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31]

Original Article

Nasopharyngeal carcinoma with headaches

as the main symptom: A potential
diagnostic pitfall
ABSTRACT Zhou-Xue Wu,
Background: The aim of this study was to investigate medical‑related reasons for misdiagnosis of nasopharyngeal carcinoma (NPC) Li Xiang1,
patients presenting with headaches alone or accompanied by other symptoms.
Jin-Feng Rong1,
Huai-Lin He1,
Patients and Methods: Two‑hundred and nineteen NPC cases describing headaches as one of the initial symptoms during primary Dan Li1
treatment were selected for this prospective study. Medical records were carefully collected and all data were summarized for final
analyses. Department of Clinical
Medicine, Xiangya
Result: Distributions of NPC stage in the patients were: Stage II, 1.4%; stage III, 46.6%; stage IVA, 36.1%; stage IVB, 7.7%; School of Medicine,
and stage IVC, 8.2%. The ratio of men to women was 2.42:1 (155/64 cases). The total misdiagnosis rate was 43.4%. Patients Central South
that only complained of headaches had the highest misdiagnosis rate of 86.4% (19/22 cases). The lowest misdiagnosis rate of University, Changsha,
10.9% (5/46 cases) was observed in patients with both headaches and epistaxis. The misdiagnosis rate in rural hospitals was more Hunan, 1Department
of Oncology, Affiliated
than two times that in provincial hospitals. Neurosurgery departments had a 100% misdiagnosis rate.
Hospital of Luzhou
Conclusion: Frequently, headaches are the only prominent symptom of NPC. Due to the various clinical manifestations, NPC patients Medical College,
encounter a high misdiagnosis rate, which leads to unsatisfactory treatment outcomes. Improved awareness of the various nonspecific Luzhou, Sichuan,
symptoms of NPC by nonspecialist physicians will be a pivotal step in decreasing the misdiagnosis rate. China

Mini Abstract: The misdiagnosis rate of nasopharyngeal carcinoma (NPC) patients with headaches was 43.4%. Improved awareness For correspondence:
of the various nonspecific symptoms of NPC is a pivotal step in decreasing the misdiagnosis rate. Dr. Li Xiang,
Department of
Oncology,
KEY WORDS: Headaches, misdiagnose, nasopharyngeal carcinoma Affiliated Hospital
of Luzhou Medical
College,
25 Taiping Road,
INTRODUCTION headache accompanied by other symptoms like Luzhou-646 000,
neck mass, nasal congestion, blood secretion, Sichuan, China.
E-mail: xl790927@
Nasopharyngeal carcinoma (NPC) is particularly diplopia, tinnitus, ear problems, etc. The
sina.com
common in southern China.[1] Due to the internal following medical examinations were performed
location of NPC and varied clinical symptoms, most to determine the precise pretreatment stage:
patients are in a locally advanced stage before General physical examination, hematological
diagnosis.[2] Headaches are the main symptom indices, nasopharyngeal fiberscope, chest X‑ray
because of the skull‑base invasion, intracranial or computed tomography (CT), ultrasound of
metastases, or skull‑base osteoradionecrosis. abdomen, magnetic resonance imaging (MRI)
Lack of knowledge about NPC and the nonspecific nasopharynx and cervical part, whole‑body bone
Zhou-Xue Wu and
symptoms makes initial and accurate diagnosis scan or position emission tomography (PET). Li Xiang are the co-first
difficult in cases with intracranial or skull Staging was conducted according to the seventh authors
lesions. We present a series of patients with edition of the American Joint Committee on
NPC complaining of headaches and in which a Cancer (AJCC).[3] Access this article online
nonspecialist played a critical role in the diagnosis Website: www.cancerjournal.net
and management. Exclusion criteria were as follows: Lack of DOI: 10.4103/0973-1482.157334
pathological diagnosis, unclear medical history, PMID: ***
PATIENTS AND METHODS previous confirmed malignant tumors, and/or Quick Response Code:

previous radiotherapy or chemotherapy.

Untreated NPC patients were confirmed by
pathological diagnosis and recruited during Attending doctors carefully collected medical records
May 2009–June 2014 in our cancer center. All when patients were hospitalized. Medical records
patients claimed to have a headache alone or a included general patient information, initial symptoms

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Wu, et al.: The high misdiagnosis rates in NPC with headaches
and the time of appearance, initial diagnosis time and result,
diagnosing hospital type, diagnosis department, and accuracy
and time of diagnosis. All data were summarized for final analysis.
RESULTS
Patient characteristics
Two‑hundred and nineteen participants (155 males and
64 females) entered our prospective trial. The median
age was 46 years (range: 23–71 years). The incidence in
patients less than 30 years old was only 6.8% (15/219). The
30–59‑year‑old patients accounted for 59.4% (130/219). We
observed a significant number (33.8%, 74/219) of NPC cases
in patients of 60 years and older. The majority of patients
were in locally advanced stages. According to the 7th AJCC
staging guidelines, individuals were classified as follows:
1.4% stage II (three cases), 46.6% stage III (102 cases), 36.1%
stage IVA (79 cases), 7.7% stage IVB (17 cases), and 8.2% stage
IVC (18 cases). Education levels in patients were as follows:
31.1% had a primary school degree (68 subjects), 57.5% had a
middle school degree (126 patients), and 11.4% had a college
degree (25 patients).
Misdiagnosis rate
One‑hundred and twenty‑four patients were confirmed or
suspected of having NPC during the initial visit. The definitive
diagnosis rate was 56.6% (124/219), making the misdiagnosis
rate 43.4% (95/219). These cases were misdiagnosed as
sinusitis, nervous headache, intracranial tumors, otitis media,
or tuberculosis. The diverse and nonspecific symptoms resulted
in late diagnosis of NPC.
The influence of symptoms on misdiagnosis
Headaches alone
There were 22 patients who only suffered from a headache.
Twenty‑one patients were assigned to Departments
of Neurology, and only one patient was assigned to a
neurosurgery department. In the neurology departments,
12 of the 21 patients had a brain CT that failed to detect
nasopharyngeal lesions due to insufficient lower edge settings,
or indistinct delineation of the skull base. Those 12 patients
were treated for a nervous or vascular headache. All of these
patients were given over‑the‑counter medication for pain
relief. However, because the pain did not respond well to
the prescribed medication, brain MRI was arranged, and
following this a diagnosis of NPC was given. The remaining
six patients with hypertension who did not receive a brain CT
were diagnosed with unstable blood pressure and subjected
to antihypertensive therapy. Fortunately, three of the patients
did receive an initial brain CT that included parts of the
nasopharynx, and therefore did reveal nasopharyngeal tumors
with upward invasion into the skull base. Consequently, those
three cases received an initial diagnosis of NPC.
The remaining 60‑year‑old male patient had daily headaches
involving the left temporal and parietal lobe areas for
210 Journal of Cancer Research and Therapeutics - January-March 2016 - Volume 12 - Issue 1
6 months. A cranial CT was done in our outpatient facilities.
He was diagnosed with hematencephalon and hospitalized
by the neurosurgery department. The cranial computed
tomography angiography (CTA) revealed a left temporal lobe
brain hemorrhage. Subsequent brain enhanced MRI analysis
revealed a regular margin ovoid mass in the left temporal lobe
with several hemorrhages [Figure 1]. The neurosurgeons made
a preliminary diagnosis of glioma or tumor apoplexy.
Under general anesthesia, craniotomy surgery and resectioning
of the mass in the left temporal lobe were performed on the
patient. The postoperative pathology (pathological number:
2014‑00140) revealed a left temporal lobe malignant tumor
and a metastatic squamous cell carcinoma. These findings
were corroborated by strong positive immunohistochemisty
staining for P63 and pancytokeratin (PCK), and negative
staining for vimentin and S‑100 proteins [Figure 2].
The second MRI of the nasopharynx showed thickening of the
soft tissue in the nasopharyngeal hanging wall and bilateral
wall with disappearing infundibuliform recesses. The mass had
also invaded the parapharyngeal spaces, skull base, and left
cavernous sinus. Soft tissue nodules surrounded the bilateral
carotid sheath, which were likely to be metastatic lymph nodes
caused by NPC [Figure 1]. Endoscopy revealed a rough mass with
clear boundaries in the left pharyngeal recess. The histological
findings and radiological examination resulted in NPC
diagnosis, and radiochemotherapy was initiated. The patient
received one cycle of cisplatin and taxotere chemotherapy as
a preradiotherapy treatment to reduce the primary disease.
Based on the data we gathered, the misdiagnosis rate was
86.4% (19/22) in the patients that initially presented only with
headaches. The neurologists were misled by the nonspecific
symptoms of nasopharyngeal cancer.
Headaches accompanied by palpable lymph nodes in neck
Fifty‑six patients complained of headache and neck mass.
Among them, 30 patients first visited general surgeon and
five of those patients were directly referred to the oncology
department as they were suspected to have NPC. The remaining
25 patients received a cytological examination of the cervical
lymph nodes. The results demonstrated metastatic squamous
cell carcinoma in 22 patients, whereas three patients were
initially diagnosed with lymphadenitis and were prescribed
anti‑inflammatory therapy. This treatment failed, further
aggravating the headaches and stability of the lymph nodes.
The patients returned to the oncology department 2 weeks
later, where a definitive diagnosis of NPC was confirmed
by endoscopic biopsy of the primary tumor. The remaining
26 patients went directly to oncology and were diagnosed
with NPC. Therefore, 31 patients received a primary diagnosis
of nasopharyngeal cancer.
The misdiagnosis rate of patients presenting with a headache
and a cervical lymph node mass was 44.6% (25/56). It is likely
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Wu, et al.: The high misdiagnosis rates in NPC with headaches

a c e

b d f
Figure 1: A 60-year-old man suffered from headaches for 6 months. Cranial computed tomography (CT) demonstrated hematencephalon
(a and b). Brain magnetic resonance imaging (MRI) revealed a homogeneously enhanced mass in the left temporal lobe accompanied with a
few hemorrhages (c and d). The second MRI demonstrated a homogeneously enhanced mass in the nasopharyngeal hanging wall and bilateral
wall, with disappearing infundibuliform recesses. The mass had also invaded the parapharyngeal spaces. The lymph nodes surrounded bilateral
carotid sheath (e and f)

Headaches accompanied by ear symptoms (including tinnitus

and diminished hearing).

Eustachian tube occlusion can occur secondary to a tumor

a b
c
Figure 2: Postoperative histology revealed a metastatic squamous
cell carcinoma, consistent with nasopharyngeal carcinoma (NPC) due
to confirmation by immunohistochemistry (a) hematoxylin and eosin
staining, ×200; (b) strong immunohistochemistry staining of P63 in
tumor cell cytoplasm, ×400; and (c) positive pancytokeratin (PCK) in
tumor cell nuclei, ×400)
that these patients knew that enlarged lymph nodes are a
warning sign of cancer. Consequently, the misdiagnosis rate
was lower than the group only suffering from headaches.
However, some patients underwent unnecessary lymph
node biopsies that could have increased the risk of distant
metastasis.
in the ostium pharyngeum tubae auditivae region, causing a
circulation disorder of inner ear lymph as well as tympanic
negative pressure. Because of the anatomical changes,
the patients were plagued by ear problems like tinnitus,
aural fullness, and hearing loss. A total of 17 patients
were primitively diagnosed with otitis media. Six patients
received the misdiagnosis in the otolaryngological
department and three patients were misdiagnosed due
to the negative findings by nasopharyngeal endoscopy.
The remaining 27 patients received a diagnosis of NPC in
otolaryngology or neurology departments. Accordingly, the
misdiagnosis rate was 38.6% (17/44) in this subpopulation
of patients.
Headaches and nasal problems (including nasal congestion
and blood secretion)
Contact bleeding is one of the only prevalent symptoms of
nasopharyngeal cancer patients. Bleeding can provide a direct
reference for doctors to make an accurate diagnosis. Hence,
the rate of correct diagnosis is almost 90% in patients with
headaches and epistaxis. In all 46 patients, the symptoms of
only five patients were mistaken for sinusitis by a neurology
department.

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Wu, et al.: The high misdiagnosis rates in NPC with headaches

In patients with a rhinobyon, however, the accurate diagnosis Table 1: Influence of initial concomitant symptoms on
rate is only 48.7% (19/39 patients). Twenty patients were misdiagnosis of NPC patients with headaches at the first visit
misdiagnosed with chronic sinusitis or an upper respiratory Concomitant Misdiagnosed Visited Misdiagnosis
tract infection, because the clinical manifestations did not manifestations cases (n) cases (n) rate (%)
Only headache 19 22 86.4
help the doctors distinguish NPC from other common diseases. With neck mass 25 56 44.6
Unfortunately, neither patients nor doctors considered an With ear problems 17 44 38.6
NPC diagnosis until the cervical lymph nodes were enlarged, With rhinobyon 20 39 51.3
or until other new symptoms appeared, which were a sign of With epistaxis 5 46 10.9
With neurological 9 12 75.0
advanced stage NPC. or other symptoms

Headaches accompanied by neurological or ocular symptoms

In this subpopulation of patients suffering from neurological Table 2: Effect of different hospital grade and departments
on misdiagnosis
symptoms of diplopia, facial numbness, proptosis, and impaired
vision; the misdiagnosis rate of 75% (9/12 patients) ranked Characteristics Misdiagnosed Visited Misdiagnosis
cases (n) cases (n) rate (%)
second among all groups. Nine patients were first diagnosed Department
with glaucoma, peripheral neuropathy, facial neuritis, and Neurosurgery 1 1 100.0
intracranial tumors by oculists and neurologists [Table 1]. General medicine 6 7 85.7
Forensic sursery 25 30 83.3
Ophthalmology 5 6 83.3
Effect of hospital type and department on misdiagnosis Neurology 38 54 70.4
Eighty‑eight patients (41.2%) first chose a provincial hospital, Otorhinolaryngology 18 94 19.1
while 111 cases (50.7%) chose a municipal hospital. Only Oncology 2 27 7.4
20 cases (9.1%) initially selected the country hospital. The Hospital level
Provincial hospital 26 88 29.5
misdiagnosis rates of the three different hospitals were as Municipal hospital 54 111 48.6
follows: 29.5% (26/88) for the provincial, 48.6% (54/111) for Country hospital 15 20 75.0
the municipal, and 75% (15/20) for the country.
diagnosis rates. In the low‑incidence provinces, however, it
As a result of significant professional advantages in the
still is difficult to assess the early lesions. In our study, the data
oncology and otorhinolaryngology departments, misdiagnosis
indicate that even stage IV NPC accounted for 52% of patients
rates were lower. Neurologists and neurosurgeons managed all
whose initial symptoms include headaches.
patients with headaches alone. Nonspecific symptoms caused
the doctors to be misguided by the headaches. Unfortunately,
There are several major problems causing misdiagnosis of
misdiagnosis was 100% in neurosurgery departments. Because
NPC. Firstly, a lack of medical knowledge and poor economic
impaired vision or diplopia is an uncommon symptom of NPC,
five patients went to an ophthalmology department without conditions amongst patients contribute to inadequate
receiving the correct diagnosis. In these cases, the oculist attention to the clinical symptoms. This is particularly the
diagnosed glaucoma or retrobulbar neuritis. Nasopharyngeal case during the early onset, as symptomatic treatments
cancer is very easily confused with other common ailments like would have increased the likelihood of cancer remission.
nervous headache, sinusitis, otitis media, etc., This confusion is When patients finally go to hospital, they may visit the wrong
related to the complexity and diversity of symptoms [Table 2]. department based on the symptoms that greatly affect their
quality of life. For example, they may see a neurologist for
DISCUSSION cephalea, an ophthalmologist for visual impairment, or a
pulmonologist for hemoptysis. Jiang et al., demonstrated that
The highest incidence rates of NPC are in southern China. patient‑related factors equally contributed to the iatrogenic
Within endemic areas of China, NPC remains a common and factors leading to delays in diagnosis.[6] Physicians who
fatal disease. The prevention strategy in China relies mainly on treat headaches must be aware that recurrent or persistent
secondary prevention, with a goal of achieving earlier detection headaches could be the initial or sole manifestation of NPC,
rates and diagnosis, which would give high‑risk populations and that subtle intracranial lesions at the skull base can be
a clinically valuable survival advantage.[4] Achievements missed by routine brain CT. In our study, majority of patients
in these areas would provide hope of encouraging results were diagnosed with NPC after brain or nasopharyx MRI,
from nasopharyngeal cancer treatment. Patients with early including the 12 patients who were excluded from a NPC
stage (stages I and II) NPC have satisfactory treatment results diagnosis due to negative findings on their previous brain CT.
and a 5‑year survival rate of up to 94%. This is significantly Thus, clinicians must understand that the routine setting of a
different from patients diagnosed with late stage NPC (stages noncontrast brain CT, which is frequently used as a screening
III and IV), who have a 5‑year survival rate lower than 80%.[5] tool for headache patients, is limited in detecting possible
Large‑scale population screenings for NPC in China have been skull base or nasopharyngeal lesions. For cases suspected
concentrated in epidemic areas and have increased early to be NPC, brain MRI is essential, even when brain CT has

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Wu, et al.: The high misdiagnosis rates in NPC with headaches
negative findings. Headaches are often the first and most
prominent symptom in ascending‑type NPC. To facilitate early
diagnosis, it is important to recognize headache patterns of
ascending‑type NPC.[7]
Secondly, if the first doctor is inexperienced with NPC, it is
more likely that a wrong diagnosis will be made based on
these atypical symptoms. The structures near nasopharynx
are complex and can have a lot of lymphatic drainage as well.
Nasopharyngeal cancer can encroach upwards towards the
skull base and intracranial tissue and extend down to the oral
cavity. It has a tendency to infiltrate peripheral organs, such
as the middle ear, parapharyngeal space, and infratemporal
fossa. Consequently, patients may suffer from symptoms that
are not exclusive to NPC. Sometimes, neck mass may be the
first clinical manifestation of NPC. Occasionally, blockage of
the Eustachian tube can produce a middle ear transudate.
Proptosis is a result of the tumor’s direct extension into the
orbit from the posterior nasal fossa via ethmoid air cells or
from the cavernous sinus through to the superior orbital
fissure. In addition, headaches or pain in the temporal or
occipital regions occur when the tumor extends to the base
of the skull.
Doctors can contribute to a delayed NPC diagnosis when they
ignore and misjudge the nonspecific early stage symptoms
that mimic other diseases. Patients with headaches alone were
misdiagnosed with nervous or vascular headaches and only a
minority of doctors considered intracranial tumors because of
the incomplete image. The misdiagnosis rate of these patients
was 86.4%. One patient even had an unnecessary craniotomy.
The misdiagnosis rates of neurosurgery departments were
highest at 100% (1/1). This phenomenon indicates that
nonspecialists do not have a complete understanding of NPC,
which is especially obvious during clinical work.
Nasopharyngeal endoscopy is the initial procedure of
choice for the detection of NPC, with a definitive diagnosis
of NPC confirmed by endoscopic biopsy of the primary
tumor.[8] The majority of misdiagnosed patients did not
undergo nasopharyngeal endoscopy, which led to adverse
outcomes. However, submucosal nasopharyngeal cancer
may not be discovered by endoscopy. Three patients had
nasopharyngeal endoscopy, but were still misdiagnosed
because they had the submucosal type.
Thirdly, the level of a hospital is an important factor in
misdiagnosis. The initial diagnosis rate of NPC in provincial
hospitals is 70.5%, but dropped to 51.4% in municipal
hospitals. The rural hospitals had the lowest diagnosis rates
of only 25%. This data indicates that the current distribution
of medical resources is extremely unbalanced and that there is
a wide gap between the provincial and basic hospitals.
Therefore, we propose that the following measures should
be taken to avoid misdiagnosis. Principally, continuing
Journal of Cancer Research and Therapeutics - January-March 2016 - Volume 12 - Issue 1
medical education for nonspecialists should be strengthened.
This would help ensure that nonspecialists conduct a
comprehensive differential diagnosis for patients with
headaches, nasal obstruction, and hearing loss. It is important
to teach clinical doctors not to simply think of headaches as
a sign of intracranial tumors, and that imaging scans should
include sufficient ranges to exclude NPC.
Submucosal carcinoma cannot be confirmed by a conventional
multiple biopsy. To improve the positive diagnosis rate, physicians
should punch the surface tissue and make a deep biopsy through
the wound. One patient was definitively diagnosed on the
seventh biopsy by our center, providing an example that the
clinically suspect cases cannot easily be eliminated.
NPC incidence rises steadily with age, peaking at 40–59 years
and then significantly declining. Headaches are the initial
symptom that elicits medical attention in almost 20% of cases.
Approximately 60–70% of patients suffer from such painful
symptoms in the definitive diagnosis.[9] The age distribution of
these subgroups from our hospital, however, had a small peak
beyond 60 years, which possibly contributed to the difficulty
in discriminating NPC from other senile diseases. In our study,
we found a similar sex‑specific incidence of NPC, with 70.8%
male and 29.2% female cases yielding a 2.42:1 ratio. The cancer
registry provides timely and dynamic information for making
national, regional, and local cancer control policies. As the
National Central Cancer Registry (NCCR) continues to expand,
primary and secondary prevention of NPC is expected to
improve.[10] Nonetheless, a general principle must stand out: If
a headache patient cannot be diagnosed with simply a primary
headache, particularly without other typical NPC features,
further examination to exclude NPC is requisite. Also, fiberoptic
nasopharyngoscopy and image scanning of the nasopharynx
are equally important. In addition, brain MRI would be more
beneficial for this purpose than CT. As far as we know, there
have not been pertinent studies of this topic. Our article is the
first to analyze the characteristics of these unique patients who
presented with headaches as their primary, or only, symptom.
To summarize, this subgroup of NPC patients who presented
with only headaches, or headaches accompanied by other
atypical presentations, suffered from a high misdiagnosis
rate. This was related to the nonspecific symptoms of NPC,
low capabilities of the basic hospitals, and patients visiting
inappropriate departments that could not provide targeted
examination and treatment. Educating hospital staff, a
decisive first step for diagnosing early stage NPC, can improve
awareness of various nonspecific symptoms and signs of NPC,
especially among high‑risk populations.
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Cite this article as: Wu ZX, Xiang L, Rong JF, He HL, Li D.
Nasopharyngeal carcinoma with headaches as the main symptom:
A potential diagnostic pitfall. J Can Res Ther 2016;12:209-14.
Source of Support: Nil, Conflict of Interest: None declared.

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