Pleura & peritoneum

• Malignant neoplasm of mesothelial differentiation that arises from mesothelial lining cells of the pleura
• Can be of epithelioid or sarcomatoid cytology or a combination thereof

• Asbestos exposure
• Erionite exposure in genetically predisposed people thought to be associated with unusual high prevalence of malignant mesothelioma in region of Cappadocia, Turkey (Cancer Res 2006;66:5063)
• Ionizing radiation for treatment of malignancy (Hodgkin lymphoma, non-Hodgkin lymphoma, testicular cancer) might be a risk factor (Cancer 2006;107:108, Cancer 2007;109:1432, J Natl Cancer Inst 2005;97:1354)
• Close family members of patients with malignant pleural mesothelioma might have increased risk (Eur Respir J 2016;48:873)
• Molecular aberrations / familial - germline pathogenic variants identified in 12% of patients including mutations in BAP1 (1 - 4%), MutS homolog 3 (MSH3), breast cancer gene 1 associated ring domain 1 (BARD1), RecQ-like helicase 4 (RECQL4), breast cancer gene 2 (BRCA2), MRE11 homolog, double strand break repair nuclease (MRE11A), SHQ1, H/ACA ribonucleoprotein assembly factor (SHQ1) (1% each) (J Thorac Oncol 2020;15:655)
• Association with SV-40 is controversial (Respirology 2005;10:2)

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Table 1. Commonly used immunohistochemical stains for the diagnosis of malignant pleural mesothelioma

Immunohistochemical  stain	Frequency of expression  in malignant mesothelioma, %	Relevant other neoplasms that might express that marker at least in  a subset of cases
Keratin AE1 / AE3a	84 - 100	Carcinomas
CAM 5.2	98 - 99	Carcinomas
WT1 (nuclear)a	64 - 82	Carcinomas of the gynecologic tract (e.g., serous carcinomas), Wilms tumor
Calretinin (nuclear and cytoplasmic)a	55 - 90	Granulosa cell tumor, squamous cell carcinoma
CK5, CK5/6a	28 - 93	Squamous cell carcinoma, NUT carcinoma, breast carcinoma, urothelial carcinoma
Podoplanin (D2-40)a	43 - 80	Squamous cell carcinoma, follicular dendritic cell tumor, angiosarcoma, seminoma, serous carcinoma
GATA3 (nuclear)b	32	Breast carcinoma, urothelial carcinoma
pCEA	1 - 5	Adenocarcinoma, squamous cell carcinoma, neuroendocrine tumors
MOC31	0 - 14	Adenocarcinoma, squamous cell carcinoma
BerEP4	0 - 14	Adenocarcinoma, squamous cell carcinoma
B72.3	4 - 13	Adenocarcinoma, squamous cell carcinoma
Claudin 4	0	Adenocarcinoma, squamous cell carcinoma, small cell carcinoma, sarcomatoid carcinoma
MUC4	0	Adenocarcinoma, squamous cell carcinoma
TTF1 (8G7G3/1)	0	Lung adenocarcinoma, thyroid carcinoma
TTF1 (SP141)	9c	Lung adenocarcinoma, thyroid carcinoma
Napsin A	0	Lung adenocarcinoma, renal cell carcinoma
p40	2	Squamous cell carcinoma, thymic carcinoma, NUT carcinoma, urothelial carcinoma
CDX2	0	Pancreatobiliary adenocarcinoma, intestinal type adenocarcinoma colorectal adenocarcinoma
PAX8	3 - 13	Renal cell carcinoma, thyroid carcinoma, thymic carcinoma (polyclonal antibody), carcinoma of gynecologic tract
Estrogen receptor	0	Breast carcinoma, carcinomas of gynecologic tract

^aLower percentages are described in sarcomatoid subtype; higher percentages in epithelioid subtype

^bGATA3, strong, diffuse expression in sarcomatoid neoplasm argues for sarcomatoid malignant mesothelioma

^cExpression only in sarcomatoid mesotheliomas described

J Clin Pathol 2016;69:136, Arch Pathol Lab Med 2020;144:446, Mod Pathol 2004;17:476, Pathol Int 2015;65:286

Table 2. Markers that aid in the distinction between reactive and malignant mesothelial proliferation

Markers	Sensitivity	Specificity
Loss of expression of nuclear BAP1     All mesothelioma   Epithelioid mesothelioma   Sarcomatoid mesothelioma	27 - 67 56 - 81 0 - 63	100
Loss of expression of cytoplasmic MTAP     Epithelioid mesothelioma   Sarcomatoid mesothelioma	37 80	100
Homozygous deletion of CDKN2A (p16) by FISH     All mesothelioma   Epithelioid mesothelioma   Sarcomatoid mesothelioma	58 - 62 48 - 78 67	100
Loss of BAP expression or homozygous deletion of CDKN2A     All mesothelioma   Epithelioid mesothelioma   Sarcomatoid mesothelioma	58 - 92 92 67 - 100	100
Loss of expression of BAP1 or MTAP     All mesothelioma   Sarcomatoid mesothelioma	76 - 90 90	100

Mod Pathol 2015;28:1043, Am J Surg Pathol 2015;39:977, Am J Surg Pathol 2016;40:714, Arch Pathol Lab Med 2018;142:1549, Hum Pathol 2017;60:86, Lung Cancer 2017;104:98, J Thorac Oncol 2015;10:565, Lung Cancer 2018;125:198, Mod Pathol 2020;33:245, Ann Diagn Pathol 2017;26:31

Contributed by Anja C. Roden, M.D.

Contributed by Anja C. Roden, M.D.

Contributed by Anja C. Roden, M.D.

• Thickened pleura due to neoplastic cells and desmoplastic stromal reaction with or without necrosis
• In contrast, benign pleura: mesothelial cells are horizontally oriented, venules are perpendicular oriented, zonation of mesothelial cells [highest cellularity near serosal surface, trailing off toward chest wall], no invasion, no tumefactive growth (J Clin Pathol 2006;59:564)
• Invasion of neoplastic cells into adipose tissue, skeletal muscle or lung
• Tumefactive growth of malignant cells
• Malignant mesothelial cells are either of epithelioid (epithelioid subtype) or spindled (sarcomatoid / desmoplastic subtype) cytology or a combination thereof (biphasic)
• Epithelioid subtype most common, 36 - 53%; sarcomatoid subtype, 12 - 27%, biphasic 11 - 19% (Thorac Cancer 2019;10:1193, Ann Thorac Surg 2018;105:432)
• If biphasic: provide percentage of sarcomatoid component
• Epithelioid:
  • Cytology usually bland
  • Patterns: solid, acinar (glandular), tubulopapillary, trabecular, micropapillary, microcystic (adenomatoid), clear cell, deciduoid, small cell
  • Psammoma bodies might be present in any pattern
  • Be aware of reactive spindle cells that might mimic sarcomatoid component
  • 2 - 5% show cytoplasmic mucin (Ultrastruct Pathol 2006;30:3)
  • Proposed nuclear grading (Mod Pathol 2012;25:260):
    • Grade I - III
    • Scoring:
      • Mitotic count: score 1 (0 - 1 mitoses/10 HPF), score 2 (2 - 4/10 HPF), score 3 (≥ 5/10 HPF)
      • Nuclear atypia: score 1, mild atypia, score 2, moderate atypia, score 3, severe atypia
      • Composite score: 2 - 3 (grade I), 4 - 5 (grade II), 6 (grade III)
• Sarcomatoid:
  • Haphazard growth of malignant cells
  • Desmoplastic variant: paucicellular, usually bland appearing spindle cells growing in a storiform pattern in a collagenized background with stromal invasion and possible bland necrosis (Arch Pathol Lab Med 2018;142:89)
• Transitional pattern appears to group closer together with sarcomatoid than epithelioid subtype (J Thorac Oncol 2020;15:1037)
• Malignant mesothelioma in situ (Histopathology 2018;72:1033):
  • Defined by
    • Single layer of surface mesothelial cells that lost BAP1 expression
    • Usually presenting as unilateral pleural effusion
    • No evidence of tumor by imaging or by direct examination of pleura
    • No invasive mesothelioma developing for at least 1 year
  • CDKN2A homozygous deletion is rare in these tumors
• Diffuse intrapulmonary malignant mesothelioma; rare, predominantly intrapulmonary growth and minimal pleural involvement clinically simulating interstitial lung disease (Am J Surg Pathol 2019;43:147)
• Recommendations by European Network for Rare Adult Solid Cancers (EURACAN) and International Association for the Study of Lung Cancer (IASLC) to update histologic classification of malignant pleural mesothelioma using a multidisciplinary approach include (J Thorac Oncol 2020;15:29):
  • To update classification to include architectural patterns and stromal and cytologic features that refine prognostication
  • Malignant mesothelioma in situ could be an additional category
  • Routinely grade epithelioid malignant pleural mesothelioma
  • Routinely stage resection specimens; amongst others
  • Many of these recommendations will likely be included in the upcoming WHO classification

Contributed by Anja C. Roden, M.D.

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Contributed by Anja C. Roden, M.D. and Andrey Bychkov, M.D., Ph.D.



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• See Table 1 and Table 2
• Keratin (e.g., AE1 / AE3):
  • Expressed in virtually all epithelioid malignant pleural mesothelioma and almost all sarcomatoid malignant pleural mesothelioma (if multiple keratins are negative consider other diagnosis)
  • Useful to:
    • Distinguish from sarcoma, malignant melanoma and other differential diagnoses
    • Identify or confirm invasion
  • Markers for mesothelial differentiation:
  • No single marker sufficiently sensitive or specific for mesothelial differentiation → panel of at least two carcinoma markers (e.g., pCEA, TTF1, among others) and two mesothelial markers (i.e., WT1, calretinin, CK5, CK5/6, D2-40) recommended (Table 1)
• MOC31 and BerEP4, although considered carcinoma markers, often at least focally expressed in malignant pleural mesothelioma

Which clinical history would be most likely for this patient?


1. 30 year old man who underwent orchiectomy for immature teratoma as a child
2. 55 year old man who is on dialysis for diabetic nephropathy
3. 60 year old man who worked in a shipyard 35 years ago
4. 65 year old man who worked in a coal mine for 30 years
5. 65 year old woman with history of breast carcinoma

C. This patient was likely exposed to asbestos 35 years ago. Unilateral pleural thickening is highly suspicious for malignant pleural mesothelioma.

Answer A is false; metastases from germ cell tumors would be usually bilateral. B is false; this patient would likely present with bilateral pleural effusion and possible bilateral pleural thickening. D is false; exposure to coal dust is not a risk factor for malignant pleural mesothelioma. E is false; metastases from breast carcinoma would be usually bilateral.

Comment Here

Reference: Diffuse malignant mesothelioma

This patient has a history of ovarian carcinoma. Which would be the most useful panel of immunostains to rule out malignant mesothelioma in this patient?


1. Calretinin, CK5, PAX8, pCEA
2. CAM 5.2, WT1, MOC31, D2-40
3. D2-40, WT1, pCEA, MOC31
4. Keratin, AE1 / AE3, WT1, estrogen receptor, MOC31
5. WT1, pCEA, MOC31, BerEP4

A. Expression of calretinin and CK5 would indicate malignant pleural mesothelioma while PAX8 and pCEA indicate metastatic ovarian carcinoma. Be aware that PAX8 can be positive in a small subset of malignant pleural mesothelioma.

Answer B is false; CAM5.2 and WT1 will be positive in both, malignant pleural mesothelioma and metastatic ovarian carcinoma; MOC31 will be expressed in metastatic carcinoma but can be at least focally expressed in malignant pleural mesothelioma. D2-40 can be expressed in serous carcinomas. C is false; although two malignant pleural mesothelioma markers (D2-40, WT1) and two carcinoma markers (pCEA and MOC31), WT1 can be positive in ovarian carcinomas and MOC31 is sometimes at least focally expressed in malignant pleural mesothelioma. D is false; keratin AE1/AE3 and WT1 will be positive in both, malignant pleural mesothelioma and metastatic ovarian carcinoma; MOC31 will be expressed in metastatic carcinoma but can be at least focally expressed in malignant pleural mesothelioma. E is false; these are three carcinoma markers (pCEA, MOC31, BerEP4) and only one malignant pleural mesothelioma marker which also is frequently expressed in ovarian carcinomas. For workup of malignant pleural mesothelioma, at least two carcinoma markers and two mesothelial markers should be used.

Comment Here

Reference: Diffuse malignant mesothelioma