Update on Mesothelioma

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1 November 8, 2012

2 Update on Mesothelioma Intro incidence and nomenclature Update on Classification Diagnostic specimens Morphologic features Epithelioid Histology Biphasic Histology Immunohistochemical features Molecular Features p16 FISH Update on Prognostic Features Histology in Lymph Nodes

3 Update on Mesothelioma Intro incidence and nomenclature Update on Classification Diagnostic specimens Morphologic features Epithelioid Histology Biphasic Histology Immunohistochemical features Molecular Features p16 FISH Update on Prognostic Features Histology in Lymph Nodes

4 2012 Update of the Consensus Statement from the IMiG

5 Mesothelioma SEER Incidence, All Races, By Sex Source: SEER 9 areas. Rates are age-adjusted to the 2000 US Std Population. Accessed April 25, 2012, National Cancer Institute.

6 Mesothelioma Diffuse malignant mesothelioma DMM Localized malignant mesothelioma LMM Well-differentiated papillary mesothelioma WDPM

7 Diffuse malignant mesothelioma DMM

8 Localized malignant mesothelioma LMM Cured by surgical excision. Excellent outcome. Recur as metastases like sarcomas

9 Well-differentiated papillary mesothelioma WDPM Distinct entity Benign tumor or tumor of low malignant potential. Excellent prognosis. Primarily involves the peritoneum in women. May grossly form polypoid or discrete nodules.

10 Prognosis of Malignant Mesothelioma is Dependent on the Histologic Type Malignant Mesothelioma Percent survival Epithelioid Mixed Sarcomatoid Time (months) Sugarbaker DJ et al, J Thorac Cardiovasc Surg Jan;117(1):54-63

11 Prognosis of Malignant Mesothelioma is Dependent on the Histologic Type Malignant Mesothelioma Percent survival Epithelioid Mixed Sarcomatoid LMM Time (months) Sugarbaker DJ et al, J Thorac Cardiovasc Surg Jan;117(1):54-63

12 Prognosis of Malignant Mesothelioma is Dependent on the Histologic Type Malignant Mesothelioma Percent survival Epithelioid Mixed Sarcomatoid WDPM Time (months) Sugarbaker DJ et al, J Thorac Cardiovasc Surg Jan;117(1):54-63

13 Update on Mesothelioma Intro incidence and nomenclature Update on Classification Diagnostic specimens Morphologic features Epithelioid Histology Biphasic Histology Immunohistochemical features Molecular Features p16 FISH Update on Prognostic Features Histology in Lymph Nodes

14 Types of Specimens Pleural biopsies. Pleurectomy/decortication (P/D). Pleurectomy removal of parietal pleural surface, diaphragm, and pericardium Decortication resection of the involved visceral pleural surface with preservation of the lung parenchyma Extrapleural pneumonectomy (EPP). Removal of parietal pleura, diaphragm and pericardium Lung

15 Importance of an Adequate Biopsy

16 Pleurectomy/Decortication (P/D) Extrapleural Pneumonectomy (EPP)

17 Extrapleural Pneumonectomy EPP

18 Extrapleural Pneumonectomy EPP

19 Extrapleural Pneumonectomy EPP

20 Extrapleural Pneumonectomy EPP

21 Extrapleural Pneumonectomy EPP

22 Extrapleural Pneumonectomy EPP

23 Concordance between the Diagnosis in the Initial Biopsy and the Diagnosis in the Matched Surgical Resection Specimen Resection Specimen Histology N=759 (% ) Epithelioid Biphasic Sarcomatoid Total Biopsy Histology Epithelioid Biphasic Sarcomatoid 463 (80) 113 (20) 576 (100) 15 (11) 120 (87) 4 (3) 139 (100) 7 (19) 29 (81) 36 (100) Total (100) Chirieac et al., submitted

24 Concordance between the Diagnosis in the Initial Biopsy and the Diagnosis in the Matched Surgical Resection Specimen Resection Specimen Histology N=759 (% ) Epithelioid Biphasic Sarcomatoid Total Biopsy Histology Epithelioid Biphasic Sarcomatoid 463 (80) 113 (20) 576 (100) 15 (11) 120 (87) 4 (3) 139 (100) 7 (19) 29 (81) 36 (100) Total (100) Chirieac et al., submitted

25 Concordance between the Diagnosis in the Initial Biopsy and the Diagnosis in the Matched Surgical Resection Specimen Resection Specimen Histology N=759 (% ) Epithelioid Biphasic Sarcomatoid Total Biopsy Histology Epithelioid Biphasic Sarcomatoid 463 (80) 113 (20) 576 (100) 15 (11) 120 (87) 4 (3) 139 (100) 7 (19) 29 (81) 36 (100) Total (100) Chirieac et al., submitted

26 Concordance between the Diagnosis in the Initial Biopsy and the Diagnosis in the Matched Surgical Resection Specimen Resection Specimen Histology N=759 (% ) Epithelioid Biphasic Sarcomatoid Total Biopsy Histology Epithelioid Biphasic Sarcomatoid 463 (80) 113 (20) 576 (100) 15 (11) 120 (87) 4 (3) 139 (100) 7 (19) 29 (81) 36 (100) Total (100) Chirieac et al., submitted

27 Concordance between the Diagnosis in the Initial Biopsy and the Diagnosis in the Matched Surgical Resection Specimen Resection Specimen Histology N=759 (% ) Epithelioid Biphasic Sarcomatoid Total Biopsy Histology Epithelioid Biphasic Sarcomatoid 463 (80) 113 (20) 576 (100) 15 (11) 120 (87) 4 (3) 139 (100) 7 (19) 29 (81) 36 (100) Total (100) Chirieac et al., submitted

28 Overall Survival in DMM According to the Initial Biopsy Specimen and Final Resection Specimen 100 Initial Biopsy 100 Resection Specimen Overall Survival (%) Sarcomatoid Biphasic P=0.24, HR=1.3 (95% CI 0.83 to 2.01) Epithelioid Overall Survival (%) Sarcomatoid Biphasic P=0.03, HR=1.7 (95% CI 1.04 to 2.72) Epithelioid Months Months Chirieac et al., submitted

29 Update on Mesothelioma Intro incidence and nomenclature Update on Classification Diagnostic specimens Morphologic features Epithelioid Histology Biphasic Histology Immunohistochemical features Molecular Features p16 FISH Update on Prognostic Features Histology in Lymph Nodes

30 Pathologic Classification of Diffuse Malignant Mesothelioma Epithelioid mesothelioma Sarcomatoid mesothelioma (spindle cell) Desmoplastic mesothelioma (variant of sarcomatoid mesothelioma) Biphasic mesothelioma

31 Epithelioid MM Sarcomatoid MM Biphasic MM Biphasic MM

32 Epithelioid Mesothelioma H&E 400x

33 Sarcomatoid Mesothelioma H&E 400x

34 Desmoplastic Mesothelioma H&E 200x

35 Biphasic/Mixed Mesothelioma

36 Prognosis of Malignant Mesothelioma is Dependent on the Histologic Type Malignant Mesothelioma Percent survival Epithelioid Mixed Sarcomatoid Time (months) Sugarbaker DJ et al, J Thorac Cardiovasc Surg Jan;117(1):54-63

37 Histologic Subtypes and Patterns of Malignant Mesothelioma Epithelioid Mesothelioma Tubulopapillary Micropapillary Trabecular Acinar Adenomatoid Solid Clear cell Deciduoid Adenoid cystic Signet ring cell Small cell Rhabdoid Pleomorphic Sarcomatoid Mesothelioma Conventional, spindle cell Desmoplastic Heterologous differentiation (osteosarcomatous, chondrosarcomatous, etc.) Lymphohistiocytoid (may also be classified as epithelioid) Biphasic/Mixed 2012 Update on the Guidelines by the IMiG Recommendations

38 Overall survival by histologic type in 305 patients with diffuse malignant pleural mesothelioma Kadota et al., J Thor Oncol May 2011

39 Update on Mesothelioma Intro incidence and nomenclature Update on Classification Diagnostic specimens Morphologic features Epithelioid Histology Biphasic Histology Immunohistochemical features Molecular Features p16 FISH Update on Prognostic Features Histology in Lymph Nodes

40 Introduction Diffuse malignant mesothelioma (MM) is classified into epithelioid, sarcomatoid, and biphasic types which have prognostic value. The biphasic type has a mixture of epithelioid and sarcomatoid components, but the predictive value of their proportions has not been documented. We investigated the clinical significance of the percentage of the sarcomatoid component in biphasic MM.

41 Biphasic Malignant Mesothelioma Predominantly Epithelioid Predominantly Sarcomatoid

42 Results The biphasic MM had a bimodal distribution: predominantly sarcomatoid (more than 50% sarcomatoid component, n=19) or predominantly epithelioid (less than 50% sarcomatoid component, n=21).

43 Survival of Patients with Malignant Mesothelioma

44 Survival of Patients with Malignant Mesothelioma

45 Results The extent of sarcomatoid component was significantly associated with overall survival (p<0.0001). Patients with predominantly sarcomatoid biphasic MM have a similar survival as patients with monophasic sarcomatoid MM (10.4 and 9.1 months). Patients with predominantly epithelioid biphasic MM had a better survival (17.5 months) than patients with predominantly sarcomatoid biphasic MM (10.4 months). Patients with monophasic epithelioid MM had the longest median survival of 30.5 months. The difference in survival was statistically significant (p<0.0001).

46 Update on Mesothelioma Intro incidence and nomenclature Update on Classification Diagnostic specimens Morphologic features Epithelioid Histology Biphasic Histology Immunohistochemical features Molecular Features p16 FISH Update on Prognostic Features Histology in Lymph Nodes

47 Immunohistochemistry Workup in Malignant Mesothelioma Benign vs. Malignant Epithelioid vs. Sarcomatoid Pleural vs. Peritoneal Type of tumor in the differential diagnosis adenocarcinoma squamous cell carcinoma malignant melanoma epithelioid hemangioendothelioma

48

49 Immunohistochemistry to Separate Reactive Mesothelial Proliferations from Mesothelioma Antibody Desmin EMA P53 GLUT1 Reactive Mesothelium 34/40 (85%) 8/40 (20%) 0/40 (0%) 0/80 (0%) Mesothelioma 6/60 (10%) 48/60 (80%) 27/60 (45%) 76/85 (89%) Modified from Attanoos et al. and with data from Kato et al. Data from Kato et al. and University of Chicago

50 GLUT1 Epithelioid Mesothelioma 400x

51 GLUT1 Sarcomatoid Mesothelioma 400x

52

53 Mesothelial hyperplasia Adenocarcinoma (Lung, other sites) Vascular tumor: epithelioid hemangioendothelioma and angiosarcoma Thymoma (metastatic or primary), non-hodgkin s lymphoma, and metastatic melanoma

54 Fibrous pleuritis Mesothelial hyperplasia Adenocarcinoma (Lung, other sites) Vascular tumor: epithelioid hemangioendothelioma and angiosarcoma Thymoma (metastatic or primary), non-hodgkin s lymphoma, and metastatic melanoma Sarcomatoid carcinoma Sarcomas: leiomyosarcoma, synovial sarcoma, epithelioid sarcoma, malignant peripheral nerve sheath tumor, undifferentiated/ pleomorphic sarcoma Localized fibrous tumor Metastatic spindle cell melanoma

55 Immunohistochemistry Workup of Epithelioid Malignant Mesothelioma Pancytokeratin is always positive Mesotheliomas Carcinomas Pancytokeratin negative - consider CD45 (LCA), CD20 or CD30 for large cell lymphomas S-100 and HMB-45 for melanoma CD31 and CD34 for angiosarcoma or epithelioid hemangioendothelioma.

56 Epithelioid Mesothelioma AE1/AE3 400x

57 AE1/AE3 200x

58 Immunohistochemical Stains Useful for the Diagnosis of Mesothelioma Immunostain Epithelioid Mesothelioma Sarcomatoid Mesothelioma Pancytokeratin Cytokeratin 5/6 Calretinin Thrombomodulin WT1 Mesothelin HBME-1 CEA BerEP4 CD15 (LeuM1) B72.3 Bg8 MOC31 TTF1 Pos Pos Pos Pos Pos Pos Pos Neg Neg Neg Neg Neg Neg Neg Pos Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Adapted from Churg et al, Tumors of the Serosal Membranes

59 Immunophenotype Epithelioid Mesothelioma Lung Adenocarcinoma CEA B72.3 (TAG-72) TTF-1 Leu-M1 (CD15) CA19-9 MOC-31 Ber-EP4 WT1 D2-40 Calretinin Cytokeratin 5/ Cytokeratin 5/6 Calretinin D2-40 WT1 Ber-EP4 M OC-31 CA19-9 Leu-M 1 (CD15) TTF-1 B72.3 (TAG-72) CEA Epithelial mesotheliomas Pulmonary adenocarcinomas

60 Immunophenotype of Sarcomatoid Malignant Mesothelioma AE1/AE3 CAM 5.2 MNF-116 Bcl-2 CD-34 Calretinin WT-1 protein D2-40 Podoplanin 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

61 AE1/AE3 400x

62 CAM x

63 WT-1 400x

64 Calretinin 400x

65 D x

66 Conclusions Immunohistochemistry is an important ancillary tool to confirm the diagnosis of malignant mesothelioma. The role of immunohistochemistry varies depending on the histologic type of mesothelioma (epithelioid versus sarcomatoid), the location of the tumor (pleural versus peritoneal) and the type of tumor (adenocarcinoma, squamous cell carcinoma, malignant melanoma, epithelioid hemangioendothelioma) considered in the differential diagnosis.

67 Conclusions Multiple antibodies with various sensitivities and specificities are commercially available. At the present time there are no rules of which antibodies to use and the selection depends on experience of the laboratory and the pathologist. An initial workup should include a panel of two positive and two negative markers.

68 Update on Mesothelioma Intro incidence and nomenclature Update on Classification Diagnostic specimens Morphologic features Epithelioid Histology Biphasic Histology Immunohistochemical features Molecular Features p16 FISH Update on Prognostic Features Histology in Lymph Nodes

69 P16 Deletions in Malignant Mesothelioma Several cytogenetic and molecular studies have reported p16/cdkn2a deletions in up to 80% of primary pleural mesotheliomas, depending on the histologic subtype % of sarcomatoid mesothelioma. 70% of epithelioid and mixed types. In contrast, this deletion occurs in approximately 25% of peritoneal mesotheliomas Therefore, the detection of deletion can be a useful approach for distinguishing benign from malignant mesothelial proliferations

70 Not deleted

71 Deleted

72 Update on Mesothelioma Intro incidence and nomenclature Update on Classification Diagnostic specimens Morphologic features Epithelioid Histology Biphasic Histology Immunohistochemical features Molecular Features p16 FISH Update on Prognostic Features Histology in Lymph Nodes

73 Prognosis of Malignant Mesothelioma is Dependent on N Status Richards WG et al, Cancer Mar 15;116(6):

74 Patterns of Lymph Node Spread to N2 Nodes from Biphasic Malignant Mesothelioma In patients with biphasic DMM the pattern of lymph node metastases is unknown. There are no studies examining which component is more likely to spread to N2 lymph nodes. The goal of this study was to characterize the histology of metastases to N2 lymph nodes from patients with biphasic DMM.

75 Patterns of Lymph Node Spread to N2 Nodes from Biphasic Malignant Mesothelioma

76 Clinicopathologic Characteristics of Patients with Biphasic Malignant Mesothelioma and Positive N2 Lymph Nodes N=65 (%) Sex Female 11 (17) Male 54 (83) Age (yrs) Median 60.1 Range Histology of Malignant Mesothelioma Mixed 65 (100) Histology of N2 metastases Epithelioid 27 (42) Sarcomatoid 0(0) Mixed 38 (58)

77 Clinicopathologic Characteristics of Patients with Biphasic Malignant Mesothelioma and Positive N2 Lymph Nodes N=65 (%) Sex Female 11 (17) Male 54 (83) Age (yrs) Median 60.1 Range Histology of Malignant Mesothelioma Mixed 65 (100) Histology of N2 metastases Epithelioid 27 (42) Sarcomatoid 0(0) Mixed 38 (58)

78 Patterns of Lymph Node Spread to N2 Nodes from Biphasic Malignant Mesothelioma Outcome of Patients with Biphasic MM and N2 Metaststases Based on N2 Histology 100 Overall Survival (%) Epitheliod and Sarcomatoid N2 Nodes Epitheliod N2 Nodes Follow Up (mo)

79 N2 lymph node metastases from biphasic malignant mesothelioma have two histologies: (1) an epithelioid histology and (2) a mixed epithelioid and sarcomatoid histology. An epithelioid histology in the mediastinal lymph node biopsies performed as an initial assessment of patients with MM does not preclude a diagnosis of biphasic MM in the primary tumor. The histological pattern of metastasis in N2 mediastinal lymph nodes from patients with biphasic DMM was significantly associated with overall survival. Our study emphasizes the heterogeneity of biphasic MM as well as the importance of accurate histologic assessment of both mediastinal lymph nodes and primary DMM specimens.

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