GIST AND CARCINOID TUMORS copy copy.pptx

Brief overview of carcinoids and GIST and overview

1. GIST AND CARCINOID TUMORS UNDER THE GUIDANCE OF : DR MADHU C P DR N PRUTHIVIKA

2. INDEX GIST- Etiology Pathophysiology Anatomy and pathology Immunohistology Clinical presentation Investigations Staging Management  surgical principles  medical therapy  monitoring and follow up

3. CARCINOID TUMORS:- Anatomy and pathology General diagnostic principles General management principles Small bowel NETs Gastric NETs Appendiceal NETs Colorectal NETs Bronchial NETs Carcinoid Syndrome Antitumor Management

4. GASTRO-INTESTINAL STROMAL TUMORS Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract, accounting for 80% of all such GI tumors. 0.1 to 3% of all gastrointestinal malignancies. GISTs most commonly present in the stomach (60%) or small intestine (20% to 30%).  GISTs may rarely occur extra gastrointestinally , where they most commonly occur in the omentum , mesentery, or retroperitoneum

5. ETIOLOGY The interstitial cell of Cajal is the normal counterpart of tumor cells. This serves as a pacemaker of gastrointestinal motility, providing an interface between autonomic nerve stimulation and the muscle layer of the gastrointestinal wall. C-kit is a tyrosine kinase receptor which is important for ICC differentiation and maintenance. A pproximately 95% of GISTs overexpress KIT. Most GISTs that lack a KIT mutation will have a mutation in platelet-derived growth factor receptor alpha (PDGFRA). SDH-deficient GIST are also seen, more commonly in young females.

6. Anatomy and pathology Seen in more than 2/3 rd of cases More common in stomach, PDGFRA mutated and SDH deficient cases

7. Immunohistologically KIT + (CD117) and DOG1 (ANO1) is the hallmark for most GISTs. CD34 is positive for most of the GISTs A negative stain for SDHB identifies the subgroup of SDH-deficient GISTs D117 has only a meaning in the pathologic differential diagnosis.

8. Clinical presentation Most GISTs manifest with nonspecific symptoms, typically with early satiety, bloating, or vague abdominal pain. Bleeding can occur and is generally in the form of melena or, less frequently, frank hematemesis. one-fourth of GISTs are diagnosed in a clinical emergency, often leading to surgical explorations resulting in the unexpected finding of the disease.

9. One fourth of GISTs are discovered incidentally during diagnostic assessments (whether an endoscopic procedure, ultrasound, or computed tomography [CT] scan) done for other reasons. The remaining are diagnosed because of symptoms of compression from an abdominal mass, or chronic anemia, fatigue, and the like.

10. INVESTIGATIONS 1) UPPER ENDOSCOPY: smooth-appearing, round, submucosal tumor can be identified, occasionally containing an area of central ulceration. 2) EUS-DIRECTED FNA results in superior diagnostic accuracy, with a sensitivity of 82% and specificity of 100% in diagnosing GIST. 3) CECT ABDOMEN AND PELVIS: used to assess metastatic disease 4) MRI: for those in whom IV contrast cannot be given or in case of rectal GISTs.

11. Endoscopic image of a submucosal GIST in stomach CECT image of GIST in body of stomach

12. Staging No conventional staging systems used Risk stratification is done on the basis of chances of relapse Current risk classification systems factor in 3 variables: mitotic count, tumor size and site of origin Mitotic count is the main prognostic factor, being directly proportional to risk of relapse Tumor size- <2cm lesion may undergo watchful surveillance, 5-10cm- has worse prognosis Gastric GISTs have better prognosis than small bowel or Rectal GISTs.

13. The combination of these three factors allows one to forecast a risk of relapse by using tools such as the Armed Forces Institute of Pathology (AFIP) risk classification the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram, or the contour maps.

14. MANAGEMENT Localized GISTs with no evidence of distant metastases are treated with surgery, followed by adjuvant medical therapy if the risk of relapse is significant. When the disease is metastatic, medical therapy with TKIs is standard treatment and should be maintained indefinitely. A ll GISTs ≥2 cm in size should be resected when possible because none of them can be considered benign . The management of GISTs <2 cm in size is more questionable. Regardless of their size, any small GIST that is symptomatic (e.g., bleeding from erosions through the mucosa) or increases in size on serial follow-up should be resected.

15. When surgery is unfeasible or could be made less mutilating or easier through downsizing, medical therapy is used if the genotype is sensitive to imatinib, possibly followed by surgery and the completion of a medical adjuvant treatment if the risk of relapse is significant. adjuvant therapy with TKIs can delay, but probably not avoid, a relapse, if this is due to occur. adjuvant therapy is recommended as a standard for 3 years and is reserved for patients with a significant risk of relapse.

16. D uration of preoperative medical therapy is generally 6 to 12 months, which corresponds to the time interval when the maximum degree of tumor shrinkage was shown to occur in studies on advanced GISTs. Positron emission tomography (PET) scans are a resource because they can demonstrate tumor responsiveness in a matter of weeks.

17. Surgical principles The goal of surgery is R0 excision. On laparotomy/laparoscopy, the abdomen should be thoroughly explored to identify and remove any previously undetected peritoneal metastatic deposits. Tumor rupture or violation of the tumor capsule during surgery are associated with a very high risk of recurrence and therefore should be avoided. Some clinicians approach ruptured GISTs as already metastatic, although there may be different kinds of rupture , possibly leading to different risk levels. A lymphadenectomy is not routinely required because lymph nodes are rarely involved (in adult patients) and are thus resected only when they are clinically suspect.

18. surgery is a wedge or segmental resection of the involved gastric or intestinal tract. Sometimes, a more extensive resection (e.g., total gastrectomy for a large proximal gastric GIST, pancreaticoduodenectomy for a periampullary GIST, or abdominoperineal resection for a low rectal GIST) is needed.

19. MONITORING AND FOLLOW-UP CECT Abdomen and pelvis is sufficient for conventional follow-up of GIST patients because metastases outside the abdomen are very uncommon. MRI is an alternative to CECT, especially in young patients Annual abdominal CT for 5 years after surgery is thought to suffice for most patients with a less than intermediate risk of recurrence. for high-risk GIST patients treated with adjuvant therapy, follow-up imaging may be done at 6-month intervals during the treatment, every 3–4 months during the first 2 years after adjuvant therapy has been stopped, and then once every 6–12 months for up to 10 years after surgery. When patients have no adjuvant therapy, an interval of 3–4 months between imaging studies may be recommended during the initial few years after surgery.

20. Carcinoid tumors

21. Carcinoid tumors are rare, slow-growing neuroendocrine tumors arising from the enterochromaffin cells ( kulchitsky cells) disseminated throughout the gastrointestinal and bronchopulmonary systems. In 1907, Oberndorfer first coined the term carcinoid , meaning “cancer-like,” to describe a rare ileal tumor with less malignant behavior than the more commonly identified large bowel carcinomas. GI NETS or carcinoid tumors compose 70% of all The incidence of GI NETs is 3.56 per 100,000 population. Small bowel NETs (midgut carcinoids) are much more common than both foregut and hindgut. The overall 5-year survival rate of all patients with GI NETs is between 35% and 43%.

22. ANATOMY AND PATHOLOGY derived from the diffuse neuroendocrine system that is composed of peptide- and amine-producing cells that may secrete different hormones depending on the site of origin. composed of monotonous sheets of small round blue cells with uniform nuclei and cytoplasm. Carcinoids are rare neuroendocrine tumors (NETs) thought to arise from the enterochromaffin cells ( Kulchitsky ) cells found throughout the crypts of Lieberkühn of the gut. the term  enterochromaffin  refers to the ability to stain with chromium or chrome salts, a common feature of 5-HT-containing cells.

23. In a Surveillance, Epidemiology, and End Results database analysis, patients with carcinoid syndrome were more likely to be Women of non-Hispanic Caucasian race have more advanced tumors have lower grade tumors the primary tumor location had a significant effect, with most being in the terminal ileum.

24. Critical factors in NET pathology include key features like: embryologic site of origin (foregut, midgut, or hindgut) functional status (defined as hormone secretion associated with symptoms of hormone excess) Grade (high grade, intermediate or low) - 2010 World Health Organization pathology classification Based on proliferation rates measured by Ki-67 antibody staining and or mitotic index

25. Low-grade tumors (grade 1) - most common, mitotic index of <2 mitoses/10 high-power fields (HPF) and a Ki-67 <3%. Intermediated tumors (grade 2) - mitotic index of 2 to 20 mitoses/10 HPF and a Ki-67 of 3% to 20%. High grade tumors (grade 3) - mitotic index >20 mitoses/10 HPF and a Ki-67 >20%.

26. All cells of the neuro-endocrine system secrete different neuroendocrine markers, such as synaptophysin, chromogranin A and neurone -specific enolase (NSE), and produce peptide hormones that are stored in granules, e.g. serotonin, somatostatin, PP or gastrin. In clinical practice chromogranin A is utilised as a tumour marker.

27. General diagnostic principles The diagnosis of GI and pulmonary NETs is often incidental, although patients with functional tumors can present with symptoms of hormone excess. The diagnostic evaluation for GI and pulmonary NETs often begins with high-resolution cross-sectional imaging with either multiphasic computed tomography (CT) or magnetic resonance imaging (MRI). Serum hormone markers are often elevated in NETs and can be a surrogate marker of symptoms of hormone excess or tumor growth, although none are sensitive enough to be used as a screening test.

28. Chromogranin A levels are elevated in approximately 80% of patients with GI NETs; sensitivity is 75%, and specificity is approximately 85%. Urine 5-hydroxyindoleacetic acid (5-HIAA), the primary metabolite of serotonin, is elevated in carcinoid syndrome. - sensitivity of 35% and specificity of 100%. (>5 mg per 24 hours) is diagnostic of carcinoid syndrome. Elevated levels of serum serotonin are also confirmatory and consistent with carcinoid syndrome, although more difficult to measure reproducibly. Less common NETs may also be identified by the specific hormone and syndrome that is produced. Eg Thymic NETs produce adrenocorticotropic hormone (ACTH) and corticotropin-releasing factor and result in ectopic Cushing syndrome. 30% of these tumors can also secrete catecholamines; therefore, 24-hour urinary catecholamine excretion should be measured as clinically indicated.

29. M ost NETs express somatostatin receptors that can bind and internalize the currently available octapeptide somatostatin analogs octreotide and lanreotide . This feature can be exploited in terms of both somatostatin receptor–based treatments and scintigraphy (SRS).

30. General management principles

31. Surgical resection remains the mainstay of treatment for resectable NETs of the GI tract and lungs. The primary goal of surgical intervention is to prolong survival. In addition to prolonged survival, surgery can also palliate symptoms of obstruction, diarrhea, flushing, and/or pain with eating. In the setting of unresectable disease, antitumor therapy is only indicated in the setting of symptoms, tumor bulk, and/or disease progression. In newly diagnosed asymptomatic patients with unresectable or metastatic disease, it is often reasonable to monitor closely without any active treatment.

32. Small bowel neuroendocrine tumors Small bowel NETs are the most common GI NET, and they are most prevalent within the ileum. They account for 42% of all GI NETs. usually occur within 20 cm of the ileocecal valve. Clinical features include: long history of vague non-localizing abdominal pain before the tumor is detected. These symptoms may be borborygmi, episodic abdominal pain or cramping, and episodic diarrhea and constipation. Others may develop clinical signs of the typical carcinoid syndrome, including diarrhea, flushing, palpitations, intolerance of certain specific foods like cheese or red wine, intestinal venous congestion, and infarction. Intermittent severe episodes of abdominal pain or even intestinal obstruction can occur as the tumor progresses.

33. Ileal NETs are commonly very small (2 to 4 mm) and multiple within the wall of the ileum, with adjacent large lymph node metastases that cause cicatrization and venous congestion that can result in small bowel obstruction. Approximately 50% of patients will have liver metastases or peritoneal carcinomatosis at the time of diagnosis. The 10-year survival rates for jejunal and ileal NETs are 53% and 50%, respectively. Surgery includes wide resection of the small bowel with the primary tumor, its mesentery, and lymph node metastases - usually requires an extended right hemicolectomy superior mesenteric artery and vein must be skeletonized . Cholecystectomy is also indicated because most of these patients with either lymph node or liver metastases will require the longterm use of somatostatin analogs, which can cause gallstones.

34. GASTRIC NEUROENDOCRINE TUMORS constitute <1% of gastric tumors and 9% of GI NETs. arise from the enterochromaffin-like (ECL) cells of the stomach that occur in the gastric fundus and body. immunoreactive to histamine, chromogranin A, and synaptophysin.

35. They are of 3 forms: Type 1 gastric carcinoids - typically occur in a state of chronic atrophic gastritis that results in achlorhydria and hypergastrinemia. (80% of gastric NETs). Multicentric, small gastric polyps Develop from E CL hyperplasia and form small, polypoid tumors Size – few mm to 1.5cm Min risk of invasion/metastasis- Lymph node metastasis- 5% and distant mets – 2% For small tumors- endoscopic surveillance and EMR Large tumors (2cm) - excision- antrectomy

36. Type-2 Gastric Carcinoids- rare, 6-8% of gastric NETs Occur in patients with MEN-1 with ZES who have been treated with prolonged PPIs Equally common in males and females Age of presentation – 45-50 years Multiple, small (<1.5cm) but larger than type-1 LN metastasis- 30% patients, distant metastasis- 10-20% patients rare cases of highly malignant gastric NETs with a poor prognosis have been described in some patients with MEN1 and ZES. These patients have diffuse involvement of the entire stomach with NETs, and total gastrectomy with adjacent lymph node dissection is recommended.

37. Type-3 Gastric Carcinoid- 15-20% of all gastric NETs Occur sporadically No association with hypergastrinemia Male predominance, 3:1 ratio Mean age- 50 years Solitary, rapidly growing, large in size ( mean size- 3cm) Usually present with distant metastases at the time of diagnosis, regional LN and Liver mets present in 70% cases Usual location- stomach fundus/body, invade full thickness wall of stomach Atypical carcinoid (>5cm) – more unfavourable prognosis and associated with release of histamine Cutaneous flushing, edema, itching, wheezing and lacrimation Tumor debulking of the primary tumor and lymph node metastases may relieve symptoms. Hepatic metastases are treated with resection, hepatic artery embolization or chemoembolization, radiofrequency ablation, and octreotide longacting release (LAR).

38. Appendiceal netS 5-8% of all GI NETs 1in 200-300 appendicectomies Most common location- tip of appendix Mean age of presentation- less than 50 years Metastasis rare, LN metastasis- 3-8%, distant mets - 0.7% Good long term survival, 95% <2cm/no wall invasion/not involving the base- appendicectomy is adequate >2cm/wall invasion/ lymp node metastasis/involving base- Right hemicolectomy is indicated

39. Colorectal nets Colon NETs – 4% of all GI NETs 1-5% of all colorectal tumors >65 years Right colon – more common Usually well differentiated If less differentiated- large, exophytic, grow more rapidly with increased incidence of lymph node and liver metastasis 5 year survival rate- 37% Treatment- hemicolectomy with retrieval of adequate lymph nodes

40. Rectal NETS : increasing incidence, most common NETS reported in recent series 27 % of GI NETS, 1-2% of all rectal tumors Most common- Asian and black population Usually discovered during endoscopy- small in size <1cm – EMR/ local excision >1cm- low anterior resection or APR

41. BRONCHIAL NEUROENDOCRINE TUMORS appear histologically like intestinal NETs more common in patients with MEN1. The bronchus is the site of a primary NET in approximately 2% of cases. Poor prognostic factors include higher mitotic index, nuclear pleomorphism, vascular and lymphatic invasion, and poorly differentiated growth pattern. occur close to the hilum on CT and MRI scan and may be confused with blood vessels

42. BENIGN/LOW GRADE MALIGNANT LOW GRADE MALIGNANT POORLY DIFFERENTIATED Typical carcinoid form Atypical carcinoid form Large cell/small cell Excellent prognosis Poor prognosis Surgical resection + lobectomy Treated primarily with chemotherapy

43. SRS can be used to complement cross-sectional imaging with multiphasic CT or MRI. Atypical carcinoid tumors have more uptake of fluorodeoxyglucose on PET scan, whereas typical carcinoid tumors have more uptake of octreotide on DOTA scan. On bronchoscopy, NETs appear as a cherry-red mass within the bronchus protruding into the lumen. It is recommended not to biopsy them because they can bleed excessively with biopsy. Bronchial carcinoids are the most common cause of ectopic ACTH syndrome, and Cushing syndrome is severe with usual clinical signs and symptoms plus severe weakness secondary to hypokalemia.

44. Carcinoid syndrome Biogenic amines and vasoactive peptides in the systemic circulation cause symptoms of the carcinoid syndrome. The classic description of the carcinoid syndrome includes vasomotor, cardiac, and gastrointestinal manifestations.

45. I n patients with liver metastases or extrahepatic tumor in sites such as the ovary or the retroperitoneum, an excessive amount of serotonin enters the systemic circulation and causes carcinoid syndrome. Small bowel NETs are most often associated with carcinoid syndrome. Common symptoms and signs include cutaneous flushing (80%); diarrhea (76%); hepatomegaly (71%); cardiac lesions, most commonly right-sided heart valvular disease (41%–70%); and asthma (25%). diarrhea associated with carcinoid syndrome is episodic (usually occurring after meals), watery, and often explosive. Cardiac lesions usually involve the right side of the heart. The three most common cardiac lesions are pulmonary stenosis (90%), tricuspid insufficiency (47%), and tricuspid stenosis (42%).

46. serotonin, histamine, and bradykinin also induce transforming growth factor β, collagen synthesis, and scarring in the mesentery of the bowel. This can lead to adhesions and bowel obstruction or venous obstruction that leads to inadequate venous outflow and bowel ischemia. Medical management of carcinoid syndrome centers around the use of somatostatin analogs all patients with small bowel NET undergoing surgical intervention should be given perioperative octreotide to prevent carcinoid crisis. The recommended dose of octreotide is 25 to 500 μg subcutaneously or intravenously 1 to 2 hours prior to the procedure. Inhibitors of serotonin synthesis are emerging as a new class of agents to treat carcinoid syndrome. Telotristat etiprate is an oral inhibitor of tryptophan hydroxylase, a key enzyme in the synthesis of peripheral serotonin.

47. Antitumor management I) SOMATOSTATIN ANALOGUES Clinical studies suggest that long-acting octreotide can also inhibit tumor growth. interacts with somatostatin receptors that stimulate phosphotyrosine phosphatases that inhibit growth factors such as insulin-like growth factor and vascular endothelial growth factor (VEGF) and thus inhibit tumor growth. octreotide LAR is now considered an appropriate first-line therapy for patients with progressive metastatic midgut NETs regardless of the presence or absence of carcinoid syndrome

48. II) Mammalian Target of Rapamycin Inhibitors Everolimus was approved by the U.S. Food and Drug Administration for the treatment of metastatic pancreatic NETs. National Comprehensive Cancer Network, do not currently recommend everolimus for management of small bowel NETs. III) INTERFERON-ALPHA Interferons (IFN) exert antitumor effects through a variety of mechanisms including stimulation of T cells, inhibition of angiogenesis, and induction of cell cycle arrest in the G1 and G0 phases. Improvement of symptoms, including palliation of diarrhea and flushing, occurs in 50% of patients. However, objective antitumor responses occur in only 10% of patients.

49. III) ANGIOGENESIS INHIBITORS NETs are highly vascular tumors that frequently overexpress the VEGF receptor and its ligand. inhibition of the VEGF pathway has been considered a promising target. Bevacizumab , Sunitinib

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