of iatrogenic pneumothorax following thoracocentesis [143-145]. The advantage
of TUS is that it can facilitate access to small effusions that would not have traditionally
undergone bedside manual thoracentesis. The diagnostic accuracy of TUS for identifying
malignant effusions in this context is unknown. However, it is typically used by many
clinicians for reasons of safety rather than for diagnostic certainty.

Although there is reduced sensitivity and variable assay methodology, it is technically


possible to evaluate molecular tumor markers on pleural fluid specimens [146-148].

Pleural biopsy — When pleural fluid cytology is negative or pleural


based abnormalities/masses are present, a pleural biopsy is indicated. Three options are
available to the clinician to biopsy the pleura: thoracoscopy (surgical or medical), image-
guided biopsy (CT or ultrasound), and closed pleural biopsy.

●Surgical or medical thoracoscopy – Surgical thoracoscopy is usually performed in


the operating room under video assistance and general anesthesia. Medical
thoracoscopy (pleuroscopy) is an endoscopic procedure usually done in the
endoscopy suite under conscious sedation. Both procedures are capable of obtaining
biopsy material from the parietal and visceral pleura under direct visualization. The
operator can randomly sample the pleura as well as biopsy macroscopically visible
lesions. Among the three options for pleural biopsy, thoracoscopy has the highest
diagnostic accuracy. Reported sensitivities range from 80 to 99 percent with negative
predictive values of 93 to 96 percent [99,132,149-154]. Lower sensitivity values may
be due to a higher percentage of false negative results in patient cohorts that include
mesothelioma, which is typically difficult to diagnose histologically on pleural biopsy
[152]. Thoracoscopy has the added advantage of providing therapeutic options to
avoid recurrent effusion such as pleurodesis or the insertion of an in-dwelling catheter
at the time of surgery. (See "An overview of medical thoracoscopy" and "Indications
for diagnostic thoracoscopy", section on 'Lung cancer'.)
●Image-guided biopsy – Image-guided biopsy is performed in the interventional
radiology suite with or without sedation. Biopsy material is obtained using CT-
guidance, or less commonly, ultrasound-guidance [155-158]. This modality is best
utilized to biopsy focal pleural lesions/abnormalities with or without associated
effusions. The reported sensitivity ranges from 76 to 88 percent with negative
predictive values of 75 to 80 percent [155-157]. The diagnostic utility of the type of
cutting needle used (Cope or Abrams needle) has not been comprehensively studied.
However, one study of cytology-negative pleural effusions used an Abrams needle
specifically to biopsy associated pleural-based masses/thickening under CT-
guidance. Compared to thoracoscopy, no difference was observed in the sensitivity
for identifying lung cancer (100 versus 93 percent) [151]. Another study reported that
CT-guided Abram’s needle biopsy had a higher sensitivity than ultrasound-guided
biopsy using a cutting needle (82 versus 67 percent) [159].
●Closed pleural biopsy – Closed pleural biopsy is rarely performed in contemporary
practice. It is a blind procedure typically performed with an Abrams needle. It is a
bedside procedure that can only be used when pleural fluid is present and can only
biopsy the parietal pleura. Pleural metastases are more common on the visceral
pleura and are sparse and focal on the parietal pleura. This feature, together with
dwindling utilization and expertise in closed biopsy, may contribute to the low
sensitivity of this modality, thereby limiting its utility.

Extrathoracic — Clinical history, examination and imaging typically alert the clinician to
suspected metastatic disease distant from the lung. (See "Overview of the initial
evaluation, diagnosis, and staging of patients with suspected lung cancer", section on
'Imaging metastatic disease'.)

Histologic confirmation of extrathoracic NSCLC is necessary to establish M1b disease


(table 1). In contrast, NSCLC in a supraclavicular node is staged at IIIB. Most forms of
extrathoracic disease are inoperable. The following sections discuss the modalities used to
biopsy suspected metastases in NSCLC
●Liver (see "Percutaneous, fine-needle aspiration, and laparoscopic liver
biopsy" and "The adrenal incidentaloma", section on 'Fine-needle aspiration
biopsy' and "Selection of modality for diagnosis and staging of patients with
suspected non-small cell lung cancer", section on 'Suspected stage IV or
supraclavicular node disease')
●Adrenal gland (see "The adrenal incidentaloma", section on 'Evaluation for
malignancy' and "The adrenal incidentaloma", section on 'Fine-needle aspiration
biopsy' and "Selection of modality for diagnosis and staging of patients with
suspected non-small cell lung cancer", section on 'Suspected stage IV or
supraclavicular node disease')
●Brain – Biopsy of brain lesions suspected to be metastatic NSCLC is rarely
performed but their evaluation is discussed separately (see "Clinical presentation and
diagnosis of brain tumors", section on 'Brain metastases' and "Selection of modality
for diagnosis and staging of patients with suspected non-small cell lung cancer",
section on 'Suspected stage IV or supraclavicular node disease')
●Bone (see "Bone tumors: Diagnosis and biopsy techniques", section on 'Biopsy
techniques' and "Selection of modality for diagnosis and staging of patients with
suspected non-small cell lung cancer", section on 'Suspected stage IV or
supraclavicular node disease')
●Supraclavicular lymph node (see "Evaluation of peripheral lymphadenopathy in
adults", section on 'Localized lymphadenopathy' and "Selection of modality for
diagnosis and staging of patients with suspected non-small cell lung cancer", section
on 'Suspected stage IV or supraclavicular node disease')

SPUTUM CYTOLOGY — Sputum cytology is a noninvasive tool that has diagnostic value
in a small population of patients with suspected NSCLC who are unable or unwilling to
undergo other diagnostic procedures. However, it does not directly provide staging
information for NSCLC, nor it is it likely to provide ideal specimens for
immunohistochemical or molecular studies [160].

Pooled data from small observational series report sensitivity values of 66 percent (range
42 to 97 percent) for the diagnosis of NSCLC [2]. Sensitivity varies by location of the
primary tumor, being highest for large, centrally located lesions, and lower for smaller or
peripheral lesions [2].

Although cytologic specimens can be diagnostic of NSCLC, not every patient produces
sputum. Thus, a negative test does not exclude the diagnosis of NSCLC and a second
procedure will often be necessary for this purpose. Similarly, when sputum cytology is
positive, additional testing will often be necessary for staging, especially when mediastinal
or distant metastases are suspected.

Thus, in practice, sputum cytology is typically most useful in patients in whom avoiding a
biopsy is desirable (eg, multiple comorbidities, contraindications to invasive biopsy,
overwhelming evidence of metastatic disease). In this context, diagnostic sputum cytology
may permit palliative or other therapy without the risk associated with biopsy.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education


materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient education: Non-small cell lung cancer (The Basics)")
●Beyond the Basics topics (see "Patient education: Non-small cell lung cancer
treatment; stage I to III cancer (Beyond the Basics)" and "Patient education: Non-
small cell lung cancer treatment; stage IV cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●There are a number of minimally invasive and invasive procedures that can be used
by the clinician to biopsy patients with suspected NSCLC. Selecting a modality
depends upon knowledge of the diagnostic accuracy of a modality for the target
lesion(s), in the context of operator proficiency, patient safety and eventual goals for
treatment. While minimally invasive techniques are generally preferred to more
invasive procedures, their imperfect sensitivity necessitates additional biopsy when
testing is negative for cancer. Sensitivity and specificity estimates for individual
modalities are usually based upon data from small studies with inadequate gold
standard comparators that lead to bias and significantly limit interpretation of the data.
The clinician should be aware of these flaws when choosing among the modalities
available for tissue acquisition. (See "Selection of modality for diagnosis and staging
of patients with suspected non-small cell lung cancer".)
●Bronchoscopic techniques often employ multiple modalities (eg, forceps biopsy,
brushings, ultrasound, needle aspiration) to increase the sensitivity for the diagnosis
and staging of NSCLC. Bronchoscopy is best utilized for accessing large, visible, or
central lesions and suspicious paratracheal and subcarinal nodes. As examples
(see 'Bronchoscopic approaches' above):
•Endobronchial-guided transbronchial needle aspiration (EBUS-TBNA) is the
first-choice modality for sampling large, central tumors and suspicious
mediastinal lymph nodes in the paratracheal, subcarinal, and hilar regions (2R,
2L, 3p, 4R, 4L, 7, 10R, 10L, 11R, 11L) (figure 1). Limitations of EBUS-TBNA
include inability to access prevascular, periaortic, paraesophageal, or pulmonary
ligament lymph node stations (3a, 5, 6, 8, 9), and variable proficiency among
operators, which may influence the rate of nondiagnostic findings.
(See 'Endobronchial ultrasound' above.)
•Electromagnetic navigational bronchoscopy (EMN) is an emerging modality for
sampling peripheral lung lesions. (See 'Electromagnetic navigational
bronchoscopy' above.)
●Transthoracic (percutaneous) needle aspiration/biopsy (TTNA/B) is a sensitive
procedure for acquiring tissue for most intraparenchymal lesions, particularly
peripheral masses and nodules. Although in theory it can access almost all
mediastinal lymph nodal stations, it is rarely used for this purpose. It is often used to
access peripheral lesions and can also be used when other procedures have failed.
Results are sometimes non-diagnostic and there is a relatively high risk of
pneumothorax. (See 'Transthoracic needle biopsy'above.)
●Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is a sensitive
staging tool for suspected NSCLC involvement in subcarinal (3, 7, 8, 9) and
paratracheal nodes (2, 4). EUS-FNA can be combined with EBUS-TBNA to enhance
mediastinal staging. (See 'Transesophageal endoscopic ultrasound' above
and 'Combined modalities' above.)
●Standard cervical mediastinoscopy (SCM) is a sensitive staging procedure when
sampling nodal stations easily accessed by this approach (1, 2, 3, 4, anterior 7, 10)
(figure 1). Use of a video mediastinoscope and systematic lymph
node sampling/dissection may enhance the accuracy of this modality. (See 'Standard
cervical mediastinoscopy' above.)
●Video-assisted thoracoscopic surgery (VATS) is an accurate modality for evaluating
the extent of invasion (chest wall, mediastinal) by the primary tumor (T), mediastinal
lymph node involvement (4, 5, 6, 7, 8, 9, 10 to 14) and pleural involvement (M) (figure
1). It is a surgical procedure that requires general anesthesia and carries higher
morbidity and mortality than other diagnostic or staging modalities. VATS is most
often used when alternative procedures cannot access the primary tumor or are non-
diagnostic. (See 'Video-assisted thoracic surgery' above.)
●Left anterior mediastinotomy (Chamberlain procedure) is often the only option for
sampling the subaortic (5) and para-aortic (6) lymph node stations. (See 'Anterior
mediastinotomy (Chamberlain procedure)' above.)
●Extended cervical mediastinoscopy (ECM), video-assisted mediastinal
lymphadenectomy (VAMLA), and transcervical extended mediastinal
lymphadenectomy (TEMLA) are surgical procedures that allow more extensive
mediastinal sampling than standard cervical mediastinoscopy. They are not widely
available and may be associated with greater morbidity than standard cervical
mediastinoscopy. Using any one of these procedures is best dictated by the expertise
of practitioners within the institution. (See 'Extended cervical mediastinoscopy' above
and 'Video-assisted mediastinal lymphadenectomy' above and 'Transcervical
extended mediastinal lymphadenectomy' above.)
●Sampling site(s) of suspected metastatic disease is necessary for tissue
confirmation. Sampling the pleural space (effusions or solid lesions) is essential in all
patients with suspected pleural involvement. Thoracentesis is typically performed first
for evaluation of pleural effusions. Pleural biopsy (image-guided or thoracoscopic) is
often performed when pleural fluid cytology is negative or to obtain tissue from a solid
pleural lesion. (See 'Sampling metastatic disease' above and 'Suspected pleural
metastases' above.)
●Sputum cytology has diagnostic value in a small population of patients with
suspected NSCLC. Sensitivity is highest for large, centrally located lesions, and lower
for small peripheral lesions. It is not useful for staging NSCLC. (See 'Sputum
cytology' above.)
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Procedures for tissue biopsy in patients with suspected non-small cell lung cancer
Authors:
Karl W Thomas, MD
Michael K Gould, MD, MS
Section Editor:
James R Jett, MD
Deputy Editor:
Geraldine Finlay, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Dec 2016. | This topic last updated: Nov 02, 2016.

INTRODUCTION — Lung cancer is the most common cancer worldwide. Non-small cell
lung cancer (NSCLC) accounts for approximately 85 percent of all lung cancers, of which,
adenocarcinoma is the most common histologic subtype [1].

Traditionally, the histopathologic diagnosis of NSCLC has been made based upon
information obtained from small biopsies. There has been a shift towards the use of
therapies targeted at specific mutations, the identification of which can be challenging on
small biopsy samples. This, together with the rising incidence of adenocarcinoma and its
classification into subgroups, has led to greater emphasis on the importance of tissue
biopsy for the diagnosis of NSCLC. (See "Pathology of lung
malignancies" and "Personalized, genotype-directed therapy for advanced non-small cell
lung cancer".)

This topic will discuss the accuracy of procedures commonly used to obtain tissue for
diagnosis and staging in patients with suspected NSCLC. The clinical presentation, initial
evaluation and staging, and approach to the selection of modality for biopsy of patients
with suspected NSCLC are discussed separately. (See "Overview of the initial evaluation,
diagnosis, and staging of patients with suspected lung cancer" and "Selection of modality
for diagnosis and staging of patients with suspected non-small cell lung cancer".)

SELECTION OF MODALITY FOR TUMOR BIOPSY — Selection of the optimal biopsy


target and modality should be driven by evidence-based and institution-specific protocols
that preferably involve a lung cancer tumor board or multidisciplinary team. When an
institution is equipped with reliable expertise, one of the minimally invasive or more
invasive tools listed in the section below may be used to biopsy a target lesion.
Importantly, estimates of sensitivity and specificity for individual modalities are usually
based upon small studies with inadequate gold standard comparators that lead to bias and
significantly limit interpretation of the data. Furthermore, the post-test probability of
malignant disease particularly in metastatic locations will depend not only on patient risk
factors, but also the local prevalence of alternative diagnoses such as granulomatous
disease. The clinician should be aware of these clinically relevant limitations when
choosing among the modalities available for tissue acquisition. (See "Selection of modality
for diagnosis and staging of patients with suspected non-small cell lung
cancer" and 'Minimally invasive procedures' below and 'Surgical staging
procedures' below.)

Prior to biopsy the following should be in place:

●A thorough history and examination with routine laboratory studies. (See "Overview
of the initial evaluation, diagnosis, and staging of patients with suspected lung
cancer", section on 'Initial evaluation'.)
●Imaging with contrast-enhanced computed tomographic (CT) scan of the chest and
upper abdomen to assess suspected stage prior to biopsy. Some patients may
require additional imaging including positron emission tomography (PET), or
integrated PET/CT (eg, IB to IIIA non-small cell lung cancer [NSCLC] to detect occult
metastases) or imaging of sites suspected to be involved with metastases (eg, those
with symptoms or focal findings). (See "Overview of the initial evaluation, diagnosis,
and staging of patients with suspected lung cancer", section on 'Radiographic
staging'.)
●Good working knowledge of the Tumor Node Metastasis (TNM) staging of NSCLC
(table 1), the International Association for the Study of Lung Cancer (IASLC) lymph
node map (figure 1), and the therapeutic strategies for the suspected stage.
(See "Management of stage I and stage II non-small cell lung
cancer" and "Management of stage III non-small cell lung cancer" and "Overview of
the treatment of advanced non-small cell lung cancer".)

Guidelines issued by the American College of Chest Physicians (ACCP), European


Society of Thoracic Surgeons (ESTS), and International Association for the Study of Lung
cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) are
available to guide the physician with modality selection [2-5].

The evidence for the diagnostic and staging accuracy of each procedure for NSCLC is
discussed in this topic. General biopsy goals and a suggested diagnostic and staging
algorithm are discussed in detail separately. (See "Selection of modality for diagnosis and
staging of patients with suspected non-small cell lung cancer", section on 'Biopsy
goals' and "Selection of modality for diagnosis and staging of patients with suspected non-
small cell lung cancer", section on 'Approach to the patient'.)

MINIMALLY INVASIVE PROCEDURES

Overview — Commonly used minimally invasive approaches employ bronchoscopic and


percutaneous modalities. Bronchoscopic techniques include endobronchial ultrasound-
guided transbronchial needle aspiration (EBUS-TBNA), bronchial washings, brushings,
forceps transbronchial biopsy, navigational-guided transbronchial biopsy, and "blind"-
TBNA. Bronchoscopic techniques may be combined in a single procedure and this
provides a potential advantage of obtaining both the diagnosis and staging in a single
procedure. Percutaneous approaches include transthoracic needle aspiration (TTNA)
or needle/core biopsy (TTNB) of the primary tumor. A combination of bronchoscopic and
percutaneous modalities may be necessary to permit sampling from several lesions or
when the first modality is non diagnostic. Selecting one of these procedures or combining
several modalities to achieve the most accurate histologic classification and staging
information relies on knowledge of the technique’s diagnostic accuracy for the target
lesion(s). Critical considerations for procedure selection also include patient-specific
details like cardiovascular status and goals of care, as well as systems factors such as
available equipment, laboratory resources, and operator proficiency. (See "Selection of
modality for diagnosis and staging of patients with suspected non-small cell lung cancer",
section on 'Approach to the patient'.)

The evidence for each minimally invasive procedure pertinent to its diagnostic and staging
accuracy for NSCLC is discussed in this section. In general, the following applies:

●Bronchoscopy with EBUS-TBNA has gained wide acceptance as a first-choice


diagnostic and staging procedure for thoracic mass lesions and enlarged lymph
nodes that are accessible by this modality. This is due to its ability to establish both a
suspected diagnosis of lung cancer as well as its high diagnostic accuracy for
sampling central lesions and lymph nodes in the paratracheal, subcarinal and hilar
regions of the mediastinum [4,6-10]. Limitations of EBUS-TBNA include inability to
access retrotracheal, periaortic, paraesophageal and pulmonary ligament lymph node
stations (3a, 5, 6, 8, 9) and variable operator proficiency, which may influence the rate
of non-diagnostic findings. (See 'Endobronchial ultrasound' below.)
●Although transthoracic (percutaneous) needle aspiration/biopsy (TTNA/TTNB) has a
high accuracy for diagnosing NSCLC, the higher risk of complications (eg,
pneumothorax) is an important limitation, and it is rarely useful for mediastinal lymph
node staging [2,4,11-16]. TTNA may be used for peripheral nodules and masses,
especially when lesions appear to directly involve the chest wall or skeleton, or as an
alternate procedure when lesions cannot be safely or reliably accessed using another
modality. (See 'Transthoracic needle biopsy' below.)
●Conventional flexible bronchoscopy with forceps biopsy, brushing, or washing is
best utilized for accessing large, central lesions and those with suspected airway
involvement. These lesions may present with hemoptysis or postobstructive
pneumonia, and direct visualization reveals endobronchial involvement or obstruction
(see 'Conventional bronchoscopy' below). Conventional bronchoscopy with blind
transbronchial needle aspiration may be utilized for diagnosis and staging of
significantly enlarged subcarinal, paratracheal, and hilar nodes (figure 1). However,
without ultrasound guidance, TBNA alone has limited sensitivity for staging of the
mediastinum. The use of ultrasound guidance for tissue biopsy enhances the ability of
bronchoscopy to sample lymph nodes and tumors outside the airways, making EBUS
the preferred bronchoscopic modality for diagnosis and staging [7]
●Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) using a
transesophageal approach is a sensitive staging tool for suspected NSCLC in
subcarinal and paratracheal nodes. EUS-FNA can be combined with EBUS-TBNA to
enhance mediastinal staging. However, it requires special expertise.
(See 'Transesophageal endoscopic ultrasound' below and 'Combined
modalities' below.)
●Electromagnetic navigational bronchoscopy (EMN) is another modality for sampling
peripheral lung lesions that is increasingly available. Its use is best determined by the
expertise of practitioners within the institution. (See 'Electromagnetic navigational
bronchoscopy' below.)

Although obtaining samples of lavage fluid or tissue for genomic analysis has been studied
as a potential diagnostic tool designed to enhance the sensitivity of bronchoscopy for the
diagnosis of lung cancer, further study is required before it can be recommended for
routine use [17]. Histologic or cytologic classification of all lung cancers remains the gold
standard. Molecular and genetic profile sub-classification should be utilized within research
protocols and in limited circumstances for treatment and prognosis considerations.

Guidelines issued by the American College of Chest Physicians (ACCP), European


Society of Thoracic Surgeons (ESTS), International Association for the Study of Lung
cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS), and
the European Society of Gastrointestinal Endoscopy (ESGE)/ERS/ESTS have
incorporated the use of minimally invasive tools in the diagnostic work-up of NSCLC [18].
Evidence to support their use is largely derived from retrospective case series or from
smaller comparative studies, many of which have inherent bias favoring one modality over
another. The clinician should be aware of this bias prior to selecting a modality for tissue
biopsy. (See "Selection of modality for diagnosis and staging of patients with suspected
non-small cell lung cancer", section on 'Individualizing the approach'.)

Bronchoscopic approaches — Although different technical bronchoscopic approaches


have been studied as separate entities and are discussed individually in this section, in
practice, most experienced bronchoscopists can use multiple modalities and combine
them to increase the overall sensitivity for the diagnosis of NSCLC.

Conventional bronchoscopy — There are several ways to obtain tissue with


conventional, flexible, white light bronchoscopy (see "Flexible bronchoscopy in adults:
Preparation, procedural technique, and complications", section on 'Diagnostic and
therapeutic procedures' and "Flexible bronchoscopy in adults: Overview"):

●Washings, brushings, or endobronchial forceps biopsy for visually obvious lesions in


the main airways.
●Transbronchial forceps for biopsy of peripheral, parenchymal lesions that are not
directly visualized. Transbronchial biopsy is typically guided by fluoroscopy, but can
also be guided by electromagnetic navigation. (See 'Electromagnetic navigational
bronchoscopy' below.)
●TBNA, for biopsy of lesions and lymph nodes that are close to or encroaching upon
the airway. Bronchoscopic TBNA can be performed based on computed tomography
(CT) imaging and anatomic relationships or under real-time guidance by
endobronchial ultrasound. Endobronchial ultrasound requires a special bronchoscope
and image processors distinct from conventional flexible bronchoscopes.
(See 'Endobronchial ultrasound' below.)

For primary lesions that are large or central, or for lesions that obstruct airways, the
diagnostic sensitivity of conventional bronchoscopy with endobronchial or transbronchial
biopsy is 65 to 88 percent [2]. For similar, centrally located lesions, the use of needle
aspiration (bronchoscopic-TBNA) increases the diagnostic sensitivity (70 to 96 percent)
[2]. Bronchoscopy has a higher sensitivity for diagnosis of the primary tumor in this setting
because proximal lesions in or close to the airway are easily visualized and accessed by
this modality. However, for smaller peripheral lesions that are not visible endoscopically or
are located distal to sub-segmental bronchi, the sensitivity decreases significantly [2,19].
(See "Image-guided bronchoscopy for biopsy of peripheral pulmonary lesions".)

For patients with central lesions and CT evidence of bronchial, carinal, or tracheal
involvement, conventional bronchoscopy is essential for accurate determination of T-factor
staging (Tumor Node Metastasis staging). Conventional bronchoscopy with blind TBNA
may also be appropriate in some cases when there is bulky, central mediastinal disease.
However, conventional bronchoscopic TBNA without ultrasound guidance has a more
limited role in mediastinal staging in most patients with hilar, paratracheal and smaller
subcarinal lymph nodes because of its significantly lower sensitivity. Bronchoscopic-TBNA
without real-time ultrasound guidance is inferior to EBUS-TBNA for the diagnosis and
staging of NSCLC (sensitivity 36 versus 69 percent) [7-9,20,21]. The limited sensitivity
associated with bronchoscopic TBNA without real-time guidance for staging the
mediastinum often prompts additional mediastinal biopsy procedures when testing is
negative for cancer. (See 'Diagnostic and staging accuracy' below.)

Bronchoscopy (preferably with TBNA if CT and/or positron emission tomography (PET)


imaging demonstrate enlarged and/or hypermetabolic lymph nodes in accessible stations)
can be considered when EBUS-TBNA is not available or when it is the only diagnostic
modality that can be performed safely in patients in whom more invasive surgical
procedures or prolonged endoscopic procedures are contraindicated [20]. (See "Selection
of modality for diagnosis and staging of patients with suspected non-small cell lung
cancer", section on 'Approach to the patient'.)

The role of bronchoscopy pertinent to the diagnosis and staging of NSCLC is discussed
here. The general indications for flexible bronchoscopy, bronchoscopic-TBNA, and their
diagnostic role in the evaluation of a solitary pulmonary nodule are discussed separately.
(See "Flexible bronchoscopy in adults: Overview" and "Transbronchial needle
aspiration" and "Diagnostic evaluation and management of the solitary pulmonary
nodule" and "Diagnostic evaluation and management of the solitary pulmonary nodule",
section on 'Bronchoscopic techniques'.)

Diagnostic and staging accuracy — Major studies examining the diagnostic accuracy of
conventional, flexible, white light bronchoscopy and blind, bronchoscopic-TBNA for
NSCLC are summarized below.

●Diagnosis of primary tumor – Conventional bronchoscopy has moderately high


diagnostic accuracy for large, central or obstructive airway lesions that can be
biopsied under direct visualization using an endobronchial biopsy forceps (65 to 88
percent) [2]. Although bronchial lavage and brushings can be diagnostic, they
generally have a low sensitivity when used in isolation (43 and 54 percent,
respectively) [2]. Bronchoscopic-TBNA without real-time image guidance, which
involves aspirating tissue by passing a needle (19 to 21 gauge) through the working
channel of a conventional bronchoscope, can sample subcarinal, paratracheal, endo-
and peri-bronchial, as well as submucosal, lesions with sensitivity between 70 and 96
percent [22-24]. (See "Diagnostic evaluation and management of the solitary
pulmonary nodule", section on 'Bronchoscopic techniques'.)
Bronchoscopy is less useful for small or peripheral lesions (ie, not directly visible
bronchoscopically; sensitivity up to 65 percent), with higher sensitivity in lesions
greater than 2 cm [2]. Thus, when bronchoscopy is non-diagnostic, and clinical
suspicion remains high, further testing to pursue a diagnosis should be sought.
●Staging – Bronchoscopy is routinely performed pre-operatively to assess for
synchronous lesions and to delineate involvement of the central bronchi [2,25].
Specifically, bronchoscopy is necessary for assessing the proximal extent of central
or endobronchial tumors (ie, tumor size [T]). Tumors >2 cm from the carina are T2
lesions and tumors <2 cm are T3 lesions (table 1). Alteration of the stage from stage
1B (T2N0M0) to stage IIB (T3N0M0) can change the operative approach by the
surgeon, as well as the advisability of adjuvant chemotherapy.
Blind bronchoscopic-TBNA (ie, using only anatomic landmarks and previously
obtained CT images) can access paratracheal (4R, 4L), subcarinal (7), and less
commonly, hilar (10R, 10L) lymph nodes (figure 1). However, a meta-analysis
showed a pooled sensitivity of only 39 percent when limited to studies that enrolled
patients with potentially resectable NSCLC [26]. In a pooled analysis of a more
heterogeneous group of 2048 patients, including those with bulky adenopathy, the
sensitivity ranged from 14 to 100 percent (median 78 percent) with a negative
predictive value of 77 percent [2]. The sensitivity of conventional TBNA without image
guidance is likely related to the size of the target lymph node with greater sensitivity
for substantially enlarged nodes (eg, >2 cm) but markedly decreased sensitivity for
nodes 1 cm or less.
Three to four needle passes of selected lymph nodes for staging are often needed to
maximize the sensitivity. One study suggested that the diagnosis was established
with the first, second, third, and fourth needle pass at 64, 87, 95, and 98 percent of
targets, respectively [27]. Although the sensitivity varied widely with target site
features (eg, size, location), the stepwise increment to the maximum sensitivity
provided by serial passes was similar across target sites. In one study of 168 patients
with hilar and mediastinal adenopathy, the addition of rapid on-site cytologic
evaluation (ROSE) did not alter the sensitivity but did reduce the number of total
needle passes and lowered the rate of complications [28].

Endobronchial ultrasound — EBUS is an endoscopic imaging tool that utilizes real-time


ultrasonographic guidance to facilitate transbronchial needle aspiration as well as forceps,
needle, or brush biopsies of peripheral lesions. Although there are important technical
differences between conventional and EBUS-guided TBNA, such as the length of the
needle used, the main benefit of ultrasound guidance is related to the ability to visualize
anatomy and precisely localize suspicious lymph nodes or peripheral lung lesions. There
are two distinct ultrasound designs used in bronchoscopy: linear EBUS and radial probe
EBUS. Linear (ie, convex probe [CP]) EBUS is incorporated into the distal tip of a
dedicated bronchoscope that guides TBNA. Linear-EBUS TBNA is ideally suited for
sampling mediastinal lymph nodes or large, central masses. Radial probe (RP) ultrasound
is catheter-based and deployed through the working channel of a conventional flexible
bronchoscope and into subsegmental and distal airways to locate peripheral lesions and
then to guide forceps or brush biopsies. Radial EBUS is most commonly used for
diagnosis of parenchymal nodules or masses. (See "Endobronchial ultrasound: Technical
aspects" and "Image-guided bronchoscopy for biopsy of peripheral pulmonary lesions",
section on 'Radial probe endobronchial ultrasound (RP-EBUS)'.)

EBUS-TBNA is most sensitive when used to sample large, central primary lesions (84 to
85 percent) and suspicious or metastatic mediastinal lymph nodes (up to 96 percent) in the
paratracheal, posterior tracheal, subcarinal and hilar regions (2R, 2L, 3p, 4R, 4L, 7, 10R,
10L,) (figure 1) [7-9,29-33]. High operator proficiency and multiple passes with ROSE
enhance the overall sensitivity [5,34-38]. EBUS-TBNA has been shown to surpass the
sensitivity of conventional flexible bronchoscopy alone for the diagnosis and staging of
NSCLC [7-9]. Several studies suggest that EBUS-TBNA is at least comparable, and may
be superior to cervical mediastinoscopy but there are concerns regarding study design
[6,39-41]. The wide ranging and imperfect sensitivity associated with EBUS-TBNA
necessitate additional biopsy, usually mediastinoscopy, when testing is negative for
cancer. (See 'Diagnostic and staging accuracy' below and "Selection of modality for
diagnosis and staging of patients with suspected non-small cell lung cancer", section on
'Approach to the patient'.)

The value of EBUS-TBNA for the diagnosis and staging of NSCLC is discussed here. The
technical aspects of EBUS and other indications for its use are discussed separately.
(See "Endobronchial ultrasound: Indications, contraindications, and
complications" and "Endobronchial ultrasound: Technical aspects" and "Endoscopic
ultrasound-guided sampling of the mediastinum: Technique, indications, contraindications,
and complications".)

Diagnostic and staging accuracy — Major studies that have examined the diagnostic
accuracy of radial EBUS-TBNA for NSCLC are summarized below. (See "Endobronchial
ultrasound: Technical aspects" and "Endobronchial ultrasound: Technical aspects", section
on 'Types of EBUS'.)

●Diagnosis of primary tumor – EBUS has a sensitivity of 73 to 85 percent for large


symptomatic (eg, hemoptysis) or visible (eg, endobronchial) lesions that are centrally
located [7-9]. Its sensitivity declines for lesions <2 cm (71 percent), particularly those
that are peripherally located (56 percent) [8,9]. Although EBUS enhances the
accuracy of conventional transbronchial biopsy, CT-guided percutaneous
transthoracic needle aspiration or core needle biopsy has comparable results if not
superior accuracy for smaller lesions [8,9,13-15]. The sensitivity of EBUS-TBNA for
identifying mediastinal lesions other than NSCLC is discussed separately.
(See "Endobronchial ultrasound: Technical aspects" and "Endobronchial ultrasound:
Indications, contraindications, and complications".)
●Staging – EBUS-TBNA can access upper and lower paratracheal posterior tracheal,
subcarinal and hilar lymph node stations (2R, 2L, 3p, 4R, 4L, 7, 10R, 10L,) (figure 1).
However, it cannot access lymph nodes in the prevascular, para-aortic,
paraesophageal, or pulmonary ligament regions of the mediastinum (3a, 5, 8, 9).
•Early studies suggested that EBUS-TBNA detected malignant lymph node
involvement with sensitivity and negative predictive values of 95 and 90 percent,
respectively [29-32]. A subsequent 2013 meta-analysis that included 2756
patients reported that the sensitivity of EBUS-TBNA was lower than that
previously reported (median 89 percent, range 46 to 97 percent) [2].
•Similarly, the negative predictive value of EBUS-TBNA is probably lower than
originally thought and wide-ranging across studies [2,39,42]. While one
systematic review reported that the negative predictive value of EBUS-TBNA
was 91 percent (60 to 97 percent), some studies report higher rates of false
negative results and non-diagnostic findings [2,39,42].
•The variability in sensitivity and negative predictive value of EBUS-TBNA may
reflect variable expertise, uncertainty related to small sample sizes, and
differences in the prevalence or extent of adenopathy and in protocols for
sample processing. Nonetheless, the variable estimates of observed diagnostic
accuracy may also reflect natural variation in general practice.
•Most published studies have used systematic lymph node sampling that
samples representative lymph nodes from each station (figure 1). The approach
taken should depend upon factors including the clinical suspicion of nodal
metastasis based on CT and PET imaging, the expectation of definitive surgical
management of the primary lesion, the utilization of surgical mediastinal lymph
node dissection as well as the expertise and resources of the management
team.
Comparatively, EBUS is superior to unguided bronchoscopic TBNA for staging
NSCLC [7-9,29,32,43]. Several studies that have directly compared EBUS-TBNA with
the original “gold standard”, cervical mediastinoscopy, suggest that EBUS-TBNA is at
least comparable if not superior to mediastinoscopy [6,39,40]:
•One prospective, single center, cross over trial in 66 patients with suspected
NSCLC showed that EBUS had a superior sensitivity to cervical
mediastinoscopy (87 versus 68 percent) [6]. However, this study was performed
in a center with high level expertise in interventional bronchoscopy which may
not be generalizable to other centers where this level of expertise is not
available. In addition, this study included a high rate of EBUS-TBNA in the
subcarinal region, a region that cannot be as easily accessed by
mediastinoscopy.
•Another prospective study of 153 patients with suspected NSCLC compared
EBUS-TBNA to cervical mediastinoscopy in patients who were potentially
resectable and in whom both procedures were performed prior to surgery [40].
The sensitivity, negative predictive value, and diagnostic accuracy were
comparable for EBUS-TBNA and mediastinoscopy (81 versus 79 percent, 91
versus 90 percent, and 93 versus 93 percent).
•Another retrospective review of patients at high risk of N2 disease (table 1) who
had undergone both procedures, reported that, compared to mediastinoscopy,
EBUS-TBNA had a higher rate of non-diagnostic findings (20 percent) resulting
in a negative predictive value of 72 percent (95% CI, 56-89%) [39].
Large prospective trials comparing EBUS-TBNA with mediastinoscopy are in
progress to further define the procedure’s sensitivity in larger, less highly-selected
patients.
The airway wall is well visualized with RP-EBUS [44-46]. This allows more accurate
determination of the distance from the carina to the proximal portion of the tumor
when the right or left main bronchi are involved. This distance is an essential
component of the T component of the TNM staging system (table 1) and will partially
determine whether the lesion is T2 or T3, which can impact the disease stage.
Convex probe (CP)-EBUS does not visualize the airway wall as well as radial probe
(RP)-EBUS; therefore, it should not be used for this purpose. (See "Overview of the
initial evaluation, diagnosis, and staging of patients with suspected lung
cancer" and "Tumor, node, metastasis (TNM) staging system for non-small cell lung
cancer".)

Limitations — The practice rate of performing EBUS-TBNA as the first diagnostic


procedure in suspected thoracic malignancy and mediastinal adenopathy appears to be
growing [10,47]. The major limitations of EBUS-TBNA are that sampled specimens can be
small in size, rates of operator proficiency are variable, and availability is institution-
specific. In addition, EBUS cannot access periaortic and posterior lymph node stations.
These limitations of EBUS-TBNA among others are listed below:

●Small specimen size – Compared to surgical biopsy, the amount of tissue obtained
by a single needle pass on EBUS-TBNA is small and may be insufficient for
architectural and molecular assessment unless additional steps are taken.
To overcome small specimen size, multiple passes (three to eight per site) with
ROSE and well defined institutional procedural protocols for processing, improve the
clinical utility of EBUS-TBNA [5,34-37,48-53]. The use of ROSE has also been
associated with a lower need for additional procedures (eg, transbronchial biopsy)
and fewer punctures during bronchoscopy [54]. Blood core clot, often obtained during
EBUS-TBNA, has also been shown to contain cellular sample that can be additive
diagnostically [55]. In general, only 140 to 400 ng of DNA are extracted from needle
aspirations [56,57]. Estimates of amounts of total DNA extracted from EBUS-TBNA
samples are approximately 280 ng which is usually adequate for molecular testing
[58-61]. Thus, with the use of multiple needle passes and ROSE by proficient
endoscopists enough tissue (up to eight needle aspirates per cell block) can be
aspirated to obtain material suitable for both cytologic diagnosis as well as additional
immunohistochemical and molecular testing [5,34-38,53].
Small tissue samples are inherent to all needle aspiration techniques but may also be
partly due to variable rates of expertise and minor technical differences within or
between institutions [5,34-37,62]. Many interventional pulmonologists use larger
needles in an attempt to aspirate more tissue. However, larger needle size (eg, 21-
gauge versus 22-gauge) has been shown in three of four studies not to have an
impact on sensitivity of EBUS-TBNA [34,37,38,63].
●Availability and operator experience – Not every facility has the equipment and
fully trained team of operators to perform EBUS-TBNA. Low operator experience may
also contribute to low sensitivity and inaccurate staging of suspected NSCLC.
Conversely, training which includes simulation practice may improve procedure
performance [64].
●Lymph node access – EBUS cannot access all stations in the mediastinum. For
example, prevascular, periaortic, paraesophageal, or pulmonary ligament lymph node
stations (3a, 5, 6, 8, 9) cannot be sampled with this modality (figure 1). The access to
the posterior and inferior lymph node stations by endoscopic-guided fine needle
aspiration (EUS-FNA) has led to the combined use of EBUS and EUS for staging
patients with suspected NSCLC. (See 'Combined modalities' below.)
●Complications – Complications of EBUS-TBNA (eg, pneumothorax, hemorrhage)
are uncommon (<1.5 percent) and discussed separately. (See "Transbronchial needle
aspiration", section on 'Complications'.)

Electromagnetic navigational bronchoscopy — Electromagnetic navigational


bronchoscopy-guided biopsies are an emerging modality available in select centers.
Electromagnetic navigation functions like a global positioning system that utilizes
previously obtained CT chest images (the map), fused with real-time, 3-dimensional
instrument position location (the coordinates). A bronchoscopically placed steerable probe
enables the operator to navigate to lesions identified on reconstructed virtual images,
including to parenchymal lung lesions that are not endoscopically visible. Choosing to use
EMN-TBNA is best dictated by the expertise and experience in the institution as well as
the unique circumstance of each patient. Further details regarding EMN and other image-
guided techniques for peripheral pulmonary lesions are provided separately. (See "Image-
guided bronchoscopy for biopsy of peripheral pulmonary lesions".)

EMN-TBNA is best used for accessing peripheral lesions, but can also access lymph node
stations 12 to 14 that are difficult to access by linear EBUS (figure 1).

●The sensitivity of EMN-TBNA in the diagnosis of peripheral lung lesions ranges from
44 to 75 percent, the details of which are discussed separately. (See "Image-guided
bronchoscopy for biopsy of peripheral pulmonary lesions", section on
'Electromagnetic navigation bronchoscopy (ENB)'.)
●The performance of EMN-TBNA for mediastinal staging NSCLC has been studied in
one prospective pilot study of 60 patients that suggested a sensitivity per procedure
of 100 percent for malignant mediastinal lymph node involvement. However, further
studies are required to validate its accuracy in staging NSCLC [65].

Transthoracic needle biopsy — Transthoracic needle biopsy involves passing a needle


percutaneously, under image guidance (usually computed tomography), to either aspirate
(TTNA) or biopsy (TTNB) tissue. The needle frequently traverses pleura and lung to either
aspirate or biopsy target tissue (lung or lymph node). The term TTNB in this section refers
to both aspirate and biopsy samples because most studies examining sensitivity do not
distinguish between these entities.

TTNB has a sensitivity of 74 to 90 percent for lung and mediastinal lesions suspected to
be malignant [2,4,11,13-16,66,67]. It can access most intraparenchymal lesions and
almost all mediastinal lymph nodal stations (figure 1). However, traversing the pleural
space and lung tissue is frequently unavoidable resulting in high rates of pneumothorax
(on average 10 to 15 percent), limiting the use of TTNB as a diagnostic and staging tool
[12,15,16,66]. As with all minimally invasive procedures, the relatively high false negative
rates associated with needle aspiration necessitate additional biopsy procedures when the
pretest probability of cancer is high but TTNB is non-diagnostic. (See 'Diagnostic and
staging accuracy' below.)

TTNB is often considered for peripheral lesions or when another procedure (eg, EBUS- or
bronchoscopic-TBNA) has failed to obtain diagnostic tissue. It is also considered when the
patient is at high risk for complications of video-assisted thorascopic surgery or cervical
mediastinoscopy. The high diagnostic accuracy of TTNB should be weighed against the
risk of pneumothorax and bleeding while considering patient preference. The risk benefit
ratio is increased in patients with concomitant emphysema, bullous disease, or chronic
respiratory failure. (See "Selection of modality for diagnosis and staging of patients with
suspected non-small cell lung cancer", section on 'Approach to the patient'.)

The value of TTNB for the diagnosis and staging of NSCLC is discussed here. The
indications and use of TTNB in the work-up of the solitary pulmonary nodule is discussed
separately. (See "Diagnostic evaluation and management of the solitary pulmonary
nodule", section on 'Transthoracic needle biopsy'.)

Diagnostic and staging accuracy — Major studies that have examined the sensitivity of
TTNB for NSCLC are summarized below.

●Diagnosis of primary tumor – In one meta-analysis of 46 studies, TTNB detected


malignancy with a sensitivity of 90 percent [2]. The diagnostic accuracy of TTNB for
malignancy is lower for smaller lesions (<3 cm) with reported sensitivity and specificity
of 67 and 100 percent respectively, and non-diagnostic results occurring in 36 percent
of cases [11]. While some studies suggest that percutaneous biopsy is not more
sensitive than aspiration for the diagnosis of NSCLC, it has the advantage of
providing the pathologist with larger amounts of material to distinguish benign from
malignant pathologies and to perform molecular testing [2]. (See "Diagnostic
evaluation and management of the solitary pulmonary nodule", section on
'Transthoracic needle biopsy'.)
●Staging – In practice, TTNB of the mediastinum is rarely performed unless there is
bulky anterior lymphadenopathy. Stations 2, 4, 5, and 6 can be accessed by an
anterior parasternal approach, and stations 4, 7, 8, and 9 by a posterior approach
(figure 1) [3]. Although some reports suggest that the sensitivity of TTNB for
suspected NSCLC is over 90 percent, studies are often inherently biased because the
study populations frequently had enlarged or bulky mediastinal disease
(ie, N2/N3 disease) which may falsely inflate the sensitivity [3,4,68-71]. Thus, these
rates may not necessarily apply to patients with small or normal-sized lymph nodes.

Compared to bronchoscopic procedures, the prevalence of pneumothorax following TTNB


is high (10 to 15 versus <1 percent) [12]. The risk is greatest when the lung is traversed
[16]. Higher rates have also been noted in older patients with COPD, in whom a higher risk
of respiratory failure requiring mechanical ventilation has also been reported [12]. The risk
of hemorrhage is low (<1 percent) but may be higher if patients are taking anticoagulants
or the target for biopsy is close to a vascular structure. Complications of TTNB are
discussed separately. (See "Diagnostic evaluation and management of the solitary
pulmonary nodule", section on 'Transthoracic needle biopsy'.)

Transesophageal endoscopic ultrasound — EUS-FNA is similar to EBUS-TBNA but


may use either a larger gastrointestinal endoscope that is inserted into the esophagus or
the smaller ultrasound bronchoscope (EUS-B-FNA). EUS-FNA was originally developed
as a diagnostic and staging modality for gastric and esophageal cancers. However, it is a
potentially useful modality for the diagnosis and staging of lung cancer, particularly, in
those with mass lesions that appear to involve the posterior and inferior mediastinum as
well as the left paratracheal lymph nodes.

EUS-FNA is a sensitive staging tool for suspected NSCLC involvement in subcarinal (3, 7,
8, 9) and paratracheal nodes (2, 4) (figure 1 and figure 2) [4]. Case series also suggest a
potential role for EUS-FNA in suspected M1b disease (eg, adrenal gland or liver) [72-74]. It
has also been used to assess direct tumor invasion of the mediastinum (T4). EUS-FNA
can be used as an additive or alternative tool to other modalities (eg, EBUS-TBNA). EUS-
FNA requires experienced, skilled endoscopists. The imperfect sensitivity associated with
fine needle aspiration techniques necessitates additional biopsy, usually mediastinoscopy,
when testing is negative for cancer. (See 'Diagnostic and staging accuracy' below
and 'Sampling metastatic disease' below and "Selection of modality for diagnosis and
staging of patients with suspected non-small cell lung cancer", section on 'Approach to the
patient' and 'Combined modalities' below.)

The value of EUS-FNA for the diagnosis and staging of NSCLC is discussed here. The
general indications and use of EUS-FNA are discussed separately. (See "Endoscopic
ultrasound-guided sampling of the mediastinum: Technique, indications, contraindications,
and complications".)

Diagnostic and staging accuracy — Major studies that have examined the diagnostic
accuracy of EUS-FNA for NSCLC are summarized below.

●Diagnosis of primary tumor – EUS-FNA can access tumors that invade the
posterior and inferior, and occasionally, superior mediastinum that are close to the
esophagus. Studies demonstrating its efficacy diagnostically compared to other
modalities are lacking. In a series of 35 patients suspected of having lung cancer
where bronchoscopy was nondiagnostic, EUS-FNA detected lung cancer in 25 of 26
patients and correctly distinguished benign from malignant disease with sensitivity
and negative predictive values of 96 and 90 percent, respectively [75]. Other studies
have demonstrated similar results [76].
●Staging – The main use of EUS-FNA is to access paratracheal (2, 4) and posterior
subcarinal lymph nodes (3, 7, 8, and 9) (figure 1) [77]. Its ability to access station 5 is
dependent on specific anatomic relationships as well as the size of the target lymph
node.
A randomized trial of suspected lung cancer patients with 2L, 3, 4L, 7
lymphadenopathy or lung masses adjacent to the mediastinum compared the
diagnostic rate of EUS-FNA with EBUS-TBNA. EUS-FNA established a specific
diagnosis in 48/55 patients (87 percent) compared to 50/55 patients (91 percent) in
the EBUS-TBNA group, a difference that was not statistically significant. Procedure
time was shorter with EUS-FNA and additional equipment was not necessary since
both the EUS and EBUS procedures were performed using an ultrasound
bronchoscope [78].
One 2013 meta-analysis of 26 studies showed pooled sensitivity and negative
predictive values of 89 and 86 percent, respectively [4]. However, the wide range of
sensitivity (45 to 100 percent) and negative predictive values (68 to 100 percent)
suggest high variability among centers and/or heterogeneous patient samples. Three
to five passes per nodal site is suggested for adequate sampling [77].
Case series and observational studies also suggest that EUS-FNA can diagnose M1b
disease due to its unique ability to access retroperitoneal and celiac nodes, the left
lobe of the liver, and adrenal glands [72-75,79-85]. However, its diagnostic accuracy
in this context for staging NSCLC has not been formally evaluated.
T4 disease, which is for the most part inoperable, is defined as tumor of any size that
invades the mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve,
esophagus, vertebral body, and carina (table 1). The preoperative identification of T4
disease can potentially result in the avoidance of futile thoracotomies. Although many
case series of EUS-FNA have included patients with T4 level of disease, only one
study examined its performance for this indication [86]. The high false positive (30
percent) and low positive predictive value (70 percent) in that study suggested that it
was not sufficiently accurate to confirm the presence of T4 disease.

Additional trials are required to compare the performance of EUS-FNA to all staging tools,
including cervical mediastinoscopy. Smaller comparative studies are described below:

●One prospective, single center study of 104 patients reported that EUS-FNA
diagnosed metastatic NSCLC in posterior lymph nodes with a sensitivity and negative
predictive value of 93 and 94 percent, respectively [79].
●In a single-center trial of 60 patients with NSCLC, compared to cervical
mediastinoscopy, EUS-FNA was able to detect lymph node involvement with higher
sensitivity (96 versus 24 percent) [87].
●In a small study of 35 patients with NSCLC, EUS-FNA identified occult N2 or N3
disease, (not previously identified by cervical mediastinoscopy), in 37 percent of
cases [88]. Most of the occult disease that was identified by EUS-FNA and missed by
cervical mediastinoscopy was in the subcarinal region (7) [88].

The major limitation of EUS-FNA is its inability to simultaneously visualize the airway and
access the primary tumor mass, although it is often performed in tandem with
bronchoscopy and EBUS-FNA. As with most needle aspirative techniques, the imperfect
sensitivity often necessitates the use of a second staging procedure, usually
mediastinoscopy should the testing be negative for cancer. In addition, it requires a skilled
endoscopist experienced in its use.

Combined modalities — Combining modalities maximizes access to the mediastinum to


improve the sensitivity of staging. More sensitive staging identifies occult disease so that
multimodality treatment can be considered. The most common staging modalities that are
combined are endobronchial ultrasound-guided transbronchial needle aspiration plus
endoscopic ultrasound-guided fine needle aspiration (EBUS-TBNA plus EUS-FNA). This is
colloquially referred to as “medical mediastinoscopy” or combined ultrasound (CUS). Less
common are the combinations of EUS-FNA plus cervical mediastinoscopy and CUS plus
cervical mediastinoscopy.

●EBUS-TBNA plus EUS-FNA, can access almost all lymph node stations in the
mediastinum (2, 3, 4, 7, 8, 9, 10, 11, +/- 12) (figure 1). Both procedures overlap for
many mediastinal lymph nodal stations (2, 3, 4, and 7) but are complimentary for
stations 8, 9 (EUS), 10, 11, +/- 12 (EBUS).
●EUS-FNA plus cervical mediastinoscopy can access more mediastinal lymph
node stations than either procedure alone (1, 2, 3, 4, 7, 8, 9) (figure 1). Both
procedures overlap for reaching lymph nodal stations 2, 3, 4, and 7, but EUS-FNA
offers the additional ability to access stations 8 and 9. Combined modalities that
utilize EUS-FNA have the advantage of also accessing potential M1b disease in the
retroperitoneal, celiac lymph nodes as well as the liver and adrenal glands [72-
74,77].
●CUS plus cervical mediastinoscopy can access almost all lymph node stations in
the mediastinum (1, 2, 3, 4, 7, 8, 9, 10, 11, +/- 12) with overlap for stations 1, 2, 4,
and 7 (figure 1).

The combined approaches are promising but their clinical utility in general practice has not
been precisely defined. For most patients, the identification of nodal tumor metastasis in
N2 or N3 stations using a single technique makes the second procedure unnecessary. For
this reason combined modalities are not routinely used for staging NSCLC unless the
initial procedure is negative but the clinical probability of nodal metastasis remains
unacceptably elevated. Routine use of combined modality for staging should be reserved
for select cases, best dictated by the expertise and clinical protocols in specific institutions
where they are available.

The sensitivity of combined modalities pertinent to staging NSCLC is discussed here. The
value of individual techniques for the diagnosis and staging of NSCLC are discussed
separately. (See 'Endobronchial ultrasound' above and 'Transesophageal endoscopic
ultrasound' above.)

Diagnostic and staging accuracy — Major studies that have examined the diagnostic
accuracy of combined modalities for NSCLC are summarized below [21,80,89-95].

●EBUS-TBNA plus EUS-FNA – One multicenter randomized study of 241 patients


with suspected N2/N3 NSCLC reported that, compared with cervical mediastinoscopy
alone, CUS plus selective mediastinoscopy (when CUS results were negative) had a
higher sensitivity (94 versus 79 percent) and resulted in fewer unnecessary
thoracotomies (7 versus 18 percent) [89]. However, a post-hoc analysis of long-term
outcomes from this trial reported no survival advantage among those staged using
CUS plus selective surgical staging compared to those who underwent surgical
staging alone [96]. Another randomized trial of 160 of histologically confirmed or
strongly suspected potentially operable NSCLC found that adding EBUS-TBNA to
EUS-FNA increased the sensitivity (92 versus 60 percent) and diagnostic accuracy
(97 versus 87 percent) when compared to EUS-FNA alone [97].
Although these modalities are complimentary, the sensitivity appears to be reduced in
patients with normal-sized lymph nodes. Two prospective studies of CUS in patients
with enlarged (138 patients) and normal-sized (120 patients) lymph nodes,
respectively, reported that, compared with either procedure alone, CUS had higher
sensitivity for staging NSCLC (93 percent for enlarged nodes versus 68 percent for
normal-sized nodes) [21,91]. The negative predictive values were unaffected by node
size (97 and 91 percent respectively).
One retrospective study of patients with NSCLC compared the staging performance
of combined EBUS/EUS with an aggressive surgical staging modality, transcervical
extended mediastinal lymphadenectomy (TEMLA) [98]. Although CUS was not as
sensitive as TEMLA (96 versus 88 percent), it was a safer procedure. This study is
discussed in detail separately. (See 'Transcervical extended mediastinal
lymphadenectomy' below.)
Bronchoscopists and thoracic surgeons may introduce EBUS bronchoscopes into the
esophagus during the same procedure as bronchoscopic EBUS-TBNA and achieve
more accurate mediastinal node sampling and greater diagnostic success [78,92,93].
This approach has been termed EUS with bronchoscope-guided needle aspirate
(EBUS-B-NA or EUS-B-FNA). EBUS-B-NA was reported to have sensitivity and
negative predictive values of 96 and 96 percent, respectively [93].
●EUS-FNA plus cervical mediastinoscopy – There is a paucity of data regarding
the staging accuracy of this combination. In one multicenter study of 107 patients with
suspected NSCLC, cervical mediastinoscopy plus EUS-FNA detected more
metastatic disease than either mediastinoscopy or EUS-FNA alone (36 versus 20 and
28 percent) and resulted in the avoidance of unnecessary thoracotomies in 16
percent of cases [80].
●EBUS-TBNA plus EUS-FNA plus cervical mediastinoscopy – One multicenter
prospective study that primarily examined the diagnostic accuracy of CUS, reported a
sensitivity of 94 percent for CUS plus cervical mediastinoscopy [89].

Together, these and other studies suggest that combined approaches have a high
sensitivity for staging mediastinal NSCLC, especially when disease is suspected by CT
scan or PET. However, other clinical priorities and objectives such as reducing the number
of subsequent required surgical staging procedures (see 'Surgical staging
procedures' below) have less supporting evidence. Based on available evidence, clinical
practice guidelines from the European Society of Gastrointestinal Endoscopy endorse an
approach of combined EBUS-TBNA and EUS-FNA or EUS-B-FNA over either test alone
[18]. Larger randomized studies are required to determine which cases are most likely to
benefit from a combined approach and to specify which combination is preferred for
staging patients with NSCLC.

The limitations of EBUS-TBNA, EUS-FNA, and the complications of cervical


mediastinoscopy are discussed separately. (See 'Limitations' above and 'Endobronchial
ultrasound' above and "Surgical evaluation of mediastinal lymphadenopathy", section on
'Complications of mediastinoscopy'.)

SURGICAL STAGING PROCEDURES

Overview — Standard cervical mediastinoscopy (SCM), video-assisted thoracoscopic


surgery (VATS) and anterior mediastinotomy (Chamberlain procedure) are the three most
common surgical modalities used for staging non-small cell lung cancer (NSCLC). Other
surgical procedures (extended cervical mediastinoscopy [ECM], video-assisted
mediastinal lymphadenectomy [VAMLA], transcervical extended mediastinal
lymphadenectomy [TEMLA]) are not as well validated and experience is more limited.
Selecting one of these surgical procedures relies on physician judgment and knowledge of
their diagnostic accuracy for the target lesion(s), in the context of operator proficiency,
patient safety and eventual goals for treatment. (See "Selection of modality for diagnosis
and staging of patients with suspected non-small cell lung cancer", section on 'Approach to
the patient'.)

Guidelines issued by the American College of Chest Physicians (ACCP), European


Society of Thoracic Surgeons (ESTS), and International Association for the Study of Lung
cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) have
incorporated the use of invasive procedures in the diagnostic work-up of NSCLC.
Evidence for these surgical procedures is largely derived from older retrospective case
series and small studies that do not compare performance with thoracotomy.
(See "Selection of modality for diagnosis and staging of patients with suspected non-small
cell lung cancer", section on 'Approach to the patient'.)

In general, the following applies:

●SCM is a sensitive staging procedure when sampling nodal stations easily accessed
by this approach (1, 2, 3, 4, anterior 7, 10) (figure 1) [99-101]. Use of a video
mediastinoscope and systematic lymph node sampling may enhance sensitivity.
Although it is the historical gold standard for staging the mediastinum, disease will not
be detected in lymph nodes stations that are not accessed by this modality: subaortic
(5), para-aortic (6), inferior (8, 9), lobar/interlobar (11 to 14), and, occasionally, the
posterior subcarinal (7) stations. SCM can be used as a staging tool for NSCLC when
other staging modalities do not identify cancer, or are not available (eg, endobronchial
ultrasound). (See "Selection of modality for diagnosis and staging of patients with
suspected non-small cell lung cancer", section on 'Approach to the
patient' and 'Standard cervical mediastinoscopy' below.)
●VATS is an accurate modality for evaluating the extent of invasion (chest wall,
mediastinal) by the primary tumor (T). VATS can also sample mediastinal lymph
nodes (4, 5, 6, 7, 8, 9, 10 to 14) but only those on the affected side (N), unless a
bilateral thoracotomy is performed (figure 1). Bilateral thoracotomy is not typically
performed due to the increased mortality and morbidity associated with this
procedure. VATS is also useful for detecting pleural involvement (M1a) (table 1).
VATS is typically used for tissue diagnosis when there is a suspicious peripheral
lesion that is amenable to wedge resection and there is no computed tomographic
(CT) and/or positron emission (PET) evidence for extrathoracic or mediastinal nodal
metastasis. VATS may also be used when percutaneous or endoscopic procedures
cannot access the primary tumor or are non-diagnostic [102-105]. (See "Selection of
modality for diagnosis and staging of patients with suspected non-small cell lung
cancer", section on 'Approach to the patient' and 'Video-assisted thoracic
surgery'below.)
●Left anterior mediastinotomy (Chamberlain procedure) is often the only option for
sampling the subaortic (aortopulmonary window) (5) and para-aortic (6) lymph node
stations (although some endoscopic ultrasound techniques can reach the AP
window). (See "Selection of modality for diagnosis and staging of patients with
suspected non-small cell lung cancer", section on 'Approach to the
patient' and 'Anterior mediastinotomy (Chamberlain procedure)' below.)
●ECM [106-108], VAMLA [109,110], and TEMLA [98,111-113], are surgical
procedures that allow more extensive mediastinal sampling. Although they are
sensitive procedures for detecting occult mediastinal disease, their use is limited
because they are not widely available and are associated with increased morbidity
when compared with SCM (eg, recurrent laryngeal nerve paralysis). (See "Selection
of modality for diagnosis and staging of patients with suspected non-small cell lung
cancer", section on 'Approach to the patient' and 'Extended cervical
mediastinoscopy' below and 'Video-assisted mediastinal lymphadenectomy' below
and 'Transcervical extended mediastinal lymphadenectomy'below.)

The evidence for each invasive procedure pertinent to its diagnostic and staging accuracy
for NSCLC is discussed in this section. The surgical management of mediastinal
lymphadenopathy and procedural aspects of VATS are discussed separately.
(See "Surgical evaluation of mediastinal lymphadenopathy" and "Overview of minimally
invasive thoracic surgery".)

Standard cervical mediastinoscopy — SCM is a surgical procedure that accesses the


mediastinum and as such is primarily a mediastinal staging tool. Its major advantage,
compared to minimally invasive tools (eg, endobronchial ultrasound), is direct visualization
of nodes for sampling and/or dissection. In addition, use of biopsy forceps provides
sufficient amounts of material for diagnosis and immunohistochemical and molecular
analysis.
SCM is the historical gold standard for mediastinal lymph node staging of NSCLC with
reported sensitivities of 78 to 90 percent [4,99-101]. Traditionally, this procedure has not
used video-assistance for sampling lymph nodes and has sampled nodes by biopsy
forceps. Much of the evidence describing its performance as a staging modality relates to
this particular approach. However, there has been a paradigm shift in the use of a video-
assisted mediastinoscope to access the mediastinum. Videomediastinoscopy improves
operator visualization, so that systematic lymph node sampling (by biopsy forceps) can be
performed. When a video mediastinoscope is used to dissect and remove an entire lymph
node, this is known as VAMLA which is discussed below. (See 'Video-assisted mediastinal
lymphadenectomy' below.)

SCM can easily access pretracheal (1, 3), paratracheal (2R, 2L, 4R, 4L), anterior
subcarinal (7) and occasionally hilar (10) nodes (figure 1). It is not able to sample subaortic
(5) or para-aortic (6), inferior (8, 9), posterior subcarinal (7), or lobar/interlobar (11 to 14)
stations. Use of the video mediastinoscope can extend access to the posterior subcarinal
nodes (station 7). SCM is best used to sample lymph nodes in these selected stations,
particularly when other staging modalities have failed or are not available.

Evidence supporting the role of SCM in staging the mediastinum in patients with
suspected NSCLC is reviewed here. The technical aspects, complications of
mediastinoscopy, and comparative studies with other staging modalities are discussed
separately. (See "Surgical evaluation of mediastinal lymphadenopathy", section on
'Complications of mediastinoscopy'and 'Diagnostic and staging accuracy' above
and 'Endobronchial ultrasound' above and 'Diagnostic and staging accuracy' above
and 'Diagnostic and staging accuracy' above.)

Staging accuracy — The largest meta-analysis evaluating the accuracy of SCM pooled
data from 9267 patients with suspected NSCLC who underwent SCM for staging the
mediastinum [4]. This analysis reported that SCM had a median sensitivity and negative
predictive value of 78 and 91 percent, respectively. However, the sensitivity is wide
ranging (32 to 92 percent). Additional techniques that may enhance the accuracy of SCM
include:

●Extensive sampling and complete lymph node dissection may increase the accuracy
of staging with a reported sensitivity of 90 percent [100].
●Systematic lymph node sampling is when the operator systematically samples at
least one node from each accessible lymph node station (typically up to five stations).
Compared to selective node sampling where lymph nodes are randomly selected by
the operator, systematic lymph node sampling may result in increased sensitivity (up
to 89 percent) [3,4,100,101,114,115].

There are relatively few comparative studies of endobronchial ultrasound-guided


transbronchial needle aspiration or transesophageal endoscopic ultrasound-guided fine
needle aspiration, with surgical modalities. (See 'Diagnostic and staging accuracy' above
and 'Endobronchial ultrasound' above and 'Combined modalities' above.)

●A comparative study of 127 patients who completed both endobronchial ultrasound-


transbronchial needle aspiration (EBUS-TBNA) followed by mediastinoscopy followed
by open surgical resection and complete lymph node dissection for all patients with
negative initial results demonstrated a sensitivity, specificity, and accuracy of EBUS-
TBNA of 88, 100, and 92.9 percent compared to 81, 100, and 89.0 percent for
mediastinoscopy respectively [41].
●In a highly selected group of 159 patients who underwent EBUS-TBNA and cervical
mediastinoscopy, the sensitivity of both procedures was comparable (81 versus 79
percent) and there were no significant differences between the negative predictive
value and overall diagnostic accuracy of the procedures (93 versus 93 percent) [40].

One limitation of many of these studies is that they are small. In addition, up to half of
cases that are reported as falsely negative are due to the inability of SCM to access
certain lymph node stations [116-121]. The variable sensitivity may also be due to poor
adherence to guidelines for the performance of SCM [122,123]. One study of four hospitals
showed that guidelines for the use of mediastinoscopy in patients with suspected lung
cancer, between the years of 1993 and 1999, were adequately followed in only two-thirds
of cases [123]. Approximately, 17 percent of patients appeared to have
unforeseen N2/3 disease, resulting in 18 percent of cases in whom thoracotomy could
have been prevented had guidelines been followed [123]. However, whether this is
reflective of practice in most institutions is not known.

Cervical mediastinoscopy is a surgical procedure. Potential complications include


hemorrhage and viscus perforation. The complications of cervical mediastinoscopy are
discussed separately. (See "Surgical evaluation of mediastinal lymphadenopathy", section
on 'Complications of mediastinoscopy'.)

Video-assisted thoracic surgery — VATS is typically used in the diagnosis and staging
of suspected NSCLC when alternative procedures cannot access the tumor or are
nondiagnostic. Alternatively, VATS can be used as a primary diagnostic modality when the
probability of cancer is high and the tumor is easily accessible to wedge resection.

The main advantage of VATS is the direct visualization of and extensive access to the
lung, thoracic cavity, and all mediastinal structures (eg, lymph nodes, vessels, and
esophagus). This allows concurrent access to both the primary tumor and to almost all
lymph nodes in the ipsilateral mediastinum (4, 5, 6, 7, 8, 9, 10 to 14) (figure 1). Thus,
VATS can easily evaluate the extent of invasion by the primary tumor (T), especially that of
the chest wall and mediastinal structures (T), malignant mediastinal lymph node
involvement (N), and pleural involvement (M1a) (table 1) [102,103]. This approach permits
rapid intraoperative diagnosis, staging and occasionally therapy, thereby shortening the
time needed to diagnose and stage NSCLC.
VATS is a major surgical procedure requiring general anesthesia. Reaching the right side
of the mediastinum with VATS is technically easier than reaching the left, particularly, the
left paratracheal nodes (4L). In addition, although access to mediastinal node stations is
extensive, typically only one side can be sampled. Occult disease on the contralateral side
can be missed unless bilateral VATS is performed. However, bilateral VATS is not
routinely performed for this indication because it greatly increases the morbidity and
mortality of the surgery. The complications and procedural aspects of VATS and surgical
management of mediastinal lymphadenopathy are discussed separately. (See "Surgical
evaluation of mediastinal lymphadenopathy" and "Overview of minimally invasive thoracic
surgery".)

Staging accuracy — One 2013 meta-analysis of four small studies reported a median
sensitivity of 99 percent (range 58 to 100 percent) and negative predictive value of 96
percent (range 88 to 100 percent) [4]. However, of the four studies included in this meta-
analysis, the study that reported the lowest sensitivity (58 percent) was a multicenter
study. The variability of results and low sensitivity seen in the multicenter study suggest
wide differences in the accuracy of VATS for staging NSCLC or heterogeneity of patient
populations. There are no studies that directly compare the diagnostic or staging accuracy
of VATS to other staging modalities.

VATS has been shown to have value in the evaluation of T4 lesions (eg, large bulky
tumors infiltrating the mediastinum) [104,124,125]. T4 lesions for the most part represent
stage III disease that is inoperable. Further staging by VATS in this setting may either
downstage the disease such that the patient may become a candidate for surgery or
upstage it when unexpected metastatic disease of the pleura is found [103,104,125-128].
The best evidence to support this comes from one prospective study of 64 patients with
NSCLC [104]. All patients were thought be ineligible for surgery based on their computed
tomography (CT) scan characteristics (eg, pleural fluid, T4 lesions). Among the 30 patients
with mediastinal infiltration on CT scan (T4 disease), nine (30 percent) were down-staged
to stage IIIA (potentially operable) and two (7 percent) to stage II (operable disease). In
addition, this study and others have reported that VATS can upstage the disease to stage
IV by the identification of unsuspected pleural disease in 6 to 60 percent of cases
[103,104].

VATS is frequently used to perform lobectomies in patients with peripheral nodules and
suspected N0 or N1 disease. For accurate staging, these patients are routinely subjected
to mediastinal lymph node sampling intraoperatively. Two controversial issues arise
intraoperatively:

●Unexpected occult N2 disease (ie, stage IIIA) – Typically, surgery is not offered as
first line therapy to patients with known stage IIIA NSCLC. However, if occult N2
disease is discovered intraoperatively, most surgeons will proceed with resection if
the diseased node can be fully resected and adjuvant chemotherapy is subsequently
offered [129]. (See "Management of stage I and stage II non-small cell lung cancer",
section on 'Video-assisted thoracoscopic surgery'.)
●Extent of lymph node dissection – It is unknown whether lymph nodes should be
sampled systematically or fully dissected intraoperatively. One randomized study of
1111 patients with NSCLC who had negative preoperative sampling of lymph nodes
who also underwent VATS suggested that, compared with lymph node sampling,
lymph node dissection discovered more occult N2 disease (4 versus 1 percent) [130].
However, dissection was not associated with a survival advantage (median survival
8.5 years in both groups) or decrease in local or regional recurrence.
(See "Management of stage I and stage II non-small cell lung cancer", section on
'Mediastinal lymph node dissection'.)

Anterior mediastinotomy (Chamberlain procedure) — A left anterior mediastinotomy


(Chamberlain procedure) is a surgical procedure that requires general anesthesia. The
incision is made over the left second or third intercostal space to access lymph nodes in
stations 5 and 6 (figure 1). Due to lymphatic drainage patterns, cancers of the left upper
lobe preferentially drain to these regions (figure 1). However, these regions are
traditionally difficult to access and cannot be reached by minimally invasive techniques or
by standard cervical mediastinoscopy.

A left anterior mediastinotomy is the traditional surgical procedure used to stage left-sided
cancer when suspected nodes are located in stations 5 and 6. It has the added advantage
of accessing left upper lobe tumors for concurrent resection, if there is no evidence of
nodal or distant disease.

Because it is often the only option when suspicious lymph nodes are identified in this
region, there is a paucity of data regarding its diagnostic accuracy. Nonetheless, one
meta-analysis of four small studies reported a sensitivity and negative predictive value of
71 and 91 percent respectively [131]. No studies have directly compared its performance
to ECM, VATS), or to endoscopic ultrasound-guided fine needle aspiration which can
occasionally reach this region. (See 'Extended cervical mediastinoscopy' below
and 'Video-assisted mediastinal lymphadenectomy' below.)

Extended cervical mediastinoscopy — ECM accesses the mediastinum and as such is


primarily a mediastinal staging tool. It extends the sampling territory of standard cervical
mediastinoscopy (1, 2, 3, 4, 7, 10) to the subaortic (5) and para-aortic (6) lymph node
stations (figure 1). Stations 5 and 6 cannot be reached using standard cervical
mediastinoscopy. Traditionally, accessing nodes in these stations requires surgical
dissection via a left anterior mediastinotomy (Chamberlain procedure). Thus, the main
advantage of ECM is that when access to stations 5 and 6 is desired to stage tumors of
the left upper lobe, it avoids the surgical risk associated with a left anterior
mediastinoscopy. The main disadvantage of ECM is that its performance is limited to the
few centers with expertise for it as a staging modality.
Two case series of 377 patients with suspected cancer of the left lung compared the
staging accuracy of routine and selective ECM [106,108]. ECM was considered routine
when it was performed in every patient with suspected NSCLC, and considered selective
when biopsy was only performed in patients with suspicious nodes identified by CT or
positron emission tomography (PET). Compared to routine ECM, selective ECM had
higher sensitivity (65 to 75 versus 44 to 45 percent) but a similar negative predictive value
(95 versus 94 percent), although these results may be explained by spectrum bias (eg,
lymph nodes were larger and/or more likely to be involved in the ECM group). The
complication rate was 2 percent and included mediastinitis, ventricular fibrillation, and
wound infection.

Another retrospective analysis of 55 patients with NSCLC reported that, compared


with PET/CT, ECM had a higher sensitivity (69 versus 53 percent), and negative predictive
value (89 versus 83 percent) [107]. ECM is not widely available and requires further study.

Video-assisted mediastinal lymphadenectomy — Video-assisted mediastinoscopes


offer improved visualization and extensive sampling of mediastinal lymph nodes for
complete removal (lymphadenectomy) (figure 1). VAMLA can sample the same lymph
node stations as standard cervical mediastinoscopy (1, 2, 3, 4, anterior 7, and 8). In
addition, they provide better access to the posterior region of the subcarinal lymph node
station (7).

●One single-center study of 144 patients reported a sensitivity for VAMLA of 100
percent [109].
●A case series of 156 patients reported that, compared to standard mediastinoscopy,
VAMLA was superior with higher sensitivity (94 versus 64 percent) and negative
predictive value (96 versus 84 percent) [110].

In both studies, the complication rate was high (3 to 6 percent) with a higher than usual
rate of recurrent laryngeal nerve injury (4 to 5 percent) [109,110].

VAMLA is not widely available and requires further study.

Transcervical extended mediastinal lymphadenectomy — TEMLA uses a sternal


retractor to widen surgical access to the mediastinum for open (not endoscopic or video-
assisted) dissection. This open access approach allows sampling of stations 1, 2, 3, 4, 5,
6, 7, and 8 (figure 1).

One prospective study of 81 patients showed sensitivity and negative predictive values of
90 and 95 percent, respectively [111]. Compared to standard cervical mediastinoscopy, a
prospective randomized study of 41 patients reported that TEMLA had higher sensitivity
(100 versus 38 percent) and negative predictive values (100 versus 67 percent) [112].
However, a major caveat of this study was its early termination due to the unusually high
false negative rate in the cervical mediastinoscopy group. The recurrent laryngeal nerve
palsy rate appears lower than for VAMLA, at 2 percent with less than 1 percent having
permanent damage [113].

One retrospective study of patients with NSCLC compared the staging performance of
endoscopic modalities (EBUS-TBNA, EUS-FNA, and combined EBUS/EUS) with TEMLA
[98]. In the 276 patients where TEMLA was preceded by negative endoscopic sampling for
primary staging, TEMLA discovered occult disease in 50 patients and deferred surgery in
three patients. Compared to endoscopic modalities, TEMLA had higher sensitivity (96
versus 88 percent) and negative predictive values (99 and 83 percent, respectively).
However, the increased sensitivity of TEMLA occurred at the expense of increased
morbidity (7.2 versus 6.4 percent), mostly recurrent laryngeal nerve palsy (3 versus 0
percent), and mortality (0.4 versus 0 percent). (See 'Combined modalities' above.)

Additional large randomized multicenter trials will be needed to validate TEMLA further
before it can be routinely used as a staging procedure for NSCLC.

SAMPLING METASTATIC DISEASE — Sites of distant metastases in NSCLC are


classified into intrathoracic and extrathoracic metastases. Common intrathoracic sites are
the pleura, contralateral lung, and pericardium (stage IV; M1a). Common extrathoracic
sites are the liver, adrenal gland, brain and bone (stage IV; M1b) (table 1). An important
exception is that NSCLC in a supraclavicular node is considered to be N3 (stage IIIB)
disease despite the fact that it is not a mediastinal node. Tissue confirmation of suspected
disease at any of these sites indicates NSCLC that is inoperable.

Discovery of sites involved with metastatic NSCLC are often prompted by clinical
assessment and/or imaging. The imaging modalities should direct site selection for tissue
confirmation of metastatic NSCLC. Typically, consideration is given to sampling metastatic
sites first rather than sampling the suspected primary lesion. This is especially important
for solitary metastases when tissue diagnosis is essential to establish clear evidence of
inoperable NSCLC. When there is evidence on imaging to support a high probability of
multiple metastases, the site of tissue biopsy is selected based upon the ease of access
and risks of the procedure.

The accuracy of specific procedures used to biopsy suspected metastases from NSCLC is
discussed here. Imaging and approach to tissue biopsy of potential metastatic disease are
discussed separately. (See "Overview of the initial evaluation, diagnosis, and staging of
patients with suspected lung cancer", section on 'Imaging metastatic
disease' and "Selection of modality for diagnosis and staging of patients with suspected
non-small cell lung cancer", section on 'Suspected stage IV or supraclavicular node
disease'.)

Intrathoracic — Metastatic NSCLC in the pleura, contralateral lung, or pericardium


constitutes stage M1a disease, which is inoperable (table 1).
●Pleura – Two common clinical presentations of pleural disease are: metastases
associated with pleural effusion or multiple pleural-based nodules, and direct
extension of the primary tumor to the pleura or chest wall. Direct extension of the
primary tumor into the visceral or parietal pleura needs to be distinguished from
metastatic NSCLC of the pleural space that is separate from the primary tumor.
Primary tumor that infiltrates visceral or parietal pleura is staged as a T2 or T3 lesion,
respectively (table 1). T2/3 lesions are potentially operable. In contrast, metastatic
NSCLC discovered as separate solid lesion(s) in the visceral or parietal pleura or as
malignant cells in an effusion represent M1a disease that is inoperable. The
diagnostic accuracy of sampling pleural lesions is discussed below. (See 'Suspected
pleural metastases' below.)
●Lung – Solitary nodules or masses in the contralateral lung require histologic
evaluation to distinguish metastasis from a synchronous primary malignant tumor or
an unrelated non-malignant diagnosis. NSCLC with a histologically similar
contralateral solitary lesion is classified as M1a disease. The diagnostic accuracy for
sampling nodules or masses suspicious for metastatic disease in the contralateral
lung is the same as sampling a primary tumor or a solitary pulmonary nodule, which
are discussed separately. (See 'Minimally invasive procedures' above and 'Video-
assisted thoracic surgery' above and "Diagnostic evaluation and management of the
solitary pulmonary nodule", section on 'Nonsurgical biopsy' and "Diagnostic
evaluation and management of the solitary pulmonary nodule", section on 'Surgical
biopsy'.)
●Pericardium – Direct extension of the tumor to the pericardium constitutes a T4
lesion (table 1). A pericardial effusion due to NSCLC is M1a disease. Most cases of
T4 pericardial NSCLC and all cases of pericardial effusions due to NSCLC are
considered inoperable. Sampling pericardial fluid or tissue is discussed separately.
(See "Pericardial disease associated with malignancy".)

Suspected pleural metastases — Pleural effusions or pleural abnormalities


(solid masses/nodule/thickening) suspicious for metastatic disease are present on imaging
in up to one-third of patients with NSCLC at the time of presentation [132]. Although some
effusions may be benign (eg, due to post-obstructive pneumonitis or atelectasis), the
majority are malignant and establish a diagnosis of M1a disease (table 1). Sampling the
pleural space (effusions or solid lesions) is essential in all patients with suspected pleural
involvement. Thoracentesis is typically performed first for evaluation of pleural effusions.
Pleural biopsy (image-guided or thoracoscopic) is often performed when pleural fluid
cytology is negative or to obtain tissue from a solid pleural lesion.

The diagnostic accuracy of thoracentesis and pleural biopsy techniques for NSCLC are
discussed here. The imaging modalities (ultrasound, computed tomography [CT], positron
emission tomography [PET]) and approach to suspected pleural disease in patients with
NSCLC are discussed separately. (See "Selection of modality for diagnosis and staging of
patients with suspected non-small cell lung cancer", section on 'Suspected stage IV or
supraclavicular node disease' and "Overview of the initial evaluation, diagnosis, and
staging of patients with suspected lung cancer", section on 'Radiographic
staging' and "Imaging of pleural effusions in adults" and "Imaging of pleural plaques,
thickening, and tumors".)

Thoracentesis — Thoracentesis removes fluid from the pleural space for cytologic
analysis. The diagnostic accuracy of pleural fluid cytology is derived from older, poorly
controlled, small studies. In addition, many of these studies report the diagnostic yield in
the setting of benign and malignant disease of varied histologic types [133-139].
Nonetheless, one meta-analysis from seven studies reported a mean sensitivity for the
diagnosis of malignancy of 72 percent (49 to 71 percent) [2]. It is the imperfect sensitivity
of thoracentesis that necessitates pleural biopsy when fluid cytology is negative.
(See "Diagnostic thoracentesis" and "Diagnostic evaluation of a pleural effusion in adults:
Initial testing" and "Overview of the risk factors, pathology, and clinical manifestations of
lung cancer", section on 'Pleural involvement' and "Selection of modality for diagnosis and
staging of patients with suspected non-small cell lung cancer", section on 'Suspected
stage IV or supraclavicular node disease'.)

The sensitivity of pleural fluid cytology increases with recurrent sampling. Up to 30 percent
of second thoracenteses are positive for cancer when the results of the initial thoracentesis
are falsely negative [136,137,140]. Other studies report variable increases in the rates of
cancer diagnoses from 5 to 25 percent after the third thoracentesis [133,136].

There is conflicting data regarding the optimal volume required for the identification of
malignant cells in pleural fluid. Studies are hampered by varied definitions of what is
considered large volume versus small volume and lack comparators. While one study
suggested higher sensitivity from samples >60 mL, particularly those >150 mL, another
study suggested that 50 mL specimens are adequate [141,142]. Two studies also reported
higher sensitivity when enough material was collected for the preparation of a cell block
[137,141]. Typically, for cell block preparation, higher volumes are needed. Although
undetermined, it has been suggested that the variability in optimal volume required for
diagnosis may simply relate to the total number of malignant cells in the sample pleural
fluid, a variable which is unknown at the time of thoracentesis. Thus, the optimal volume
varies among institutions and interventional clinicians. In general, when feasible, volumes
of at least 50 to 60 mL processed by cell block preparation are recommended.
(See "Diagnostic thoracentesis", section on 'Technique' and "Diagnostic thoracentesis",
section on 'Complications' and "Large volume thoracentesis" and "Measurement of pleural
pressure".)

There has been a paradigm shift with the increased use of bedside thoracic ultrasound
(TUS) to guide the operator in performing thoracentesis safely. TUS decreases the
incidence of iatrogenic pneumothorax following thoracocentesis [143-145]. The advantage
of TUS is that it can facilitate access to small effusions that would not have traditionally
undergone bedside manual thoracentesis. The diagnostic accuracy of TUS for identifying
malignant effusions in this context is unknown. However, it is typically used by many
clinicians for reasons of safety rather than for diagnostic certainty.

Although there is reduced sensitivity and variable assay methodology, it is technically


possible to evaluate molecular tumor markers on pleural fluid specimens [146-148].

Pleural biopsy — When pleural fluid cytology is negative or pleural


based abnormalities/masses are present, a pleural biopsy is indicated. Three options are
available to the clinician to biopsy the pleura: thoracoscopy (surgical or medical), image-
guided biopsy (CT or ultrasound), and closed pleural biopsy.

●Surgical or medical thoracoscopy – Surgical thoracoscopy is usually performed in


the operating room under video assistance and general anesthesia. Medical
thoracoscopy (pleuroscopy) is an endoscopic procedure usually done in the
endoscopy suite under conscious sedation. Both procedures are capable of obtaining
biopsy material from the parietal and visceral pleura under direct visualization. The
operator can randomly sample the pleura as well as biopsy macroscopically visible
lesions. Among the three options for pleural biopsy, thoracoscopy has the highest
diagnostic accuracy. Reported sensitivities range from 80 to 99 percent with negative
predictive values of 93 to 96 percent [99,132,149-154]. Lower sensitivity values may
be due to a higher percentage of false negative results in patient cohorts that include
mesothelioma, which is typically difficult to diagnose histologically on pleural biopsy
[152]. Thoracoscopy has the added advantage of providing therapeutic options to
avoid recurrent effusion such as pleurodesis or the insertion of an in-dwelling catheter
at the time of surgery. (See "An overview of medical thoracoscopy" and "Indications
for diagnostic thoracoscopy", section on 'Lung cancer'.)
●Image-guided biopsy – Image-guided biopsy is performed in the interventional
radiology suite with or without sedation. Biopsy material is obtained using CT-
guidance, or less commonly, ultrasound-guidance [155-158]. This modality is best
utilized to biopsy focal pleural lesions/abnormalities with or without associated
effusions. The reported sensitivity ranges from 76 to 88 percent with negative
predictive values of 75 to 80 percent [155-157]. The diagnostic utility of the type of
cutting needle used (Cope or Abrams needle) has not been comprehensively studied.
However, one study of cytology-negative pleural effusions used an Abrams needle
specifically to biopsy associated pleural-based masses/thickening under CT-
guidance. Compared to thoracoscopy, no difference was observed in the sensitivity
for identifying lung cancer (100 versus 93 percent) [151]. Another study reported that
CT-guided Abram’s needle biopsy had a higher sensitivity than ultrasound-guided
biopsy using a cutting needle (82 versus 67 percent) [159].
●Closed pleural biopsy – Closed pleural biopsy is rarely performed in contemporary
practice. It is a blind procedure typically performed with an Abrams needle. It is a
bedside procedure that can only be used when pleural fluid is present and can only
biopsy the parietal pleura. Pleural metastases are more common on the visceral
pleura and are sparse and focal on the parietal pleura. This feature, together with
dwindling utilization and expertise in closed biopsy, may contribute to the low
sensitivity of this modality, thereby limiting its utility.

Extrathoracic — Clinical history, examination and imaging typically alert the clinician to
suspected metastatic disease distant from the lung. (See "Overview of the initial
evaluation, diagnosis, and staging of patients with suspected lung cancer", section on
'Imaging metastatic disease'.)

Histologic confirmation of extrathoracic NSCLC is necessary to establish M1b disease


(table 1). In contrast, NSCLC in a supraclavicular node is staged at IIIB. Most forms of
extrathoracic disease are inoperable. The following sections discuss the modalities used to
biopsy suspected metastases in NSCLC

●Liver (see "Percutaneous, fine-needle aspiration, and laparoscopic liver


biopsy" and "The adrenal incidentaloma", section on 'Fine-needle aspiration
biopsy' and "Selection of modality for diagnosis and staging of patients with
suspected non-small cell lung cancer", section on 'Suspected stage IV or
supraclavicular node disease')
●Adrenal gland (see "The adrenal incidentaloma", section on 'Evaluation for
malignancy' and "The adrenal incidentaloma", section on 'Fine-needle aspiration
biopsy' and "Selection of modality for diagnosis and staging of patients with
suspected non-small cell lung cancer", section on 'Suspected stage IV or
supraclavicular node disease')
●Brain – Biopsy of brain lesions suspected to be metastatic NSCLC is rarely
performed but their evaluation is discussed separately (see "Clinical presentation and
diagnosis of brain tumors", section on 'Brain metastases' and "Selection of modality
for diagnosis and staging of patients with suspected non-small cell lung cancer",
section on 'Suspected stage IV or supraclavicular node disease')
●Bone (see "Bone tumors: Diagnosis and biopsy techniques", section on 'Biopsy
techniques' and "Selection of modality for diagnosis and staging of patients with
suspected non-small cell lung cancer", section on 'Suspected stage IV or
supraclavicular node disease')
●Supraclavicular lymph node (see "Evaluation of peripheral lymphadenopathy in
adults", section on 'Localized lymphadenopathy' and "Selection of modality for
diagnosis and staging of patients with suspected non-small cell lung cancer", section
on 'Suspected stage IV or supraclavicular node disease')

SPUTUM CYTOLOGY — Sputum cytology is a noninvasive tool that has diagnostic value
in a small population of patients with suspected NSCLC who are unable or unwilling to
undergo other diagnostic procedures. However, it does not directly provide staging
information for NSCLC, nor it is it likely to provide ideal specimens for
immunohistochemical or molecular studies [160].
Pooled data from small observational series report sensitivity values of 66 percent (range
42 to 97 percent) for the diagnosis of NSCLC [2]. Sensitivity varies by location of the
primary tumor, being highest for large, centrally located lesions, and lower for smaller or
peripheral lesions [2].

Although cytologic specimens can be diagnostic of NSCLC, not every patient produces
sputum. Thus, a negative test does not exclude the diagnosis of NSCLC and a second
procedure will often be necessary for this purpose. Similarly, when sputum cytology is
positive, additional testing will often be necessary for staging, especially when mediastinal
or distant metastases are suspected.

Thus, in practice, sputum cytology is typically most useful in patients in whom avoiding a
biopsy is desirable (eg, multiple comorbidities, contraindications to invasive biopsy,
overwhelming evidence of metastatic disease). In this context, diagnostic sputum cytology
may permit palliative or other therapy without the risk associated with biopsy.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education


materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient education: Non-small cell lung cancer (The Basics)")
●Beyond the Basics topics (see "Patient education: Non-small cell lung cancer
treatment; stage I to III cancer (Beyond the Basics)" and "Patient education: Non-
small cell lung cancer treatment; stage IV cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●There are a number of minimally invasive and invasive procedures that can be used
by the clinician to biopsy patients with suspected NSCLC. Selecting a modality
depends upon knowledge of the diagnostic accuracy of a modality for the target
lesion(s), in the context of operator proficiency, patient safety and eventual goals for
treatment. While minimally invasive techniques are generally preferred to more
invasive procedures, their imperfect sensitivity necessitates additional biopsy when
testing is negative for cancer. Sensitivity and specificity estimates for individual
modalities are usually based upon data from small studies with inadequate gold
standard comparators that lead to bias and significantly limit interpretation of the data.
The clinician should be aware of these flaws when choosing among the modalities
available for tissue acquisition. (See "Selection of modality for diagnosis and staging
of patients with suspected non-small cell lung cancer".)
●Bronchoscopic techniques often employ multiple modalities (eg, forceps biopsy,
brushings, ultrasound, needle aspiration) to increase the sensitivity for the diagnosis
and staging of NSCLC. Bronchoscopy is best utilized for accessing large, visible, or
central lesions and suspicious paratracheal and subcarinal nodes. As examples
(see 'Bronchoscopic approaches' above):
•Endobronchial-guided transbronchial needle aspiration (EBUS-TBNA) is the
first-choice modality for sampling large, central tumors and suspicious
mediastinal lymph nodes in the paratracheal, subcarinal, and hilar regions (2R,
2L, 3p, 4R, 4L, 7, 10R, 10L, 11R, 11L) (figure 1). Limitations of EBUS-TBNA
include inability to access prevascular, periaortic, paraesophageal, or pulmonary
ligament lymph node stations (3a, 5, 6, 8, 9), and variable proficiency among
operators, which may influence the rate of nondiagnostic findings.
(See 'Endobronchial ultrasound' above.)
•Electromagnetic navigational bronchoscopy (EMN) is an emerging modality for
sampling peripheral lung lesions. (See 'Electromagnetic navigational
bronchoscopy' above.)
●Transthoracic (percutaneous) needle aspiration/biopsy (TTNA/B) is a sensitive
procedure for acquiring tissue for most intraparenchymal lesions, particularly
peripheral masses and nodules. Although in theory it can access almost all
mediastinal lymph nodal stations, it is rarely used for this purpose. It is often used to
access peripheral lesions and can also be used when other procedures have failed.
Results are sometimes non-diagnostic and there is a relatively high risk of
pneumothorax. (See 'Transthoracic needle biopsy'above.)
●Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is a sensitive
staging tool for suspected NSCLC involvement in subcarinal (3, 7, 8, 9) and
paratracheal nodes (2, 4). EUS-FNA can be combined with EBUS-TBNA to enhance
mediastinal staging. (See 'Transesophageal endoscopic ultrasound' above
and 'Combined modalities' above.)
●Standard cervical mediastinoscopy (SCM) is a sensitive staging procedure when
sampling nodal stations easily accessed by this approach (1, 2, 3, 4, anterior 7, 10)
(figure 1). Use of a video mediastinoscope and systematic lymph
node sampling/dissection may enhance the accuracy of this modality. (See 'Standard
cervical mediastinoscopy' above.)
●Video-assisted thoracoscopic surgery (VATS) is an accurate modality for evaluating
the extent of invasion (chest wall, mediastinal) by the primary tumor (T), mediastinal
lymph node involvement (4, 5, 6, 7, 8, 9, 10 to 14) and pleural involvement (M) (figure
1). It is a surgical procedure that requires general anesthesia and carries higher
morbidity and mortality than other diagnostic or staging modalities. VATS is most
often used when alternative procedures cannot access the primary tumor or are non-
diagnostic. (See 'Video-assisted thoracic surgery' above.)
●Left anterior mediastinotomy (Chamberlain procedure) is often the only option for
sampling the subaortic (5) and para-aortic (6) lymph node stations. (See 'Anterior
mediastinotomy (Chamberlain procedure)' above.)
●Extended cervical mediastinoscopy (ECM), video-assisted mediastinal
lymphadenectomy (VAMLA), and transcervical extended mediastinal
lymphadenectomy (TEMLA) are surgical procedures that allow more extensive
mediastinal sampling than standard cervical mediastinoscopy. They are not widely
available and may be associated with greater morbidity than standard cervical
mediastinoscopy. Using any one of these procedures is best dictated by the expertise
of practitioners within the institution. (See 'Extended cervical mediastinoscopy' above
and 'Video-assisted mediastinal lymphadenectomy' above and 'Transcervical
extended mediastinal lymphadenectomy' above.)
●Sampling site(s) of suspected metastatic disease is necessary for tissue
confirmation. Sampling the pleural space (effusions or solid lesions) is essential in all
patients with suspected pleural involvement. Thoracentesis is typically performed first
for evaluation of pleural effusions. Pleural biopsy (image-guided or thoracoscopic) is
often performed when pleural fluid cytology is negative or to obtain tissue from a solid
pleural lesion. (See 'Sampling metastatic disease' above and 'Suspected pleural
metastases' above.)
●Sputum cytology has diagnostic value in a small population of patients with
suspected NSCLC. Sensitivity is highest for large, centrally located lesions, and lower
for small peripheral lesions. It is not useful for staging NSCLC. (See 'Sputum
cytology' above.)
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Screening for lung cancer


Authors:
Mark E Deffebach, MD
Linda Humphrey, MD
Section Editors:
Joann G Elmore, MD, MPH
David E Midthun, MD
Deputy Editor:
Sadhna R Vora, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Dec 2016. | This topic last updated: Jun 10, 2016.

INTRODUCTION — Lung cancer is the leading cause of cancer-related death among men
and women [1]. Some [2,3], but not all [4], studies suggest that for any level of smoking,
women are at higher risk of developing cancer than men. In the year 2016, the American
Cancer Society predicts that there will be approximately 224,000 new cases of lung cancer
diagnosed, and approximately 158,000 lung cancer-associated deaths in the United States
[5]. Worldwide, it is estimated that there were 1.59 million deaths in the year 2012 [6].

Unfortunately, 75 percent of patients with lung cancer present with symptoms due to
advanced local or metastatic disease that is not amenable to cure [7]. Despite advances in
therapy, five-year survival rates average approximately 16 percent for all individuals with
lung cancer [8].

Prevention, rather than screening, is the most effective strategy for reducing the burden of
lung cancer in the long term. Most lung cancer is attributed to smoking, including lung
cancer in nonsmokers in whom a significant proportion of cancer is attributed to
environmental smoke exposure [9]. The promotion of smoking cessation is essential, as
cigarette smoking is thought to be causal in 85 to 90 percent of all lung cancer [10].
Progress in smoking cessation is now reflected in declining lung cancer rates and mortality
in men in the United States. However, the smoking rate in the United States remains high,
at 19 percent in 2011 [11], and is increasing in many parts of the world. In addition, a high
percentage of lung cancer occurs in former smokers since the risk for lung cancer does
not decline for many years following smoking cessation [12-15].

Screening for lung cancer will be reviewed here. General principles of screening, risk
factors associated with the development of lung cancer, and techniques for smoking
cessation are discussed separately. (See "Evidence-based approach to
prevention" and "Overview of smoking cessation management in adults" and "Cigarette
smoking and other possible risk factors for lung cancer".)

POTENTIAL BENEFITS OF SCREENING — Many characteristics of lung cancer suggest


that screening should be effective: high morbidity and mortality, significant prevalence (0.5
to 2.2 percent), identified risk factors allowing targeted screening for high-risk individuals, a
lengthy preclinical phase for some types of lung cancer, and evidence that therapy is more
effective in early-stage disease [16,17]. Clinical outcome for non-small cell lung cancer is
directly related to stage at the time of diagnosis, ranging from over 60 percent five-year
survival for stage I disease, to less than 5 percent for stage IV disease (table 1 and figure
1) [18]. In addition, within early lung cancers (stage I), there is a relationship between
tumor size and survival [19]. Available data are more limited for patients with small cell
lung cancer but also support an improved outcome when disease is diagnosed at an early
stage.

The potential of screening to detect early cancers may both increase the overall cure rate
and allow more limited surgical resection to achieve cure. However, screening may not
accomplish these goals unless it takes place in the context of a multidisciplinary program
to ensure that screening is properly performed and results properly interpreted, and
followed up, and that disease, when detected, is managed appropriately.

The success of lung cancer screening can be assessed using various outcome measures,
including cancer detection rates, stage at detection, survival, disease-specific mortality,
and overall mortality. For a lethal disease such as lung cancer, which requires invasive
procedures for detection and treatment, the most important outcomes to assess are
disease-specific and overall mortality.

POTENTIAL HARMS OF SCREENING — While screening for lung cancer has the
potential benefits of decreased morbidity and mortality from lung cancer, it also has
potential harms, which include:

●Consequences of evaluating abnormal findings – Detection of abnormalities that


require further evaluation, most of which are benign nodules. Evaluation may involve
needle biopsy and/or surgery, with associated morbidity and mortality [20,21]. In the
National Lung Screening Trial (NLST), over 53,000 high-risk individuals were
randomly assigned to low-dose computerized tomography (LDCT) scan or chest
radiograph screening [22]. Among abnormal results (24.2 percent of LDCT scans and
6.9 percent of radiographs), 96 percent were false-positive (that is, did not lead to a
diagnosis of lung cancer) and 11 percent of the positive results led to an invasive
study. Most positive studies are resolved with imaging and prove to be false-positive
exams.
●Radiation exposure – Radiation from serial imaging in a screening program may
add independently to the risk of developing cancers, including lung cancer [23]. Since
screening typically occurs over several rounds and positive studies require further
evaluation, the cumulative radiation dose is also important. (See "Radiation-related
risks of imaging studies".)
●Patient distress – Prolonged follow-up of nodules, often lasting several years, may
cause anxiety related to fear of having lung cancer. Few trials have evaluated patient
distress with LDCT screening. A 2014 systematic review of five randomized trials and
one cohort study found that low-dose CT screening may be associated with short-
term psychologic discomfort but did not affect distress, worry, or health-related quality
of life [24]. False-positive results were associated with short-term increases in
distress. A subsequent study evaluated health-related quality of life and anxiety in
2800 patients who were a subset of participants in the NLST [25]. Compared with
patients who had negative screens, the study found no differences in outcomes at
one and six months in those with false-positive screens or screens with significant
incidental findings.
●Overdiagnosis – Some cancers identified at screening, if never found, would not
have affected morbidity or mortality during the patient's lifetime [26]. Identification of
such cancers is referred to as "overdiagnosis." Overdiagnosis could be expected to
have greater impact in screening programs where subjects are at increased risk for
other potentially life-threatening comorbidities, as is the case for smokers [27]. The
risk for unnecessary invasive studies and therapy for "overdiagnosed" lung cancer
might be greatest in this population. Observational studies of screening for lung
cancer with LDCT have estimated the extent of overdiagnosis to range between 13
and 27 percent [28,29].
Although randomized trials demonstrate that screening with LDCT scan can reduce
lung cancer and all-cause mortality, some cancers detected by screening may still
represent overdiagnosis and lead to unnecessarily aggressive treatment. After 6.5
years of follow-up in the NLST, there were 119 more lung cancers identified in the
LDCT group compared with the chest radiograph group (1060 versus 941) [22]. One
study has used the NLST data to estimate an upper limit of overdiagnosis [30], but
this model has been criticized for not taking into account lead or length time bias
[31,32]. Only long-term follow-up can provide a true estimate of overdiagnosis.

SCREENING MODALITIES

Chest radiograph/sputum cytology — Screening for lung cancer by chest


radiograph and/or sputum cytology is not recommended. There have been at least seven
large scale controlled clinical (six randomized, one non-randomized) trials of chest
radiograph screening for lung cancer [33-48]. These studies began as early as 1960, and
a 20-year follow-up analysis has been published for one randomized trial [44,49,50]. None
of the randomized trials have demonstrated a mortality benefit for chest radiograph
screening; however, only the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer
screening trial compared screening with no screening [51].

The PLCO Cancer Screening Trial is a large randomized trial (n = 154,942) evaluating the
impact of screening individuals aged 55 through 74 for several cancers, including lung
cancer [52]. Screening for lung cancer consisted of a single posterior-anterior chest
radiograph performed at baseline and annually for three years, while the control group
received usual care. This study differs from prior chest radiograph screening trials in
several important aspects: the cohort includes men and women in equal numbers,
participants are not specifically high risk (51.6 percent current or former smokers), and
prevalence screening results are included in the trial and analysis, allowing a true
comparison of screening with no screening.

At the initial screening, 5991 (8.9 percent) of all chest radiographs were abnormal, ranging
from 11.0 percent in current smokers to 8.0 percent in never smokers [53]. After up to
three rounds of annual screening (nonsmokers did not participate in the third screening
round), participants were followed through 13 years, with a screening adherence of 86.6
percent at baseline and 79.0 to 84.0 percent during years 1 through 3 [54]. After 13 years
of follow-up, there was no significant difference in lung cancer incidence rates between the
screening and usual care groups (20.1 and 19.2 per 10,000 person-years, relative risk
[RR] 1.05, 95% CI 0.98-1.12), and no difference in lung cancer mortality rates (RR 0.99,
95% CI 0.87-1.22) or stage of disease. Lung cancer incidence was higher in those with
prior or current smoking exposure than in nonsmokers, but there was no difference in
incidence or mortality between smokers who were in the screening or control groups (RR
0.94, 95% CI 0.18-1.10 after six years and RR 0.99, 95% CI 0.87-1.22 after 13 years of
follow-up). Only approximately 20 percent of the cancers in the screening group were
detected by screening. Thus, annual screening with chest radiograph, compared with
usual care, did not reduce lung cancer mortality.

The lung cancer arm of the PLCO trial was designed to be completed in 2015. However,
the monitoring board thought that results would be unlikely to change with longer follow-up
and that the current findings had public health significance because of the recent report of
the National Lung Screening Trial (NLST) that compared low-dose computerized
tomography (LDCT) screening with chest radiograph screening in a high-risk population.
Data from the PLCO trial were also analyzed for a subset of patients who would meet the
criteria for the NLST. (See 'National Lung Screening Trial' below.)

Low-dose chest CT — Because of the lack of a mortality benefit from chest radiograph
screening [55-61], refinements of CT scanning techniques led to the evaluation of low-
dose helical computerized tomography (LDCT) for lung cancer screening [62]. New
multidetector CT scanners generate high-resolution imaging with radiation exposure
significantly less than for diagnostic chest CT scanning. LDCT refers to a noncontrast
study obtained with a multidetector CT scanner during a single maximal inspiratory breath-
hold with a scanning time under 25 seconds. High-resolution (1.0 to 2.5 mm interval)
images are reconstructed using a soft tissue or thin-section algorithm. The overall average
effective dose of LDCT used in the National Lung Screening Trial was 2 millisievert (mSv),
compared with 7 mSv for a standard-dose diagnostic chest CT examination [63].
(See 'National Lung Screening Trial' below.)

A 2012 systematic review of the benefits and harms of screening with LDCT scan
identified the NLST as the only trial demonstrating a mortality benefit, with other trials
either too small, still preliminary, or with study design flaws precluding meaningful
interpretation [64]. Similarly, a 2013 systematic review also found the NLST to provide the
best quality available data regarding screening [65].

Several observational studies of LDCT scanning have been published and demonstrate
that screening with low-dose chest CT can identify early-stage asymptomatic lung cancer.
The larger observational studies include the Early Lung Cancer Action Program (ELCAP)
[66,67], the International ELCAP [68], the Mayo Clinic CT study [69-72], and the
Continuous Observation of Smoking (COSMOS) study [73]. However, results from
randomized trials are more pertinent to decisions about screening.

National Lung Screening Trial — The National Lung Screening Trial (NLST) was a
randomized trial comparing annual screening by low-dose chest CT scanning with chest
radiograph for three years in 53,454 high-risk persons at 33 United States medical centers
[22,74-76]. Participants were men and women 55 to 74 years of age with a history of at
least 30 pack-years of smoking, and included current smokers and those who had
discontinued smoking within 15 years of enrollment. The NLST demonstrated that LDCT
screening reduced mortality in a high-risk population (based on age and smoking history),
compared with screening by radiograph (and by inference from the PLCO trial data,
compared with usual care). For those undergoing at least one screen, the number needed
to screen with LDCT to prevent one lung cancer death was 320.

The trial was stopped early after an interim analysis found a statistically significant benefit
for LDCT scanning [22]. At a median follow-up of 6.5 years, there were 645 cases of lung
cancer per 100,000 person-years (1060 cancers) in the LDCT group, and 572 cases per
100,000 person-years (941 cancers) in the chest radiograph group, resulting in an
incidence rate ratio of 1.13 (95% CI 1.03-1.23). Per 100,000 person years, there were 247
lung cancer deaths in the CT group and 309 in the radiograph group, yielding a relative
mortality reduction of 20 percent (CI 3.8-26.7) and an absolute reduction of 62 lung cancer
deaths per 100,000 person years. Importantly, there was also a 6.7 percent (CI 1.2-13.6)
relative reduction in all-cause mortality in the LDCT group and an absolute reduction of 74
deaths per 100,000 person-years.
Positive findings were defined as a noncalcified nodule ≥4 mm on LDCT scan or any
noncalcified nodule on radiograph. Over all three screening rounds, 24.2 of LDCT scans
and 6.9 percent of radiographs were abnormal. The cumulative rate of false-positive
findings was high: 96.4 and 94.5 percent for LDCT and radiograph screening, respectively.
Follow-up for false-positive findings was at the discretion of the institution, 90.4 and 92.7
percent of false-positive screens led to at least one diagnostic procedure, mostly imaging,
but including surgery in 297 patients who had LDCT scan and 121 who had radiograph
screening [76]. The rate of adverse events related to complications from the diagnostic
work-up was low: among participants with a positive finding, at least one complication
occurred in 1.4 percent of the LDCT group and 1.6 percent of the radiograph group (table
2).

The rate of detection of lung cancer did not diminish between screening years, suggesting
that ongoing screening would be necessary. A retrospective cohort analysis of this study
examined the effect of extending the interval of screening for those with an initial negative
study [77]. In this study, participants with a negative initial screening LDCT (19,066 out of
26,231) had an overall lower incidence of lung cancer and lung cancer-related mortality
than did all participants. The yield of lung cancer diagnosis at the next annual LDCT
screening study for these patients was lower compared with all participants (0.34 versus
1.0 percent, respectively). Extrapolating from this, the authors concluded that screening
participants with a negative initial LDCT at one year would, at most, result in 28 fewer lung
cancer deaths in the annual screening group (decreasing mortality from 212.1 [186.8 to
240.0] per 100,000 person-years to 185.8 [95% CI 162.3-211.9]). Because more frequent
screening might cause harm, the study’s authors concluded that in subjects with a
negative initial screening study, increasing the screening interval from one year might be
warranted.

Fewer stage IV cancers were observed in the LDCT group than the chest radiograph
group with the second and third screening rounds suggesting that diagnosis of earlier-
stage cancers reduced the occurrence of later-stage lung cancers. Lung cancers detected
by screening were mostly stage I or II (70 percent of CT detected and 56.7 percent of
radiograph detected), except for small cell cancers that accounted for less than 10 percent
of detected cancers. Chest LDCT identified a preponderance of adenocarcinomas. More
detailed results of the first round of screening (T0) in the NLST show that stage I cancer
was detected in 158 participants in the LDCT group and 70 participants in the radiograph
group; stage IIB to IV cancers were found in 120 versus 112 participants [76]. Thus, the
difference in cancer detection between groups was in the increased identification of early-
stage cancers with LDCT scan in the first screen. Based on data collected for three years
following the screening rounds, sensitivity and specificity for LDCT were 93.8 and 73.4
percent and for radiograph were 73.5 and 91.3 percent, respectively. Additional details
about screening rounds 2 and 3 (T1 and T2) and incident lung cancers indicate that 27.9
and 16.8 percent of T1 and T2 LDCT scans, respectively, were positive [78]. The positive
predictive value for cancer was 2.4 and 5.2 percent at T1 and T2, respectively. The higher
predictive value at T2 was likely related to classification of a nodule that had been stable
over three screenings as "negative." Consistent with results from T0, lung cancers
detected by LDCT scan were more likely to be stage 1A (at T1, 47.5 percent of cancers
identified by LDCT compared with 23.5 percent of those identified by radiograph).

Generalizability of these findings may be affected by the following factors: trial participants
had a higher education level and were younger than tobacco users identified in United
States census data, a low complication rate of follow-up procedures may reflect the
expertise at the participating academic centers, and radiologic performance and
interpretation may not be representative of community-based radiology [79].

Since the control group in the NLST had screening with chest radiograph rather than usual
care, findings of the PLCO trial, in which participants were randomly assigned to usual
care or annual chest radiography, are pertinent [80]. Results of the PLCO trial were
analyzed for the subset of patients who would meet criteria for participation in the NLST.
There was no significant difference in mortality at six-year follow-up for the PLCO trial
high-risk subset that was assigned to chest radiograph screening or usual care (RR 0.94,
95% CI 0.81-1.10).

Other trials — Seven randomized trials of LDCT screening remain in progress in Europe
[81]. The trials differ in recruitment strategies and number of screening rounds, though all
include only past or current heavy smokers, and all control groups had no screening (in
contrast to the NLST where the control arm had chest radiograph screening). The only
individual trial of large enough size to possibly show a mortality reduction is the NELSON
trial. However, there is a plan to analyze pooled data from the seven trials.

●The NELSON trial is a randomized LDCT-based lung cancer trial being conducted in
the Netherlands and Belgium; LDCT screening at increasing length of screening
interval (1, 2, and 2.5 years) is being compared with no screening in 15,822 current or
former smokers [82,83]. The study is powered to detect a 25 percent decrease in lung
cancer mortality after 10 years, as well as the effects of screening on quality of life,
smoking cessation, and an estimate of cost effectiveness. Unlike other screening
studies, five-year lung cancer survivors, a group at very high risk of developing a new
lung cancer, are also eligible for enrollment. This is the only large-scale randomized
trial to compare LDCT screening with no screening. Information is available
at www.trialregister.nl/trialreg/admin/rctview.asp?TC=636.
In a prespecified analysis, after a median of 8.16 years of follow-up, there were 196
screen-detected cancers in 187 (3 percent) of the 7155 screened participants [83].
The proportion of stage I cancers detected by LDCT was 66 percent. Among patients
who were screened with LDCT, 34 patients were diagnosed with 35 interval lung
cancers. Interval cancers were more likely to be more advanced stage, more likely to
be small cell carcinoma, and less likely to be adenocarcinoma.
LDCT screening results (indeterminate versus negative) did not significantly impact
the smoking abstinence rate among male smokers in this trial [84]. However, smokers
with an indeterminate result on LDCT scanning reported more quit attempts than
those with a negative scan.

According to this study, new solid nodules were detected at each screening round in 5 to 7
percent of participants receiving LDCT scans, with 6 percent of these nodules being
diagnosed as lung cancer [85]. Nodule volume had a high discriminatory power, with the
frequency of cancer being 0.5 percent among nodules smaller than 27 mm3, 3.1 percent
among those with a volume of 27 mm3 to 206 mm3, and 17 percent among those larger
than 206 mm3. A volume cutoff of 27 mm3 or greater had a sensitivity exceeding 95 percent
for the detection of lung cancer.

●The DANTE trial, a randomized trial in Italy that enrolled 2472 male smokers age 60
to 74 years, was designed to assess lung cancer-specific mortality over 10 years,
comparing five years of annual screening by single-slice spiral LDCT scan or annual
clinical follow-up; the control group received baseline screening with chest radiograph
and sputum cytology [86]. Follow-up at an average of 8.35 years from enrollment and
after completion of the baseline and annual screens has been reported [87]. Lung
cancer was found in 8.2 percent of patients who received LDCT screening and in 6
percent of controls. Although there were more stage I cancers detected in the
screened group (3.7 versus 1.3 percent), the numbers of advanced lung cancer cases
and lung cancer mortality were the same (543 versus 544 per 100,000 person-years)
for both groups. The authors caution that because of the small trial size, it is unlikely
to be of sufficient power to detect a mortality difference.
●The Danish Randomized Lung Cancer CT Screening Trial (DLCST) is another
randomized trial of 4104 smokers (at least 20 pack-years) age 50 to 70 years [88].
Baseline data found a prevalence of lung cancer of 0.83 percent (17 cases in 2052
participants). Employing the algorithm from the I-ELCAP study for follow-up of
abnormal initial findings on LDCT scan, 9 of the 17 cases were stage I. After five
annual screening rounds, there was an increase in the number of stage I to IIB non-
small cell lung cancers in the screened group compared with the nonscreened group,
with no difference in high-stage lung cancer [89]. Long-term results from the DLCST
have been reported, with outcomes reported up to five years from the last round of
screening LDCT. There was no difference in lung cancer-specific or overall mortality
[90]. Compared with the NLST, there are several differences that may account for the
lack of benefit seen. Overall, the DLCST population had a lower lung cancer risk, and
it has been shown that the benefit of screening is lower in low-risk populations. The
definition of an abnormal study in DLCST reduced the false-positive rate but may
have resulted in more advanced cancers at time of detection. Lastly, DLCST was
underpowered to detect reductions in mortality [90].
●The Multicentric Italian Lung Detection (MILD) study compared annual or biennial
LDCT screening with no screening in 4099 smokers (>20 pack-years, current or quit
within 10 years) age 49 years or older [91]. It did not find any differences in lung
cancer mortality among the groups [65]. However, the trial is judged to be of low
quality and at high risk of bias because of inadequate randomization, the addition of
the control group later in the trial, and overall lower risk for lung cancer among
participants compared with other trials.
●The German Lung Cancer Screening Intervention Study (LUSI) compared annual
LDCT scan for four years with no intervention in 4052 patients 50 to 69 years old with
a history of heavy smoking (defined as ≥25 years of smoking at least 15 cigarettes a
day or ≥30 years of smoking at least 10 cigarettes a day) [92]. Results from the first
three years of follow-up found that in the first round of screening, 22 percent of
patients were recalled to be evaluated for suspicious findings. Most recall patients
received repeat imaging in three to six months, 1.6 percent of all participants received
a biopsy, and there was a 1.1 percent detection rate for cancer. In the second through
fourth rounds of screening, the recall rate decreased to 3 to 4 percent, and the
detection rate for cancer was about 0.5 percent for each round.

SYNTHESIZING THE AVAILABLE EVIDENCE

Summary — In summary, randomized controlled trials and cohort studies of screening


with chest radiograph or low-dose computerized tomography (LDCT) demonstrate:

●Chest radiograph screening does not reduce mortality from lung cancer, although
there are limited data in women.
●LDCT screening is significantly more sensitive than chest radiograph for identifying
small, asymptomatic lung cancers.
●Chest radiograph and LDCT screening have high rates of "false-positive"
(noncancer) findings leading to additional testing that usually includes serial imaging
but may include invasive procedures. The most common incidental findings are
emphysema and coronary artery calcifications.
●The National Lung Screening Trial (NLST), a large randomized trial of screening
LDCT in high-risk individuals, demonstrated a lung cancer mortality benefit of 20
percent, with all-cause mortality reduced by 6.7 percent [22]. For the "typical" NLST
participant, screening would prevent 3.9 deaths over six years per 1000 persons,
which equates to screening 256 persons annually for three years to prevent one lung
cancer death over six years [93]. In one model, estimating that 8.6 million people in
the United States would have met NLST criteria for screening (based on 2010 data)
and assuming full screening implementation, screening could potentially avert 12,000
deaths from lung cancer per year in the United States [94]. However, another study
suggested that screening-eligible patients in the United States were older and have
more comorbidities when compared with NLST participants [95]. The benefits and
harms of screening may be different in the screening-eligible patient population
compared with the NLST trial.
●The question of cost-effectiveness is a major issue because of the significant costs
associated with screening and, especially, follow-up of the many false-positive tests
identified with LDCT screening in this trial. Additionally, relatively low procedural
complication rates in the NLST trial may not be reproducible in other settings and,
thus, harms may be greater than reported. (See 'Cost-effectiveness' below.)

Limitations of the available evidence — Questions remain regarding the optimal


screening frequency and duration, appropriate population targets, defining criteria for a
"positive" finding, and identifying diagnostic follow-up protocols that minimize evaluations
of false-positive findings [96-98].

●Older age – The best evidence regarding screening comes from the NLST, but only
25 percent of participants in the NLST were ≥65 years and none older than 75 [99]. A
secondary analysis of the NLST results found that compared with patients <65 years,
those ≥65 years were more likely to have false-positive screens but higher prevalence
and positive predictive value for cancer (4.9 versus 3.0 percent) [100].
●Radiologic parameters – The criteria used to define an "abnormal" result affects
the risk of cancer and the performance characteristics of a screening program. The
NLST identified a noncalcified nodule >4 mm as an abnormality with a high false-
positive rate of screening [22]. Studies have suggested that the false-positive rate
could be decreased with different radiologic criteria, but it is not clear how to define
the optimal parameters for screening.
A retrospective interpretation of data from the International Early Lung Cancer Action
Program (I-ELCAP) study cohort and NLST suggested that setting a more
conservative threshold (eg, >6 mm) would decrease the false-positive rate (resulting
in fewer unnecessary procedures or follow-up studies) with minimal impact on the
detection of cancers [101,102]. Another retrospective study applied the Lung Imaging
Reporting and Data System (Lung-RADS) criteria from the American College of
Radiology to the NLST data [103]. The study found a decrease in the false-positive
rate but also a concomitant decrease in the sensitivity of screening. Compared with
the NLST, the Lung-RADS criteria have a more conservative threshold for a positive
baseline screen (>6 mm) and require growth for pre-existing nodules.
It is possible that a range of nodule sizes should be considered "abnormal,"
determined by an individual's specific risks for cancer [104]. A predictive tool has
been developed and validated to estimate the probability that a nodule is malignant
based on characteristics of the patient and the nodule in the Pan-Canadian screening
study [105]. The investigation of a solitary pulmonary nodule is discussed in greater
detail separately. (See "Diagnostic evaluation and management of the solitary
pulmonary nodule".)
●Risk prediction models – Trials to date have selected participants who are
considered to be at high risk for lung cancer on the basis of smoking history.
However, the benefits from screening could be improved if it were possible to more
precisely identify a high-risk population. Risk prediction models that incorporate
factors in addition to smoking have been proposed to better identify high-risk groups
[106-112]. Prospective studies are needed, however, to determine whether a
population can be readily identified using risk models in which screening would have
greater benefit than the 20 percent lung cancer-mortality benefit identified in the
NLST. In addition, how to implement and operationalize individual risk-based
screening remains a major challenge.
There is evidence to suggest that targeting screening to higher-risk individuals could
result in greater benefits with lower risks. In a retrospective study using NLST
participants, a risk prediction model was used to divide participants into five quintiles
[113]. The study found that 88 percent of the screen-prevented lung cancer deaths
occurred among participants in the three highest-risk quintiles, and only 1 percent of
prevented deaths occurred in the lowest-risk quintile. A model derived from data from
the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial
incorporates age, education, body mass index (BMI), family history, history of chronic
lung disease, and smoking status, and it performed well with external validation
[111,114]. A study applying this model to the PLCO and NLST cohorts suggested that
smokers age 66 to 80 years would benefit more from screening than those age 55 to
64 years, and that never-smokers would not benefit from screening [115].

In a subsequent study, an empirical individual risk model incorporating smoking history,


family history, presence of lung disease, sex, education, race, and BMI was validated in
the PLCO and NLST cohorts and in the United States (US) general population, and
compared with US Preventive Services Task Force (USPSTF) and The Centers for
Medicare and Medicaid Services (CMS) recommendations for screening [106]. The
individual risk assessment model improved both effectiveness and efficiency of screening;
if the same number of ever-smokers were screened, individual risk-based screening would
avert 20 percent more deaths compared with application of the USPSTF criteria. It would
also reduce the number needed to screen to prevent a death (NNS) by 17 percent. With
this approach, there are USPSTF-ineligible individuals with sufficient lung cancer risk who
would benefit from screening, replacing 36 percent of USPSTF-eligible, low-risk individuals
who are unlikely to benefit from screening. This strategy also results in increasing the
number of African Americans and women recommended for screening.

As a final example, the Liverpool Lung Project (LLP) risk model incorporates smoking
duration, history of pneumonia, history of cancer, family history of lung cancer, and
asbestos exposure into a risk score [107]. The model was validated in three independent
populations and found to have better discrimination than smoking history or family history
alone in identifying high-risk patients.

Cost-effectiveness — Decisions regarding implementation of a lung cancer screening


program should in part be based upon a cost-effectiveness analysis of a screening
program. Based on the NLST trial, the cost of screening per life saved is unknown but
likely to be high, given the high (approximately 95 percent) false-positive rate leading to
the need for additional studies, the need for ongoing screening, and the relatively low
absolute number of deaths prevented (73 per 100,000 person years) [22].
Modeling studies will be needed to determine actual cost-effectiveness. One analysis,
based upon a model designed prior to completion of the NLST, suggested that LDCT
screening might decrease lung cancer mortality at 10 years by 18 to 25 percent, at a cost
ranging from $126,000 to $269,000 per quality-adjusted life year (QALY) [116].
Additionally, the model found that a smoking cessation program was more cost-effective
than LDCT screening alone or LDCT screening combined with smoking cessation. Another
model, done after the completion of the NLST, estimated LDCT screening would cost
$81,000 per QALY [117]. The model noted that estimates varied widely depending on
subgroups, with LDCT screening being more cost-effective in women and in groups with a
higher risk of lung cancer.

Recommendations by expert groups — Many expert United States screening groups


have incorporated results from the NLST in their recommendations (table 3):

●AATS – The American Association for Thoracic Surgery (AATS) also released
guidelines in 2012 that recommend LDCT screening for high-risk individuals who
meet the NLST criteria [118]. The AATS guidelines extend the age for screening,
advising screening for high-risk individuals from age 55 to 79 years and advise
initiating screening at age 50 for those with a cumulative risk of 5 percent or greater
over the next five years.
●ACP/ASCO/ACS – Guidelines incorporating high-risk criteria from the NLST were
issued from the American College of Chest Physicians (ACP), the American Society
of Clinical Oncology (ASCO) [64,119], and the American Cancer Society (ACS) in
2013 [120]. These guidelines (table 3) advise patient counseling on the risks and
benefits of screening; the development of a registry to collect data on follow-up
testing, smoking behavior, radiation exposure, and patient experience; the
development of quality metrics for CT interpretation, similar to quality control for
mammography; and also emphasize the importance of smoking cessation.
●Canadian Task Force on Preventive Health Care – The Canadian Task Force on
Preventive Health Care recommends screening asymptomatic adults age 55 to 74
years with at least a 30 pack-year smoking history who smoke or quit smoking <15
years ago with LDCT every year for three consecutive years [121].
●NCCN – The National Comprehensive Cancer Network (NCCN) guidelines
recommend discussion of screening with annual LDCT scan screening for those at
high risk; they recommend no routine screening for moderate- or low-risk individuals
[122]. High risk was defined as age 55 to 74 years with a ≥30 pack-year history of
smoking and, if no longer smoking, smoking cessation within 15 years, or age ≥50
years with a 20 pack-year history of smoking with one additional risk factor (other
than secondhand smoke exposure). Although the guidelines note that the duration of
screening is uncertain, they advise a minimum of three scans and suggest annual
LDCT until patients are no longer eligible for definitive treatments. The guidelines
emphasize that lung cancer screening should be done within the context of a
multidisciplinary program (that may include radiology, pulmonary medicine, internal
medicine, thoracic oncology, and/or thoracic surgery) to manage downstream testing.
●USPSTF – A 2013 systematic review for the US Preventive Services Task Force
(USPSTF) [65] serves as the basis for revised guidelines for the USPSTF [123,124].
The USPSTF recommends annual LDCT scan for high-risk adults 55 to 80 years old
(30 pack-year smoking history and current smoker or quit within the past 15 years),
with discontinuation of screening once the individual has not smoked for 15 years or
has a limited life expectancy [123].

Similar to the United States guidelines, a multidisciplinary expert group from France,
representing the intergroup for thoracic oncology and French-speaking oncology (the
French Intergroup [IFCT] and the Groupe d'Oncologie de Langue Française [GOLF]),
advised screening a target population (age 55 to 74 years who have a 30-pack-year
smoking history) with LDCT scan, after informing individuals about the risks and benefits of
screening [125]. The Cancer Care Ontario Programme (CCOP) issued guidelines in 2013
targeting the same group of patients but suggesting biennial screening after two
consecutive years of negative scanning [126].

Counseling for screening — Any program of lung cancer screening requires more than
LDCT capability [127,128]. Screening should only be performed when the clinician and
patient are committed to pursuing follow-up investigations, including serial imaging and
possible surgical lung biopsy, and where there is expertise in chest radiography and lung
cancer management [129,130].

The National Cancer Institute has developed a guide for patients and clinicians to review
the data from the NLST to facilitate communication about the benefits and harms of
screening [131].

Providers need to be experienced in the principles of screening and the management of


small lung nodules. If these components are in place and at-risk individuals (mostly
through smoking and occupational exposure) are highly motivated to be screened for lung
cancer, the following points should be discussed with the patient before beginning
screening. Some have advocated formal informed consent including these points:

●Smoking cessation is a more proven and powerful intervention for preventing death
and complications from lung cancer and other diseases than screening.
(See "Cigarette smoking and other possible risk factors for lung cancer".)
●Lung cancer screening requires an ongoing commitment; cancers are detected on
initial and annual studies, and a single baseline study is insufficient.
●The most likely "positive" result of screening is detection of benign nodules requiring
further evaluation, and this evaluation may require invasive studies, possibly even
surgery.
For patients who would opt to be screened after appropriate counseling, and pending
results of cost-effectiveness analyses and ongoing randomized trials, we suggest annual
screening with low-dose helical CT scanning only for those who meet all of the following
criteria:

●Are in general good health.


●Are at increased risk for lung cancer (similar to the risk of the group participating in
the NLST trial). High-risk criteria for participation in the NLST were age 55 to 74
years, a history of smoking at least 30 pack-years and, if former smoker, had quit
within the previous 15 years.
●Have access to centers whose radiologic, pathologic, surgical, and other treatment
capabilities in the management of indeterminate lung lesions are equivalent to those
in the NLST trial.
●Understand the possible need for subsequent evaluation of abnormal findings.
●Are able to manage the cost of annual screening. The role of insurance coverage in
screening has not been determined following the NLST results, and insurance may
not cover the cost of screening. As of February 2015, Medicare will cover low-dose
helical CT scanning for asymptomatic patients age 55 to 77 years with a history of
smoking at least 30 pack-years and, if a former smoker, quit within the previous 15
years [132]. Orders for screening must also fulfill specific counseling criteria as
outlined by the Centers for Medicare and Medicaid Services. For former smokers,
annual screening should continue until 15 years has elapsed from the date of
smoking cessation.

FUTURE DIRECTIONS — Other modalities and techniques being investigated for lung
cancer screening include positron emission tomography, biomarkers, and assessing tumor
growth patterns:

●Positron emission tomography – At least two studies evaluated annual low-dose


computed tomography (CT) followed by positron emission tomography (PET) with
fluorodeoxyglucose (FDG) for evaluating patients with noncalcified lesions ≥7 mm in
diameter, each with similar results [133,134]. In one study, FDG-PET correctly
diagnosed 19 of 25 indeterminate nodules [133]. The sensitivity, specificity, positive
predictive value, and negative predictive value of FDG-PET for the diagnosis of
malignancy were 69, 91, 90, and 71 percent, respectively. When a negative FDG-
PET was followed three months later with a repeat CT, the negative predictive value
was 100 percent. If these results are validated by future studies, the simple algorithm
employed could have substantial implications for incorporation of PET imaging into
large-scale screening programs. (See "Thoracic positron emission
tomography" and "Computed tomographic and positron emission tomographic
scanning of pulmonary nodules".)
●Nonradiographic technologies – Nonradiographic technologies, including
identification of molecular and protein-based tumor biomarkers, may also contribute
to the early detection of lung cancer. Detection and treatment of small lung tumors
(prior to radiographic visualization) may produce superior outcomes, though the
possibility of lead-time and other types of bias influencing the assessment of these
technologies is great. Outcome benefits must be thoroughly investigated prior to their
widespread use [135].
These techniques may also help identify people with significantly higher lung cancer
risk, in whom the likelihood that radiographic studies would detect early-stage lung
cancer is increased.
Potential biosamples for biomarker analysis include airway epithelium (including
buccal mucosa), sputum, exhaled breath, and blood [136]. The National Lung
Screening Trial (NLST) has established a biospecimen repository of blood, sputum,
and urine samples serially collected from over 10,000 NLST participants, for future
investigation.
Technologies under investigation include:
•Immunostaining or molecular analysis of sputum for tumor markers. As
examples, p16 ink4a promoter hypermethylation and p53 mutations have been
shown to occur in chronic smokers before there is clinical evidence of neoplasia
[137-141].
•Automated image cytometry of sputum [142].
•Fluorescence bronchoscopy [143,144]. (See "Fluorescence bronchoscopy".)
•Exhaled breath analysis of volatile organic compounds, which appear to be
more common in patients with lung cancer [145-147].
•Genomic and proteomic analysis of bronchoscopic samples [148,149].
•Serum protein microarrays for detecting molecular markers [150].
●Assessing tumor growth patterns – The COSMOS study investigated whether
estimation of the volume doubling time (VDT) or growth rate of tumors detected by
low-dose CT scans could be used to determine which tumors may represent indolent
cancers and thus potential overdiagnosis [151]. VDT was estimated on the basis of
change in tumor size with serial scans; a tumor with a VDT <400 days was
considered to be fast growing, 400 to 599 days as slow growing, and >600 days as
indolent. VDT correlated with lung cancer mortality rates (9.2 percent per year for
fast-growing and 0.9 percent per year for slow-growing or indolent cancers). Ten
percent of the cancers identified in the COSMOS cohort had a VDT of 600 days or
more, and 25 percent had a VDT of 400 or more days and thus might represent
overdiagnosis; such tumors might reasonably be managed with less aggressive
intervention.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education


materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Lung cancer screening (The Basics)")
●Beyond the Basics topic (see "Patient education: Lung cancer prevention and
screening (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Lung cancer is the leading cause of cancer-related death. Prevention (promoting


smoking cessation) is likely to have far greater impact on lung cancer mortality than is
screening. Nonetheless, lung cancer screening with low-dose computed tomography
(LDCT) has the potential to significantly reduce the burden of lung cancer.
(See 'Introduction' above.)
●Early trials of chest radiograph screening in males at high risk for lung cancer found
no mortality benefit for radiograph alone or radiograph plus sputum cytology. A large
randomized trial (the Prostate, Lung, Colorectal, and Ovarian [PLCO] trial) of single-
view chest radiograph in men and women found no decrease in lung cancer
incidence or mortality with screening. (See 'Chest radiograph/sputum
cytology' above.)
●LDCT refers to a noncontrast study obtained with a multidetector CT scanner during
a single maximal inspiratory breath-hold with a scanning time under 25 seconds.
Radiation dose exposure is less than a third of a standard-dose diagnostic chest CT
examination. (See 'Low-dose chest CT' above.)
●A large randomized trial (National Lung Screening Trial [NLST]) of annual LDCT
screening in patients with a 30 pack-year history of smoking, including those who quit
smoking in the preceding 15 years, demonstrated a decrease in lung cancer and all-
cause mortality. These results have led to revised guidelines from multiple
professional organizations. (See 'National Lung Screening Trial' above
and 'Recommendations by expert groups' above.)
●All patients who smoke should be strongly counseled to quit smoking, as this is the
most effective intervention to reduce the risk of lung cancer. Patients who currently
smoke or have a history of smoking should be advised of the risks and benefits of
screening for lung cancer (see 'Counseling for screening' above):
•For patients in good health who are thought to have a risk for lung cancer at
least as great as those in the NLST and who have access to centers with
radiologic, diagnostic, and treatment capabilities similar to those in the NLST,
and for whom the cost of screening is not an issue, we suggest annual screening
with low-dose helical CT (Grade 2A). High-risk criteria for participation in the
NLST were age 55 to 74 years, a history of smoking at least 30 pack-years and,
if a former smoker, had quit within the previous 15 years. Consistent with
modeling studies subsequent to the NLST and with recommendations from the
US Preventive Services Task Force (USPSTF), we also suggest screening for
high-risk patients in good health to age 80 (Grade 2C). For former smokers,
annual screening should continue until 15 years has elapsed from the date of
smoking cessation.
•Plain chest radiograph screening has been shown to be ineffective for lung
cancer screening. We recommend not screening for lung cancer with chest
radiograph (Grade 1A).
Use of UpToDate is subject to the Subscription and License Agreement.
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Selection of modality for diagnosis and staging of patients with suspected non-
small cell lung cancer
Authors:
Karl W Thomas, MD
Michael K Gould, MD, MS
Section Editor:
David E Midthun, MD
Deputy Editor:
Geraldine Finlay, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Dec 2016. | This topic last updated: Jul 14, 2016.

INTRODUCTION — Non-small cell lung cancer (NSCLC) accounts for approximately 85


percent of all lung cancers [1]. The two most common histopathologic subtypes are
adenocarcinoma followed by squamous carcinoma. Tissue biopsy is necessary for the
diagnosis of NSCLC. It is especially important that enough tumor tissue is obtained to
allow for accurate histopathologic and molecular assessment so that appropriate therapies
can be administered in a timely fashion. (See "Personalized, genotype-directed therapy for
advanced non-small cell lung cancer".)

This topic will discuss the general approach to selecting a modality to obtain tissue from a
target biopsy site (primary tumor, lymph node, distant metastasis) for the histopathologic
diagnosis and staging of NSCLC. The approach to patients with a solitary pulmonary
nodule, overview of the initial evaluation and imaging of NSCLC, procedures used for
tissue biopsy of NSCLC, and the 7th edition of the Tumor Node Metastasis staging system
for NSCLC are discussed in detail separately. (See "Diagnostic evaluation and
management of the solitary pulmonary nodule" and "Overview of the risk factors,
pathology, and clinical manifestations of lung cancer" and "Overview of the initial
evaluation, treatment and prognosis of lung cancer" and "Overview of the initial evaluation,
diagnosis, and staging of patients with suspected lung cancer" and "Procedures for tissue
biopsy in patients with suspected non-small cell lung cancer" and "Tumor, node,
metastasis (TNM) staging system for non-small cell lung cancer".)

BIOPSY INDICATIONS — Histopathology is essential for the diagnosis of all types of lung
cancer. A tissue biopsy is required to achieve the following goals:

●Determine whether the primary lesion is malignant or benign


●Distinguish primary lung cancer from a metastasis of a non-pulmonary primary site
●Establish a specific histologic subtype
●Determine whether an identifiable mutation is present
●Confirm suspected intrathoracic or extrathoracic metastatic disease

The target for biopsy should be selected based upon an initial evaluation consisting of
history, physical exam, routine laboratory studies, and chest computed tomography (CT)
(table 1). Positron emission tomographic (PET) imaging or PET/CT should be considered
in select cases prior to biopsy (eg, clinical stage IB to IIIA disease to identify occult
metastases). The clinical evaluation and imaging of patients with suspected lung cancer
and with solitary pulmonary nodule are discussed separately. (See "Overview of the initial
evaluation, diagnosis, and staging of patients with suspected lung cancer", section on
'Radiographic staging' and "Diagnostic evaluation and management of the solitary
pulmonary nodule".)

Tissue sampling is especially important for selecting and predicting the response to
targeted therapies, particularly for patients with advanced adenocarcinoma. Obtaining
enough tissue for molecular analysis (eg, epidermal growth factor receptor [EGFR]
mutations and anaplastic lymphoma kinase [ALK] status), is increasingly recognized as
valuable in the treatment of advanced and recurrent disease. The value of molecular
analysis in NSCLC and additional details regarding the procedures used to obtain tissue in
patients with suspected NSCLC are discussed separately. (See "Personalized, genotype-
directed therapy for advanced non-small cell lung cancer" and "Procedures for tissue
biopsy in patients with suspected non-small cell lung cancer".)
BIOPSY GOALS — The acquisition of tissue from lung, lymph node, or distant organ (eg,
bone, liver) will ideally provide enough material for accurate histopathologic and molecular
assessment. Computed tomographic (CT), positron emission tomographic (PET)
scanning and/or other imaging modalities (eg, magnetic resonance imaging [MRI], bone
scan) help guide the clinician in choosing the optimal site(s) for tissue sampling with the
following goals:

●Minimize the number of procedures required to diagnose and stage the disease
(see 'Efficient diagnosis and procedures' below)
●Acquire sufficient material for current and future immunohistochemical and
molecular characterization studies (see 'Adequate biopsy size' below)

Achieving both goals should maximize the chances of achieving a diagnosis while
minimizing patient risk. (See "Procedures for tissue biopsy in patients with suspected non-
small cell lung cancer" and 'Assessing patient risk' below.)

Efficient diagnosis and procedures — The preferred site for tissue biopsy is one that
will simultaneously diagnose and accurately stage the disease so that multiple procedures
can be avoided, a rapid diagnosis can be achieved, and therapy instituted in a timely
fashion (table 1). However, this is not always practical and frequently more than one
procedure will be needed.

In order to achieve this goal, it is critical to assess disease stage in the context of expected
therapy. Imaging determines anatomic location and tumor size (T) and guides the clinician
in choosing a site that is suspicious for lymph nodal (N) or metastatic (M) disease. The
TNM staging system for NSCLC, and imaging characteristics of pulmonary nodules and
lymph nodes that are considered suspicious, either by size and shape (CT), or metabolic
activity (PET), are discussed separately. (See "Tumor, node, metastasis (TNM) staging
system for non-small cell lung cancer" and "Overview of the initial evaluation, diagnosis,
and staging of patients with suspected lung cancer", section on 'Radiographic
staging' and "Diagnostic evaluation and management of the solitary pulmonary nodule",
section on 'Imaging'.)

Imaging studies are not diagnostic of NSCLC and histopathologic confirmation of


suspected mediastinal or distant spread of NSCLC is required unless there is
overwhelming evidence of metastasis on non-invasive imaging (table 1). Examples of
utilizing the same procedure to acquire tissue for simultaneous diagnosis and staging of
suspected NSCLC include the following:

●Suspected stage IA (T1bN0M0): When imaging identifies a small (eg, ≤3 cm)


peripheral lung lesion with no suspicious mediastinal nodal or distant disease,
surgical resection of the lung lesion with intraoperative mediastinal lymph node
sampling can confirm stage I/II disease. All patients in this category are presumed to
be candidates for surgery. Pathology from lymph nodes sampled at the time of
surgery can then dictate whether further therapy is warranted; no further therapy is
needed when nodal sampling is negative (stage 1A) while adjuvant chemotherapy is
given when nodal sampling is positive (stage II) (image 1 and image 2).
●Suspected M1b: When imaging identifies an isolated adrenal or liver mass, an
adrenal or liver biopsy may reveal NSCLC. In this setting, the identification of stage IV
disease (M1b), obviates the need for more invasive testing, and allows the patient to
proceed rapidly to treatment with appropriate therapy (image 3).
●Suspected stage IIIA/B (ie, N2/N3 involvement): When imaging identifies
mediastinal N2 (ipsilateral) or N3 (contralateral) lymph node enlargement, biopsy
targeted at the affected lymph node(s) confirms the presence of stage IIIA or IIIB
disease, respectively. The distinction between IIIA and IIIB disease is potentially
important because some cases of IIIA may be eligible for treatment with induction
chemotherapy followed by surgery, while patients with IIIB NSCLC are not surgical
candidates (image 4 and image 5).

The approach to selecting a modality and procedures used to biopsy suspected NSCLC
are discussed separately. (See 'Approach to the patient' below and "Procedures for tissue
biopsy in patients with suspected non-small cell lung cancer" and "Procedures for tissue
biopsy in patients with suspected non-small cell lung cancer", section on 'Sampling
metastatic disease'.)

Adequate biopsy size — At minimum, tissue sampling should ensure the provision of
adequate material for histopathology. Strong consideration should also be given to
providing enough material for supplemental immunohistochemical and molecular
characterization studies [2-6]. Although not well defined, most pathology laboratories
consider a tissue volume of 1 mm3 to be adequate for diagnostic and supplemental
studies. Many of the techniques used to sample NSCLC produce small biopsies and
cytologic samples that may not be adequate for supplemental studies (eg, needle
aspirates, pleural fluid cytology). Depending upon the yield with these studies, repeat
biopsy may be necessary. Supplemental characterization studies that require sufficient
material include the following:

●Immunohistochemical (IHC) analysis – IHC markers are commonly used to


appropriately classify lung cancer (eg, adenocarcinoma versus squamous carcinoma)
and to determine the tissue of origin for cancers identified in the lung (eg, thyroid
transcription factor-1 [TTF-1] positivity indicates likely lung primary). (See "Pathology
of lung malignancies", section on 'Classification schemes'.)
●Mutational analysis – EGFR and EML4-ALK mutations in adenocarcinoma can be
useful in predicting the response to therapy. Targeted therapies can be used at the
time of diagnosis of metastatic disease or as second line therapy when conventional
chemotherapy fails to control disease [2-5]. Archiving tissue at the time of diagnosis
for future molecular characterization should also be considered to allow testing
for mutations/therapies discovered between the time of diagnosis and disease
recurrence. (See "Personalized, genotype-directed therapy for advanced non-small
cell lung cancer" and "Anaplastic lymphoma kinase (ALK) fusion oncogene positive
non-small cell lung cancer".)

The procedures with the largest sample size involve surgical excision of tumor or lymph
node. These include video-assisted thorascopic biopsy and cervical mediastinoscopy. The
procedures with the smallest volume are techniques involving needle aspiration of tissue
or body fluids. However, the yield from such procedures can be enhanced. For example,
several studies have shown that sufficient material can be obtained by endobronchial
ultrasound guided–transbronchial needle aspiration (EBUS-TBNA) when multiple passes
with rapid onsite cytologic evaluation (ROSE) are performed by a well-trained endoscopist
in an institution with well-defined procedural protocols for processing [4,7-16].
(See "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer",
section on 'Limitations'.)

The accuracy of each procedure is discussed separately. (See "Procedures for tissue
biopsy in patients with suspected non-small cell lung cancer".)

ASSESSING PATIENT RISK — Many patients who undergo evaluation for suspected
NSCLC have comorbidities that influence life expectancy as well as procedural and
surgical safety. In all cases, individual assessment should weigh the benefits of the
diagnostic yield of a specific procedure against the risk associated with that procedure in
the context of patient preference.

●General assessment – Comorbidities identified by computed tomography (eg,


emphysema) or by history (eg, heart failure, chronic obstructive pulmonary disease)
may prompt consideration of additional tests (eg, pulmonary function testing,
echocardiography or cardiopulmonary exercise testing). Performance status can also
be assessed clinically by the Karnofsky scale or by the Eastern Cooperative
Oncology Group (ECOG) Performance Scale (table 2 and table 3). These measures
are also helpful when assessing the safety of therapy after the diagnosis is made.
●Assessment for surgery – Candidates for surgical resection or surgical procedures
should undergo pulmonary function testing and consultation with a cardiothoracic
surgeon. Patients with borderline pulmonary function or worrisome cardiorespiratory
symptoms should also undergo functional cardiopulmonary testing or a myocardial
perfusion study. The indications and tests involved in the preoperative evaluation of
patients with suspected lung cancer is discussed elsewhere. (See "Preoperative
evaluation for lung resection" and "Evaluation of preoperative pulmonary
risk" and "Overview of the initial evaluation, treatment and prognosis of lung cancer",
section on 'Initial evaluation'.)
●Assessment for minimally invasive modalities – Minimally invasive modalities
include endobronchial ultrasound-guided transbronchial needle aspiration [EBUS-
TBNA], transthoracic needle aspiration [TTNA], bronchoscopy and transesophageal
endoscopic ultrasound (EUS). In general, these procedures are considered relatively
safe, although few population-based studies of procedure-related complications have
been performed [17]. While less invasive than surgical biopsy, they are not
completely without risk and individual assessment is necessary to evaluate the ability
of the patient to tolerate conscious sedation as well as assess the risk for potential
complications of the procedure. (See "Procedures for tissue biopsy in patients with
suspected non-small cell lung cancer", section on 'Minimally invasive procedures'.)

It is critical to assess the value the patient places on diagnosis and the risks he or she is
willing to take to attain a diagnosis. This assessment should occur in the context of life
expectancy from their underlying comorbid condition(s). For example, an intraparenchymal
nodule in the contralateral lung, suspected to be metastatic NSCLC, may be surrounded
by large emphysematous bullae or occur in a patient with chronic respiratory failure. In this
setting, even minimally invasive procedures can be associated with a relatively high risk of
pneumothorax that can progress to acute respiratory failure requiring mechanical
ventilation [17]. Thus, a risk-averse patient or patient with poor life expectancy from
chronic obstructive pulmonary disease (COPD) may opt for a low-risk modality (eg,
thoracentesis) or choose to avoid diagnosis completely. (See "Legal aspects in palliative
and end of life care" and "Ethical issues in palliative care".)

APPROACH TO THE PATIENT — The general approach to the diagnosis and staging of
patients with suspected NSCLC is discussed here with the basic assumption that the
diagnosis is unknown. The same approach can be used to stage NSCLC in patients in
whom the diagnosis is known. This approach is in general agreement with the guidelines
from the American College of Chest Physicians (ACCP), the National Comprehensive
Cancer Network (NCCN), the European Society of Thoracic Surgeons
(ESTS), International Association for the Study of Lung cancer/American Thoracic
Society/European Respiratory Society (IASLC/ATS/ERS), and European Society of
Gastrointestinal Endoscopy [18-22]. (See "Computed tomographic and positron emission
tomographic scanning of pulmonary nodules" and "Diagnostic evaluation and management
of the solitary pulmonary nodule".)

Many institutions promote a multi-disciplinary team approach to draft protocols for the
diagnostic work-up and staging of suspected NSCLC [23]. The goal of such protocols is
the provision of a standard of care for patients with suspected NSCLC that is tailored to
the expertise and availability of modalities at the institution. All suggested approaches,
including the one proposed below, should be tailored to the individual patient according to
risk, benefit, and patient preferences. (See 'Individualizing the approach' below and 'Role
of multidisciplinary teams' below.)

Overview — The ideal approach would minimize procedures and maximize safety to
achieve an accurate diagnosis and tumor node metastasis (TNM) stage (table 1) in a
timely fashion. In general, minimally invasive modalities (eg, endoscopic procedures) are
preferred over more invasive modalities (eg, mediastinoscopy) for the initial biopsy.
However, more than one procedure will sometimes be necessary, particularly when initial
tissue sampling provides inconclusive results or is insufficient for molecular
characterization. The selection of a second biopsy procedure should favor modalities that
are more likely to yield a diagnosis. The procedures used to biopsy suspected NSCLC are
discussed in detail separately. (See "Procedures for tissue biopsy in patients with
suspected non-small cell lung cancer".)

Assessing radiologic stage — Prior to biopsy, every patient with suspected NSCLC
should undergo chest computed tomography (CT) with imaging through the upper
abdomen, liver and adrenal glands [18,20,24-26]. If the CT or clinical exam does not
demonstrate distant metastases, whole body positron emission tomography (PET) or
integrated PET/CT can be performed in select populations (eg, operable patients with CT
stage IB to IIIA disease to detect occult metastases). These imaging tests provide the
basis for initial assessment of the TNM stage of disease (table 1). Good knowledge of the
TNM staging system, the mediastinal lymph node map (figure 1), and therapeutic options
for each stage of NSCLC, are necessary prior to making a decision regarding the best
biopsy site. Initial imaging of patients with suspected NSCLC is discussed in detail
separately. (See "Overview of the initial evaluation, diagnosis, and staging of patients with
suspected lung cancer", section on 'Radiographic staging'.)

Our approach — The diagnostic approach below is based upon suspected stage
following imaging. This approach is, in general, consistent with guidelines of the American
College of Chest Physicians (ACCP) [18,19]. The accuracy of the procedures used in this
approach is discussed in detail separately. (See "Procedures for tissue biopsy in patients
with suspected non-small cell lung cancer".)

Suspected stage IA — We and others agree that preoperative staging of the mediastinum
can be omitted for patients with small (<3 cm) peripheral tumors and suspected stage 1A
(T1N0M0) disease (table 1 and algorithm 1). Such patients can proceed to surgical
resection with intraoperative mediastinal sampling to ensure accurate staging for
postoperative management. It is controversial whether lymph nodes should be sampled or
fully dissected intraoperatively. In contrast, those with central tumors or larger peripheral
tumors (>3 cm) require pathologic assessment of N2/3 nodes prior to surgical resection.
(See "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer",
section on 'Staging accuracy' and "Management of stage I and stage II non-small cell lung
cancer", section on 'Mediastinal lymph node dissection'.)

Support for this approach comes from randomized trials that report a low prevalence of
metastatic disease in patients with suspected stage 1A NSCLC (table 1) [27-30]. However,
these data apply specifically to smaller (<3 cm) peripheral tumors, that are not centrally
located, close to, or involving N1 nodes (ie, ipsilateral peribronchial and/or ipsilateral hilar
lymph nodes and intrapulmonary nodes) (table 1). Centrally located tumors can obscure
nodal involvement on imaging studies, thereby lowering the negative predictive value.
The caveat to this approach is that a certain percentage of this population will have occult
disease for which surgery is not indicated. While studies have attempted to identify
populations with peripherally located stage 1A disease that may benefit from further testing
prior to surgery, such a population remains undefined. As an example, one study
suggested that occult disease is more likely to be missed in women and in tumors that do
not classically show PET avidity (eg, carcinoid and low grade adenocarcinoma) [27].
Preoperative sampling can be considered but is not mandatory in this setting.

Thus, for patients with suspected peripheral stage IA NSCLC, we suggest primary
resection rather than preoperative invasive mediastinal staging. This preference
acknowledges a small but potential risk of missing occult N1 or N2 disease.
(See "Management of stage I and stage II non-small cell lung cancer".)

Suspected stage IB, II, or III disease — The sequence of tissue biopsy for diagnosis and
staging should be individualized according to patient characteristics, preference,
radiographic stage, and local expertise. For example, for suspected stage IB or II NSCLC
with a centrally located primary tumor, biopsy of the primary tumor together with
mediastinal sampling (preferably with endobronchial ultrasound) is preferable (ie, a single
procedure). In contrast, for a peripheral mass without obvious radiologic lymph nodes,
biopsy of the peripheral mass or surgical resection followed by mediastinal sampling is
reasonable. For those with obvious stage III or IV disease, targeting the mediastinum or
the metastatic lesion first is prudent.

Population — As a general rule, invasive mediastinal staging is required for most cases of
suspected stage IB, II, and III NSCLC (table 1). Nodes that are suspected to be involved
with NSCLC include lymph nodes that are enlarged on CT (eg, >1 cm) and PET-avid
lymph nodes regardless of their size.

Specifically, for patients not suspected to have distant metastases by CT and/or PET,
mediastinal sampling should be performed in the following cases (algorithm 1):

●Intermediate risk N2 and N3 nodal involvement: central tumor of any size, peripheral
tumor >5 cm, or enlarged ipsilateral hilar lymph nodes (stage IB and
stage IIA/B) (image 6).
●High risk N2 (stage IIIA) or N3 (stage IIIB) nodal involvement (table 1):
enlarged and/or 18-fluoro-2-deoxyglucose (FDG)-avid mediastinal lymph nodes or
contralateral hilar lymph nodes (image 4 and image 5).

N1 nodes are ipsilateral hilar, peribronchial, and intrapulmonary nodes (table 1). N1
disease increases the likelihood of N2 and N3 involvement, such that patients who are
viewed as high risk for N1 disease are intermediate risk for N2/3 NSCLC (algorithm 1).
Examples of patients in this category include those with radiologically-identified N1
disease and those with large (>5 cm) or centrally located tumors. For centrally located
tumors, N1 nodes are at high risk for involvement, either because the tumor is close to a
N1 node, or is located in a N1 nodal region (eg, hilum). In this setting, suspicious activity in
a N1 region is not easily determined by CT or PET scan. In support of this approach, the
high false negative rate (up to 25 percent) of imaging in this setting, suggests that the risk
of missing occult N2/3 disease is high [28-31]. For patients with T2a lesions (stage IB),
preoperative staging of the mediastinum is controversial. However, we prefer mediastinal
staging given the significant prevalence (10 to 15 percent) of occult N2 disease in this
population [31].

N2 nodes are ipsilateral mediastinal and/or subcarinal lymph node(s). N3 nodes are
contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or
supraclavicular lymph node(s). Patients with suspected mediastinal N2 (stage IIIA) or N3
(stage IIIB) disease by CT or PET scan, are clearly high risk for pathologically
proven N2/3 NSCLC. Biopsy should be targeted to the suspected lymph node regardless
of which modality indicates suspicion (table 1). There are two exceptions to this rule:

●Patients with bulky disease infiltrating the mediastinum (ie, mostly T4 disease) are
generally not considered to be surgical candidates (image 7). Thus, in this setting,
radiologic imaging is considered acceptable for assessment of disease stage and the
primary goal of biopsy is solely diagnostic (table 1). (See "Management of stage III
non-small cell lung cancer" and "Procedures for tissue biopsy in patients with
suspected non-small cell lung cancer".)
●Patients with suspected N3 disease in a supraclavicular node should undergo
biopsy of the supraclavicular node rather than the mediastinum. (See 'Suspected
stage IV or supraclavicular node disease' below.)

Modality choice — The selection of a biopsy procedure for patients with suspected 1B
through IIIB disease is made in the context of the location of the primary tumor and
suspected lymph nodes, available expertise, treatment options for the suspected stage,
and patient safety and preferences. When choosing one modality over another, knowledge
of the accessibility of the primary tumor and lymph nodes (figure 1) by the wide variety of
minimally invasive and invasive procedures is critical. In general, endobronchial
ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) with or without
transesophageal endoscopic ultrasound fine needle aspiration (EUS-FNA) aspiration are
the preferred first-step procedures for sampling accessible tumors or metastases
(algorithm 1). Recognizing that not all cases of suspected NSCLC are suitable candidates
for this approach, alternative modalities and modifications are suggested based upon
procedure availability, institutional expertise, and patient-specific factors.
(See 'Individualizing the approach' below.)

Although microarrays have been studied as potential diagnostic tools designed to enhance
the sensitivity of bronchoscopy for the diagnosis of lung cancer, further study is required
before they can be recommended for routine use [32].
EBUS/EUS needle aspiration — EBUS-TBNA with or without EUS-FNA is the preferred
first-step procedure for large, centrally located tumors and for suspicious nodal
involvement in the anterior and superior mediastinum (2R, 2L, 3p, 4R, 4L, 7, 10R, 10L,
11R, 11L) (figure 1). This preference is based upon the reported high sensitivity of
bronchoscopy with EBUS-TBNA to stage and diagnose NSCLC in this setting and its
ability to access more nodal stations than the traditional gold standard, cervical
mediastinoscopy [33-39]. Multiple needle passes by an experienced operator and rapid on
site cytologic evaluation (ROSE) are suggested to increase the diagnostic yield of EBUS-
TBNA samples [4,7-13,40,41]. The general use of EBUS and the studies that describe its
sensitivity for the diagnosis and staging of NSCLC are discussed separately.
(See "Endobronchial ultrasound: Indications, contraindications, and
complications" and "Procedures for tissue biopsy in patients with suspected non-small cell
lung cancer", section on 'Endobronchial ultrasound'.)

Consideration can be given to the addition of EUS-FNA to provide additional access to the
posterior and inferior mediastinal lymph nodal stations (3p, 7, 8, and 9) (figure 1). Support
for the combined approach (EBUS-TBNA plus EUS-FNA) comes from small randomized
trials that suggested the combined approach enhance the accuracy of staging and may
reduce the incidence of futile thoracotomies [42,43]. This study and the diagnostic
accuracy of the combined approach to mediastinal staging are discussed in detail
separately. (See "Procedures for tissue biopsy in patients with suspected non-small cell
lung cancer", section on 'Combined modalities'.)

When EBUS-TBNA (+/- EUS-FNA) is available, the following general guidelines can be
applied:

●When EBUS-TBNA (+/- EUS-FNA) confirms NSCLC in a suspected lymph node, the
disease can be adequately clinically staged (cTNM) provided the clinician is confident
that the lymph node with the highest suspected stage has been biopsied. Thus, when
positive, no further diagnostic or staging workup is necessary. (See "Procedures for
tissue biopsy in patients with suspected non-small cell lung cancer", section on
'Diagnostic and staging accuracy'.)
●When EBUS-TBNA (+/- EUS-FNA) is negative or inconclusive, disease can be
missed and staging is imprecise. Thus, in this setting further biopsy is indicated.
When possible, we prefer to proceed with a more invasive surgical approach (usually
mediastinoscopy) rather than performing repeat endoscopic sampling.
(See "Procedures for tissue biopsy in patients with suspected non-small cell lung
cancer", section on 'Diagnostic and staging accuracy' and "Procedures for tissue
biopsy in patients with suspected non-small cell lung cancer", section on
'Limitations' and "Procedures for tissue biopsy in patients with suspected non-small
cell lung cancer", section on 'Surgical staging procedures'.)

The investigating clinician should always weigh the accuracy of EBUS-TBNA in the context
of its limitations (eg, inability to access inferior [8, 9] and para-aortic [5, 6] nodes and
variable operator proficiency). The limitations of EBUS-TBNA and the importance of
individualizing the approach are discussed separately. (See "Procedures for tissue biopsy
in patients with suspected non-small cell lung cancer", section on
'Limitations' and 'Individualizing the approach' below.)

Alternative modalities — Alternative modalities should be sought when lymph node


enlargement is not amenable to EBUS-TBNA (eg, para-aortic and subaortic lymph node
[stations 5 and 6]) or when EBUS-TBNA is not available or has failed to obtain adequate
material for a diagnosis (either from a primary tumor or a lymph node) (algorithm 1).

The safest modality that maximizes the ability to achieve a diagnosis should be chosen for
a specific target lesion. The options available for sampling the primary lesion are the
following:

●Conventional bronchoscopy (with bronchoalveolar lavage, bronchial biopsy,


transbronchial biopsy, transbronchial needle aspiration [bronchoscopic-TBNA]), is
useful for biopsy of large central lesions (see "Procedures for tissue biopsy in patients
with suspected non-small cell lung cancer", section on 'Conventional bronchoscopy')
●Image-guided transthoracic needle aspiration (TTNA) (see "Procedures for tissue
biopsy in patients with suspected non-small cell lung cancer", section on
'Transthoracic needle biopsy')
●Electromagnetic navigational bronchoscopy, although potentially useful, is not
widely available (see "Procedures for tissue biopsy in patients with suspected non-
small cell lung cancer", section on 'Electromagnetic navigational bronchoscopy')
●Video-assisted thoracic surgery (VATS) can access most primary tumors, but
carries a higher risk of perioperative morbidity and mortality (see "Procedures for
tissue biopsy in patients with suspected non-small cell lung cancer", section on
'Video-assisted thoracic surgery')

When a biopsy of the primary lesion is the initial target, an additional staging procedure
may be needed:

●Cervical mediastinoscopy, the historical gold standard for staging the mediastinum,
is a sensitive staging procedure for nodal stations easily accessed by this approach
(1, 2, 3, 4, anterior 7, 10) (figure 1). (See "Procedures for tissue biopsy in patients
with suspected non-small cell lung cancer", section on 'Staging accuracy'.)
●VATS is considered when other procedures have failed to acquire adequate tissue
to diagnose and stage suspected NSCLC. It is an accurate modality for evaluating the
extent of invasion (chest wall, mediastinal) by the primary tumor (T). It is also useful
for sampling ipsilateral mediastinal lymph nodes (4, 5, 6, 7, 8, 9, 10 to 14) (figure 1)
(N) and for detecting pleural involvement (M1a) (table 1). It typically cannot sample
the contralateral side. (See "Procedures for tissue biopsy in patients with suspected
non-small cell lung cancer", section on 'Video-assisted thoracic surgery'.)
●Anterior mediastinotomy (chamberlain procedure) is often the only option when
suspicious lymph nodes are identified in the para-aortic and subaortic lymph node
stations (station 5 and 6). EUS-FNA can reach the anterior-posterior window but is
not readily available in many institutions. (See "Procedures for tissue biopsy in
patients with suspected non-small cell lung cancer", section on 'Anterior
mediastinotomy (Chamberlain procedure)'.)
●Extended mediastinal cervical mediastinoscopy (ECM), video-assisted mediastinal
lymphadenectomy (VAMLA), and transcervical extended mediastinal
lymphadenectomy (TEMLA) are staging procedures that are not widely available.
Their use is best dictated by expertise at the practicing institution. (See "Procedures
for tissue biopsy in patients with suspected non-small cell lung cancer", section on
'Extended cervical mediastinoscopy' and "Procedures for tissue biopsy in patients
with suspected non-small cell lung cancer", section on 'Video-assisted mediastinal
lymphadenectomy' and "Procedures for tissue biopsy in patients with suspected non-
small cell lung cancer", section on 'Transcervical extended mediastinal
lymphadenectomy'.)

Suspected stage IV or supraclavicular node disease — When isolated distant (M1a,


M1b) disease (table 1), or supraclavicular node involvement (N3, stage IIIB) is suspected,
additional imaging and invasive sampling of these sites is indicated for pathological
confirmation (algorithm 1). Many of the techniques used to sample distant metastases
depend upon small biopsies and cytology for diagnosis. Thus, consideration should be
given to obtaining enough material at the time of biopsy for diagnosis,
immunohistochemistry, and mutational analysis. (See 'Adequate biopsy size' above.)

Biopsy of distant sites is crucial because a positive sample (eg, liver or bone) will confirm
stage IV disease and direct the patient to treatment with chemotherapy and/or radiation.
Comparatively, a negative biopsy (eg, benign nodule in the contralateral lung or benign
pleural pathology) can dramatically change disease stage and open up the possibility for
curative surgery and improved life expectancy. When radiographic evidence is
overwhelming for multiple sites of metastases, choosing the safest or easiest approach for
pathologic confirmation of suspected NSCLC is preferable. (See "Management of stage I
and stage II non-small cell lung cancer" and "Overview of the treatment of advanced non-
small cell lung cancer" and "Management of stage III non-small cell lung cancer".)

Suggested procedures to obtain tissue for extrathoracic sites are discussed in this section.
Imaging and accuracy of sampling distant sites is discussed separately. (See "Overview of
the initial evaluation, diagnosis, and staging of patients with suspected lung cancer",
section on 'Imaging metastatic disease' and "Procedures for tissue biopsy in patients with
suspected non-small cell lung cancer", section on 'Sampling metastatic disease'.)

●Pleural (M1a) – Two common clinical presentations of pleural disease are:


metastases associated with pleural effusion or multiple pleural-based nodules and
direct extension of the primary tumor to the pleura or chest wall. Direct extension of
the primary tumor into the visceral or parietal pleura needs to be distinguished from
metastatic NSCLC of the pleural space. Primary tumor that infiltrates visceral or
parietal pleura is staged as a T2 or T3 lesion, respectively (table 1). T2/3 lesions are
potentially operable. In contrast, metastatic NSCLC discovered as solid lesion(s) in
the visceral or parietal pleura that is distinct from the primary tumor or as malignant
cells in an effusion represent M1a disease that is inoperable. Thus, when pleural
metastases are suspected, it is essential to sample the pleural space by
thoracentesis for pleural fluid cytology and/or pleural biopsy [18,19,44-47]. In general,
the following applies:
•For patients with effusions suspected to be due to NSCLC, thoracentesis is
indicated. Thoracentesis is performed preferably under ultrasound guidance with
a goal of drawing at least 50 mL of pleural fluid. If cytology is negative for cancer,
repeated sampling can be considered before proceeding to biopsy. In the event
that thoracentesis is unrevealing diagnostically, a thoracoscopic biopsy is
indicated. (See "Procedures for tissue biopsy in patients with suspected non-
small cell lung cancer", section on 'Suspected pleural metastases'.)
•For patients with solid pleural lesions or thickening, a thoracoscopic or image-
guided biopsy is necessary to confirm suspected NSCLC. Compared to either of
these modalities, closed pleural biopsy has limited utility for sampling suspected
pleural NSCLC. (See "Procedures for tissue biopsy in patients with suspected
non-small cell lung cancer", section on 'Suspected pleural metastases'.)
●Lung (M1a) – Selecting a diagnostic procedure for potential metastases in the
contralateral lung uses the same principles as tool selection for diagnosis of the
primary lung cancer. The approach to solitary pulmonary lesions and procedures
used to biopsy suspected NSCLC are discussed in detail elsewhere. (See "Diagnostic
evaluation and management of the solitary pulmonary nodule", section on
'Management strategy' and "Procedures for tissue biopsy in patients with suspected
non-small cell lung cancer", section on 'Intrathoracic'.)
●Pericardium (M1a) – Sampling and treating suspected malignant disease of the
pericardium is discussed separately. (See "Pericardial disease associated with
malignancy" and "Procedures for tissue biopsy in patients with suspected non-small
cell lung cancer", section on 'Intrathoracic'.)
●Liver (M1b) – Liver lesions can be sampled by CT-guided percutaneous fine
needle aspiration/biopsy or by EUS-FNA [48]. The choice of modality will depend
upon local expertise. (See "Percutaneous, fine-needle aspiration, and laparoscopic
liver biopsy" and "The adrenal incidentaloma", section on 'Fine-needle aspiration
biopsy'.)
●Adrenal gland – Adrenal gland lesions with radiographic features suspicious for
malignancy can be sampled by percutaneous fine needle aspiration/biopsy or less
commonly, by EUS-FNA [49-51]. However, the choice of modality for adrenal gland
biopsy will depend upon local expertise. (See "Percutaneous, fine-needle aspiration,
and laparoscopic liver biopsy" and "The adrenal incidentaloma", section on 'Fine-
needle aspiration biopsy' and "Procedures for tissue biopsy in patients with suspected
non-small cell lung cancer", section on 'Extrathoracic'.)
●Brain – Biopsy of the brain is sometimes performed when patients present with
neurological symptoms or signs and a focal abnormality on brain imaging without
prior knowledge of primary NSCLC in the chest. In contrast, brain biopsies are
considered high risk procedures and only rarely performed when a symptomatic or
asymptomatic brain lesion is detected by imaging during the evaluation of a patient
with NSCLC. In these circumstances, biopsy of the primary lesion is the preferred
initial procedure, and neurosurgical consultation should be obtained to help weigh the
potential benefits and harms of brain biopsy in the individual patient. (See "Clinical
presentation and diagnosis of brain tumors", section on 'Brain metastases'.)
●Bone – Typically, a core biopsy by CT guidance is performed when the suspected
lesion can be readily imaged by CT. However, practice may vary locally. Techniques
used to biopsy bone are discussed separately. Bone biopsies are suboptimal for
molecular diagnostic studies due to the need for decalcification. Biopsy of other
metastatic sites is preferable if they are present. (See "Bone tumors: Diagnosis and
biopsy techniques", section on 'Biopsy techniques'.)
●Supraclavicular lymph node – Needle aspiration or biopsy of the supraclavicular
lymph node is a simple, low-risk procedure that is frequently used to identify
suspected NSCLC involvement of a supraclavicular lymph node. (See "Evaluation of
peripheral lymphadenopathy in adults", section on 'Localized lymphadenopathy'.)

INDIVIDUALIZING THE APPROACH — Despite the increasing availability of guidelines


and algorithms for the diagnosis of NSCLC, there must remain room for individualization.
As such, the algorithm should be tailored to the individual patient. Factors that influence
what site to biopsy and what modality to use include tumor location and characteristics,
patient comorbidities, and local expertise, as well as patient values and preferences. It is
critical that physicians be knowledgeable regarding the accuracy of each modality to
access the specific tumor or node undergoing evaluation and discuss this information with
the patient. In addition, institution-specific factors such as availability of equipment,
procedural proficiency and training of clinicians for minimally invasive and invasive
interventions, and pathological protocols, can alter the choice of test for tissue sampling
[9,12]. The accuracy of each procedure is discussed separately. (See "Procedures for
tissue biopsy in patients with suspected non-small cell lung cancer".)

Role of multidisciplinary teams — There has been a shift in practice towards a


collaborative approach, such that many cancer centers incorporate a multidisciplinary
team (MDT) for the discussion of collective decisions focused on the diagnosis and
treatment of patients with lung cancer [2-6,20,23,44,52]. Lung cancer MDTs involve any
combination of the following sub-specialties: a pulmonologist, interventional pulmonologist,
medical and radiation oncologists, thoracic surgeon, pathologist, radiologist, and specialist
nurse. The ease of communication between specialists for discussions regarding selection
of tests and treatments has fueled the growth of MDTs within hospitals and clinics. In
addition, MDTs can participate in drafting institutional protocols to optimize the utilization of
available services and standardize their approach to the evaluation and treatment of
patients with suspected NSCLC. Guidelines from the American College of Chest
Physicians (ACCP), European Society of Thoracic Surgeons (ESTS), and International
Association for the Study of Lung cancer/American Thoracic Society/European Respiratory
Society (IASLC/ATS/ERS) can be used as resources for each institution to develop their
own approach to tissue biopsy for the diagnosis and staging of NSCLC [4,18,20,21].

TNM STAGING — The 7th edition of the tumor node metastasis (TNM) staging system for
NSCLC is essential to guiding management and determining prognosis in patients with
NSCLC (table 1). The TNM staging system for NSCLC, the value of assessing radiologic
stage prior to biopsy, and therapies for each stage are discussed separately. (See "Tumor,
node, metastasis (TNM) staging system for non-small cell lung cancer" and "Management
of stage I and stage II non-small cell lung cancer" and "Management of stage III non-small
cell lung cancer" and "Overview of the treatment of advanced non-small cell lung
cancer" and 'Assessing radiologic stage' above.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education


materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Non-small cell lung cancer (The Basics)")
●Beyond the Basics topics (see "Patient education: Non-small cell lung cancer
treatment; stage I to III cancer (Beyond the Basics)" and "Patient education: Non-
small cell lung cancer treatment; stage IV cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●The appropriate management of patients with non-small cell lung cancer (NSCLC)
requires pathologic confirmation of the disease and accurate staging to determine
treatment and prognosis. The target for biopsy should be selected based upon an
initial evaluation consisting of a detailed history, physical exam, routine laboratory
studies and imaging. The approach should be tailored to the individual patient
according to risk, benefit, and patient preferences (algorithm 1). (See 'Biopsy
indications' above.)
●For all patients with suspected NSCLC, biopsy of the lung, lymph node, or distant
organ should aim to provide enough material for an accurate histopathologic,
immunohistochemical, and molecular assessment. Most pathology laboratories
consider a tissue volume of 1 mm3 to be adequate. Clinicians should aim to diagnose
and stage NSCLC with the minimal number of invasive procedures. Despite this,
many patients will require more than one biopsy procedure. (See 'Adequate biopsy
size' above and 'Efficient diagnosis and procedures' above.)
●All patients with suspected NSCLC should undergo computed tomography (CT) of
the chest, liver, and adrenal glands (preferably contrast-enhanced) prior to biopsy. In
addition, we perform whole body positron emission tomography (PET) or
integrated PET/CT in those with potentially operable disease with clinical stage IB to
IIIA disease to detect occult nodal disease or metastases. These imaging tests
provide the basis for the initial assessment of the tumor node metastasis (TNM) stage
(table 1) of disease and guide the clinician toward choosing the optimal biopsy site
(algorithm 1). (See 'Assessing radiologic stage' above.)
●For patients with peripheral tumors and suspected stage IA (T1N0M0) preoperative
invasive staging of the mediastinum can be omitted. These patients can proceed to
surgical resection with intraoperative mediastinal sampling (algorithm 1).
(See 'Suspected stage IA' above.)
●For most patients with suspected stage IB, II, and III NSCLC, mediastinal lymph
node sampling is indicated. Sampling is particularly important in those with suspected
intermediate risk N2/N3 nodal involvement (stage IB and stage IIA/B) and those with
high risk N2/N3 (stage IIIA/B) nodal involvement (table 1 and algorithm 1)
(see 'Suspected stage IB, II, or III disease' above):
•For most patients with suspected IB, II, and III NSCLC, invasive mediastinal
sampling is indicated. The modality for tissue sampling is selected in the context
of the location of the primary tumor and suspected lymph nodes, available
expertise, and patient safety and preferences. In general, the following applies:
-Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-
TBNA) with or without transesophageal endoscopic ultrasound fine needle
aspiration (EUS-FNA) is the preferred approach for tissue biopsy for
accessible nodes. When EBUS-TBNA (+/- EUS-FNA) confirms NSCLC, no
further diagnostic or staging workup is necessary. When EBUS-
TBNA (+/- EUS-FNA) is negative or inconclusive, disease can be missed
and mediastinoscopy is usually indicated. (See 'EBUS/EUS needle
aspiration' above.)
-In patients with suspected NSCLC who are not suitable candidates
for EBUS-TBNA/EUS-FNA or in whom EBUS-TBNA/EUS-FNA is
inconclusive, an alternative modality (usually mediastinoscopy) is selected
based upon procedure availability, institutional expertise, and patient-
specific factors. (See 'Alternative modalities' above.)
•For patients with suspected NSCLC who have radiologic evidence on CT of
bulky disease infiltrating the mediastinum, radiologic imaging is considered
acceptable for the assessment of disease stage and the primary goal of biopsy is
tumor sampling to confirm the diagnosis. (See 'Suspected stage IB, II, or III
disease' above.)
●For patients with suspected NSCLC in whom isolated distant (M1a, M1b) disease
(table 1) or supraclavicular node involvement (N3, stage IIIB) is suspected, invasive
sampling of these sites for pathological confirmation is indicated. When radiographic
evidence is overwhelming for multiple sites of metastases, choosing the safest or
easiest approach for pathologic confirmation of suspected NSCLC is preferred
(algorithm 1). (See 'Suspected stage IV or supraclavicular node disease' above.)
•For patients with suspected NSCLC and a pleural effusion, thoracentesis is
indicated. Thoracentesis is performed preferably under ultrasound guidance with
a goal of drawing at least 50 mL of pleural fluid. If cytology is negative or
inconclusive, repeated sampling can be considered before proceeding to
thoracoscopic biopsy.
•For patients with solid pleural lesions or thickening, a thorascopic or image-
guided biopsy is necessary to confirm suspected NSCLC. Closed pleural biopsy
has limited utility for sampling suspected pleural NSCLC.
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Tumor, node, metastasis (TNM) staging system for non-small cell lung cancer
Authors:
Karl W Thomas, MD
Michael K Gould, MD, MS
Section Editors:
James R Jett, MD
Rogerio C Lilenbaum, MD, FACP
Deputy Editor:
Sadhna R Vora, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Dec 2016. | This topic last updated: Jan 16, 2017.

INTRODUCTION — The Tumor, Node, Metastasis (TNM) staging system for non-small
cell lung cancer (NSCLC) is an internationally accepted system used to characterize the
extent of disease. The TNM system combines features of the tumor into disease stage
groups that correlate with survival and are linked to recommendations for treatment.
Despite the evolving staging system, the links between stage and treatment have become
weaker, given that older studies of stage-specific treatments were performed at a time that
predated the staging techniques and treatments of modern clinical practice.

The purpose of TNM staging is to provide a description of the anatomic extent of cancer
that can be easily communicated to others, assist in treatment decisions, and serve as an
indicator of prognosis. It allows a way to compare cases, particularly in regards to the
outcomes associated with different therapeutic options. In clinical practice, TNM stage is
combined with the unique clinical characteristics of the patient and, in some cases, the
molecular features of the tumor itself to guide prognostic assessment and treatment
selections.

The eighth edition of the TNM staging system and the evidence supporting it are described
in this topic (table 1 and table 2) [1,2]. The eighth edition will replace earlier editions of the
TNM staging system beginning January 1, 2018. All newly diagnosed cases through
December 31, 2017 should be staged with the seventh edition (table 3). Other relevant
topics include:

●(See "Overview of the risk factors, pathology, and clinical manifestations of lung
cancer".)
●(See "Overview of the initial evaluation, diagnosis, and staging of patients with
suspected lung cancer".)
●(See "Overview of the initial evaluation, treatment and prognosis of lung cancer".)
●(See "Management of stage I and stage II non-small cell lung cancer".)
●(See "Adjuvant systemic therapy in resectable non-small cell lung cancer".)
●(See "Management of stage III non-small cell lung cancer".)
●(See "Overview of the treatment of advanced non-small cell lung cancer".)

RATIONALE FOR DISTINCTION BETWEEN NSCLC AND SCLC — Lung cancer has
been subclassified into these two major categories (NSCLC and small cell lung carcinoma
[SCLC]) as the result of differences in clinical features, approach to treatment, and clinical
outcomes. In general, SCLC tends to have a faster growth rate, more central and
mediastinal localization, earlier metastasis to extrathoracic sites, and shorter overall
survival time.

Small cell carcinoma is usually staged and managed using a simplified system of clinical
limited or clinical extensive disease. The main role for TNM staging in SCLC is to improve
the specificity of information contained in clinical cancer registries and clinical research.
(See "Pathobiology and staging of small cell carcinoma of the lung", section on 'Staging'.)

EIGHTH EDITION OF THE TNM SYSTEM — The eighth edition was a planned revision to
incorporate new survival data gained from advances in imaging techniques, clinical testing,
and therapeutics [2].

To inform the eighth edition of the TNM staging system, the International Association for
the Study of Lung Cancer (IASLC) developed a database of approximately 95,000 patients
with lung cancer who were treated in 16 countries between 1999 and 2010 (table
1 and table 4) [1,3,4]. Comparison with seventh edition staging is shown in the table (table
2). This database was composed of data from diverse sources (90,041 patients) and
cases from an electronic data capture system developed by Cancer Research And
Biostatistics (CRAB, 4667 patients). Data from 70,967 patients with NSCLC were used to
retrospectively validate the prognostic value of the TNM descriptors [3].

As with previous editions, the current edition of the TNM staging system categorizes
tumors on the basis of primary tumor characteristics (T), the presence or absence of
regional lymph node involvement (N), and the presence or absence of distant metastases
(M). Molecular tumor features of lung cancer are not included in the TNM system. The
overall stage of the tumor (stage I through IV) is determined by the combination of T, N,
and M descriptors. The suffix "X" is attached (eg, TX, NX, or MX) if the extent of disease
cannot be assessed for any of these features. The same TNM staging system is used to
determine the clinical-diagnostic stage, surgical-pathologic stage, retreatment stage, and
autopsy stage.

Differences between eighth and seventh editions — Revisions to the seventh edition
were made in order to improve the prognostic ability of the staging categories and cut-off
points. The eighth edition will replace earlier editions of the TNM staging system beginning
January 1, 2018 (table 1 and table 2) [2]. The seventh edition is shown for reference in the
following table (table 3) [5].

Primary tumor — Major changes between the seventh and the eighth editions include the
following [1,2]:

●T1 changes – New stage groupings divide T1 tumors into T1a (≤1 cm), T1b (>1 to
≤2 cm), and T1c (>2 to ≤3 cm).
●T2 changes – T2 tumors have a size cutoff of 5 cm now, rather than 7 cm.
Involvement of the mainstem bronchus, regardless of distance from carina, is now T2
rather than T3. Both partial and total atelectasis/pneumonitis are now T2.
●T3 and T4 changes – Tumors greater than 5 to less than or equal to 7 cm are now
T3 instead of T2; tumors greater than 7 cm now fall into a new T4A grouping.
Diaphragm invasion is now T4 rather than T3.
A new stage category has been developed for T3 and T4 tumors, which are now
classified as stage IIIC when accompanied by contralateral lymph node (N3)
involvement. (See 'Changes to the stage groupings' below.)

These changes were made based on analysis of outcomes of 33,115 patients who had
either a clinical or a pathologic classification, known tumor size, sufficient T information,
and no metastases. An analysis of survival is summarized below [6]:

●A clear downward shift in survival with each centimeter increase in tumor size was
observed, suggesting that a new T staging system with more subsets that differed in
size by 1 cm was needed (figure 1).
●Tumors greater than 5 cm but equal to or less than 7 cm aligned better with a T3
prognosis than with a T2b, and those larger than 7 cm had a survival similar to that of
T4 tumors. These observations led to the new size cutoffs for T3 and T4 tumors.
●Invasion of the bronchus less than 2 cm from the carina, a T3 descriptor in the
previous classification, had a better prognosis than was previously thought, aligning
with that of T2 tumors.

Regional lymph nodes — Although N descriptors from the seventh edition consistently
predicted prognosis and were carried forward in the eighth edition, an exploratory
subclassification of pathologic N1 and N2 disease based on the number of involved nodal
stations and individual nodes was proposed (figure 2) [2,7]:
●pN1 – Involvement of ipsilateral intrapulmonary, peribronchial, or hilar lymph nodes.
•pN1a: Single station metastasis
•pN1b: Multiple station metastasis
●pN2 – Involvement of ipsilateral mediastinal or subcarinal lymph nodes.
•pN2a1: Single N2 station without concurrent N1 station involvement (skip
metastasis)
•pN2a2: Single N2 station with concurrent N1 involvement
•pN2b: Multiple N2 station metastasis

For the analysis of the clinical (c)N and pathologic (p)N status, 38,910 and 31,426 patients
with NSCLC were available, respectively [7]. The five-year survival rates according to the
cN and pN status were 60 and 75 percent (N0), 37 and 49 percent (N1), 23 and 36 percent
(N2), and 9 and 20 percent (N3), respectively. The differences between nodal categories
were all significant.

For pathologic staging, additional analyses revealed separation in survival based on the
number of unique lymph nodes involved in N1 and N2 stations [7], leading to the new
subdivisions proposed in the eighth edition. The presence of a "skip" metastasis, in which
a single focus of N2 disease is present without N1 disease (pN2a1), was associated with
an improved survival compared with disease in which both an N2 focus and an N1 focus
were present (N2a2). No statistically significant differences in survival were observed for
those with pN1b and pN2a disease, both of which had five-year survival rates of
approximately 50 percent. Because these new subclassifications of nodal metastasis were
based on smaller numbers of patients from a limited number of institutions, it is proposed
that these be routinely recorded and considered for inclusion in future staging paradigm
revisions. These nodal designations by themselves do not determine treatment options,
but rather should be considered together with patient-specific factors in clinical decision-
making.

As in previous staging systems, regional lymph nodes are divided into stations by laterality
(right versus left) and location. Lymph node stations are designated by numbers 1 through
14 according to an internationally accepted schema (figure 3) [8].

Metastasis — In the eighth edition of the TNM staging system, metastatic disease
continues to be classified as M1a if it is limited to the chest (cases
with pleural/pericardialeffusions, contralateral lung or pleural nodules, or a combination of
these factors) [2,9]. If not confined to the chest, there is now a new category, M1b,
designating a single extrathoracic metastasis, which is distinguished from M1c, in which
there are multiple metastatic lesions (in one or multiple organs) (table 1). These changes
led to the designation of stage IVa disease, in which disease is limited to either
intrathoracic metastatic involvement or a single extrathoracic metastasis, versus stage IVb
disease, in which multiple extrathoracic metastases exist. It is intended that this degree of
precision will ultimately help guide treatment options for oligometastatic disease.
These changes were based on overall survival results from 1059 cases of metastatic
NSCLC [9]. In this analysis, patients with M1a and M1b disease had similar survival, which
differed from that of patients with M1c disease (11.5 months, 95% CI 10 to 13.8 months;
11.4 months, 95% CI 9.6 to 13.7 months; and 6.3 months, 95% CI 4.8 to 7 months,
respectively) (figure 4).

Changes to the stage groupings — Changes made in the eighth edition TNM categories
have resulted in alterations in assigned disease stage (table 2) [2]. For example [1]:

●Some tumors that are now assigned to a different T category result in a different
stage. For example, tumors that invade the diaphragm are now T4, making them at
least stage IIIA disease rather than stage IIB disease.
●Some T descriptors have been assigned to a higher stage. For example, all T1N1
tumors are now stage IIB rather than IIA disease.
●In some situations, both of these influences apply. For example, tumors that are
larger than 5 cm are now T3 rather than T2b, causing them to be grouped into higher
stages, regardless of the N category.

A new disease category stage IIIC has been created for patients with N3 disease and
either a T3 or T4 primary lesion [1]. This new category reflects the poor prognosis of such
cancers relative to stage IIIB cancers. Although the prognosis for stage IIIC disease is
similar to stage IV disease, the distinction is made due to different treatment approaches
available for locally advanced, nonmetastatic disease. (See "Management of stage III non-
small cell lung cancer", section on 'Mediastinal (N2, N3) lymph node
disease' and "Overview of the treatment of advanced non-small cell lung cancer".)

Prognosis by stage — Under the eighth edition of the TNM staging system, the median
survival correlates with both the clinical stage and surgical-pathologic stage. The survival
according to clinical and pathologic staging for the eighth edition (and seventh edition, for
comparison) is shown in the tables (figure 5 and figure 6).

For most distinct disease categories, there was a difference in survival relative to the next
lower and higher stage. In cases where this was not the case, differences in treatment
approach between disease categories have driven the separation, for example between
stage IIIC and stage IVA disease.

SEVENTH EDITION OF THE TNM SYSTEM — The seventh edition of the TNM staging
system for NSCLC was in place starting January 1, 2010 and will continue until December
31, 2017 [1]. The seventh edition is shown in the table (table 3).

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education


materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
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patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Lung cancer risks, symptoms,
and diagnosis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●The Tumor, Node, Metastasis (TNM) staging system for non-small cell lung cancer
(NSCLC) is an internationally accepted system used to determine the extent of
disease. The purpose of TNM staging is to provide a description of the extent of
cancer that can be easily communicated to others, assist in treatment decisions, and
serve as a prognostic indicator. (See 'Introduction' above.)
●The TNM staging system relies on anatomic groupings of disease with similar
prognoses rather than on molecular characterization. (See 'Introduction' above.)
●The TNM staging system predicts survival, but should not be used alone to dictate
treatment. Periodic revisions are necessary because advanced imaging techniques
and treatments continue to evolve and impact survival. (See 'Eighth edition of the
TNM system' above.)
●The most recent version of the TNM staging system is the eighth edition of the "TNM
Classification of Malignant Tumors," which goes into effect as of January 1, 2018. All
newly diagnosed cases through December 31, 2017 should be staged with the
seventh edition (table 3). The eighth edition includes new tumor stage groupings and
refinements of the T and M descriptors (table 1 and table 4). (See 'Differences
between eighth and seventh editions' above.)
•The eighth edition continues the trend initiated in previous additions to
emphasize size cutoffs, such that there are distinct categories for each cm
increase in size from 1 to 5 cm. (See 'Primary tumor' above.)
•Although there were no changes in the N descriptors from the seventh to the
eighth editions, the eighth edition makes the additional recommendation to
quantify nodal disease by the number of involved nodal stations. (See 'Regional
lymph nodes' above.)
•Metastatic disease is divided according to whether metastatic disease is limited
to the chest, and if not, whether there are single or multiple extrathoracic sites of
metastasis. (See 'Metastasis' above.)
●Several changes in disease groupings were made in the eighth edition of the TNM
staging system (table 2). The new tumor stages better reflect prognosis of disease
than previous staging systems. (See 'Changes to the stage groupings' above
and 'Prognosis by stage' above.)
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REFERENCES

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