neuroendocrine tumor Lecture - Copy.pptx

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1. Gastroenteropancreatic neuroendocrine tumours PROF DR : ABDEL RAHMAN A MOKHTAR Internal Medicine – Mansoura University

2. Definition and characters: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are considered to be rare, heterogeneous and complex neoplasms. They include the pancreatic (PNETs) and gastrointestinal (GI) neuroendocrine tumours (GI-NETs) or carcinoids , which share their origin of cells from the diffuse neuroendocrine system , but further show many differences regarding pathogenesis, clinical behaviour and prognostic outcome. Characteristic for GEP-NETs is their ability to produce bioactive substances Based on the clinical symptoms and syndrome caused by these peptides, they can be divided into functioning (F-NETs) and non-functioning tumours (NF-NETs). Although GEP-NETs are generally more indolent than carcinomas, the majority are malignant, showing aggressive tumour behaviour and presenting with metastases at diagnosis. GEP-NETs can occur sporadically, or as part of a hereditary syndrome such as multiple endocrine neoplasia syndrome type 1 (MEN-1), von- Hippel Lindau disease ( vHLD ), neurofibromatosis type 1, or tuberous sclerosis.

3. NOMENCLATURE ISSUES Endocrine versus neuroendocrine Originally, the concept of neuroendocrine neoplasia reflected the hypothesis that the cells from which these tumors were derived originated from the embryonic neural crest. This concept was disproved years ago, causing some authorities to advocate abandoning the term neuroendocrine in favor of endocrine. However, the neoplastic cells also possess features of neural and epithelial cells, and for this reason, the most recent edition of the WHO classification of tumors of the digestive system has once again recommended the use of neuroendocrine Tumor instead of neoplasm Certainly, all of the entities under discussion are neoplastic , and neoplasm is therefore a more accurate term than tumor, which means only a mass. However, neuroendocrine tumor (NET) has achieved widespread acceptance in many systems and will be used here in stead of the more correct but less accepted alternative, neuroendocrine neoplasm.

4. Classification :

5. GI Neuroendocrine Tumors Pancreatic NETs • Insulinoma • Glucagonoma • VIPoma • Pancreatic polypeptidoma Foregut • Thymus • Esophagus • Lung • Stomach • Duodenum Midgut • Appendix • Ileum • Cecum • Ascending colon Hindgut • Distal large bowel • Rectum Other NETS

6. Differentiation and Grading ISSUES Differentiation refers to the extent that neoplastic cells resemble their non-neoplastic counterparts GRADE : refers to the inherent biologic aggressiveness of the tumor

7. 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 0.00 1.00 2.00 3.00 4.00 5.00 6.00 100 200 300 400 500 600 Incidence per 100,000 - NETs Incidence per 100,000 – All malignant neoplasms All malignant neoplasms Neuroendocrine tumors Yao JC et al. J Clin Oncol . 2008;2 6:3063-3072. Incidence of NETs Increasing

8. Increasing incidences of NET Increased incidence of carcinoid tumours, US population 1973–2005 Overall increase recorded for all primary sites during this period. Data from SEER database, US National Cancer Institute Modlin et al. Lancet Oncol 2008; 9: 61–72

9. NETs are the Second Most Prevalent Type of GI Malignancy 2x more prevalent than pancreatic cancer ] 1. National Cancer Institute. SEER Cancer Statistics Review, 1975-2004. http://seer.cancer.gov/csr/1975_2004. 2. Modlin IM, Lye KD, Kidd M. Cancer . 2003;97(4):934-959. ]

10. Epidemiologic notes for the clinician 1) It is important to realise that GEP-NETs frequently occur as or together with a second primary malignancy. The presence of a simultaneous second primary or metastatic malignancy must be thoroughly examined, as several case reports describe the existence of a second tumour synchronous with a carcinoid lesion. For example, gastrointestinal stromal tumours (GIST) are frequently seen in combination with (gastric) carcinoids . Therefore, alertness for synchronous ( neuroendocrine ) tumours among clinicians is advocated. 2) Patients suffering from hereditary syndromes such as MEN-1, vHLD , neurofibromatosis type 1 or tuberous sclerosis, are at increased risk for a GEP-NET . So, members from hereditary GEP-NET disorder families should be checked for such tumours , preferably by genetic counselling and, if possible, DNA profile, or by measurement of markers for these or associated tumours .

11. 3) Another difficulty in diagnosing GEP-NETs arises as these tumours show a relatively high frequency of ‘ectopic occurrence’. For example, gastrinomas, which are usually located in the pancreaticoduodenal region and lymphnodes, have been reported on ectopic locations such as ovaries, biliary tract, kidneys, stomach and liver. Some authors believe that it is uncertain whether these ectopic locations comprise primary gastrinomas rather than metastases of occult primaries. GEP-NETs have been reported in rare locations such as the oesophagus, gallbladder and biliary ducts, Meckel’s diverticulum, ampulla of Vater, genital tract and skin. Lack of awareness that neuroendocrine lesions can also occur on these unusual sites results in the consequence that these tumours are frequently misdiagnosed or overlooked. Therefore, it is recommended that when imaging is not successful in detecting a neuroendocrine tumour in the usual sites, an intensive search for occult tumours at unusual sites should be started. Additionally, it is important to realise that

12. PRESENTATION Asymptomatic . Vague symptoms, CARCINOID SYNDROME. Gastrointestinal NET. PANCREATIC NET..functioning & nonfunctioning. Bronchial NET. Metastatic disease.

13. Menopause Irritable Bowel Syndrome Functional Bowel Disease Anxiety Neurosis Food Allergy Asthma Alcoholism Thyrotoxicosis Peptic Ulcer NET 1 . Vinik A, Moattari AR. Dig Dis Sci . 1989;34(3)( suppl ):14S-27S. 2. Toth-Fejel S, Pommier RF. Am J Surg . 2004;187(5):575-579. Symptoms • Sweating • Flushing • Diarrhea • Intermittent abdominal pain • Bronchoconstriction • GI bleeding • Cardiac disease VAGUE SYMPTOMS

14. Nonspecific Symptoms Often Lead to a Delayed Diagnosis 1. Modlin IM, Moss SF, Chung DC, Jensen RT, Snyderwine E. J Natl Cancer Inst . 2008;100(18):1282-1289. Presents to primary care Vague abdominal symptoms • May be diagnosed as IBS • May be referred to specialists for evaluation when symptoms do not resolve Referred to multiple specialists Symptoms become worse or patient consults for another reason • Diagnosis remains unclear Seen by gastroenterologist or other specialist who orders imaging A referral leads to a scan or patient scanned for another reason • Liver metastasis or primary lesion is visualized • May be an incidental finding Surgeon, pathologist perform biopsy or resection Biopsy provides diagnosis of NET • Patient is referred to surgical oncologist, medical oncologist, or endocrinologist • Treatment depends on stage, histology, symptoms Estimated time to diagnosis: 5 to 7 years 1

15. Vague abdominal symptoms Primary tumor Flushing Metastases Diarrhea Death NETs Are Often Diagnosed Late Time Vinik A, Moattari AR. Dig Dis Sci . 1989;34[Suppl]:14S-27S.

16. PRESENTATION Asymptomatic . Vague symptoms, CARCINOID SYNDROME. Gastrointestinal NET. PANCREATIC NET..functioning & nonfunctioning. Bronchial NET. Metastatic disease.

17. Carcinoid syndrome is the clinical manifestation of excess serotonin production Inpatients with early-stage carcinoid tumours that secrete serotonin, Systemic symptoms do not occur, as active hormone enters the portal circulation and is rapidly degraded by hepatic enzymes. Carcinoid syndrome, which occurs in about 10% of carcinoid tumours, manifests only when the tumour has metastasised to the liver or extra-peritoneal abdominal organs such as the ovary, allowing hormone to enter the systemic circulation, thereby escaping hepatic degradation. Characteristic symptoms of carcinoid syndrome include: • Intermittent or progressive facial flushing . • Secretory diarrhoea (characterised by lack of response to fasting). • Abdominal cramps. • Wheezing A carcinoid crisis (prolonged severe flushing, diarrhoea , hypotension, tachycardia, severe dyspnoea , peripheral cyanosis and sometimes haemodynamic instability) can occur if large amounts of hormone are secreted acutely. This can be triggered by diet, alcohol, surgery or chemotherapy.

18. Carcinoid syndrome About 50% of patients with carcinoid syndrome have cardiac abnormalities caused by chronic exposure of the heart valves to serotonin, which causes fibrosis and thickening of the tricuspid and pulmonary valves, resulting in regurgitation or, less commonly, stenosis. Right heart failure and congestive cardiac failure can result. .Ascites and oedema can also occur. The consequent hepatic congestion results in a decreased capacity of the liver to degrade hormones, which further exacerbates symptoms and can result in acute decompensation.

19. PRESENTATION Asymptomatic . Vague symptoms, CARCINOID SYNDROME. Gastrointestinal NET. PANCREATIC NET..functioning & nonfunctioning. Bronchial NET. Metastatic disease.

20. Gastrointestinal NETs Small-bowel carcinoids are frequently asymptomatic or present with vague abdominal symptoms that can be mistaken for irritable bowel syndrome. Some patients present with intermittent or acute bowel obstruction. Production of serotonin or other bioactive amines is a typical feature of small-bowel carcinoids, and local secretion causes mesenteric fibrosis that predisposes to bowel obstruction or can compress mesenteric vessels, resulting in bowel ischaemia and malabsorption. Most gastric, appendiceal and rectal carcinoids present as incidental findings. These tumours are usually non-functioning and remain asymptomatic until advanced.

21. PRESENTATION Asymptomatic . Vague symptoms, CARCINOID SYNDROME. Gastrointestinal NET. PANCREATIC NET..functioning & nonfunctioning. Bronchial NET. Metastatic disease.

22. Pancreatic NETs Non-functioning pancreatic NETs may grow for a long time without causing symptoms. When large enough, obstruction of bile or pancreatic ducts may cause obstructive jaundice or symptoms due to pancreatic enzyme insufficiency, such as diarrhoea.

23. About half of pancreatic NETs are functional , producing a range of hormones resulting in characteristic syndromes .

24. PRESENTATION Asymptomatic . Vague symptoms, CARCINOID SYNDROME. Gastrointestinal NET. PANCREATIC NET..functioning & nonfunctioning. Bronchial NET. Metastatic disease.

25. Bronchial NETs Bronchial carcinoid tumours can cause Recurrent pneumonia from airway obstruction, Pleurisy, haemoptysis and shortness of breath. A small proportion of these tumours produce serotonin or similar bioactive hormones, resulting in carcinoid syndrome, or ACTH, resulting in Cushing’s syndrome.

26. PRESENTATION Asymptomatic . Vague symptoms, CARCINOID SYNDROME. Gastrointestinal NET. PANCREATIC NET..functioning & nonfunctioning. Bronchial NET. Metastatic disease.

27. Metastatic disease Common sites of metastatic disease include : - Local or distant lymph nodes, Liver, bone and peritoneum. In females the ovary can be a site of metastatic disease. Some patients present with symptoms of fatigue and weight loss. Unlike other malignancies in which untreated metastatic disease is usually rapidly progressive, even widely spread metastatic NETs can be indolent, sometimes referred to as ‘cancer in slow motion’. It is not uncommon for it to present initially as a cancer of unknown primary, as the burden of metastatic disease can be large, while the primary site remains small and difficult to locate.

28. Investigation

29. CgA is an acidic glycoprotein expressed in the secretory granules of most normal and neoplastic neuroendocrine cell types.

30. Chromogranin A ( CgA ): A Valuable Diagnostic and Prognostic Tool Highly elevated serum CgA and/or immunohistochemical (IHC) staining of tumor for CgA is diagnostic of NETs Offers 85% sensitivity and 96% specificity for NETs 1 CgA can be used to monitor treatment response More sensitive than radiology for measuring progression 2 References: 1. Campana D, Nori F, Piscitelli L, et al. J Clin Oncol . 2007;25(15):1967-1973. 2. Eriksson B, Öberg K, Stridsberg M. Digestion . 2000;62(suppl 1):33-38.

31. Challenges Present with CgA Testing Other conditions can cause elevated CgA Risk of false positives Severe hypertension Gastric acid suppression (PPI’s) Renal insufficiency Chronic atrophic gastritis. CgA values vary considerably Between different types of NET Test kits not universally standardized Different standards, units of measures Different antibodies Different detection system

32. If suspicion of a specific synd , tests for hormone excesses are indicated

33. 5 HIAA (24-hr urine collection) Serotonin (blood, more variable) 5-HIAA = 5-hydroxyindoleacetic acid 5-Hydroxyindole acetic acid (5-HIAA) is the urinary breakdown product of serotonin and can be measured using a 24-hour urine collection in patients with features of carcinoid syndrome. Some foods, including pineapples, bananas, eggplants, tomatoes, avocados and walnuts contain high levels of serotonin, which can increase urinary levels of 5-HIAA, and should be avoided three days before collection. 5-HIAA can also be increased in patients with untreated malabsorption such as in coeliac disease. A variety of medications can also increase or decrease 5-HIAA levels. CgA measurement is more sensitive and is increasingly replacing use of urinary 5-HIAA

34. Other Markers in Functional Tumors Fasting measurements when possible

35. RADIOLOGIC DIAGNOSIS CT MRI US Somatostatin Receptor Scintigraphy (SRS) – based on presence of somatostatin receptors in 80-90% of NET PET to evaluate tumor metastasis Endoscopic ultrasound – sensitivity/specificity appx 80% for tumors in pancreas and duodenum and can allow for FNA

36. Somatostatin Receptor Scintigraphy (SRS By virtue of SSTR expression in most NETs, various radiolabelled somatostatin analogues have been developed for diagnostic imaging. These have three basic components — a radiometal that emits radiation detectable outside the body, linked via a chelating agent to a peptide that binds to the SSTR. The only commercially available and approved agent for SSTR-imaging is Indium-111 DTPA-octreotide (Octreoscan). Although widely available, Octreoscan imaging is an expensive test and quite difficult to interpret. An inherent drawback is the absence of anatomical information, precluding lesion characterisation or precise localisation, leading to difficulty distinguishing physiological or benign uptake from pathological uptake. These limitations can be overcome with hybrid SPECT–CT scanners, which provide both functional (SPECT) and anatomical (CT) information. Octreoscan imaging is best performed on a multi-slice SPECT–CT device and is significantly more sensitive than conventional imaging, with a large impact on patient management .

37. Echocardiography Carcinoid heart disease is seen in a high proportion of patients with longstanding carcinoid syndrome, and echocardiography is needed to assess this. Specific features are thickening of valvular cusps and chordae, which results in regurgitation or stenosis (usually of the tricuspid valve) leading to right ventricular dilation and reduced function, as well as right atrial dilation

38. Diagnostic algorithm

39. Diagnostic algorithm

40. Diagnostic algorithm

41. TREATMENT Given the complexity and heterogeneity of this disease, therapy is individualised based on several factors, including: • Disease extent. • Rate of growth determined by temporal change on imaging and histological grade/proliferative index. • Level of SSTR expression . • Disease-related symptoms with regard to the primary lesion or metastatic deposits. • Patient comorbidities.

42. Treatment options Surgery (curative vs debulking) Radiofrequency ablation Chemo-embolization Somatostatin analogue (hormonal treatment) Chemotherapy or other medical therapy (targeted kinase inhibitors) Biologic therapy. Radionuclide therapy

43. The two currently available SSAs are octreotide (Sandostatin 100-500μ g [a short-acting preparation] and Sandostatin LAR 10- 30mg [a long-acting repeatable depot preparation]) and lanreotide (Lanreotide Autogel 60, 90, 120mg [a depot preparation]). The short-acting is SC has a half-life of 1.5-2 hours and is used for the treatment of breakthrough secretory symptoms. The depot preparations are given once every four weeks by deep SC or IM injections and are used for long-term control. These agents do have adverse effects, including: • Nausea. • Cramping. • Diarrhoea. • Steatorrhoea. • Cardiac conduction abnormalities. • Endocrine dysfunction hpothyroidism, hypo- and hyperglycaemia). • Cholelithiasis in up to 50% of patients (although cholecystitis develops in fewer than 5%). Patients undergoing surgical resection of NETs should be considered for prophylactic cholecystectomy to facilitate later use of SSAs.

44. Radiofrequency ablation

45. Chemoembolisation

46. Chemoembolisation

47. Peptide receptor radionuclide therapy The use of beta particle emitters , Indium111,Y-90 and lutetium-177 (Lu-177). The last 2 in the form of Y-90 and Lu-177 DOTATATE (LuTate) are now preferred and have demonstrated excellent objective response rates (about 70%) with low toxicity. High-energy beta particles from Y- 90 can travel up to a centimetre in tissue whereas lower-energy particles from Lu-177 travel 1-2mm. Both result in ‘crossfire’, whereby each cell irradiates its neighbours, resulting in efficient radiation delivery to aggregations of cancer cells.

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