Carcinoid tumor - Descriptive Slides for Undergraduates

Carcinoid tumor

1. Dr Akshaykumar H JR S3 unit Department of General Surgery MCH,Kozhikode Carcinoid Tumour

2. History Theodor Langhans was the first to describe the histology of a carcinoid tumor in 1867 Otto Lubarsch -the first report of 2 patients with ileal carcinoid tumors discovered at autopsy,

3. The history of the term Carcinoid 1907 Siegfried Obendorfer - German pathologist at the University of Munich coined the term karzinoide , or “carcinoma-like”, to describe the unique feature of behaving like a benign tumor despite resembling a carcinoma microscopically small size and multiple foci Undifferentiated cellular formations Well defined borders No /less metastatic potential Slow growing and harmless

4. Discovery of serotonin Recognition of the endocrine-related properties of carcinoid tumors did not occur until much later. In 1948, Rapport and colleagues isolated and named serotonin (5-HT) initially identified as a vasoconstrictor substance in the serum by 1952, it was determined that the origin of this amine was the Kulchitsky cell Just one year later , Lembeck identified serotonin in an ileal carcinoid and confirmed it as the major hormone responsible for the carcinoid syndrome

5. Now no longer classified as Carcinoid Rather called NETS Well differentiated neuroendocrine tumours most commonly originiationg in GI Tract and lung and rarely GU tract But still preferred term is NET/NEN

6. Carcinoid tumour biology Slow-growing tumors of the neuroendocrine system that belong to APUD system Are thought to arise from Enterochromaffin cells also known as KULCHITSKY CELLS Enterochromaffin-Ability to stain with potassium chromate-feature of serotonin Neuroendocrine cells Neuro because they can be stimulated by nerves Endocrine because they can release hormones

7. Somatostatin receptor present on cell surface 5 somatostatin receptors(SSTR 1-5) 80% NETS over express SSTR2 Octreotide has strongest affinitry for SSTR2 Octreoscan and 68GA DOTA TATE PET/CT detect presence of SSTR2

8. NET-comprise a broad family of tumours Carcinoid tumours - m/c arising in the lungs and bronchi Small intestine,appendix,rectum,thymus P-NETS Other less common NETS incluse those arising from parathyroid,thyroid,adrenal and pituitarys

9. Incidence SEER datatbase ( Surveillance,Epidemiology and End Results) NET-5.25 per 1,00,000 Non pancreatic NETS-4.7/1,00000 Approx 2/3 rd in GIT and 1/3 rd in lungs and thymus GI NETS or carcinoids -70% of all NETS GI NETS-3.56 per 1,00,000 population and increasing Carcinoid are the second most prevalent type of GI malignancy African americans >whites M>F Median age 63 years

10. M/C SITE A controversy Small intestine overall B>I>R>A>C>S

11. Sporadic Inherited Genetic syndromes MEN sx Familial paragangliomatosis Neurofibromatosis type 1 VHL Tuberous sclerosis

12. Pathology Composed of monotonous sheets of small round cells with uniform nuclei and cytoplasm and mitotic figures are rare Pathologist cannot differentiate benign from malignant carcinoid tumors based on histologic analysis Malignancy –determined if invasion+/distant mets +

13. Special stains- Synaptophysin Chromogranin A

14. Histological Classification WHO CLASSIFICATION Based on tumor differentiation(well or poorly)-extent to which neoplastic cells resemble their non neoplastic counterparts Based on tumour grade(1-3) Most NETs fall in 3 broad histologic categories(WHO) Well differentiated,Low grade(G1) Well differentiated,intermediate grade(G2) Poorly differentiated,High grade(G3)

15. Grade (proliferative activity of tumor) is defined by mitotic count /Ki 67 index whichever is higher In some cases tumours may not fall clearly into one category Ex:A morphologically well differentiated NET with Low MI may have KI 67 index into high grade category Hence clinical judgement should be made for such cases calssified as high grade THE CLASSIFICATION OF LUNG AND THYMUS CARCINOIDS DOESNOT INCLUDE KI 67 –INCLUDES ASSESSMENT OF NECROSIS

16. Site of origin(Embryological classification) NETS are generally classified as Fore gut Mid gut Hind gut Depending on their embryonic origin

17. Pathways of tryptophan and serotonin metabolism in the carcinoid tumor cell. Patients with the carcinoid syndrome often have increased levels of 5-hydroxyindoleacetic acid (5-HIAA) excretion in the urine serotonin in the blood; urinary serotonin excretion is either normal or slightly increased

18. Clinical Features MIDGUT Usually incidental-asymptomatic at presentation Periodic abdominal pain(40%) Intestinal obstruction with ileus(25%) Abdominal tumor(17%) GI bleeding(1%) Features of acute appendicitis Hepatomegaly Duodenal NETS –duodenal /biliary obstruction

19. Abdominal pain Vague,nonspecific like IBS Due to intussusception/mesenteric ischemia Often by mesenteric kinking by tumor bulk Ln invasion/secondary severe desmoplastic reaction Added up by the vasospastic activity of serotonin

20. Rectal Bleeding Constipation Diarrhoea Bronchial Pneumonia Hemoptysis Cough

21. Sytemic symptoms are consequence of the peptide released by the tumor

22. Carcinoid syndrome Cushings syndrome Acromegaly Peptic ulcer disease Valvular heart diseases

23. Specific markers for Carcinoid tumours Biochemical markers Chromogranin A in about 80% with GI nets Sensitivity is 75% and specificity 85% False positive results –with PPI/H2 receptor antagonist,hepatic or renal failure Testing should be done in fasting Due to its relatively low specificity-not recommended for screening Used as marker to ascess disease progression in a established case/or post sx or rx

24. Urine 5-HIAA The end product of serotonin metabolism Sensitivity is 35% and specificity is 100% Sensitivity is high if carcinoid syndrome is present Abnormal levels(>5mg/24hr) is diagnostic To avoid false positive results- diet( banana,pineapples,tomatoes,plums,eggplant,avocado,kiwi,fruits and nuts avoided for 3 days)-tryptophan/serotonin rich stop specific medication- PPIs,Cough and antihistamine rx,chlorpromazine and prochlorperazinr,nasal drobs,antihypertensives,acetaminophene etc ….

25. ACTH Thymic carcinoid produces Results in ectopic cushing syndrome 24 hour urinary catecholamines 30% of the tumour produde catecholamines

26. Systematic approach to diagnosing NETS GI endoscopy Bronchoscopy CT/MRI PET scan

27. Endoscopy Gastric and rectal carcinoids are often asymptomatic m/c imaged on screening or diagnostic endoscopy EUS –helps in charecterisation of these tumours

28. CT scan Multiphasic contrast enhanced CT is recommended Except for tumors with low probability of spread Type1 and 2 Gastric NETS Small (<1 to 2cm) superficial (T1) rectal NETS NETS originating in the jejunum and ileum are often difficult to identify in CT due to small size

29. SI nets often produce mesenteric mass with dense desmoplatic fibrosis Due to direct extension or LN mets Classical finding-mass like process with soft tissue spokes radiating into mesenteric fat with bowel angulation and tethering

30. Appendiceal NETS may not be seen due to small size-only finding will be a appendicitis with diffuse thickening of appendix or periappendiceal fat stranding Colonic mets -tend to be larger >2cm Cannot differentiate b/w adenocarcinoma which is m/c Liver mets -enhanced in early arterial(20 sec after iv contrast)

31. MRI Most sensitive for detecting liver mets Gadoxetate contrast agent ( Eovist ) But underestimates smaller tumours and hence miss evaluate total tumour burden

32. Somatostatin receptor based imaging SRS NETS express STSR Octreoscan - 111 in-labeled diethylene triamine penta acetic acid(DPTA) 80-90% sensitivity and specificity Limitation-sensitivity is only 60% in pt who donot exhibit carcinoid syndrome

33. PET FDG PET –good sensitivity and specificity for carcinoid with high proliferative activity or are poorly differentiated GA-88 DOTATATE is newer somatostatin based PET SCAN better than octreoscan

34. 131 I metaiodobenzyl guanidine scans(MIBG) Helpful in patients who are maintained on long term octreotide therapy Or whose tumor secrete catecholamines

35. Echocardiography To diagnose carcinoid heart disease 40% of patients with carcinoid syndrome Mainly involve Tricuspid and pulmonary valve and endocardium Increased synthesis of collagen secondary to serotonin induced transforming growth factor Beta secetion Transthoracic echo is indicated in patient with urinary 5 HIAA >100mg/day

36. General Management Principles Management of NETS falls under two main categories Therapies directed at tumor control Therapies directed at controlling symptoms of hormone excess

37. General management principles Surgical resection-remains mainstay Rx for esctable NETS of GI tract and lungs In addition to prolonged survival,surgery can also palliate symptoms of obstruction,diarhea,flushing and pain with eating In the setting of unressectable tumour,antitumor therapy is only indicated in the setting of symptoms ,tumor bulk and disease progression In newly diagnosed asymptomatic patients with unresectable or metastatic disease,it is often reasonable to monitor closely without any active RX

38. Management by primary tumor site ESOPHAGEAL NET Very uncommon(<1% of GI NETS) Distal esophagus just proximal to the esophageal gastric junction EUS and SRS are indicated for staging because LN mets occur in 50% Endoscopic mucosal resection(EMR)-is done if no evidence of LN mets and the tumor is amenable to complete excison Open resection is done is LN desection is requires (m/c a IVOR LEWIS esophogastrectomy )

39. Gastric Carcinoids 9% of GINETS,arise from ECL cells of the stomach that occur in fundus and body 3/1000 gastric neoplasms 3 types TYPE I- Atropic gastritis TYPE II-ZES TYPE III- no hypergastrinemias Hypergastrinemia

40. Two subtypes are associated with hypergastrinemic states Chronic atrophic gastritis(TYPE I ;80%) ZES(TYPE II ;6%) There is allelic loss at the MEN-1 Locus on chr 11q13 Thus fundic gastric carcinoid tumors are now included in MEN-1 tumours These tumors generally are Benign With 9-30% LN mets , distant mets 10-20% Usually multicentric and small With infiltration restricted to the mucosa and submucosa Size a few mm to 1.5cm

41. TYPE III(15-20%)-Sporadic ECL tumors occurs without hypergastrinemia Often large(mean size 3cm) Solitary tumours Pursue a more aggressive coarse Most lesion invade full thickness of the stomach Located in the body or fundus Regional LN mets /liver mets in 70% 50% have atypical histological features and some develop carcinoid syndrome

42. Duodenal Carcinoid tumours <4% of all GI NETS m/c in proximal duodenum Usually small <5mm (30-70%) spread to regional LNs such that adjacent LN sampling is recommended No commonly spread to distant sites In contrast to jejunoileal carcinoid tumours ,duodenal carcinoid are often discovered by endoscopy

43. Small intestinal carcinoid tumours m/c (42% of all GI NETS) Most prevelant in ileum within 20 cm from the ileocecal valve Ileal mets are commonly very small(2-4mm) Multiple within the wall of ileum With adjacent large LN mets that cause cicatrization and venous congetion -SBO Approx 50% will have liver mets and peritoneal carcinomatosis at the time of dx Cholecystectomy +(most of these pt require long term octreotide rx )

44. Appendiceal carcinoid tumours In the past carcinoid tumors were most frequently reported in appendix(40%) However more recently SI ,Bronchus and lung are the m/c sites A carcinoid tumour is discovered in approx. one out of every 200 to 300 appendicectomies Most occur in the tip of appendix The majority( i.e 90%) are less than 1cm in diameter without mets

45. Colo Rectal carcinoid tumours Rectal Carcinoid tumours 4% of GI NETS 1-5% of all colorectal tumours m/c site Right Colon Majority of them are well differentiated But some are less differentiated, exophytic and have higher incidence of LN/Liver mets The 5 year survival for colon NETS is 37% 27% of GI NETS 1-2% of all rectal tumours

46. Surveillance

47. Carcinoid syndrome Clinical entity marked by flushing, diarrhea,abdominal cramping, wheezing,heart valve dysfunction and pellagra

48. It is found in 10-18% of all patients with carcinoid tumours Incidence increses to 40-50% in advanced metstatic disease Carcinoid tumour produce a large number of substances including serotonin,tachykinins and histamine It’s the action of serotonin that lead to many of the manifestations Develops in the presence of hepatic mets -due to lack of inactivation active metabolites of seratonin

49. 91% cases –presents only after distant mets to liver Exception Lung carcinoids Ovarian carcinoids Pancreatic NETS

50. Embryological origin and carcinoid sx Typical Carcinoid syndrome Midgut carcinoids are the common source Because they produce high levels of serotonin 90% with Sx have a midgut primary Atypical Carcinoid syndrome Foregut carcinoids lack aromatic amino acid decarboxylase required to convert %HT to serotonin and hence no Sx Gastric carcinoids release large amount of histamine rather than serotonin Hindgut carcinoids lack ability to convert tryptophan to serotonin hence no Sx develops even with mets

51. Rx Avoid stress and precipitating factors Diuretics-heart failure Bronchodilators-wheezing( b2 agonist avoided because they increase biogenic amines and peptides and worsens ) Antidiarrhoeal agents Niacin supplementation(over use of tryptophan =niacin -pellagra) Somatostatin analogues(octreotide)-100ug s/c 8hourly

52. New rx Inhibitors of serotonin synthesis are emerging as a new class of agents to treat Carcinoid Sx – TELOTRISTAT ETIPRATE TELESTAR- teloristat etiprate for somatostatin analog not adequately controlled carcinoid syndrome TELEPATH- teloristat etiprate -expanded treatment for patients with carcinoid symptoms

53. Carcinoid crisis Occurs in patients with carcinoid syndrome who undergo anesthesia or surgery and are not sufficiently blocked by somatostatin analogues c/f=Flushing/hypotension/bronchospasm/arrhythmias Prevention Preoperative octreotide 25-500ug s/c /iv 1-2 hours prior to the procedure Avoid adrenergic drugs Surgical manipulations should be halted if a crisis ( i.e intraop hypo/rash)occurs Additional octreotide (500-1000ug iv f/b 50-200ug per hour) and steroids infused

54. Management of metastatic disease Cytoreductive treatment Surgery/Local ablative therapy Hepatic artery chemo embolization Systemic CT

55. Surgical therapy Approach to treatment of metastatic disease is based on symptoms Resection of primary site in setting of unresectable mets -not indicated if pt is aymptomatic Resection of primary tumor+metasectomy –only in case of limited hepatic mets Non curative debulking sx considered if pt is symptomatic with tumour bulk/hormone production This prevents complications from primary tumor growth like obstruction,pain,bleeding -especially in midgut carcinoids and provides good survival outcome

56. Surgery is aimed to remove more than 90% of tumour burden via anatomic or wedge resection There is symptom reduction in 95% of cases With Median symptom free duration of 45months Five year survival improvement {40-50%in nonoperated pts v/s 60-82% in operated pt}

57. Patient whose tumor is unresectable or in whom reduction of greater than 90% of the tumour is not feasible Liver directed therapies are done RFA Cryotherapy Hepatic artery embolization Chemoembolisation

58. Orthotopic liver transplantation True role in Rx pts with metastatic carcinoid remains unclear Better if done in well differentiated tumors Can yield a 5 year survival of upto 69%

59. Antitumor Medical Therapy Somatostatin analogues m/c used therapy-inhibits tumour growth by inhibiting GF like ILGF and VEGF m/c octreotide Due to the short half life of octreotide requires continuous or twice daily infusion The LAR(long acting release) formulation is commonly used Standard dose of octreotide LAR are 20-30mg IM every 4 weeks Therapeutic levels are not achieved for 10-14 days after LAR inj Short acting octreotide (150-250mcg s/c 3times daily)

60. Lanreotide is administered every 10 to 14days(60-120mg) s/e Sinus bradycardia Arrhythmias GB stones Steatorrhea Hypothyroidism Hypoglycemia

61. PROMID trial Trail showed efficacy of LAR lanreotide therapy CLARINET trial Trail showed efficacy of LAR octreotide therapy

62. Interferon –Alpha Potential side effects Not initiated until failure of somatostatin analog therapy Mammalian Target of Rapamycin inhibitors Everolimus Approved by US FDA for metastic pancreatic NETS

63. Angiogenesis Inhibitors Bevacizumab - MAB to circulating VEGF Combined with octreotide Sunitinib Oral TKI Inhibits VEGF , PDGF,cKIT

64. Systemic CT Poorly differentiated NETS regardless of primary site are typically treated like small cell lung cancer Platinum/Etoposide based regime No best systemic CT available

65. Thank you