Pathology of malignant pleural mesothelioma

Author
Leslie A Litzky, MD
Section Editors
Andrew Nicholson, MD
James R Jett, MD
Joseph S Friedberg, MD
Rogerio C Lilenbaum, MD, FACP
Deputy Editor
Michael E Ross, MD
Disclosures: Leslie A Litzky, MD Nothing to disclose. Andrew Nicholson, MD Grant/Research/Clinical Trial Support: Astra Zeneca [lung
cancer (Gefitinib)]; Boehringer Ingelheim [interstitial lung disease (Nindetanib). Speakers Bureau: Eli Lilly, Roche [lung cancer]; Intermune
[interstitial lung disease (Pirfenidone)]. Consultant/Advisory Boards: Astra Zeneca; Boehringer Ingelheim; Pfizer; Novartis [lung cancer
(Gefitinib; Crizotinib)]. Glaxo Smith Klein [interstitial lung disease]. James R Jett, MD Grant/Research/Clinical Trial Support: Oncimmune [lung
cancer biomarkers (early CDT lung blood test)]; Metabolomx [biomarker lung cancer (breath and urine test in development)].
Consultant/Advisory Boards: Quest Diagnostics [lung cancer biomarkers (blood test in development)]. Joseph S Friedberg,
MD Consultant/Advisory Boards: Varian (radiation therapy). Rogerio C Lilenbaum, MD, FACP Consultant/Advisory Boards: Genentech [Lung
Cancer (Bevacizumab)]; Boehringer-Ingelheim [Lung Cancer (Afatinib)]. Michael E Ross, MD Employee of UpToDate, Inc.
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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2014. | This topic last updated: Apr 02, 2014.
INTRODUCTION Mesothelioma is a malignant tumor that arises from the mesothelial surfaces of the pleural and
peritoneal cavities, the tunica vaginalis, or the pericardium. Eighty percent of all cases are pleural in origin.
The pathology of malignant mesothelioma, focusing on the most common form, diffuse pleural malignant mesothelioma, will
be reviewed here. The pathology of peritoneal mesothelioma is discussed separately, as are other aspects of pleural
mesothelioma. (See "Malignant peritoneal mesothelioma: Epidemiology, risk factors, clinical presentation, diagnosis, and
staging", section on 'Histology' and "Epidemiology of malignant pleural mesothelioma" and "Clinical presentation, diagnosis,
and staging of malignant pleural mesothelioma" and "Management of malignant pleural mesothelioma".)
DIAGNOSTIC DIFFICULTIES Multiple factors have made the diagnosis of malignant mesothelioma a particular challenge
for most practicing pathologists.
Malignant mesothelioma is rare, except in large referral centers or epidemiologic hotspots.
In many cases, only a limited amount of tissue is available for histologic evaluation and special studies. The use of
video-assisted thoracoscopy (VAT) biopsies has made this issue less frequent in many practice settings. VAT has
greatly improved the size of pleural biopsies and the choice of sampling sites, usually providing enough tissue for
definitive diagnosis.
Malignant mesothelioma can vary greatly in histologic appearance within any one patient. In addition, a number of
other tumors, either originating within the thorax or metastatic from an extrathoracic site, can mimic malignant
mesothelioma. There are also a number of benign pleural diseases that may be difficult to separate from pleural
malignancy.
The widespread availability and use of immunohistochemistry has greatly improved the accuracy of diagnosis in recent
years. Molecular studies, although not always available, have also improved diagnostic accuracy in certain situations.
Finally, a thorough clinical history that includes a history of prior malignancy as well as past medical diseases and previous
therapies is essential to appropriate pathologic examination. High quality radiographic studies and astute radiographic
assessment can also make a substantial contribution to pathologic diagnosis.

GROSS PATHOLOGY Early stage malignant pleural mesothelioma presents as multiple small nodules that
characteristically are more pronounced on the parietal pleura but can also involve the visceral pleura [1]. As the tumor
progresses, these nodules coalesce to form a thickened rind of tumor that fuses the parietal and visceral pleurae.
At a more advanced stage, the tumor typically encases the entire lung and extends along the interlobar fissures (picture 1).
This thick rind of tumor can reach diameters of several centimeters or more, despite only minimal invasion of the underlying
lung parenchyma. The consistency of the tumor varies from firm to gelatinous.
Adjacent structures can be involved at an early stage, with invasion of the chest wall, pericardium, and diaphragm. Seventy
percent of patients will have mediastinal lymph node involvement at autopsy. Hematogenous metastases are more common
than many clinicians assume, particularly to liver, lung, bone, and adrenal glands. Rare localized variants of malignant
mesothelioma have also been described [2].
The gross appearance is not pathognomonic for mesothelioma and there are other primary and secondary pleural
malignancies that can diffusely involve the pleura.
HISTOLOGY Malignant mesothelioma is typically classified into three broad histologic subtypes - epithelioid, sarcomatoid,
and biphasic (mixed) [1]. Although there are a number of unusual and rare variants, this categorization has general
diagnostic utility in that the differential diagnosis of both benign and malignant lesions, as well as the subsequent
immunohistochemical work-up, is guided by this subclassification.
The epithelioid variant is the most common, comprising about 60 percent of all mesotheliomas. Typical histologic
appearances of this subtype include tubulopapillary, acinar (glandular), adenomatoid and solid epithelioid patterns
(picture 2). In addition to reactive mesothelial hyperplasia, the differential diagnosis includes metastatic carcinomas
and other epithelioid tumors.
Sarcomatoid mesotheliomas are composed of malignant spindle cells which may mimic malignant mesenchymal
tumors, such as leiomyosarcoma or synovial sarcoma. Desmoplastic mesothelioma, which consists of bland tumor
cells between dense bands of collagenous stroma, is considered to be a subtype of sarcomatoid mesothelioma. In
addition to fibrous pleurisy, the differential diagnosis includes sarcomatoid carcinoma and other sarcomas.
Biphasic or mixed mesotheliomas have epithelioid and sarcomatoid features, but multiple tissue sections or larger
samples may be needed to demonstrate both components. Synovial sarcoma, as well as other mixed or biphasic
tumors, are typically considered within this differential diagnosis.
Some malignant mesotheliomas are so poorly differentiated and discohesive that lymphomas and non-neoplastic
inflammatory disorders must be included within the differential diagnosis [3].
Well-differentiated papillary mesothelioma is a rare tumor with a distinctive papillary architecture and bland features that
tends to spread superficially without invasion [1]. This type of tumor is more commonly diagnosed in the peritoneum.
(See "Malignant peritoneal mesothelioma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging".)
Histologic criteria have been described to distinguish reactive mesothelial hyperplasia from epithelioid malignant
mesothelioma and fibrous pleurisy from the desmoplastic variant of sarcomatoid mesothelioma [4,5]:
Reactive mesothelial hyperplasia can be caused by infections, connective tissue disease, pulmonary infarct, drug
reactions, pneumothorax, subpleural lung carcinomas, surgery, or traumatic injury.
Fibrous pleurisy can be the result of asbestos exposure, infection, connective tissue disease, or traumatic injury.
The most reliable criterion for distinguishing reactive mesothelial hyperplasia and fibrous pleurisy from malignancy is the
demonstration of stromal invasion. Although the recognition of stromal invasion can be highlighted by positive cytokeratin
staining, definitive diagnosis is best achieved by adequate biopsies that include some underlying fibroadipose tissue or, in
special circumstances, the pulmonary parenchyma.
Immunohistochemistry The use of immunohistochemical panels is an integral part of the diagnosis of malignant
mesothelioma.
There is no single marker that has sufficiently high sensitivity and specificity for malignant mesothelioma, and it is, therefore,
standard practice for pathologists to employ a panel of markers (both positive and negative). Institutions vary somewhat in
their selection of which markers to include, and panels are typically refined as publications appear with studies comparing
the utility of different markers. As a general rule, it is recommended that the marker have either sensitivity or specificity
greater than 80 percent for the tumors being considered. When interpreting positivity, both the localization of the stain
(nuclear versus cytoplasmic) and the percentage of cells staining positively (>10 percent is suggested for cytoplasmic

markers) is recommended [6]. Marker utility is further subdivided into panels which will be more helpful when the tumor
appears to be epithelioid, sarcomatoid, or poorly differentiated [6].
Some general principles can be summarized as follows:
Pancytokeratin stains are very useful in the diagnosis of mesothelioma and will stain the vast majority of
mesotheliomas. If the tumor is pancytokeratin negative, then the screening panel should be broadened to include
stains to exclude lymphoma, melanoma, angiosarcoma or epithelioid hemangioendothelioma. There are rare
sarcomatoid mesotheliomas which are cytokeratin negative, particularly those with osteosarcomatous differentiation.
For epithelioid mesothelioma, common positive immunohistochemical markers that can be used to support a
diagnosis of malignant mesothelioma include calretinin, CK5/6, the Wilms' tumor-I (WT1) antigen (nuclear staining),
and D2-40 (podoplanin) [1]. Useful markers that are positive in pulmonary adenocarcinoma include MOC-31, BG8,
carcinoembryonic antigen (monoclonal), B72.3, Ber-EP4, TTF-1, and Napsin A (Leu-M1) [6]. When the differential
diagnosis is broadened to include other subtypes of lung tumors such as squamous cell carcinoma or metastases from
other primary sites such as the kidney or ovary, then the panel must be more specifically directed toward those
considerations and the significance of a positive or negative result must be carefully evaluated.
For sarcomatoid or biphasic mesothelioma, cytokeratin reactivity does not necessarily differentiate malignant
mesothelioma from other sarcomas, particularly if the cytokeratin staining is focal. Multiple cytokeratin antibodies such
as AE1/3 or CAM5.2 should be used since cytokeratin expression can be focal, weak or variable [7]. Significant
cytokeratin positivity can also be seen in sarcomatoid carcinoma or metastatic sarcomatoid renal cell carcinoma. D2-40
and calretinin are the most reliable of the affirmative mesothelioma markers [8,9]. D2-40 and calretinin do show overlap
reactivity with other types of sarcoma, but a positive result may be useful for confirming a diagnosis of sarcomatoid
mesothelioma when combined with strong cytokeratin positivity [8,9]. The possibility of synovial sarcoma can usually
be confirmed by molecular testing for the specific X:18 translocation.
Electron microscopy As the number of antibodies suitable for immunohistochemistry on routine formalin-fixed paraffin
embedded tissue has increased and included the addition of affirmative mesothelioma markers, immunohistochemistry has
largely replaced electron microscopy in its traditional use as the "gold standard" for diagnosing malignant mesothelioma.
Electron microscopy is still occasionally useful in establishing the diagnosis of well to moderately differentiated epithelioid
tumors, when the immunohistochemical results are equivocal [10]. The electron microscopic features of malignant
mesothelioma have been well characterized [11]. The predominant epithelioid form is composed of polygonal cells with
numerous long surface microvilli, prominent desmosomes, and abundant tonofilaments (picture 3).
SUMMARY
Mesothelioma is a malignant tumor that arises from the mesothelial surfaces, most commonly in the pleural cavity, but
occasionally in the peritoneal cavity or elsewhere. Malignant mesotheliomas are classified into three major subtypes:
epithelioid, sarcomatoid, and biphasic (mixed). (See 'Histology' above.)
The diagnosis of mesothelioma can be difficult for several reasons. Various metastatic tumors can present in the
pleural cavity. Histologically these can look similar to mesotheliomas, as can benign lesions arising in the pleural cavity.
(See 'Diagnostic difficulties' above.)
Immunohistochemistry panels are an integral part of the diagnostic approach to these tumors in addition to routine
histologic examination. Electron microscopy may be useful when the immunohistochemistry results are equivocal.
(See 'Immunohistochemistry' above and 'Electron microscopy' above.)
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