Pleura & peritoneum
Pleura mesothelial tumors
Diffuse malignant mesothelioma

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Anja C. Roden, M.D.

Minor changes: 1 September 2020

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PubMed Search: Diffuse malignant mesothelioma[TI]

Anja C. Roden, M.D.
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Cite this page: Roden AC. Diffuse malignant mesothelioma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/pleuramesothelioma.html. Accessed October 26th, 2020.
Definition / general
  • 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
Essential features
  • Aggressive neoplasm of mesothelial differentiation
  • Epithelioid, biphasic or sarcomatoid subtype
  • Overall survival, 4 - 27 months, depending on subtype
  • Most commonly associated with remote (up to 40 years prior) asbestos exposure
  • Loss of expression of BRCA1 associated protein (BAP1) or methylthioadenosine phosphorylase (MTAP) or homozygous deletion of cyclin dependent kinase inhibitor 2A (CDKN2A) (p16) by FISH helps to distinguish reactive mesothelial proliferation from malignant pleural mesothelioma
ICD coding
  • ICD-10: C45.0 - mesothelioma of pleura
  • ICD-11: 2C26.0 - mesothelioma of pleura
Epidemiology
Sites
  • Parietal, visceral, mediastinal or diaphragmatic pleura
Pathophysiology
  • Hypotheses for how asbestos causes malignant pleural mesothelioma include (Respirology 2005;10:2):
    • Toxic oxygen radical generation
    • Chronic pleural irritation
    • Persistent kinase mediated signaling
  • Asbestos fibers exert cytotoxic and genotoxic effects
  • Long and thin fibers associated with higher mutagenesis (Transl Lung Cancer Res 2020;9:S39)
  • Erionite and zeolite fibers are specifically linked to malignant pleural mesothelioma and likely more potent carcinogens than other asbestos fibers (Semin Oncol 2002;29:2)
  • Common inactivated tumor suppressors in malignant pleural mesothelioma: BAP1, neurofibromin 2 (NF2), CDKN2A
  • Malignant mesothelioma in situ has high risk of developing invasive mesothelioma (Proc Natl Acad Sci U S A 1988;85:6571)
Etiology
  • 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)
Diagrams / tables
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
  • Clinical features
    • Shortness of breath
    • Chest wall pain, pleurisy
    • Cough
    • Weight loss
    • Recurrent unilateral pleural effusion; might be hemorrhagic
    • Occasionally asymptomatic when discovered at early stage
    Diagnosis
    • Pleural thickening or recurrent pleural effusion on chest Xray followed up with contrast enhanced chest CT scan
    • Thoracocentesis acquiring pleural fluid for cytology (in the past, was often considered not sufficient for definite diagnosis; with BAP1 and MTAP immunostaining and FISH for homozygous deletion of CDKN2A, diagnosis of malignant pleural mesothelioma possible on at least a subset of fluids) (Cancer Cytopathol 2018;126:54)
    • Pleural biopsy (e.g., video assisted thoracoscopic surgery [preferred], CT guided core biopsy, open biopsy)
    • Mediastinoscopy with lymph node sampling
    Laboratory
    Radiology description
    • Chest Xray:
      • Unilateral effusion
    • CT scan ideally with contrast enhancement (Surg Pathol Clin 2020;13:73):
      • Unilateral pleural effusion
      • Loculated, nodular or diffuse pleural thickening
      • Multifocal nodules studding pleural surfaces including visceral, parietal and diaphragmatic pleura and possibly extending into fissures
      • Thick rind of pleura
    • Localized pleural or subpleural mass, rare, might measure up to 15 cm (Surg Pathol Clin 2020;13:73)
    • Anterior mediastinal mass, rare, might invade into abdomen including liver
    • Benign pleural plaques of parietal pleura, usually bilateral, might be seen in addition to malignant pleural mesothelioma; indicate exposure to asbestos; they are not a sign of malignant pleural mesothelioma
    • MRI and PET / CT: complementary to contrast enhanced CT
      • MRI might help to better delineate relationship of malignant pleural mesothelioma to adjacent structures and organs
      • PET / CT might help to identify metastatic disease
    Radiology images

    Contributed by Anja C. Roden, M.D.
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    Malignant pleural mesothelioma

    Prognostic factors
    Case reports
    Treatment
    • Management by multidisciplinary team
    • Most patients (40%): no specific modality of treatment (Ann Thorac Surg 2018;105:432)
    • Chemotherapy alone: most common treatment (Ann Thorac Surg 2018;105:432)
    • Trimodality treatment (chemotherapy, surgical resection, radiation therapy): best survival > combination chemotherapy and resection (Ann Thorac Surg 2018;105:432)
    • Surgery within multimodal therapy suggested only to suitable patients (i.e., young patients with early stage epithelioid histology; good performance status, epithelioid or possibly biphasic morphology) (Thorac Cancer 2019;10:1193)
    • NCCN guidelines (Version 1.2020):
      • Clinical stage I - IIIA and epithelioid or biphasic morphology (surgery should be considered for biphasic if early stage disease)
      • Induction chemotherapy followed by surgical exploration (pleurectomy / decortication or extrapleural pneumonectomy; mediastinal lymph node sampling)
        • If pleurectomy / decortication: followed by observation or radiation
        • If extrapleural pneumonectomy: followed by hemithoracic radiation; if found unresectable, chemotherapy
      • Surgical exploration (pleurectomy / decortication or extrapleural pneumonectomy; mediastinal lymph node sampling)
        • If pleurectomy / decortication: followed by chemotherapy followed by observation or radiation
        • If extrapleural pneumonectomy: followed by sequential chemotherapy and hemithoracic radiation; if found unresectable chemotherapy
    • Surgery associated with morbidity and mortality; extrapleural pneumonectomy and extended pleurectomy / decortication: perioperative mortality of 6.8% and 2.9%; morbidity of 62% and 27.9%, respectively (Lung Cancer 2014;83:240)
    • Sarcomatoid and desmoplastic mesothelioma or patients with poor performance status: chemotherapy or supportive care only
    • Supportive care: pleurodesis or pleural catheter if recurrent pleural effusion
    • Anti-PD1 or anti-PDL1 treatment on occasion, not standardized
    Gross description
    • Thick rind of pleura possibly extending into fissures
    • Studding of pleura
    • Multiple pleural nodules
    • Single pleural based mass rare (localized malignant pleural mesothelioma) (Mod Pathol 2020;33:281)
    • Optimal orientation of specimen important for assessment of invasion: pleural sections submitted perpendicular to surface; should contain entire pleural thickness together with adjacent structures such as lung, adipose tissue or skeletal muscle
    Gross images

    Contributed by Anja C. Roden, M.D.
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    Malignant mesothelioma of left pleura

    Frozen section description
    • Assess adequacy of sampled tissue that includes tissue to assess growth pattern and invasion
    • Distinction between metastatic carcinoma, sarcoma, melanoma and mesothelioma is in general not possible; neither is it important at time of frozen section evaluation
    Frozen section images

    Contributed by Anja C. Roden, M.D.
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    Pleural biopsy with malignant mesothelioma, epithelioid type

    Microscopic (histologic) description
    • Thickened pleura due to neoplastic cells and desmoplastic stromal reaction with or without necrosis
    • Distorted architecture of pleura (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
    Microscopic (histologic) images

    Contributed by Anja C. Roden, M.D.
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    Malignant pleural mesothelioma, epithelioid type


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    Malignant pleural mesothelioma, epithelioid type


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    Malignant pleural mesothelioma, epithelioid type, acinar (glandular) pattern


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    Malignant pleural mesothelioma, biphasic type

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    Malignant pleural mesothelioma, sarcomatoid type


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    Malignant pleural mesothelioma, sarcomatoid type

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    Malignant pleural mesothelioma, epithelioid type in vicinity to pleurodesis

    Virtual slides

    Images hosted on other servers:
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    Lung, malignant mesothelioma

    Cytology description
    • In general, only epithelioid malignant pleural mesothelioma shed into pleural effusion
    • Epithelioid cells in sheets, clusters, morules, papillae
    • Usually bland cytology, can be pleomorphic
    • Psammoma bodies possible
    • Loss of BAP1 or MTAP expression or homozygous deletion of CDKN2A helpful in establishing the diagnosis of malignant pleural mesothelioma (see below) (Cancer 2003;99:51)
    • On cytology specimens (Klin Khir 1995;2:53):
      • Lack of MTAP and BAP1 expression by immunohistochemistry: 100% specific for malignant pleural mesothelioma (versus reactive mesothelial proliferation); 42 and 60% sensitive, respectively
      • Loss of MTAP or BAP1 expression: 78% sensitive for malignant pleural mesothelioma
      • Homozygous deletion of CDKN2A by FISH: 62% sensitive for malignant pleural mesothelioma, 100% specific
      • Combination of loss of BAP1 expression or homozygous deletion of CDKN2A by FISH 84% sensitive for malignant pleural mesothelioma
      • Loss of MTAP expression: sensitivity and specificity for homozygous deletion of CDKN2A by FISH; 68 and 100%, respectively
    • Exclude metastatic carcinoma using immunostains (see below)
    Cytology images

    Contributed by Anja C. Roden, M.D.
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    Pleural fluid with malignant mesothelioma, epithelioid type

    Positive stains
    • 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
    Negative stains
    Electron microscopy description
    • In general not used anymore in the distinction from adenocarcinoma (Arch Pathol Lab Med 2018;142:89)
    • Numerous long, thin, sinuous microvilli that are not covered by a glycocalyx (in contrast to adenocarcinoma in which microvilli are usually also shorter) (Ultrastruct Pathol 2006;30:3)
    • Large desmosomes and prominent junctional complexes
    • Tonofilaments frequently in a perinuclear distribution
    Molecular / cytogenetics description
    Sample pathology report
    • Pleura, right, pleurectomy:
      • Malignant mesothelioma, epithelioid type (see synoptic report)
      • 1 of 2 lymph nodes involved by malignant mesothelioma
    Differential diagnosis
    Board review style question #1

      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
    Board review answer #1
    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
    Board review style question #2

      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
    Board review answer #2
    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
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