Pathology of GIST and GIST mimics. Eva Wardelmann, Institute of Pathology, University Hospital Cologne, Germany

Transcription

1 Pathology of GIST and GIST mimics Eva Wardelmann, Institute of Pathology, University Hospital Cologne, Germany

2 Disclosure slide Honoraria, research and travel grants from Novartis Oncology Advisory Boards from MSD, PharmaMar

3 Introduction Most frequent mesenchymal tumors in the GI tract Up to 50% of GIST recur and/or metastasize 5-years survival rate (historically) 30 to 40% up to 90% of GIST carry KIT or PDGFRA mutations KIT and PDGFRA can be targeted by tyrosine kinase inhibitors which has revolutionized the treatment and prognosis of GIST

4 Location (GIST Registry Cologne/Bonn n=1943) esophagus 1,1% stomach 59,1% small bowel 32,2% large bowel (pref. rectum) 5,2% E-GIST 2,4%

5 GIST: Microscopical Subtypes (n=1614) spindled mixed: epithelioid intermediate or biphasic n=1039 n=366 n=209 64,4% 22,7% 12,9%

6 How to diagnose a GIST? 70-80% 95% CD34 KIT 98% 80% DOG1* PDGFR *monoclonal, clone SP31, 1:100, MW, ph 8, Medac (Spring Bioscience)

7 Results of the GIST and Sarcoma Registry Cologne/Bonn Allred-Score DOG1 8, ,5 63 7, ,5 14 6,0 20 5,5 5 5,0 4 4,5 1 4,0 4 3,5 1 3,0 2,5 2,0 1,5 1,0 0,0 13 missing 19 total 706 Allred-Score positive (8-4) negative (below 4) DOG % 1.99%

8 Other sarcomas Subgroup DOG1 positive* WDLS/DDLS (n=150) 8.39% MLS (n=31) 9.68% PLS (n=11) 0% LMS (n=70) 5.17% ASA (n=27) 7.41% SS (n=16) 6.25% MPNST (n=21) 9.25% MFH (n=35) 0% SS = synovial sarcoma, LMS = leiomyosarcoma, WDLS = well differentiated liposarcoma, dedifferentiated liposarcoma, MLS = myxoid liposarcoma, ASA = angiosarcoma, PLS = pleomorphic liposarcoma, MPNST = malignant peripheral nerve sheath tumor, MFH = pleomorphic high grade sarcoma DOG1

9 Additional markers to diagnose a GIST protein kinase-c theta sensitive but less specific, biomarker? nestin sensitive but less specific carboanhydrase II prognostic biomarker? Nestin in GISTs

10 0,6% 1,9% 0,8% 1,8% 8,8% 8,8% 15,3% 61,9% KIT exon 11 KIT exon 9 KIT exon 13 KIT exon 17 wild type PDGFRA exon 12 PDGFRA exon 14 PDGFRA exon 18 GSRCB* (n=1231) *GSRCB = GIST and Sarcoma Registry Cologne/Bonn Mutation analysis in KIT and PDGFRA is not needed to diagnose a GIST!

11 Mimics of GIST Spindle cell tumors such as schwannoma, leiomyoma, leiomyosarcoma, MPNST, solitary fibrous tumor, fibromatosis, inflammatory myofibroblastic tumor, angiosarcoma, dedifferentiated liposarcoma, inflammatory fibroid polyp, calcifying fibrous tumor, perineurioma Epithelioid tumors such as NEC, epithelioid MPNST, glomus tumor, CCS, PEComa, epithelioid LMS

12 Schwannoma S100 allways benign preferentially in the stomach wall lymphoid cuffs are characteristic pleomorphic cells may occur no Antoni A/B pattern strong S100 expression

13 Leiomyoma in the gastroesophageal junction and the proximal stomach more frequent than GIST Specific subtype: leiomyoma of the muscularis propria in the colon allways benign low cellularity strong expression of sm-actin, h-caldesmon and desmin high CD117-positive mast cell content may mimic a GIST

14 Antral plexiform Fibromyxoma located nearly exclusively in the stomach vascular invasion may occur tumor cells express SMA may express CD10 no KIT, no DOG1, no S100 benign behavior molecular pathogenesis unclear

15 Inflammatory fibrous polyp/tumor Prof. Matthias Evert, Dep. of Pathology Uni Greifswald always benign located in the stomach and small bowel different histomorphological subtypes (with/ without inflammation) CD34 PDGFRA

16 Inflammatory fibroid polyps carry PDGFRA mutations n (total cases) n (mutations) Ratio (% mutation) Schildhaus et al., Lasota et al., Calabuig-Farinas et al., Daum et al., Our current study* Total Schildhaus HU et al., J Pathol, 2008; *Huss S et al., Histopathology 2012 (epub ahead Mar 6)

17 Calcifying fibrous tumor always benign molecular pathogenesis unclear regressive stage of another mesenchymal tumor entity?

18 Fibromatosis T C T wt C C T mut point mutation in codon 45 (Ser-45Pro) Intermediate biology locally aggressive in > 90% nuclear β- catenin expression > 70% CTNNB1-mutation Gardner syndrome has to be excluded KIT expression has been reported

19 Solitary fibrous tumor CD34 intermediate biology rarely metastatic molecular pathogenesis unclear (PDGFRB?) CD99 LSD1

20 PEComa HMB45 KIT SMA myomelanocytic differentiation tumors of perivascular epithelioid cells diverse biological behavior may express KIT associated with TSC2

21 Ryan et al.: PEComas in the GI tract

22 Angiosarcoma CD31 only rarely detected in the GI tract Very aggressive behavior may express Kit and CD34 HHV8 helps to confirm Kaposi sarcoma secondary angiosarcoma after radiation often show myc amplification KIT CD34

23 Leiomyosarcoma preferentially in the colon cellular pleomorphism strong expression of at least two smooth muscle markers leiomyosarcomatous component of a DDLS has to be excluded sma/desmin h-caldesmon

24 Dedifferentiated liposarcoma CDK4 located in retroperitoneum or peritoneum can express CD34 can expression smooth muscle markers only rarely R0 resection low metastatic potential, very high rate of local recurrence MDM2 MDM2-FISH

25 Pitfalls in GIST diagnosis Non-GIST expressing KIT (CD117) angiosarcoma, PEComa, melanoma, seminoma/dysgerminoma Non-GIST not expressing KIT (CD117) but CD34 Inflammatory fibroid polyp (IFP), solitary fibrous tumor (SFT), angiosarcoma, DDLS GIST without KIT expression epithelioid gastric GIST with multinucleated giant cells and PDGFRA mutations, DOG1+

26 Institute of Pathology, Cologne: Reinhard Büttner, Hans-Ulrich Schildhaus, Sabine Merkelbach-Bruse, Jana Fassunke, Wolfgang Hartmann, Nikolaus Friedrichs, Sebastian Huss, Michaela Kleine, Helen Künstlinger, Elisabeth Sievers, Dagmar Kindler, Magdalene Fielenbach, Wiebke Jeske, Theresa Buhl, Ellen Paggen, Elke Binot, Carina Heydt, Anna Sotnikov partners: Peter Hohenberger, Chirurgie UM Mannheim Peter Reichardt, Sarkomzentrum Berlin-Brandenburg Florian Haller, Abbas Agaimy, Pathologie Erlangen Gunhild Mechtersheimer, Marcus Renner, Pathologie Heidelberg Jerzy Lasota, Marku Miettinen, Pathology, NCI/NIH Bethesda Heikki Joensuu, Helsinki University Central Hospital