Diagnosis of Mesothelioma

Pitfalls and Practical Information

Mary Beth Beasley, M.D.
Mt Sinai Medical Ctr Dept of Pathology
One Gustave L Levy Place
New York, NY 10029
(212) 241-5307
mbbeasleymd@yahoo.com

Mary Beth Beasley, M.D., is an Associate Professor of Pathology at Mt. Sinai

Medical Center. She is the author or co-author on over 100 book chapters and peer
reviewed articles on various aspects of pulmonary pathology and serves on several
national and international committees.

Diagnosis of MesotheliomaPitfalls
and Practical Information

Table of Contents

I. Mesothelial ProliferationsBenign or Malignant.................................................................................1047
II. Epithelioid Malignant Mesothelioma......................................................................................................1047
III. Sarcomatoid Mesothelioma......................................................................................................................1049
IV. Summary...................................................................................................................................................1049
V. References..................................................................................................................................................1050

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Diagnosis of MesotheliomaPitfalls and Practical Information

I. Mesothelial ProliferationsBenign or Malignant

a. Determining whether or not a mesothelial proliferation is benign or malignant is one of the most
difficult aspects of pleural pathology
b. Tissue invasion is the definitive defining feature determining whether or not a proliferation is
benign or malignant
i. Cytology specimens lack surrounding tissue and extreme caution must be used in interpreting
pleural/peritoneal fluid cytology specimensreactive proliferations may look very atypical
ii. Pleural biopsy issues
1. Reactive vs neoplastic--epithelioid
a. sidedness of proliferation
b. Perpendicular blood vessels
c. INVASIONpresent or absent
2. Entrapment vs invasion
a. Tangential or en face sectioning may lead to the appearance of mesothelial cells
within fibrous tissue
b. ?linear pattern versus infiltrating/irregular /complex growth
c. PitfallFake fat
3. Pleural fibrosis vs desmoplastic mesothelioma
a. Criteria of Mangano, et al.
i. Linear vs storiform growth
ii. Bland necrosisDMM
iii. Invasion of chest wall/lung
iv. Frankly sarcomatoid areas
v. Distant metastases
4. ? Ancillary techniques
a. No single immunostain can reliably discriminate a malignant cell from a benign one
i. Desmin positivefavors reactive over neoplastic
ii. P53, GLUT-1, IMP3positive staining favors malignant over benign
b. Homozygous p16 deletion by FISHseen in up to 80% of epithelioid mesotheliomas
and close to 100% of sarcomatoid mesotheliomas

II. Epithelioid Malignant Mesothelioma

a. Differential diagnosis
i. Carcinomausually adenocarcinoma, usually lung origin, other primary sites or origin may be
considerations

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 ii. Epithelioid vascular malignanciesepithelioid hemangioendotheioma, epithelioid angiosarcoma

iii. Malignant melanoma
iv. Lymphoma
b. Immunostains
i. No single immunostain is perfecta panel is recommended to increase sensitivity and specificity
ii. Mesothelioma versus adenocarcinoma panel
1. Positive in mesothelioma: calretinin, WT-1, D2-40/podoplanin, CK5/6, thrombomodulin
2. Positive in adenocarcinoma:
a. General adenocarcinoma markers: CEA, Leu-M1 (CD15), BER-EP4, B72.3, MOC31, BG-8
b. Organ specific markers: TTF-1 (Lung, thyroid),PSA (prostate), PSAP(Prostate),
cdx-2 (Gastrointestinal), BRST-2/GCDPF-15, mammaglobin (Breast) thyroglobulin
(thyroid)
iii. Pitfalls
1. Each individual mesothelioma or carcinoma marker may paradoxically stain a small
percentage of the opposite tumor. Many of these markers stain tumors other than mesothelioma or adenocarcinoma. Be particularly cautious if a diagnosis is made based on a single
marker.
2. Pitfalls of mesothelioma markers
a. Calretinin- will stain approx 10% of adenocarcinomas and 40% of squamous carcinomas (usually focal); will also stain certain ovarian tumors and thymomas.
b. CK 5/6- Positive in virtually all squamous cell carcinomas (squamous should also be
positive for p63 or p40 which is typically negative in mesothelioma) and a significant
percentage of breast carcinomas, gynecologic malignancies, pancreatic adenocarcinomas
c. WT-1nuclear stain in mesothelioma; will also stain ovarian serous carcinomas and
melanoma
i. Additional pitfallstains capillaries and lymphatics which may be mis-interpreted
as tumor staining
d. D2-40- Stains vascular malignancies, squamous cell carcinomas.
i. Similar pitfall to WT-1 with positive background capillaries and lymphatics.
3. Pitfalls of adenocarcinoma markers
a. Not every adenocarcinoma will stain for every marker
i. Example- CEA is positive in up to 90% of lung carcinomas, which means it will be
negative in 10%; additionally, kidney, prostate and ovarian tumors are often negative
ii. Issues with renal cell carcinoma
1. Often negative for adenocarcinoma markers

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 2. Markers often used for renal cell such as CD10 and RCC-Ma may be positive in
mesothelioma
3. Newer markers PAX-8, PAX-2 so far negative in renal cell
4. Renal cell rarely positive for WT-1, negative for calretinin, CK5/6 and D-40
4. Malignant vascular tumorsmay be positive for keratin and will be positive for D2-40; will
be positive for other vascular markers such as CD31, CD34, ERG and FLI-1
5. Lymphomamaybe in differential of lymphohistiocytoid variant of mesothelioma in particular
6. MelanomaSmall percentage may be positive for low molecular weight cytokeratin but
is generally negative. Will be positive for WT-1 either nuclear or cytoplasmic. Positive for
S-100, HMB-45, melan-A
7. Other-Primitive neuroectodermal tumor (PNET), desmoplastic small round cell tumor

III. Sarcomatoid Mesothelioma

a. Differential diagnosis
i. Sarcomatoid carcinomamost problematic
1. Sarcomatoid mesotheliomadiffuse pleural involvement or multiple pleural nodules; positive for cytokeratin, variable percentage positive for calretinin, WT-1, D2-40; CK5/6 generally negative
2. Sarcomatoid carcinomalarge parenchymal massonly rare reports of distribution similar to meso; positive for keratin, usually negative for other carcinoma markers.
3. Stains may be helpful but disease distribution is critical, especially if only keratin is positive
4. Metastatic sarcomatoid carcinomas involving the pleura i.e sarcomatoid renal cell carcinoma may be impossible to sort out without appropriate radiology.
ii. Sarcomas
1. Synovial sarcomamay be positive for cytokeratin and calretinin; t(X;18) translocation
useful in problematic cases
2. Othersliposarcoma, leiomyosarcoma, etcrare
iii. Solitary fibrous tumorlocalized as opposed to diffuse involvement, negative keratin, positive
CD34, bcl-2usually only an issue in a small biopsy without clinical or radiographic information.

IV. Summary
a. In all situations, evaluation must be made in the context of tissue morphology, stains and clinical/
radiographic information
b. Potential red flags to look for in a mesothelioma diagnosis
i. Diagnosis made based on only one positive immunostain
ii. Inappropriate disease distribution for mesothelioma

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 V. References
1: Husain AN, Colby T, Ordonez N, Krausz T, Attanoos R, Beasley MB, Borczuk AC, Butnor K, Cagle PT,
Chirieac LR, Churg A, Dacic S, Fraire A, Galateau-Salle F, Gibbs A, Gown A, Hammar S, Litzky L, Marchevsky
AM, Nicholson AG, Roggli V,Travis WD, Wick M; International Mesothelioma Interest Group. Guidelines for
pathologic diagnosis of malignant mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med. 2013 May;137(5):647-67.
2: Churg A, Cagle P, Colby TV, Corson JM, Gibbs AR, Hammar S, Ordonez N, Roggli VL, Tazelaar HD, Travis
WD, Wick M; US-Canadian Mesothelioma Reference Panel. The fake fat phenomenon in organizing pleuritis: a
source of confusion with desmoplastic malignant mesotheliomas. Am J Surg Pathol. 2011 Dec;35(12):1823-9.
3: Churg A, Galateau-Salle F. The separation of benign and malignant mesothelial proliferations. Arch Pathol
Lab Med. 2012 Oct;136(10):1217-26.
4: Tochigi N, Attanoos R, Chirieac LR, Allen TC, Cagle PT, Dacic S. p16 Deletion in sarcomatoid tumors of the
lung and pleura. Arch Pathol Lab Med. 2013 May;137(5):632-6.
5: Guinee DG, Allen TC. Primary pleural neoplasia: entities other than diffuse malignant mesothelioma. Arch
Pathol Lab Med. 2008 Jul;132(7):1149-70.
6: Mangano WE, Cagle PT, Churg A, Vollmer RT, Roggli VL. The diagnosis of desmoplastic malignant mesothelioma and its distinction from fibrous pleurisy: a histologic and immunohistochemical analysis of 31 cases
including p53 immunostaining. Am J Clin Pathol. 1998 Aug;110(2):191-9.

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