Neuroendocrine Tumours If you don t suspect it you can t detect it! Dr JWS Devar HPB Surgeon University of Witwatersrand E-AHPBA CHBAH & WDGMC

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1 Neuroendocrine Tumours If you don t suspect it you can t detect it! Dr JWS Devar HPB Surgeon University of Witwatersrand E-AHPBA CHBAH & WDGMC

2 Case Study 43 yr old female with a history of a left mastectomy in 2014 and adjuvant chemo and DXT for Breast Ca. No medical co morbidities March 2018 complaining of abd pain, particularly post prandially Clinical Examination non contributary FBC/U&E/LFT/INR/CEA/Ca 19.9/AFP normal

3 CT scan

4 CT scan & DDx?

5 FNA Grade 1 Neuroendocrine Tumour Dotatoc PET CT scan confirmed neuroendocrine tumour in the HOP and metastases in the Right liver. Options?

6 Pancreaticoduodenectomy

7 Cells of Origin Stem cell Gastrointestinal neuroendocrine lineages arise from a common stem cell precursor in the base of the intestinal crypts or in the neck of the gastric glands Differentiate into diverse types of neuroendocrine cells under the influence of transcription factors Math1 and neurogenin 3 (NGN3) Non-secretory cell lineage Secretory lineages Math1+ NGN3+ Enterocytes Goblet cells Paneth cells Endocrine cell lineages Beta2 Pax4 Pax6 Endocrine cell types Gastrin Secretin CCK SST GIP 5-HT SP GLP-1, PYY/NT Image courtesy of IM Modlin.

8 PITUITARY THYROID, PARATHYROID LUNG, THYMUS ADRENAL MEDULLA & PARAGANGLIA GI tract, PANCREAS SKIN

9

10 GEP-NET Registry 1005 patients July 2009 Dec 2012 PNETs 42% 60% non-functional NETS

11 Background Heterogenous group of tumors of the diffuse neuroendocrine system Histology intracellular markers of endocrine cells (serotonin, cathecholamines, neuron specific enolase, synaptophysin, chromogranins A/B ) Majority Sporadic and 40-50% have metastatic disease at presentation 60-90% are Non Functional Minority Genetic Syndromes(MEN 1,MEN 2,NF, von Hippel Lindau and Tuberous sclerosis)

12 NET Are the Second Most Prevalent Type of Gastrointestinal Malignancy 1,200, 000 1,100, 000 2x more prevalent than pancreatic cancer 100, Colorectal 1 GEP-NET 2 Stomach 1 Pancreas 1 Esophagus 1 Hepatobiliary 1 Prevalence in SEER Database 1. National Cancer Institute. SEER Cancer Statistics Review, Modlin IM, Lye KD, Kidd M. Cancer. 2003;97(4):

13 Incidence of NETs per 100,000 Incidence of all malignant neoplasms per 100,000 The Overall Incidence of NET Is Increasing Compared With All Malignant Neoplasms 6.00 Incidence of all malignant neoplasms Incidence of neuroendocrine tumours Year The incidence and prevalence of NET has increased approximately 500% over the past 30 years which may be partially due to improved diagnosis 0 Source: US SEER database. Adapted with permission from Yao JC, et al. J Clin Oncol. 2008:26:

14 Oncogenesis

15 Diagnosis/staging Majority are found incidentally during routine imaging Functional symptoms related to the cell of origin(diarrhoea, flushing, sweating, palpitations, swinging blood pressures) Biochemistry: Screening tests: U-5HIAA, U-VMA,cortisol General markers: chromogranins Specific markers: hormones, pro-hormones, gastrin, etc

16 Neuroendocrine Cells Are Peptide Hormone-Producing Cells that Share a Neural-Endocrine Phenotype Synaptophysin Small synaptic vesicles Chromogranin A Membrane protein of neurosecretory granules Peptide hormone In neurosecretory granule Secreted into the serum biomarkers Klöppel G. et al. International Collaboration on Neuroendocrine Tumours. Vienna, Austria NET

17 Chromogranin/Secretogranins Water-soluble acidic glycoproteins in NETs CgA: 439 peptide molecule most used CgB: secretogranin I selective use CgC: secretogranin II - rarely used Cgs are NOT secreted by non-nets

18 Usefulness of Cgs Plasma CgA is increased in most NETs pcga levels are proportionate to tumor size Plasma Cg more reliable than urine metabolites CgB can be used as a complement and clinical trials

19 Non-tumor increases of CgA Renal & Liver Failure Chronic gastritis PPIs Stimulation of the sympathetic nervous system IBD

20 How to diagnose NET s Anatomical Imaging CT scan MRI bone, spine, now liver Functional Imaging Octreoscan sstr2 MIBG Gallium PET (Dotatate/Dotanoc/Dotatoc) G1 and G2 Ki 67 <10% GLP1 for Insulinomas FDG PET G2/G3 lesions Ki67>10%

21 How to diagnose a NET EUS FNA make the diagnosis Cell block can help with grading Core Biopsy best for establishing the Grade

22 Ki67 Counting Options to quantify Ki67 1. Percentage of actively dividing tumour cells in a 2000 cell count 1. Using a computerized digital image analysis system to measure the positive percentage The result should be reported as a single percentage

23 WHO 2010

24 WHO 2017 Grading Change

25 WHO 2017

26 Cumulative Survival Grading of GEP-NENs According to ENETS/WHO/AJCC G1 G G1 vs. G2 G1 vs. G3 G2 vs. G3 P=0.040 P P G Time (months) * 10 High power field (HPF) = 2 mm 2 at least 40 fields (40x magnification) evaluated in areas of highest mitotic density Percent of 2000 tumour cells in areas of highest nuclear labelling with MIB1 antibody. Pape UF et al. Cancer. 2008;113:

27 Indications for Surgery Resectable Primary NETS - surgery best option Resectable metastatic disease Resection of the primary lesion in non-resectable metastatic disease? Unresectable Symptomatic Primary Debulking Hepatic Metastatic disease with good prognostic indices Liver Transplant

28 Laparoscopic Distal pancreatectomy

29 Who should receive Debulking Surgery? Patients with obstructive symptoms Mesenteric vascular compromise Life threatening hormone related symptoms Ideally aim for 90% debulking Other debulking options RFA Microwave ablation Arterial & chemoembolisation Cryotherapy Radioembolisation - SIRT

30

31 Advanced locoregional Functional tumours Symptom control Symptom control SSA sandostatin/lanreotide Locoregional therapies/debulking surgery Pasireotide no benefit COOPERATE 2 trial IFN-alpha Telotristat serotonin synthesis inhibitor

32 Management of metastatic Midgut NENs First line Therapy

33 Advanced locoregional Disease Non Functional tumour Antiproliferation effect. Watch wait - low Ki67 and low tumour burden Sandostatin/Lanreotide Midgut G1/G2 NET s Promid/Clarinet Studies PNET s Ki67 index < 10% High liver tumour burden >25%

34 Disease Progression in PNETs Everolimus/Sunitinib

35 Radiant-4 Lung and midgut NENs Everolimus PFS 11mnths Placebo 3.9 mnths Confirmed findings in Radiant-2 Now part of ENETs guidelines for midgut & Lung SUNLAND trial still pending Sunitinib.

36 Disease Progression in Mid Gut NET s

37

38

39 Role of Systemic chemotherapy G2 disease with rapid progression < 6mnths or Ki67 >10% 5FU/Streptozocin Temozolomide/Capecitabine G3b Ki67% >20 & poor differentation Cisplatinum and Etoposide

40 Median survival (months) Improving Access to Specialised Care Potentially Improves Patient Outcomes 160 Median survival of patients Multidisciplinary centres have improved survival Median survival of patients is 3 times in high volume centres Data are consistent between centres of excellence Median survival of patients Centre-specific 1-3 data Population based data SEER database 1 SEER database 1 SEER database 1 (all NET patients) (all NET patients) (all NET patients) Midgut metastatic carcinoid only Moffitt Cancer Centre 2 Midgut metastatic carcinoid only Uppsala Centre 3 Midgut metastatic carcinoid only Berlin / Paris 4 1. Yao JC, et al. J Clin Oncol 2008;26: Strosberg J. Poster presented at ASCO GI 2008; 3. Öberg K. Oral presentations at ENETS, CCNETS, and NANETS, Jann et al Cancer, 2011;117:

41

42 Take Home Second most important GIT malignancy Incidence is on the rise Surgery upfront if resectable Metastatic disease can be well controlled Overall survival is better if treated in a high volume centre New trials for targeted therapy Radiant 4 - positive Netter 1- positive Importance of a NET MDT

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