An Overview of NETS. Richard R.P. Warner M.D

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1 An Overview of NETS Richard R.P. Warner M.D

2 Diagnosis and Treatment Approaches Carcinoid (and other NETs) not as benign as originally described 13-50% of all carcinoids have distant metastases when first diagnosed Pendulum of Management Swinging to Earlier and more Aggressive Treatment

3 Canine Family: Heterogeniety

4 Types of Neuroendocrine Tumors Neuroendocrine tumors (NETs): solid malignant tumors that arise from neuroendocrine cells 1 Neuroendocrine cells are enterochromaffin-like cells Able to produce peptides and cause hormonal syndromes Functional and nonfunctional tumors 2 NETs are classified by: Location 3 Foregut: thymus, esophagus, lung, stomach, duodenum, and pancreas Midgut: appendix, ileum, cecum, and ascending colon Hindgut: distal large bowel and rectum Additional: ovary, parathyroid, and adrenal Peptides produced 3 Pathological grade and differentiation 4 1. Yao JC et al. One hundred years after carcinoid : epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol.2008;26: National Comprehensive Cancer Network. NCCN Clinical Practice Guideline in Oncology: Neuroendocrine Tumors V.I Accessed November Öberg K et al. Neuroendocrine gastroenteropancreatic tumours: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21:v223 v Klimstra DS et al. The pathological classification of neuroendocrine tumors. Pancreas. 2010;39:

5 Incidence of Carcinoid in the U.S. Review of 35,618 cases( SEER Registry) Yao et al Carcinoid more frequently diagnosed now (twice as often each of the last three decades). 5.2 clinically significant new cases/100,000 at present. Prevalence-103,000 cases.

6 Incidence of Carcinoid/NETs % Carcinoid--- GEP 67 Pulmonary 26 Other sites (Breast, Kidney, pancreas, Ovary, etc.) 7 TOTAL Pancreatic NETs ---Nonfunctioning (PPoma) (Islet Cell) 30 Insulinoma 32 Gastrinoma 18 Vipoma 4 Glucogonoma 2 Somatostatinoma 1 Others 13 TOTAL 75% of NETs 25% of NETs

7 Distribution of Carcinoid Tumors by Site Bronchopulmonary System % 2.3 Other Pancreas 1 28% Digestive System 28.6 Colon and Rectum Colon, except the appendix 9 Appendix 5 Rectum 14 Other 8% 64% 28.5 Small Intestine Duodenum 3 Jejunum 2 Ileum 15 NOS Stomach Other 0.5 NOS, not otherwise specified. 1. Modlin IM et al. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003;97:

8 Extent of Disease Extent of Disease at Diagnosis 1 5% 4% 28% 30% 92% 23% 41% 49% 29% Selected Sites of Location Diagnosis is often delayed 5 to 7 years on average, and the probability of metastatic disease at diagnosis is increased 2 1. Yao JC et al. One hundred years after carcinoid : epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26: Modlin IM et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 2008;9:61 72.

9 Carcinoid - NETS 2% of all GEP malignant tumors Functioning and non functioning Microscopically All look alike Determination of type, depends on special stains and chemical products (markers)

10 Carcinoid Survival Prognosis 1 site (appendix, rectum, lungs, gut, pancreas) 1 size (better < 2 cm) Depth of invasion of supporting tissue Histologic growth (best worst: insular, trabecular, glandular, mixed, undifferentiated) CS tumors Px worse than without CS Wide variation in similar cases makes prediction very unreliable

11 Carcinoid - Course Slow growth Small intestine 20% metastasize Metastases relate to size of 1 tumor, likelihood > 60% if tumor is 1-2cm S.I. Carcinoids 25% multiple 1 Carcinoid syndrome (CS) in < 40% cases with mets. Usually require liver mets

12 Genetic Familial Syndromes MEN-1 von Hippel-Lindau Neurofibromatosis-1 Tuberous sclerosis Familial Carcinoid?

13 Clinical Manifestations of Carcinoid Syndrome MAJOR Flushing Diarrhea Pellagra Venous telangectasia Bronchospasm Cardiac Manifestation Hepatomegaly MINOR Peptic Ulcer Hypoalbuminemia Muscle Wasting, arthralgia (joint pain) Myopathy, Fibrosis Brawny Edema Hyperglycemia

14 .

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17 Sudden Flushing Carcinoid Crisis Hypotension (infrequently Hypertension) Tachycardia Weakness, Collapse, fever Dyspnea, Bronchospasm Variant crisis-patchy flush, agitation, heart failure, long lasting. Provocative test-epinephrine, Pentagastrin, calcium infusion.

18 Midgut Carcinoid Tumors Commonest Presenting Features Abdominal pain Obstruction Bleeding Mass CS

19 Carcinoid of the Lung Presenting Features Incidental finding Recurrent infection (pneumonia) Hemoptysis Chronic Cough Distant metastases Endocrine syndrome (Carcinoid, Cushing s, etc.)

20 Suspicion Markers Imaging Biopsy Diagnosis of Carcinoid

21 Carcinoid Tumor Markers Urine 5-HIAA Serotonin (5-HT) Chromogranin A (CgA)

22 Carcinoid Tumor Markers (2) Neuron specific enolase (NSE) Substance P Pancreatic poly peptide (PP) Pancreastatin Neurokinin A /ß subunits of HCG

23 Tryptophan Serotonin Metabolic Pathway Protein, Nicotinic 5-Hydroxytryptophan (5-HTP) 5-Hydroxytryptamine (5-HT, serotonin) 5-Hydroxyindole-3- acetaldehyde 5- Hydroxyindoleacetic acid (5-HIAA)

24 Standard Imaging Techniques X-Ray CT-scan MRI- scan Ultrasound scan (sonography) (EUS) Isotope bone scan *Octreoscan (SRS) NET specific FDG PET scan

25 Octreoscan

26 Octreoscan - II

27 Imaging Octreoscan probably will be replaced by Gallium 68 scan EUS best for pancreas Wireless capsule for small bowel lesions Double balloon enteroscopy allows biopsy

28 Carcinoid Metachronous or synchronous cancer 25% of cases (colon, lung, breast, prostate) Indicates the importance of annual general exam, surveillance colonoscopy, mammography, chest X-ray and PSA blood testing

29 Treatment of Carcinoid Tumors and Syndrome I. Supportive II. Surgery III. Antiproliferative

30 Medical Supportive Treatments Anti-diarrhea Drugs --- Diphenoxylate/atropine, Loperamide/simethicon, Anti-Cholinergic, Opiates, Cyproheptadine, Cholestyramine, Pancreatic extract, Somatostatin analogues. Nutritional Factors --- Diet, Niacin, MCT s, Hematinics. Electrolytes --- Potassium, Magnesium. Anti-ulcer Medication

31 BX for DX Surgery Resection for cure, debulking, control of bleeding, relief of obstruction, exclusion of ischemic bowel RFA, cryoablation, liver tumor regression by hepatic artery embo or chemo embo injection Heart valve replacement Relief of ascites by drainage, Denver shunt Stent placement Liver transplant

32 Anti-proliferative Treatment Biotherapy --- Somatostatin Analogs, Alpha Interferon Radiotherapy --- External Beam; Internal - I131 MIBG, IN111, Y90, Theraspheres, Sirspheres); Lu177 Octreotate, Y90 Octreotide (PRRT) Chemotherapy ---Standard, New agents.

33 Molecular Targeted Drugs Inhibit VEGF and other growth pathways Bevacizumab (monoclonal antibody) Everolimus (mtor inhibitor-blocks multiple downstream kinase activated pathways) Sunitinib (multikinase inhibitor) Sorafenib (blocks multiple growth pathways) Other experimental drugs

34 DIAGNOSIS No Treatment Surgery Medical Treatment Cure Debulking Surveillance Palliation Tumor Regression

35 MEDICAL TREATMENT Supportive Biologic Chemotherapy Antitumor Antitumor Radiation Treatment Treatment Octreotide, External Internal Systemic -IFN, Beam Targeted (PRRT antiangiogenesis Cytotoxic (Y90 particles) LU-77 and Y-90) New Specific Target Drugs

36 CONCLUSION Complete permanent cure Surgical Resection Palliation and survival benefit Customized for each case- Early aggressive surgery + Sequential multimodality treatment (biotherapy, RFA, HACE, chemotherapy, internal radiotherapy, PRRT) New therapies-very promising-need to be more available

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