Mesothelioma Pathobasic Lukas Bubendorf Pathology
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
J Thorac Oncol 2016; 11:142-154 et al. Arch Pathol Lab Med 2017 Jul 7
Diagnosis of mesothelioma can be difficult Review panels: French mesothelioma review panel Diagnosis confirmed 67% Eastern China 57% Carbone & Hang, Ann Transl Med 2017
European Mesothelioma Panel A: unequivocal B: probable C: possible D: probably not E: no mesothelioma Junker & Pathologe 2014
2015 WHO Classification of Tumors of the Pleura
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
Histological subtype of MM & prognosis
Diffuse malignant mesothelioma, epithelioid type Papillary pattern Tubular pattern
Diffuse malignant mesothelioma, epithelioid type Pleomorphic pattern Solid pattern Calretinin Micropapillary pattern Galateau-Salle F et al, JTO 2016
Diffuse malignant mesothelioma, epithelioid type Pleomorphic pattern B09.37776
Diffuse malignant mesothelioma, sarcomatoid type
B03.27591 - biphasisch
Histological key criteria of mesothelioma 1. Infiltration of the subpleural fatty tissue 2. Solid tumor growth, expansive nodule
Zonation Churg et al, Am J Surg Pathol 2000
Calretinin CK5/6 WT IHC BerEP-4 neg Desmin neg
Desmoplastic DMPM IHC in sarcomatoid/desmoplastic mesothelioma CK22 B10.1757 Calretinin +: 30% CK5/6+: <50% WT-1 +: <50% D2-40+: >50% Pancytokeratin: 95%
B10.2873
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%)
IHC: Mesothelioma vs. Adenocarcinoma Marker Mesothelioma Lung AC Calretinin -100% (c&n) 5-10% CK 5/6 75-100% 2-20% WT1 70-95% (n) - D2-40 (Podoplanin) 90-100% (m) <15% TTF1-80% BER-EP4 <20% 95-100% CEA <5% 80-100% MOC31 2-10% (focal) 95-100% (SC) B72.3 very few 75-85% BG8 (Lewis) 3-7% (focal) 90-100% CD15 <5% 70-100% 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
CD15
Recommended IHC Panel TTF1 2 AC Markers 2 Mesothelioma Markers
IHC: Mesothelioma vs. Squamous cell carcinoma Marker Mesothelioma Lung SqCC WT1 70-95% (n) - p40 2-7% (focal) 100% D2-40 (Podoplanin) 90-100% (m) -50% CK 5/6 75-100% 100% Claudin4-95% MOC31 2-10% (focal) 97-100% (SC) Calretinin -100% (c&n) -40% (focal) BG8 (Lewis) 3-7% (focal) 80% BER-EP4 <20% 85-100% Modified from: Husain AN et al; APLM 2017
Pleural fibrosis Pancytokeratin Fake fat Husain et al, APLM 2017
Fake fat True fat S100 laminin Collagen IV Husain et la APLM 2017
Reactive mesothelial hyperplasia Mesothelioma with infiltration of fatty tissue Husain et al, Arch Pathol Lab Med 2009
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
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
FISH for detection of chromosomal aberrations in urinary cytology UroVysion (Abbott Mol.) normal Chromosome 3 7 17 9p21 tumor + other cancers, e.g. mesothelioma
Desmin Del 9p21 Mesothelioma in situ 27.2.07
9p21 Deletion + Polysomies 6 Mths Mesothelioma in situ Malignant mesothelioma
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
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