Pathology of malignant pleural mesothelioma

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 "Presentation, initial evaluation, and prognosis of malignant pleural mesothelioma" and "Initial 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 cytologic material or a limited amount of tissue is available for pathologic 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. 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. Although not yet formally incorporated into the Mesothelioma Consensus Guidelines, a number of published studies have supported the utility of a nuclear grading system specifically for epithelioid mesothelioma in addition to pleomorphic features [3]. The grading system is based on a score for nuclear atypia and mitotic count, as well as the presence or absence of necrosis. Although grading of epithelioid mesothelioma was not routinely performed in many medical centers prior to the 2021 World Health Organization (WHO) classification, it is now recommended in both biopsy and resection specimens to help in the identification of tumors that may behave in a more aggressive fashion [1]. Pleomorphic features (specifically prominent anaplastic/bizarre nuclei and multinucleated giant cells) can be seen in the epithelioid type and should be noted. Lymphohistiocytoid features (characterized by dense lymphoid infiltrates composed mainly of CD8-positive T-cells that obscure the malignant histiocytoid-appearing tumor cells) similarly should be reported. Both pleomorphic and lymphohistiocytoid features can be seen in biphasic or sarcomatoid subtypes and should be recorded as well.

●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 [4].

The entity previously termed as "well-differentiated papillary mesothelioma" has been removed from the mesothelioma WHO classification and is now its own distinct entity. This particular entity has been renamed "well-differentiated papillary mesothelial tumor" and is restricted to a rare and distinctive mesothelial tumor that is composed of papillary stromal formations covered by cytologically bland mesothelial cells lacking 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 [5,6]:

●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 [7]. Marker utility is further subdivided into panels which will be more helpful when the tumor appears to be epithelioid, sarcomatoid, or poorly differentiated [7].

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) (image 1) [7]. 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 [8]. 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 [9,10]. 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 [9,10]. 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 effectively 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 [11]. The electron microscopic features of malignant mesothelioma have been well characterized [12]. The predominant epithelioid form is composed of polygonal cells with numerous long surface microvilli, prominent desmosomes, and abundant tonofilaments (picture 3).

Molecular markers — The use of fluorescent in-situ hybridization (FISH) to detect p16 deletion is now used in challenging cases where the differential diagnosis is benign versus malignant mesothelial proliferations [7]. This type of testing is available at high-volume referral hospitals and through some commercial laboratories. In a similar strategy, detection of loss of breast cancer susceptibility gene 1 (BRCA1)-associated protein (BAP1) by immunohistochemistry can be used to distinguish malignant mesothelioma from reactive mesothelial proliferation [13,14].

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.)