1. IOANNIS PILPILIDIS, MD, FEBGH DEPT of GASTROENTEROLOGY - ONCOLOGY “THEAGENEIO” ANTICANCER HOSPITAL of THESSALONIKI Athens, 6-6-2015 GALLBLADDER CARCINOMA WITH MIXED POPULATIONS

2. Case Presentation 73 year-old woman, good health, no major comorbidities Cholecystectomy because of symptomatic cholelithiasis: 19-2-2015 Incidentaloma: Tumor 2cm x 1cm x 0,4 (depth of Invasion)

3. Case Presentation Pathology report (1 st ): mixed adeno-neuroendocrine carcinoma (2cm) – T2, N1, Mx, Gx. Neuroendocrine component: poorly differentiated, less than 20% of all neoplastic cells, with metastatic involvement of the cystic artery lymph node. Adenocarcinoma component: well differentiated, exceeds 80% of the neoplastic cells, NO lymph node involvement

4. Case Presentation Pathology report (2 nd consultation): well differentiated adenocarcinoma of the gallbladder - T2 (subserosal invasion), N1, Mx, G1. Coexistence of: - poorly differentiated, SMALL CELL NEC population - Chr A (+), Syn (+), LMWCK (+) - - 10% of the neoplastic cells, - with ki-67 65% (G3), and - invasion of the lymphatic vessels - and metastatic involvement of a lymph node.

5. Case Presentation A C B A: subserosal invasion of adenoCA B: SC NEC C: Mixted carcinoma

6. Case Presentation A: chromo A B: synaptophysin C: ki-67 A B C

7. Question (1) 1.Adenocarcinoma 2.Adenocarcinoma with neuroendocrine differentiation 3.Mixed adeno-neuroendocrine carcinoma 4.Coexistence of two carcinomas WHAT IS THE DIAGNOSIS

11. DIAGNOSIS: -30% -Chr Α, Syn, CD56 (2/3) -LMWCK (+) -TTF1, hASH1 (Achaete-scute homolog 1) -CDX2 (colon), CD117 (prognosis)

12. BIOLOGIC RULE, NOT CLINICAL RULE: IN GI TRACT, NOT IN LUNG CANCER

15. Pathogenesis – case reports Α) CRC-like evolution: metaplasia - dysplasia – carcinoma pathway. MANEC: composed of an intestinal-type adenocarcinoma and a LC NEC, arising in a background of enteric metaplasia with extensive high-grade dysplasia Acosta AM, Int J Surg Pathol 2015

16. B) Field differentiation: transdifferentiation (or dedifferentiation) from poorly differentiated biliary type adenoCA to LC NEC a) A case of a mixed adenoneuroendocrine carcinoma arising from an intracystic papillary neoplasm (high-grade dysplasia and slight invasion into the muscular layer Meguro Y, Pathol Int 2014 b) The neuroendocrine component could be a dedifferentiated adenoCA with a NE phenotype Gurzu S, WJG 2015 Pathogenesis – case reports

17. C) Divergent differentiation: biphenotypic stem/progenitor cell tumor of the gallbladder LC NEC and papillary adenoCA of the gallbladder with transitional tumor cells (of both histological components) located at the areas where the two tumor types merged Paniz Mondolfi AE, Pathol Int 2011 Five of the 6 MANECs presented an overlapping mutational profile in both components, suggesting a monoclonal origin of the two MANEC components. Scardoni M, Neuroendocrinol 2014 Pathogenesis – case reports

18. Question (2) 1.Local control 2.Prevent metastases 3.Both WHAT IS THE AIM OF TREATMENT

20. 1.Local control Invasiveness of adenoCa 2.Prevent metastases (histopathology of matastatic disease) NEC75%, MANEC20%, adenoCA5% The aggressiveness seems to depend on the endocrine component, independent of its proportion. Gurzu S, WJG 2015 Gastric MANEC with trilineage cell differentiation (NEC + adenocarcinoma + squamous cell carcinoma), of which only the NEC component metastasised to the liver. Pericleous M, Case Rep Oncol 2012, Zhang W, Int J Clin Exp Pathol 2014

21. Question (3) 1.Additional liver resection (gallbladder bed) 2.Adjuvant chemotherapy 3.Wait and watch WHAT IS THE NEXT STEP

23. 1.Additional liver resection (gallbladder bed) Stantard of care in GB carcinomas > T1, but poor prognosis carcinoma because of the SC NEC component. 2.Adjuvant chemotherapy < 50% NEC component and overexpression of TS are good prognostic factors 3.Wait and watch because rules exist but no data

25. 1.Additional liver resection (gallbladder bed) Stantard of care in GB carcinomas > T1, but poor prognosis carcinoma because of the SC NEC. 2.Adjuvant chemotherapy < 50% NEC component and overexpression of TS are good prognostic factors 3.Wait and watch because rules exist but no data

27. Case Presentation Baseline CT scan (a month after cholecystectomy): - local reccurence (GB bed) - single met in segment VI PS = 0

28. Question (4) 1.Biopsy of the liver met 2.Systemic chemotherapy for adenoCa domination rule (>80% of neoplastic cells) 3.Systemic chemotherapy for NEC prognosis rule (G3 vs G1) – (75% vs 20% vs 5%) TREATMENT OF METASTATIC DISEASE (THE AIM IS TO PREVENT DEATH)

30. Take home messages 1.DEFINITION: “magic” figure – 30% 2.DIAGNOSIS: describe all distinct populations - specifically NE: SC, G3 irrespective of % 3.BIOLOGIC vs CLINICAL “rule” 4.MANECs: both components share common genetic alterations, but different genetics from pure adenoCa or NECs. 5.Each component has different biologic/clinical behavior. LCNEC vs SCNEC?

31. Take home messages The spectrum of MANECs is the result of an evolutionary process. Their phenotype may change under the pressure of environment or treatment. Sequist L, Sci Transl Med 2011