The develpemental origin of mesothelium

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1 Mesothelioma Tallinn Henrik Wolff Finnish Institute of Occupational Health The develpemental origin of mesothelium Mesodermal cavities (pleura, peritoneum and pericardium ) are lined with mesenchymal cells with a flattened surface layer (mesothelium) with a submesothelial layer of connective tissue. 1

2 Mesothelioma in historical perspective First possible reference in litterature 1767, E.Wagner recognized as a pathological entity in Minot used term mesothelioma in Adami used term in Mesothelioma in historical perspective Scepticism concerning the origin of (diffuse malignant) mesothelioma (DMM) persisted till the middle third of 20:th century Terms like endothelioma, endothelial cancer, pleural cancer and pleural sarcoma also in use. Wagner et al in 1960 revealed that many persons in South Africa with this tumour were exposed to asbestos. 2

3 Mesothelioma in historical perspective Especially for epidemiological reasons it became imperative to identfy DMM as accurately as possible. The diagnosis of mesotheliomas in historical perspective For a long time it was considered that a diagnosis of mesothelioma could only be made after autopsy ( to exclude other tumours). Mesothelioma, especially a typical well- differentiated one, has a fairly specific morphology and behaviour, however even this can be mimicked by various carcinomas. 3

4 Well Differentiated mesothelioma Well Differentiated mesothelioma 4

5 Pseudomesotheliomatous adenocarcimopa affecting the pleura Well Differentiated mesothelioma H+E 5

6 Well Differentiated mesothelioma EM mesothelial tumours (WHO 2004) Diffuse malignant mesothelioma (DMM) Sarcomatoid Epithelial Desmoplastic Biphasic Localized mesothelioma Other tumours of mesothelial origin Well differentiated papillary mesothelioma. Adenomatoid tumour 6

7 epithelial DMM Cytology is usually not very helpful and histology is needed for the final diagnosis. If necessary however a combination of immunocytology and tomogrphy can be sufficient for diagnosis. Differential diagnosis of epithelial DMM Well differentiated: mesothelial hyperplasia Moderately differentiated: Tubulopapillary or tubular adenocarcinoma Poorly differentiated: Poorly differentiated carcinoma 7

8 Differential diagnosis of epithelial DMM In addition to dfferent degrees of differentation mesotheliomas can also show surprising morphologies. -Deciduoid mesothelioma -Lymphohistiocytoid mesothelioma -Small cell mesothelioma -Signet cell mesothelioma -Clear cell mesothelioma Differential diagnosis of epithelial DMM With immunohistochemistry the diagnosis is usually easy. The biggest problem can be to differentiate mesothelial reactive hyperplasia from a well differentiated mesothelioma, immunohistochemistry does not help, caution is adviced. 8

9 Peritoneal mesothelial hyperplasia peritoneal mesothelioma 9

10 Periotoneal mesothelioma: needle biopsy peritoneal mesothelioma: needle biopsy: calretinin 10

11 Differential diagnosis of epithelial DMM Based on morphology alone is it usually not possible to exclude a mesothelioma in a pleural biopsy showing a epithelial malignacy. Exceptions -Keratinizing squamous cell carcinomas (some reports of keratinizing mesotheliomas associated with empyema). -Metastases of known and compared tumours. Differential diagnosis of epithelial DMM Mucin stains : Diastase PAS, demonstration of hyaluronic acid Immunohistochemistry Positive markers for mesothelioma: Calretinin (nuclear positivity), cytokeratin 5/6, D2-40. WT-1 Markers for adenocarcinoma CEA, Leu-M1 (CD15), EP-4, MOC-31 31, B

12 Well Differentiated mesothelioma: Calretinin Differential diagnosis of epithelial DMM Calretin stains: 89% of epithelial mesotheliomas (Immunoquery meta-anlysis anlysis 18 reports) 13% of adenocarcinomas of the lung (11 reports) 80 % of metastatic ovarian cystadenocarcinomas (1 report) 12

13 Differential diagnosis of epithelial DMM Remarks concerning immunohistochemistry None of the immunohistochemical markers are exclusive for mesothelioma or exclude all mesotheliomas thus a panel of immunohistochemistry is needed. pleura 13

14 pleura pleura calretinin 14

15 pleura CK 5/6 pleura CEA 15

16 pleura CD15 Pleural biopsy of mesothelioma 16

17 Pleural mesothelioma, solid pattern Differential diagnosis of epithelial DMM Serosal carcinomas Serosal carcinomas that arise from ovaries or are primary to peritoneum are from a developemental biology perspective originating from the secondary mullerian system. They respond to treatment much better than mesotheliomas. 17

18 Primary peritoneal serosal carcinoma Primary peritoneal serosal carcinoma, EP4 18

19 epitheloid hemangiendotheliomoma epitheloid hemangioendothelioma CD34 19

20 Sarcomatoid DMM Diagnostic criteria for sarcomatous mesotheliomas. Typical mesothelial growth pattern. Often strong positivity for cytokeratin. Exclusioon of other sarcomatous tumours. Sarcomatoid DMM Differential diagnosis Spread of sarcomas or spindle cell carcinomas from adjacent structures Metastases of sarcomas or spindle cell carcinomas. Cellular serosal fibrosis. 20

21 Sarcomatoid DMM The diagnosis is much less straightforward than for epithelial mesotheliomas, spindle cell carcinomas from lung or metastaic from kidney can usually only excluded with acces to clinical or autopsy information. Sarcomatous mesothelioma in pleura 21

22 Sarcomatoid DMM /role of cytokertin stain in diagnosis Cytokeratin is the only "positive" marker Cytokeratin positivity is not seen in about 10 % of sarcomatoid mesotheliomas. Reactive pleural fibroblasts can be cytokeratin positive. Spindle cell carcinomas are cytokeratin positive. Reactive fibroblasts in pleura positive for cytokeratin 22

23 Cytokeratin in sarcomatoid DMM CAM 5.2 (+) sarcomatoid DMM 1 CK7 + CK20 AE1/AE3 + EMA + CALRETININ (+) CK5/6 (+) S-100 Ber-EP4 CD15 TTF-1 CEA - 23

24 sarcomatoid DMM 2 Diff dg: Pleomorfinen karsinooma CK7 (+) CK20 CAM 5.2 (+) EMA - CALRETININ - CK5/6 Vimentin + WT-1 + CEA - TTF-1 Sarcomatoid DMM The most common sarcomas of the pleura Pleura Epitheloid hemangioendothelioma Malignant solitary fibrous tumour of the pleura Liposarcoma Synovialsarcoma Exstraskeletal osteosarcoma Leiomyosarcoma 24

25 Leiomyosarcoma CK7 (+) CAM5.2 - CK20 - EMA - CALRETININ - CK5/6 WT-1 - CD34 SMA + S Muscle actin + Myxoid liposarcoma CAM5.2 - CK 5/6 - CALRETININ (+) S-100 (+) 25

26 Myxoid liposarcoma CAM5.2 - CK 5/6 - CALRETININ (+) S-100 (+) MFH calretinin + 26

27 Epithelioid sarcoma CK7 - CK 20 - AE1/AE3 + EMA + Vimentin + CALRETININ - CK5/6 CD34 + HMB-45, MART-1 - S PSA - CEA, CD15, Ber-EP4 - HCG, PLAP, AFP - CGH (comparative genomic hybridization) findings in sarcomatoid mesotheliomas deletion % amplifications % N/type of tumour ref. 4p 4q 9p 5p 41/SM /SM Björkqvist ym., Br J Cancer 1998; 77: /SM Krismann ym., J Pathol 2002; 197: /SM Knuuttila ym., Virchows Arch 2005; 437: Sarc. 51/Osteosarcoma /Liposarcoma /Synovialsarcoma /Leiomyosarcoma lung cancer 50/NSCLC Petersen ym., Cancer Res 1997; 57:

28 Criteria for desmoplastic mesothelioma More than 50 % of tumor is collagenous and hypocellular Areas with cellular atypia Invasion Necrosis Diff.dg. Fibrosing pleuritis Desmoplastic DMM CK7 (+) CK20 CAM CALRETININ - CK5/6 Vimentin + WT-1 CEA - 28

29 Desmoplastic DMM Differential diagnosis of Biphasic DMM Because of the epithelial component is present the diagnostic approach similar to epithelial mesotheliomas. It is sometimes difficult to separate reactive mesenchyme from truly sarcomatous growth of spindle cells. 29

30 localized fibrous tumour of the pleura CD34 + (formerly localized fibrous mesothelioma) Well differentiated papillary mesothelioma of the peritoneum typically women years old tubules and papillae lined with single layers of cells and minimal atypia. Can be localized or diffusely spread. Slight invasion. much better prognosis than for DMM. 30

31 Localized mesothelioma Rare and somewhat controversial, Looks like any Diffuse Malignant Mesothelioma but does not spread in the diffuse manner typical for mesothelioma. Resectable surgically. Localized mesothelioma and well differentiated papillary mesothelioma. Diffuse spread Atypia Invasion Well diff. papillary mesoth. 0/ +++ (+) (+) Localized mesothelioma 0 +/ DMM +++ +/ Term benign (papillary) mesotheliom has been used, these in my personal view where either reactive proliferatins or WDPM tumours. The term Localized fibrous mesothelioma was formerly used for localized fibrous tumours of the pleura 31

32 Take home messages Diagnosis of epithelial mesothelioma is usually straightforward but a immunohistochemistry panel of antibodies has to be used. Sarcomatous mesotheliomas require exlusions of sarcomas and information about the growth pattern of the tumour. Acknowledgements Sisko Anttila / TTL Kristiina Joensuu ja Maritta Metsä- Seppälä/ / Kymenlaakson keskussairaala 32

33 Thank you Mesothelioma Tallinn

34 pleural hemangiosarcoma pleurabiopsia cytok 5/6 34

35 Solitary fibrous tumour of the pleura HE In this presentatin i will discuss mesotheliomas (diffuse malignant mesotheliomas) from a clinical point of view, concentrating on the more common presentations. please feel free to ask questions. 35

36 Desmoplastic DMM 36