gastrointestinal Neuro endocrine tumors , GIT NET
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This document provides an overview of neuroendocrine tumors (NETs) that originate in the gastrointestinal tract (GIT). It discusses the classification, grading, epidemiology, pathophysiology, clinical features, and molecular biology of GIT-NETs. Some key points include: - GIT-NETs are classified as well-differentiated or poorly-differentiated and further graded based on proliferation rate. - The ileum is a common primary site. Symptoms vary depending on secretion of hormones. - Carcinoid syndrome results from secretion of substances like serotonin that cause flushing, diarrhea, and heart disease. - Molecular drivers include growth factors but causes are still not fully understood. Prognosis depends on
gastrointestinal Neuro endocrine tumors , GIT NET
- 1. GIT-Neuroendocrine Tumors/NET Dr Gebrekirstos Hagos Clinical Oncology R-I AAU-SoM October 30,2018
- 2. Outlines of presentation: • Introduction • NET-Distribution -classification -Grade -Epidemiology - Pathophysiology -Molecular biology - Clinical features
- 3. Introduction • Neuroendocrine cells are cells that receive neuronal input (neurotransmitter) release messaging molecules (hormone) to the blood. • These hormones control many body functions. • So they brings neural and endocrine integration,a process know as neuroendocrine integration.
- 4. Introduction… • Pituitary gland, parathyroid glands and inner layer of adrenal gland (adrenal medulla) are almost made up of neuroendocrine cells. • Other NEC are found scattered through out, mainly GIT, Respiratory tract and pancreases. • These NEC found scattered throughout these organs are referred to as the diffuse neuroendocrine system
- 6. • This diffuse neuroendocrine cells don’t form an actual organ like the adrenal or thyroid glands(Instead scattered) • GIT has more neuroendocrine cells than any other part of the body so is commonest origin of NET(64% of NET cases).
- 7. Neuroendocrine tumors/NET • Derived from the diffuse neuroendocrine system that is composed of peptide- and amine- producing cells which secrete different hormones depending on the site of origin. • NETs are composed of monotonous sheets of small round cells with uniform nuclei and cytoplasm. • Traditionally classified based on their embryonic divisions (foregut, midgut, or hindgut) of the alimentary tract
- 9. GIT-NET • Gastroenteropancreatic NENs has evolved over the past two decades & divided into two major categories: I) Well-differentiated neuroendocrine tumors (NET) II) Poorly differentiated neuroendocrine carcinomas (NEC)
- 10. GIT-NET…Well differentiated • Show a solid, trabecular, with fairly uniform nuclei, coarsely stippled chromatin, and finely granular cytoplasm. • Traditionally referred to as carcinoid tumors in GIT and pancreatic NETs (islet cell tumors) in pancreases.
- 11. GIT-NET…Poorly differentiated • Are high-grade carcinomas that resemble small cell or large cell NEC of the lung. • Often associated with a rapid clinical course, so bad prognosis compared to well- differentiated NET.
- 12. • Well-differentiated NETs, are further subdivided into low grade and intermediate grade based on proliferative rate.
- 13. Grading GIT-NET • WHO classification of GIT-NET is based on proliferative rate ,divided in to: - Low-grade(G1) well- -Intermediate-grade(G2) differentiated -High-grade tumor(G3) poorly differentiated Proliferative rate is measured using either mitotic counts or Ki-67 labeling index.
- 15. GIT-NET • progression from a lower grade (G1 or G2) well-differentiated NET to a G3 NET can occur. • Evidence of progression can be: -increase in the proliferative rate -change in tumor morphology(↑ nuclear atypia, or development of significant necrosis)
- 16. Molecular pathogenesis • Little is known about the induction & growth of carcinoid tumors. • Gastric NET ↑ hypergastrinemia conditions (pernicious anemia, atrophic gastritis, ZES). • other growth factors in some carcinoid tumors are : - transforming growth factor-alpha -insulin like growth factor- 1 -VEGF -acidic and basic fibroblast growth factor -epidermal growth factor
- 17. Epidemiology • Generally GIT-NET are uncommon, but GIT common primary site NETs(6.2/100,000) • Incidence is increasing due to multifactorial -increased awareness (if you don’t suspect NET you will not Dx it!) -improved endoscopic methods detection Small bowel NETs (midgut carcinoids) are more common than both foregut and hindgut
- 18. Esophageal NET • Rare (<1% of GI NET) • Common in men >60 yrs • Seen in distal esophagus, proximal to GEJ • On EUS they are sub mucosal mass, dimple the mucosa.
- 19. Stomach-NET • Subdivided into three categories which have different biologic behavior and prognosis • Type 1 -70-80 % all gastric NETs -associated with chronic atrophic gastritis -more common in women -derived from enterochromaffin-like (ECL) cells -non functioning - Endoscopically →<1 cm →multiple → polypoid lesions → small central ulceration
- 21. • Type 2 — associated with Zollinger-Ellison syndrome, in the setting of MEN-1 -6-8% gastric NETs -Men=women -develop in a hyperplasia-dysplasia-neoplasia sequence -arise from ECL cells -stimulated by elevated serum gastrin levels
- 22. Gastric NET • Type 3 -sporadic, no association with hypergastrinemia. -15-20% of gastric NETs -solitary, and grow more rapidly. -Present with metastasis at Dx -M:F,3:1
- 23. Small bowel NETs Small bowel NETs — incidence increased in part due to increased detection on endoscopy and imaging studies • NETs surpassed adenocarcinomas as the most common small bowel tumor. • Patients usually present in their 60s or 70s. • Commonly located in the ileum within 60 cm of the ileocecal valve & 42% of GI-NETs • 25% patients will have more than one small bowel NET at the time of discovery.
- 24. Small bowel NET… • Many are asymptomatic at presentation and are found incidentally. • If symptomatic ,abdominal pain(51%) followed bowel obstruction(31%),abdominal mass(17)and GI bleeding(11%). • Metastases to LN/liver are common, even if the primary tumor is <2 cm in size. • Commonly presented with carcinoid syndrome.
- 25. Small bowel NET… • Pts with metastatic NET with unknown primary, they can harbor occult primary in the ileum. • So exploration and palpation of the bowel can allow detection of the sub mucosal primary which feel like little pea in the bowel wall.
- 26. • Appendix — NETs are the most common neoplasms in the appendix. • NET is discovered incidentally (1 in 300 appendectomies, commonly at the tip). • Common at age of 40s or 50s • more common in women
- 27. Hind gut NET • Includes NET of transverse,descending colon & rectum. • Are non secretory(not associated with carcinoid syndrome, even when metastatic) • If symptomatic, it is same CR adenocarcinoma ( changes in bowel habits, bleeding)
- 28. • Colon — in pts at their 70s during evaluation for abdominal pain, anorexia, or weight loss. • Incidence of functioning tumors is very low. • More on Rt side of colon.
- 29. • Rectum — majority are asymptomatic . • Found incidentally on colonoscopy that is performed for other reason. • Accounts 27% of GIT-NETs,1-2% rectal tumors • 75-85% are localized at diagnosis
- 30. METASTATIC TUMORS • Regardless of primary site, NETs are characterized by metastasize to the liver. • Patients with liver metastases may experience symptoms related to tumor burden (eg, pain, jaundice, early satiety) or hormonal symptoms (eg, flushing and diarrhea, the main symptoms of carcinoid syndrome).
- 32. PATHOPHYSIOLOGY • Around 40 secretory products have been identified in various NETs. • The most prominent of these are: -Serotonin - Tachykinins -Histamine -Kallikrein -Prostaglandin
- 34. Tryptophan metabolism • Altered metabolism of tryptophan occurs in almost all patients with the carcinoid syndrome. • In normal subjects, approximately 1 % of dietary tryptophan is converted to serotonin; (↑ to 70% in pts with carcinoid syndrome). • Serotonin is then metabolized to 5- hydroxyindoleacetic acid (5-HIAA)
- 36. Clinical features • Can occur at any age, media age 63 • M:F, 48:52% • Dx delayed for average 2yrs (can range for 20 yrs) due vague symptoms. • The clinical presentation of carcinoid tumors far underestimates their occurrence because many are asymptomatic • Symptoms are caused by local tumor growth, metastatic spread or excess hormonal.
- 37. Carcinoid syndrome • Symptoms mediated by various humoral factors. Common in setting of liver metastasis b/c liver failed to deactivate the products. • Common mid gut, but lung & stomach NET present with atypical carcinoid syndrome. Flushing attack Diarrhea Cardiac manifestation Wheezing and asthma like symptom Retroperitoneal & intra-abdominal fibrosis
- 38. Cutaneous flushing • Episodic flushing is the clinical hallmark of carcinoid syndrome . • occurs in 85 % of patients. • Typical flush associated with midgut NET • Begins suddenly and lasts for 30 sec to 30 min. • Involves the face, neck, and upper chest, which become red to violaceous or purple.
- 39. Cutaneous flush… • Most episodes occur spontaneously, but they can be provoked by eating, drinking alcohol, defecation, emotional events, palpation of the liver, and anesthesia. • Carcinoid crisis:
- 40. Diarrhea • present in 67% to 84% • Occurs -with flushing(85% of cases) -alone(15% of cases) . • Described as watery and less commonly as frothy bulky stool of steatorrhea. • Number of stools ranges from 2 -30/day • Most debilitating component of the syndrome
- 41. Cardiac valvular lesions • occur i n 11-66% • Carcinoid heart disease is characterized by pathognomonic plaque-like deposits of fibrous tissue. • Common on right side of the heart because inactivation of humoral substances by the lung protects the left heart. • Bronchospasm-10-20% of pts with the carcinoid syndrome have wheezing and dyspnea, often during flushing episodes.
- 43. References: • Devita ------9th & 10th e • Uptodate --2018 • NCCN------2017
- 44. Thank You!