Prognostic factors and treatment of gastroenteropancreatic G3 neuroendocrine carcinomas.

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1 Prognostic factors and treatment of gastroenteropancreatic G3 neuroendocrine carcinomas. Halfdan Sorbye Medical Oncologist Professor, MD Dept of Oncology Haukeland Univ Hospital Bergen, Norway

2 Gastroenteropancreatic G3 neuroendocrine carcinomas neoplasms 1. talk: What does the oncologist need from the pathologist to make to best treatment decision? 2. talk: How should the pathologist report on a high-grade neuroendocrine neoplasm case.

3 WHO classification, 2010 Neuroendocrine neoplasms Neuroendocrine tumour, G1 Well differentiated morphology Ki-67 index 2% or mitotic index < 2 (/2 mm²) Neuroendocrine tumour, G2 Well differentiated morphology Ki-67: 3-20% or mitotic index: 2-20 Neuroendocrine carcinoma (NEC) G3 Ki-67 > 20% or mitotic index > 20 Poorly differentiated morphology, small cell type Poorly differentiated morphology, large cell type LOW GRADE HIGH GRADE

4 G3- a different disease G1 G2 G3 Primary Small intestine Pancreas GEP (colon, pancreas, gastric) Ki % 5-10 % >20 %. Usually % Differentiation Well Well 80-90% Poorly, 10-20% well Metastatic treatment mos stage 4 medically treated SSA, PRRT, Everolimus, interferon SSA, Tem/cap, Ever/suni PPRT,SZT/5FU Cisplatin/carboplatin + etoposide years 3-4 years 11 months

5 Why important to diagnose NEN G3 Many misclassified as poorly diff adenocarcinoma. Treatment strategy different for NEC vs. adenocarcinoma. Urgent referral (See an oncologist within a week or not at all, mos for GEP-NEC 1 m without treatment). More cautious approach to surgery / radiotherapy. Different adjuvant and palliative chemotherapy schedules. Consider standard staining for synaptophysin in poorly differentiated GEP tumors to avoid misclassification.

6 2010 classification Two morphological NEN G3 subtypes large-cell small-cell At present not relevant for treatment decision.

7 Up to 2012 easy: Treatment decision in advanced GEP-NEN G3 We all (included the WHO) assumed that all NEN with a Ki67 >20% were poorly differentiated and should be treated as one disease entity. Metastatic disease and Ki67 > 20% : automatically chemotherapy with cisplatin/carboplatin and etoposide. Two observations in 2013 made it more complicated.

8 Annals of Oncology 24: , 2013 Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): The NORDIC NEC study H. Sorbye, S. Welin, SW. Langer, LW. Vestermark, N. Holt, P. Osterlund, S. Dueland, E. Hofsli, MG. Guren, K. Ohrling, E. Birkemeyer, E. Thiis- Evensen, M. Biagini, H. Gronbaek, LM. Soveri, IH. Olsen, B. Federspiel, J. Assmus, ET. Janson & U. Knigge

9 NEC: Variation of Ki-67 Ki-67 40%. Ki-67 90%

10 252 patients treated with platinum-based 1-line chemotherapy.

11 252 patients treated with platinum-based 1-line chemotherapy..

12 Questions raised by Nordic NEC study Not correct to consider all GEP-NEN with a Ki-67 > 20% as one single disease entity. Should NEN G3 with a Ki-67 of 21-55% be treated differently? Like NET G2?

13 Highly differentiated NEN G3. 2 reports showing well differentiated morphology among large-cell tumors with a Ki-67 > 20%, mainly in pancreas. Patients with well-differentiated pancreatic NEN G3 had longer OS than patients with poorly-differentiated NEN G3 (32 vs 15 m). Basturk O, et al: 102nd United States and Canadian Academy of Pathology Annual Meeting, 2013 Baltimore, United States. Laboratory Investigation. 2013;93:p.423A.

14 Are G3 ENETS neuroendocrine neoplasms heterogeneous? Velayoudom-Cephise FL: Endocr Relat Cancer. 2013;20: Retrospective study: 28 cases of non-small cell NEN G3 16 poorly differentiated 12 «well differentiated» Prognostic relevance Survival longer in WD NEC vs. PD NEC (40 vs. 17 m) Well differentiated (NET) G3: NET G3

15 Heetfeld M: Characteristics and treatment of patients with G3 GEP-NEN. Endocr Rel Cancer 22, , NEN G3 patients, 72% stage IV 15 % Well differentiated tumors (no re-assessment) NET G3 Median Ki-67: 30% PD-NEC G3 Median Ki-67: 70%

16 Pathological re-assessment in 210 Nordic GEP-NEN G3 patients (Perren, Tang, Scoazec, Fiederspiel: in preparation) 40% had Ki-67 < 51% 12% WD morphology (15% Heetfeld et al) All low Ki-67 G3 tumors (<60%) are not WD. Most WD NET G3 are in the pancreas (2/3), uncertain relevance for other primary sites.

17 Milione M et al:neuroendocrinology 2016 March A: NET G3 B: NEC Ki % C: NEC Ki-67 >55% 5

18 Pathology guiding NEN G3 treatment; NET G3 or Ki % Stronger case for considering surgery, also metastatic surgery. Adjuvant therapy no treatment or other options than cisplatin/carboplatin + etoposide? Palliative chemotherapy; considered to change from standard cis/carboplatinbased chemotherapy to a another schedule. NET G2 treatments an option. Temozolomide/ capecitabine (Welin et al Cancer 2012).

19 Pathology answer decides NEN G3 treatment strategi! First line chemotherapy WD vs. PD NEC (Heetfeld et al) Table 5. Type of first line Chemotherapy Poorly differentiated NEC G3 Well differentiated (NET) G3 Type of Chemotherapy Number (%) Type of Chemotherapy Number (%) Platinum based + Etoposide 124 (84%) Platinum based + Etoposide 7 (24%) FOLFOX/XELOX/CAPOX 10 (7%) Temozolomide based 5 (17%) FOLFIRI 2 (1%) Dacarbazine based 4 (14%) Docetaxel/Cisplatin/5-FU 2 (1%) FOLFOX/XELOX/CAPOX 3 (10%) Other 6 (4%) Other 10 (35%) 76% non-platinum based ctx