Diagnosis of MesotheliomaPitfalls 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 InformationBeasley1045

Diagnosis of MesotheliomaPitfalls and Practical Information

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

Table of Contents

Diagnosis of MesotheliomaPitfalls and Practical InformationBeasley1047

Diagnosis of MesotheliomaPitfalls and Practical Information

I. Mesothelial ProliferationsBenign or Malignanta. Determining whether or not a mesothelial proliferation is benign or malignant is one of the most

difficult aspects of pleural pathologyb. 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 Mesotheliomaa. 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 angiosar-coma

iii. Malignant melanoma iv. Lymphomab. Immunostains i. No single immunostain is perfecta panel is recommended to increase sensitivity and specific-

ity 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 mesothe-lioma 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 carcino-

mas (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 adenocarcino-mas

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

Diagnosis of MesotheliomaPitfalls and Practical InformationBeasley1049

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 par-ticular

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 Mesotheliomaa. Differential diagnosis i. Sarcomatoid carcinomamost problematic

1. Sarcomatoid mesotheliomadiffuse pleural involvement or multiple pleural nodules; posi-tive for cytokeratin, variable percentage positive for calretinin, WT-1, D2-40; CK5/6 gener-ally negative

2. Sarcomatoid carcinomalarge parenchymal massonly rare reports of distribution simi-lar 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 carci-

noma 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 informa-tion.

IV. Summarya. In all situations, evaluation must be made in the context of tissue morphology, stains and clinical/

radiographic informationb. 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. References1: 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 Interna-tional 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 meso-thelioma 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.

Asbestos MedicineCourse Materials Table of ContentsDiagnosis of Mesothelioma-Pitfalls and Practical InformationMary Beth Beasley, M.D.Table of ContentsI.Mesothelial ProliferationsBenign or MalignantII.Epithelioid Malignant MesotheliomaIII.Sarcomatoid MesotheliomaIV.SummaryV.References