IOANNIS PILPILIDIS, MD, FEBGHDEPT of GASTROENTEROLOGY - ONCOLOGY“THEAGENEIO” ANTICANCER HOSPITAL of THESSALONIKI Athens, 6-6-2015

GALLBLADDER CARCINOMA WITH MIXED POPULATIONS

Case Presentation

73 year-old woman, good health, no majorcomorbidities

Cholecystectomy because of symptomaticcholelithiasis: 19-2-2015

Incidentaloma: Tumor 2cm x 1cm x 0,4 (depth ofInvasion)

Case Presentation

Pathology report (1st): mixed adeno-neuroendocrinecarcinoma (2cm) – T2, N1, Mx, Gx.

Neuroendocrine component: poorly differentiated,less than 20% of all neoplastic cells, with metastaticinvolvement of the cystic artery lymph node.

Adenocarcinoma component: well differentiated, exceeds80% of the neoplastic cells, NO lymph node involvement

Case Presentation

Pathology report (2nd consultation): welldifferentiated 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.

Case Presentation

A

C

B

A: subserosal invasion of adenoCAB: SC NECC: Mixted carcinoma

Case Presentation

A: chromo AB: synaptophysinC: ki-67

A B

C

Question (1)

1.Adenocarcinoma

2.Adenocarcinoma with neuroendocrine differentiation

3.Mixed adeno-neuroendocrine carcinoma

4.Coexistence of two carcinomas

WHAT IS THE DIAGNOSIS

DIAGNOSIS:

-30%

-Chr Α, Syn, CD56 (2/3)-LMWCK (+)

-TTF1, hASH1 (Achaete-scute homolog 1)

-CDX2 (colon), CD117 (prognosis)

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

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

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

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

Question (2)

1.Local control

2.Prevent metastases

3.Both

WHAT IS THE AIM OF TREATMENT

1.Local controlInvasiveness of adenoCa

2.Prevent metastases (histopathology of matastatic disease)

NEC 75%, MANEC 20%, adenoCA 5%

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

Question (3)

1.Additional liver resection (gallbladder bed)

2.Adjuvant chemotherapy

3.Wait and watch

WHAT IS THE NEXT STEP

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 TSare good prognostic factors

3.Wait and watchbecause rules exist but no data

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 TSare good prognostic factors

3.Wait and watchbecause rules exist but no data

Case Presentation

Baseline CT scan (a month after cholecystectomy):- local reccurence (GB bed)- single met in segment VI

PS = 0

Question (4)

1.Biopsy of the liver met

2.Systemic chemotherapy for adenoCa domination rule (>80% of neoplastic cells)

3.Systemic chemotherapy for NECprognosis rule (G3 vs G1) – (75% vs 20% vs 5%)

TREATMENT OF METASTATIC DISEASE(THE AIM IS TO PREVENT DEATH)

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?

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