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Pleural Pathology and Mesothelioma

Overview

Pleural pathology ranges from reactive mesothelial proliferations to malignant mesothelioma. Distinguishing reactive mesothelial hyperplasia from mesothelioma and separating mesothelioma from metastatic carcinoma are two of the most challenging diagnostic problems in surgical pathology. Modern immunohistochemistry panels including BAP1 and MTAP have transformed the diagnostic approach.

Reactive Mesothelial Hyperplasia

Histologic Features

Reactive mesothelial hyperplasia is a proliferation of mesothelial cells in response to inflammation, infection, or effusion. The arrangement remains orderly, though cells may form papillary clusters or sheets. Mild cytologic atypia with reactive features (prominent nucleoli, brisk mitoses, multinucleation) can be present. Entrapment within organizing fibrin or granulation tissue may simulate invasion. Key features favoring a reactive process include zonation (decreasing cellularity away from the surface), absence of true stromal invasion, no necrosis, and retained BAP1 expression.

Pitfalls

Entrapped mesothelial cells in organizing pleuritis can closely mimic invasion. Atypical mesothelial hyperplasia with florid papillary proliferation may closely resemble epithelioid mesothelioma. Clinical context (known effusion, empyema, recent surgery) is essential for correct interpretation.

Malignant Mesothelioma

Epidemiology

Mesothelioma has a strong association with asbestos exposure, with a latency period of 20 to 40 years. Amphibole fibers (crocidolite, amosite) are more carcinogenic than chrysotile (serpentine). Asbestos bodies are golden-brown, beaded, dumbbell-shaped iron-coated fibers found in the lung parenchyma rather than the pleura itself. Other risk factors include radiation, erionite (a zeolite fiber), germline BAP1 mutations, and possibly SV40 (controversial).

Histologic Types

Epithelioid Mesothelioma (60-70%)

Epithelioid mesothelioma is the most common subtype and carries the best prognosis. It grows in tubular, papillary, solid, trabecular, or adenomatoid patterns, with the tubulopapillary pattern being most common. The cells are bland to moderately atypical mesothelial cells with abundant eosinophilic cytoplasm.

Sarcomatoid Mesothelioma (10-20%)

Sarcomatoid mesothelioma consists of a spindle cell proliferation resembling fibrosarcoma or other spindle cell sarcomas. The desmoplastic variant features dense collagenous stroma with bland spindle cells and may closely mimic fibrous pleurisy. It carries the worst prognosis and responds poorly to chemotherapy. Keratin positivity (often focal) is essential for diagnosis, and mesothelial markers may be lost.

Biphasic Mesothelioma (20-30%)

Biphasic mesothelioma contains both epithelioid and sarcomatoid components, each comprising at least 10 percent of the tumor. Prognosis is intermediate and depends on the proportion of sarcomatoid component.

Mesothelioma In Situ (MIS)

Mesothelioma in situ is a flat proliferation of atypical mesothelial cells on the pleural surface without invasion. Diagnosis requires BAP1 loss by IHC or p16 homozygous deletion by FISH. It is a recognized entity in the WHO 5th edition and may present with recurrent unexplained effusions years before invasive disease develops.

Staging

The AJCC TNM 8th edition is used for pleural mesothelioma staging. T1 involves the ipsilateral parietal pleura only. T2 involves the ipsilateral visceral pleura, pulmonary parenchyma, or diaphragm. T3 represents locally advanced but potentially resectable disease. T4 is unresectable (contralateral pleura, peritoneum, spine, or mediastinal organs).

IHC for Mesothelioma Diagnosis

Mesothelioma vs. Metastatic Carcinoma (Epithelioid)

A panel approach using at least 2 mesothelial markers and at least 2 carcinoma markers is essential.

Mesothelial Markers (Positive in Mesothelioma)

Calretinin shows nuclear and cytoplasmic staining and is the most sensitive mesothelial marker. WT1 shows nuclear staining (also positive in ovarian serous carcinoma). D2-40 (podoplanin) shows membranous staining. CK5/6 shows cytoplasmic staining (also positive in squamous carcinoma).

Carcinoma Markers (Positive in Carcinoma, Negative in Mesothelioma)

CEA (monoclonal) shows membranous and cytoplasmic staining. MOC-31 (EpCAM) shows membranous staining. BerEP4 shows membranous and cytoplasmic staining. Claudin-4 shows membranous staining and is highly specific for carcinoma. TTF-1 identifies lung and thyroid carcinoma. PAX8 identifies renal, ovarian, and thyroid carcinoma. Napsin A identifies lung adenocarcinoma.

Reactive Mesothelial Hyperplasia vs. Mesothelioma

BAP1 (BRCA1-associated protein 1)

Loss of nuclear BAP1 expression occurs in approximately 60 to 70 percent of epithelioid mesotheliomas. It is retained in all reactive mesothelial proliferations, giving it 100 percent specificity for malignancy when lost. Loss indicates BAP1 inactivation through deletion or mutation. Germline BAP1 mutations define the BAP1 tumor predisposition syndrome, which includes mesothelioma, uveal melanoma, renal cell carcinoma, and cutaneous melanocytic tumors.

MTAP (Methylthioadenosine Phosphorylase)

Loss of MTAP expression correlates with p16/CDKN2A homozygous deletion, as these are adjacent genes on chromosome 9p21. MTAP IHC is replacing p16 FISH as the preferred method for detecting 9p21 deletion because it is less expensive, more accessible, and requires no FISH equipment. Loss occurs in approximately 40 to 70 percent of mesotheliomas while being retained in reactive mesothelial cells. Combined BAP1 loss plus MTAP loss provides high sensitivity and specificity for mesothelioma.

p16 FISH (Homozygous Deletion)

Homozygous deletion of CDKN2A/p16 at 9p21 occurs in approximately 70 percent of mesotheliomas and is not seen in reactive mesothelial proliferations. This test is being replaced by MTAP IHC.

Other Helpful Markers

EZH2 overexpression (strong nuclear staining) occurs in mesothelioma but is low or absent in reactive mesothelium. Ki-67 shows a higher proliferation index in mesothelioma compared to reactive proliferations, though it is not definitive alone. GLUT1 (glucose transporter 1) is positive in mesothelioma and negative in reactive mesothelium. 5-hydroxymethylcytosine (5-hmC) is lost in mesothelioma but retained in reactive mesothelium.

Diagnostic Algorithm

The diagnostic approach proceeds in steps. First, determine whether the process is mesothelial or epithelial (carcinoma) using the IHC panel (calretinin, WT1, D2-40 versus CEA, MOC-31, BerEP4, claudin-4). Second, if mesothelial, determine whether it is reactive or malignant using BAP1 and MTAP IHC (if both are retained, consider p16 FISH or EZH2). Third, if malignant, classify the subtype as epithelioid, sarcomatoid, or biphasic. Clinical and radiologic correlation is essential at every step.

Metastatic Tumors to Pleura

Metastatic tumors to the pleura are more common than primary pleural malignancies. Lung adenocarcinoma is the most common metastasis to the pleura, followed by breast, ovarian, renal, and GI carcinomas. Lymphoma may present as pleural effusion or mass. Metastatic disease should always be considered before diagnosing mesothelioma.

<image>A medical illustration of mesothelioma histologic types. Panel A (Epithelioid mesothelioma, tubulopapillary pattern): Papillary structures and tubular spaces lined by bland to moderately atypical cuboidal mesothelial cells with abundant eosinophilic cytoplasm, invading into chest wall adipose tissue. Panel B (Sarcomatoid mesothelioma): Dense spindle cell proliferation with storiform architecture, moderate nuclear atypia, and scattered mitoses, invading skeletal muscle. Cytokeratin IHC inset showing focal positivity in spindle cells. Panel C (Biphasic mesothelioma): Transition zone showing epithelioid component (tubulopapillary) merging with sarcomatoid component (spindle cell fascicles). Panel D (Desmoplastic mesothelioma): Paucicellular dense collagenous tissue with scattered bland spindle cells infiltrating chest wall fat, mimicking fibrous pleurisy.</image>

<image>A medical illustration of the IHC panel for mesothelioma diagnosis. Upper row (Mesothelioma): Calretinin showing strong nuclear and cytoplasmic positivity, WT1 showing nuclear positivity, D2-40 showing membranous positivity, and CK5/6 showing cytoplasmic positivity. Lower row (Metastatic adenocarcinoma): CEA showing membranous and cytoplasmic positivity, MOC-31 showing strong membranous positivity, claudin-4 showing membranous positivity, and TTF-1 showing nuclear positivity. Center label indicating the diagnostic panel approach with >=2 positive mesothelial markers and >=2 positive carcinoma markers required.</image>

<image>A medical illustration comparing reactive mesothelial hyperplasia with mesothelioma in situ and invasive mesothelioma using BAP1 and MTAP IHC. Panel A (Reactive mesothelial hyperplasia): Flat to papillary mesothelial proliferation on the pleural surface with BAP1 IHC showing retained nuclear expression (positive) and MTAP IHC showing retained cytoplasmic expression (positive). Panel B (Mesothelioma in situ): Flat atypical mesothelial proliferation on the pleural surface with BAP1 IHC showing complete loss of nuclear staining in mesothelial cells (negative) with retained staining in stromal cells as internal control. Panel C (Invasive epithelioid mesothelioma): Invasive tubulopapillary tumor with both BAP1 loss and MTAP loss, stromal cells retaining expression as internal controls.</image>

Clinical Pearls

BAP1 loss by IHC is the single most useful marker for distinguishing reactive mesothelial proliferations from mesothelioma. It is 100 percent specific for malignancy (never lost in reactive mesothelium) but only approximately 60 to 70 percent sensitive, so retained BAP1 does not exclude mesothelioma. MTAP IHC is replacing p16 FISH as the preferred ancillary test for mesothelioma diagnosis because it is cheaper, faster, and more widely available; loss of MTAP correlates with CDKN2A homozygous deletion.

In sarcomatoid mesothelioma, mesothelial markers (calretinin, WT1, D2-40) may be lost; pan-keratin positivity (often focal) in a pleural spindle cell proliferation is the key to diagnosis. Mesothelioma in situ is a newly recognized entity requiring BAP1 loss or CDKN2A homozygous deletion for diagnosis and may present with recurrent unexplained effusions years before invasive disease develops.

Desmoplastic mesothelioma is the most diagnostically challenging variant because it closely mimics fibrous pleurisy. Invasion into chest wall fat or lung parenchyma is required for diagnosis, making adequate biopsy depth essential. Finally, metastatic carcinoma should always be excluded before diagnosing mesothelioma, since lung adenocarcinoma metastatic to the pleura is far more common than primary mesothelioma.

References

• WHO Classification of Tumours Editorial Board. Thoracic Tumours. 5th ed. IARC; 2021.
• Churg A, et al. Mesothelioma. In: WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. IARC; 2021.
• Chapel DB, et al. MTAP immunohistochemistry is an accurate and reproducible surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant pleural mesothelioma. Mod Pathol. 2020;33(2):245-254.
• Husain AN, et al. Guidelines for pathologic diagnosis of malignant mesothelioma: 2023 update of the consensus statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med. 2023;147(12):1365-1385.
• Hwang HC, et al. BAP1 immunohistochemistry and p16 FISH in the diagnosis of sarcomatous and desmoplastic mesotheliomas. Am J Surg Pathol. 2016;40(5):714-718.

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