Mesothelioma Pathobasic. Lukas Bubendorf Pathology
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1 Mesothelioma Pathobasic Lukas Bubendorf Pathology
2 Mechanisms of Asbestos Carcinogenesis in Mesothelioma Asprin High-mobility group protein B1 master switch HMGB1 Initiation/ perpetuation of inflamm. response Hyperacetylated HMGB1: Serum biomarker for mesothelioma Prolonged biopersistence SV40 as Co-factor? Carbone & Jang, Clin Cancer Res 2012 & Ann Transl Med 2017
3 J Thorac Oncol 2016; 11: et al. Arch Pathol Lab Med 2017 Jul 7
4 Diagnosis of mesothelioma can be difficult Review panels: French mesothelioma review panel Diagnosis confirmed 67% Eastern China 57% Carbone & Hang, Ann Transl Med 2017
5 European Mesothelioma Panel A: unequivocal B: probable C: possible D: probably not E: no mesothelioma Junker & Pathologe 2014
6 2015 WHO Classification of Tumors of the Pleura
7 Histological classification of mesothelioma Epitheloid Tubulo-papillary, papillary, solid, trabecular, pleomorphic DD: Adenocarcinoma, reactive hyperplasia Biphasic Sarcomatoid Desmoplastic DD: Synovial Sarcoma t(x;18), sarcomatoid NSCLC; SFT, reactive fibrosis/organizing pleuritis
8 Histological subtype of MM & prognosis
9 Diffuse malignant mesothelioma, epithelioid type Papillary pattern Tubular pattern
10 Diffuse malignant mesothelioma, epithelioid type Pleomorphic pattern Solid pattern Calretinin Micropapillary pattern Galateau-Salle F et al, JTO 2016
11 Diffuse malignant mesothelioma, epithelioid type Pleomorphic pattern B
12 Diffuse malignant mesothelioma, sarcomatoid type
13 B biphasisch
14 Histological key criteria of mesothelioma 1. Infiltration of the subpleural fatty tissue 2. Solid tumor growth, expansive nodule
15
16 Zonation Churg et al, Am J Surg Pathol 2000
17 Calretinin CK5/6 WT IHC BerEP-4 neg Desmin neg
18 Desmoplastic DMPM IHC in sarcomatoid/desmoplastic mesothelioma CK22 B Calretinin +: 30% CK5/6+: <50% WT-1 +: <50% D2-40+: >50% Pancytokeratin: 95%
19 B
20 Differential diagnosis of DPMM Diagnosis IHC Molecular markers Organizing pleuritis (Glut-1) FISH (9p21) - BAP1 normal Reactive mesothelial proliferation - FISH (9p21) - BAP1 normal Solitary fibrous tumor STAT6, Bcl2, CD34 NAB2-STAT6 fusion Synovial sarcoma Epithelioid hemangioendothelioma Desmoid-type fibromatosis ERG, CD31, CD34, FLI1 ncl. β-catenin (-75%) SYT WWTR1-CAMTA1 (FISH) CTNNB1 mutation (85%)
21
22 IHC: Mesothelioma vs. Adenocarcinoma Marker Mesothelioma Lung AC Calretinin -100% (c&n) 5-10% CK 5/ % 2-20% WT % (n) - D2-40 (Podoplanin) % (m) <15% TTF1-80% BER-EP4 <20% % CEA <5% % MOC % (focal) % (SC) B72.3 very few 75-85% BG8 (Lewis) 3-7% (focal) % CD15 <5% % Cut-off for positive staining: 10% Mohammad A et al, Am J Surg Pathol 2012 Kao SC et al, Pathology 2011 Modified from: Husain AN et al; APLM 2017
23 CD15
24 Recommended IHC Panel TTF1 2 AC Markers 2 Mesothelioma Markers
25 IHC: Mesothelioma vs. Squamous cell carcinoma Marker Mesothelioma Lung SqCC WT % (n) - p40 2-7% (focal) 100% D2-40 (Podoplanin) % (m) -50% CK 5/ % 100% Claudin4-95% MOC % (focal) % (SC) Calretinin -100% (c&n) -40% (focal) BG8 (Lewis) 3-7% (focal) 80% BER-EP4 <20% % Modified from: Husain AN et al; APLM 2017
26 Pleural fibrosis Pancytokeratin Fake fat Husain et al, APLM 2017
27 Fake fat True fat S100 laminin Collagen IV Husain et la APLM 2017
28 Reactive mesothelial hyperplasia Mesothelioma with infiltration of fatty tissue Husain et al, Arch Pathol Lab Med 2009
29 Diagnostic Markers for Diagnosis of DMM Marker Sensitivity Specificity Deletion of 9p21 (p16) (FISH) Loss of BAP1 expression (IHC) 70% (epithelioid., pleural) >90% sarcomatoid 20% (peritoneal) 40-60% (epithelioid) <20% (sarcomatoid) 100% 100% Other proposed diagnostic IHC markers: Glut1 (neg. in sarcomatoid mesothelioma), P53 overexpression P16 (loss) Desmin (loss) still a Basel favourite! Not recommendend
30 BAP1 (BRCA1-associated protein 1) Mutated in 40-60% of MM expression loss BAP1 cancer syndrome (germline mutations; USA; Swiss ancestor born in 1588) Small added value over 9p21 FISH? Not exclusive for mesothelioma
31 FISH for detection of chromosomal aberrations in urinary cytology UroVysion (Abbott Mol.) normal Chromosome p21 tumor + other cancers, e.g. mesothelioma
32 Desmin Del 9p21 Mesothelioma in situ
33 9p21 Deletion + Polysomies 6 Mths Mesothelioma in situ Malignant mesothelioma
34 Well-differentiated papillary mesothelioma (WDPM) Peritoneal > pleural Usually 2cm Superficial spreading Papillary formations Broad fibrovascular cores & myxoid stroma No or limited invasion DD papillary DMM
35 Summary Histological diagnosis of MM can be difficult (+ IHC) Recommend 2nd opinion FISH & BAP1 differentiates between MM and reactive mesothelial cells Definitive diagnosis of MM by cytology is possible
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