NET 2-20 per 10 Intermed. 3-20 Carcinoid, Neuroendocrine tumor, - PowerPoint PPT Presentation

3/7/2015 GI and Pancreatic NETs Disclosures • Ipsen NET Advisory Board The Postgraduate Course in Breast and Endocrine Surgery Marines’ Memorial Club and Hotel San Francisco, CA Treatment of GI and Pancreatic Neuroendocrine Tumors Eric K. Nakakura San Francisco, CA March 6, 2015 Decision Tree GI and Pancreatic NETs Neuroendocrine tumors (NETs) Histologic classification “carcinoid” “carcinoid” Differentiation Grade Mitotic Ki-67 Traditional ENETS, WHO Count index Classification Classification (%) Well- Low < 2 per 10 ≤ 2 Carcinoid, Neuroendocrine tumor, Well- Well- HPF (G1) islet cell, grade 1 differentiated PNET PNET pancreatic differentiated differentiated neuroendocrine tumor NET 2-20 per 10 Intermed. 3-20 Carcinoid, Neuroendocrine tumor, HPF (G2) atypical grade 2 carcinoid, Paraganglioma/pheochromocytoma Paraganglioma/pheochromocytoma Islet cell, pancreatic neuroendocrine tumor Poorly Poorly Poorly High > 20 per 10 > 20 Small cell Neuroendocrine carcinoma, differentiated differentiated HPF carcinoma grade 3, small cell differentiated (G3) Platinum- Platinum- (high grade) (high grade) Large cell Neuroendocrine carcinoma, based chemotx based chemotx grade 3, large cell neuroendocrine carcinoma ENETS, European Neuroendocrine Tumor Society; WHO, World Health Organization; HPF, high-power fields 1

3/7/2015 GI and Pancreatic Neuroendocrine CASE 1 tumors (NETs) Diverse diseases Laparoscopic enucleation of insulinoma • Insulinoma • Gastrinoma • Small intestine NET (carcinoid) • Nonfunctioning pancreatic NET (NF-PNET) • Others… • Pancreas • Specimen CASE 2 CASE 3 Multifocal NETs (N = 18) in ileum (carcinoid) Duodenal gastrinoma • Duodenum • Specimen 2

3/7/2015 CASE 4 CASE 5 Whipple procedure for NF-PNET Total pancreatectomy for NF-PNET (12 cm) GI and Pancreatic Neuroendocrine tumors (NETs) Overview • Focus on a very confusing issue in NETs – NETs of Unknown Primary Neuroendocrine Tumors of Unknown Primary: • It’s not so confusing after all Is the Primary Tumor • History and experience have shone us the Site Really Not Known? light Eric K. Nakakura • Seeing is believing San Francisco, CA March 6, 2015 3

3/7/2015 GI and Pancreatic Neuroendocrine NETs of Unknown Primary tumors (NETs) If you remember only two things What does “unknown primary” mean? • NETs of unrecognized primary site are typically hiding in the ileum • NETs of the ileum are often multifocal � must palpate NETs of Unknown Primary NETs of Unknown Primary What does “unknown primary” mean? • The location where the NET originated is not known. • Well-differentiated NET liver metastases • Where did the tumor originate? 4

3/7/2015 NETs of Unknown Primary NETs of Unknown Primary What does “unknown primary” mean? Does finding the primary tumor matter? • The location where the NET originated is not known • Possible primary sites: • Small intestine (ileum, jejunum, duodenum) • Pancreas • Colon/rectum • Bronchopulmonary • Stomach… NETs of Unknown Primary Small intestine (ileum) NET Reasons for finding the primary tumor Intestinal ischemia • Symptoms • Abdominal pain, weight loss • Asymptomatic • Resect the primary as part of surgery to remove all gross disease • Prevent bowel obstruction • Prevent ischemia • Improve outcome? Hellman et al. World J Surg 2002 Boudreaux et al. Ann Surg 2005 Givi et al. Surgery 2006 . 5

3/7/2015 Small intestine (ileum) NET Small intestine (ileum) NET Intestinal ischemia Intestinal obstruction Small intestine (ileum) NET NETs of Unknown Primary Intestinal ischemia and obstruction Reasons for finding the primary tumor • Treatment increasingly depends on site • Everolimus, sunitinib for pancreatic NETs • Octreotide for well differentiated midgut NETs • Lanreotide for well-differentiated NF GI and pancreatic NETs • Systemic chemotherapy for pancreatic NETs • Participation in clinical trials Bergsland and Nakakura. JAMA Surg 2014 . 6

3/7/2015 NETs of Unknown Primary NETs of Unknown Primary What tests should be done to find it? What tests should be done to find it? • Currently, there is no consensus on what minimum tests should be done before the primary site is considered unknown NETs of Unknown Primary NETs of Unknown Primary What tests should be done to find it? UCSF study • Study design: Pathology database (1993-2008) • CT? • MRI? • Setting: UCSF • OctreoScan? • 68 Ga-DOTA-TATE or 68 Ga-DOTA-NOC PET-CT • Patients: 123 patients with NET liver metastases • Upper/lower endoscopy? • Endoscopic ultrasound? • Outcomes: 1) Detection of primary tumor preop • Enteroclysis? 2) Laparoscopic or open surgery to • Capsule endoscopy? find and remove an unknown • Double-balloon enteroscopy? primary tumor • Gene expression profiling? Wang et al. Arch Surg 2010 . 7

3/7/2015 NETs of Unknown Primary NETs of Unknown Primary UCSF study Where is the primary site likely to be? • Despite extensive evaluation, 13.8% had occult primary tumors. Wang et al. Arch Surg 2010 . Siegfried Oberndorfer Gastrointestinal NETs Epidemiology (1876-1944) Carcinoid site (1950-1971) (1973-1999) (no islet cell) n = 2425 n = 6996 • 1907: Pathological Institute of Geneva % % • 1) multiple tumors in submucosa of ileum Stomach 2.5 7 • 2) slow growth • 3) borders sharply circumscribed Small intestine 25 44 • 4) (do not metastasize) Appendix 48 7 • Karzinoide: “carcinoma-like” Colon 8 13 Rectum 17 24 • 1929: He recognized potential to metastasize Modlin et al. Hum Path 2004 Modlin et al. Cancer 2003 . . 8

3/7/2015 NETs of Unknown Primary NETs of Unknown Primary UCSF study results Multicenter results • Primary site found in 13/15 patients (87%) by surgery • All primary tumors in small intestine (12 ileum, 1 jejunum) • Primary tumors small (1.4 cm) and often multifocal (54%) • Careful palpation of small intestine is essential ~ 84% success in finding primary Wang et al. Arch Surg 2010 Bergsland and Nakakura. JAMA Surg 2014 . . NETs of Unknown Primary Karnovsky Memorial Lecture Laparoscopic identification of tumor in ileum An Odyssey in the Land of Small Tumors • Small intestine NETs – Most (193/209; 92%) arise from ileum – Multifocal (46/183; 25%) • Primary tumors small, deep mucosal site of origin • Nature of spread – First invades muscle layer � serosa � mesentery (outward spread) • Nature of obstruction – Fibroblastic reaction in mesentery � buckling of bowel wall � kinking of bowel wall (like an accordian) Wang et al. Arch Surg 2010 Moertel CG. J Clin Oncol 1987 . . 9

3/7/2015 NETs of Unknown Primary NETs of Unknown Primary Laparoscopic identification of tumor in ileum Laparoscopic identification of tumor in ileum with Meckel’s diverticulum NETs of Unknown Primary NETs of Unknown Primary Laparoscopic identification of tumor in ileum Multifocal primary tumors (N = 11) in ileum with regional adenopathy 10

3/7/2015 NETs of Unknown Primary NETs of Unknown Primary Multifocal primary tumors (N = 11) in ileum Multifocal primary tumors (N = 11) in ileum NETs of Unknown Primary NETs of Unknown Primary Multifocal primary tumors (N = 11) in ileum (#2) Multifocal primary tumors (N = 11) in ileum (#2) 11

3/7/2015 Finding the Primary Tumor NETs of Unknown Primary What tests should be done to find it? Potentially seen on colonoscopy • CT scan: chest, abdomen/pelvis (multiphase, thin slice) • Somatostatin receptor scintigraphy (OctreoScan) • Urine 24-h 5-HIAA • Upper and lower endoscopy • Immunohistochemical markers (TTF-1, CDX2, PAX8, Islet 1) • Careful review by multidisciplinary team • terminal ileum NET Finding the Primary Tumor NETs of Unknown Primary Potentially seen on colonoscopy Take home points • For most patients with WD-NETs and unknown primary the primary site is most likely in the ileum • If surgery planned, appropriate preoperative tests should be done • Many other tests (enteroclysis, capsule endoscopy, double-balloon enteroscopy, and endoscopic ultrasound) unnecessary since will not affect patient care and only delay treatment • Must carefully palpate small intestine because ileum NETs are frequently multifocal • terminal ileum NET 12

3/7/2015 NETs of Unknown Primary NETs of Unknown Primary Patient example Patient example • A 60-year-old man • Fall 2008: abdominal pain • Evaluated at a local hospital • Bilobar liver masses • Core needle biopsy: CgA +, Syn + • Well-differentiated NET • Unknown primary site NETs of Unknown Primary NETs of Unknown Primary Patient example • A 60-year-old man with NET liver metastases and unknown primary • Fall 2008: Started Sandostatin • Patient informed his disease was inoperable • UCSF for second opinion by multidisciplinary GI oncology group • Winter 2008: • Laparoscopic identification and resection of ileum primary tumor Wang et al. Arch Surg 2010 . 13