Diagnosis of Mesothelioma Pitfalls and Practical Information

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1 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 (212) mbbeasleymd@yahoo.com

2 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.

She is the author or co-author on over 100 book chapters and peer

3 Diagnosis of Mesothelioma Pitfalls and Practical Information Table of Contents I. Mesothelial Proliferations Benign or Malignant II. Epithelioid Malignant Mesothelioma III. Sarcomatoid Mesothelioma IV. Summary V. References Diagnosis of Mesothelioma Pitfalls and Practical Information Beasley 1045

Epithelioid Malignant Mesothelioma...1047 III. Sarcomatoid Mesothelioma...1049 IV.

5 Diagnosis of Mesothelioma Pitfalls and Practical Information I. Mesothelial Proliferations Benign 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 specimens reactive proliferations may look very atypical ii. Pleural biopsy issues 1. Reactive vs neoplastic--epithelioid a. sidedness of proliferation b. Perpendicular blood vessels c. INVASION present 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. Pitfall Fake fat 3. Pleural fibrosis vs desmoplastic mesothelioma a. Criteria of Mangano, et al. i. Linear vs storiform growth ii. Bland necrosis DMM 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 positive favors reactive over neoplastic ii. P53, GLUT-1, IMP3 positive staining favors malignant over benign b. Homozygous p16 deletion by FISH seen in up to 80% of epithelioid mesotheliomas and close to 100% of sarcomatoid mesotheliomas II. Epithelioid Malignant Mesothelioma a. Differential diagnosis i. Carcinoma usually adenocarcinoma, usually lung origin, other primary sites or origin may be considerations Diagnosis of Mesothelioma Pitfalls and Practical Information Beasley 1047

Tissue invasion is the definitive defining feature determining whether or not a proliferation is benign or malignant i.

6 ii. Epithelioid vascular malignancies epithelioid hemangioendotheioma, epithelioid angiosarcoma iii. Malignant melanoma iv. Lymphoma b. Immunostains i. No single immunostain is perfect a 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, MOC- 31, 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-1 nuclear stain in mesothelioma; will also stain ovarian serous carcinomas and melanoma i. Additional pitfall stains 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 1048 Asbestos Medicine November 2014

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.

7 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 Malignant vascular tumors may 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. Lymphoma maybe in differential of lymphohistiocytoid variant of mesothelioma in particular 6. Melanoma Small 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 carcinoma most problematic 1. Sarcomatoid mesothelioma diffuse pleural involvement or multiple pleural nodules; positive for cytokeratin, variable percentage positive for calretinin, WT-1, D2-40; CK5/6 generally negative 2. Sarcomatoid carcinoma large parenchymal mass only 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 sarcoma may be positive for cytokeratin and calretinin; t(x;18) translocation useful in problematic cases 2. Others liposarcoma, leiomyosarcoma, etc rare iii. Solitary fibrous tumor localized as opposed to diffuse involvement, negative keratin, positive CD34, bcl-2 usually 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 Diagnosis of Mesothelioma Pitfalls and Practical Information Beasley 1049

Malignant vascular tumors may 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.

8 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 May;137(5): : 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 Dec;35(12): : Churg A, Galateau-Salle F. The separation of benign and malignant mesothelial proliferations. Arch Pathol Lab Med Oct;136(10): : 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 May;137(5): : Guinee DG, Allen TC. Primary pleural neoplasia: entities other than diffuse malignant mesothelioma. Arch Pathol Lab Med Jul;132(7): : 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 Aug;110(2): Asbestos Medicine November 2014

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.

MALIGNANT MESOTHELIOMA UPDATE ON PATHOLOGY AND IMMUNOHISTOCHEMISTRY

MALIGNANT MESOTHELIOMA CLASSIFICATION MALIGNANT MESOTHELIOMA UPDATE ON PATHOLOGY AND IMMUNOHISTOCHEMISTRY Sisko Anttila, MD, PhD Jorvi Hospital Laboratory of Pathology Helsinki University Hospital Espoo,