Surgery for NET Challenges and specific aspects Raymond Aerts, MD Department of Abdominal Surgery and Liver Transplantation University Clinics Leuven ESMO Preceptorship on GI neuroendocrine tumours (NETs) Leuven, Belgium, 28-29 November 2014
Incidence and Prevalence NET (SEER 1973-2004) Rare Increasing Incidence - 1973: 1/100 000/ y - 2004: 5/ 100 000/y 29 y Prevalence: 35/100 000 Yao, J Clin Oncol 2008;26:3063-3072
Incidence GEP-NET 60% GEP-NET small bowel rectum pancreas stomach caecum colon appendix Yao, J Clin Oncol 2008;26:3063-3072
Prognosis GEP-NET Better A. Frilling et al, Lancet Oncol 2014; 15: e8-21
Surgery for NET Rationale: only chance for cure prolong survival control symptoms prevent, control local complications Primary tumour: aggressive resection Metastases: 15-25% surgical candidates only for G1-G2 tumours curative resection: R0-R1 primary tumour curative resected or resectable no extrahepatic non resectable metastases resectable liver lesions debulking: R2 > 90%: control symptoms (limited indication) transplantation (limited indication) primary tumour curative resected no extrahepatic metastases
Aggressive surgery primary tumour SiNET Prevention of complications Ohrvall et al, WJS 2000; 24: 1402-1408 Akerstrom et al, Best Pract,2007; 21: 87-109
nodal complex primary tumour
ischemia necrosis
Aggressive surgery primary tumour SiNET Impact on survival Uppsala 314 patients Intestinal resection + lymphadenectomy only 11 liver resections Biotherapy: SSA, IFN Hellman, WJS 2002; 26: 997-2002
Case SiNET 55 y old male patient 3 mo history of abdominal cramps and obstipation 8 kg weight loss
Case SiNET Tumour markers CEA 2,4 µg/l CA19,9 20 ku/l CgA 156 µg/l FDG-PET/CT
Case SiNET Surgery: SiNET type 4 Mesenterial mass Retraction Ischemia terminal ileum Extended right hemicolectomy and resection 2 m ileum Resection tail pancreas, splenectomy, splenic flexure colon Pathology SiNET: 3 small G2 tumours Ki67: 3-20% pt3n1 (17/25) Inflammatory myofibroblast tumour in Mesenteric fibrotic mass Pancreatic tail
Incidence and malignancy in PNET frequency malignant % Non functional PNET > 50% 50-90% Insulinoma 25% 10% Gastrinoma 10% > 60% Glucagonoma > 60% VIPoma 60-80% Somatostatinoma 80% PTH-RP 80-90% GRF 30% ACTH > 90% Carcinoid pancreas 70-90%
PNET Hormone secretion endocrinopathy Non functional mass effect Mostly malignant metastases LN peritoneum, liver >> bone > lung Slowly growing = natural history better prognosis than other pancreatic malignancy Association MEN-1
Diagnosis PNET Insulinoma < 2 cm Gastrinoma < 2cm (0,5 cm) Others large > 5-15 cm localisation think PNET Tumour markers Chromogranin A Neuron specific enolase
Non functional PNET large: 5-15 cm mass effect 60% head pancreas Mostly solitary 80-90% malignant Diagnosis: think PNET! surgery: PD, debulking Prognosis Cure: 25-40% 50-65% 5 y survival
Non functional PNET
Aggressive surgery primary tumour Prevention of complications
Insulinoma 1 / million/ year Solitary: 90% (10% MEN-1: multiple) <2cm benigne > 90% Diffuse distribution in pancreas (tail > head?) Symptoms: neuroglycopenia Diagnosis Hypoglycemie < 40 mg/dl Fasting proof Control Diet Diazoxine Ca blockers
Insulinoma treatment: Enucleation: Wirsung! Resection tail Central pancreatic resection Rarely PD Prognosis Benign: cure Malignant: 75% 10 y survival Special cases Nesidioblastosis Insulinomatosis
Insulinoma
Gastrinoma 0.5/million/year > 50% multiple 25% MEN-1 < 2 cm Gastrinoma triangle >60% in wall proximal duodenum: 2-5 mm Primary in LN, liver, ovary? > 60% malignant (> 90% if > 1-2 cm) 1/2 metastases at diagnosis! early diagnosis ZES: recurrent peptic ulcera, oesophagitis, diarrhoea
Gastrinoma Diagnosis: Gastrine > 200-1000 pg/ml Secretine stimulation > 200 pg/ml increase Control: PPI surgery Enucleation for small duodenal wall tumours palpation, transillumination, duodenotomy Oncological resection for large tumours Potentially resection or debulking metastases Prognosis Without metastases: 95% 10 year survival With metastases : 5 y: 50%, 10 y: 30 % survival
Case gastrinoma 2006: 61 y old woman 3 mo history of peptic ulcer, esophagitis, diarrhoea and weight loss (diet?) Gastrin > 1000pg/ml ZES No family history sporadic R/ 160 mg pantoprazol/day 111In Octreotide: negative 18-FDG-PET/CT: negative 2007 CgA: 2200 µg/l 68Ga-Dotatoc PET/CT: 2 metastatic LN Good clinical control with PPI 2010 Recurrent episodes deshydration due to vomiting and diarrhoea CgA: 6860 µg/l Gastrin: 2930 pg/ml Surgical exploration 3 mm gastrinoma in the bulbus 3 metastatic LN 10-2014 No complaints, no PPI since 4 mo postoperatively CgA: 260 µg/l Gastrin: 49 pg/ml
MEN-1 syndrome Hypohysis prolactinoma, parathyroid adenoma, multiple PNET MEN-1 gen chromosome 11q13 Multiple PNET with mostly dominant secretion and multiple non functioning tumours 50% gastrinoma 20% insulinoma Prognosis MEN-1 gastrinoma better than sporadic resection if > 2 cm
MEN-1 syndrome 1994 diagnosis ZES in known MEN-1 family Resection 3 parathyroid glands for primary hyperparathyroidy Gastrin 600 pg/ml Liver metastasis segment1, 2 hypervascular pancreas lesions Reluctant to take PPI 1995: surgical exploration Resection metastasis segment 1: NET metastasis, gastrin + Resection 5 PNET, gastrin - Normalisation gastrin 2003: CgA: 345 µg/l, gastrin: 162 pg/ml (nl <111) normal Ca 2007 CgA: 850 µg/l, gastrin 360 pg/ml Liver metastasis segment 5: reresection Since then no complaints except tiredness (2-2014) normalisation Ca, CgA, gastrin
Epidemiology NELM SEER database (Yao) ref centers Localized 50% preselection Regional 24% Distal 26% 44-73% M+ correlates with differentiation, proliferation G1 21% 38% (Spanisch registry) G2 30% G3 50% 67% (Spanisch registry) G4 100% M+ correlates with primary tumor localisation Pancreas 64% 77% Caecum 44% Colon 32% Small bowel 30% 91% Rectum, duodenum, appendix, stomach: 5-15%
Incidence LM vs size primary GI NET M+ correlates with primary tumor size (carcinoid) Rorstad, J Surg Oncol 2005; 89: 151-160) Rorstad, J Surg Oncol 2005; 89: 151-160
Incidence NET and NELM different data depending on the composition of the registry - population based - reference centers synchronous : 50-75% metachronous: 25-50% B. Lawrence, End Met Clin NA 2011; 40:1-18 A. Frilling, Lancet Oncol 2014; 15: e8-21
Type NELM Type I single metastasis (size independent) or unilateral 20-25% Type II isolated metastatic bulk accompaniesd by smaller deposits, always bilateral 10-15% Type III disseminated metastatic spread always bilateral varying size of single lesion 60-70% T. Steinmüller, Neuroendocrinology 2008; 87: 47-62
Therapy for NELM: multimodal Surgical Resection +/- local ablation transplantation Medical SSA IF Targetted therapy: sunitinib, everolimus chemotherapy Radiologic TAE, TACE, SIRT, DEB Nuclear medicin PRRT
Surgery for NELM Well to moderately differentiated G1-G2 tumours Absence non resectable intra or extraabdominal metastases Curative resectable lesion: (resection ± RFA) lesions can be completely resected (R0) preservation of enough functional liver tissue with adequate vascular inflow and outflow and biliary drainage the volume of the liver remaining after resection ie future remnant liver (FRL) will be adequate 20-30 % for normal liver 30 40 % for steatosis or after chemotherapy Debulking: > 90 tumour reduction: limited indication for symptom control (resection ± RFA) General condition Absence right heart failure Prevention carcinoid crisis: SSA Acceptable mortality, morbidity
Surgery for NELM Timing Synchronous Simultaneous resection (primary + limited NELM) Staged resection (primary + left lobe), right lobe in second step Metachronous 1 or 2 step
Surgical anatomy and anatomical surgery right hemihepatectomy 5-6-7-8 right trisectionectomy 4-5-6-7-8 bisegmentectomies 6-7, 5-8, 5-6 left hemihepatectomy 2-3-4 left trisectionectomy 2-3-4-5-8 bisegmentectomy 2-3 central hepatectomy 4-5-8 segmentectomy
Nonanatomical resections
Strategies to increase resectability Surgical strategies: Portal vein embolisation Combination resection with local ablation techniques Staged hepatectomy ALPPS (in situ splitting +PVL) Repeat hepatectomy Neo-adjuvant therapy
Staged hepatectomy R. Adam
A. Saxena, Surgical Oncology 2012; 21:e131-e141
A. Saxena, Surgical Oncology 2012; 21:e131-e141
A. Saxena, Surgical Oncology 2012; 21:e131-e141
Prognostic factors NELM systematic review Overall survival Univeriate multivariate R2 resection Extrahepatic disease Synchronous presentation Non-functional/pancreatic histopathology Tumour burden Poorly differentiation PFS Univariate Pancreatic/non-colonic poor differentiation Synchronous presentation postop complications R2 resection Tumour burden A. Saxena, Surgical Oncology 2012; 21:e131-e141
S. Mayo, Ann Surg Oncol 2010; 17: 3129-3136
Skye et al, J Am Coll Surg 2013; 26: 123-134
Aggressive surgery for NELM D. Elias et al D. Elias, Surgery 2003; 133: 375-382 D. Elias, EJSO 2009; 35: 1092-1097
Patients and Methods: Eleven patients with a metastatic endocrine tumor were selected before undergoing a right hepatectomy or a left hepatectomy passing along the median hepatic vein. Before the hepatectomy, patients underwent somatostatin receptor scintigraphy, computed tomography, magnetic resonance imaging, and ultrasonography (US). An intraoperative assessment (palpation and US) was also performed. Liver specimens were systematically cut into thin serial slices, 3- to 4-mm thick. A final histologic count of the total number of LM was obtained and compared with findings from each imaging technique Results: Compared with the final histologic count of LM, fewer than 50% of the LM were detected preoperatively. The accuracy was 24% for somatostatin receptor scintigraphy, 38% for computed tomography and US, and 49% for magnetic resonance imaging (the only imaging technique that detected half the number of LM). The size of the smallest LM was not greater than 2 mm in 54% of the patients. Conclusion: Half the number of LM from neuroendocrine tumors are undetectable on preoperative imaging. (Ann Surg 2010;251: 307 310) D. Elias, Ann Surg 2010; 251: 307-310
S. Mayo, Ann Surg Oncol 2010; 17: 3129-3136
S. Fan, HPB 2014
S. Fan et al, HPB 2014
Y. Le Treut et al, Ann Surg 2013; 257: 807-815
Criteria for LTX for NELM Mazzaferro Well differentiated Ki67 < 5% Primary curative resected No associated extrahepatic resection No extrahepatic Mets Tumor load < 50% Portal drainage Age < 55 year Stable disease > 6 mo Le Treut Well differentiated Ki67 < 10% (up to 20?) Primary curative resected No associated extrahepatic resection No extrahepatic Mets No hepatomegaly Age < 45 Longer waiting time V. Mazzafferro, Journal of Hepatology 2007; 47: 454-475 Y. Le Treut et al, Ann Surg 2013; 257: 807-815
Results therapy for NELM No RCT Selection bias? A. Frilling et al, Lancet Oncol 2014; 15: e8-21
Effect of therapy on survival NELM 40% 25% Yao, J Clin Oncol 2008;26:3063-3072
Conclusion NET Rare but increasing Natural history: slowly growing Treatment Surgery at the moment only potential curative treatment Surgery important in Treatment primary tumour Treatment LM in G1-G2 tumours but high recurrence rate Multimodal multidisciplinary discussion No RCT