Management of Neoplasms of Small Intestine.pptx

A presentation for general surgery residents for University examinations

1. Neoplasia of small bowel Nabin Paudyal

2. General considerations Small intestine has less than 2% of total GI malignant neoplasms Mean age at presentation is 62 for benign neoplasms and 57 for malignant neoplasms Malignant neoplasms account for 75% of small bowel symptoms that lead to surgery Stromal tumors and adenomas are the most frequent diagnosed benign tumors Adenocarcinoma represents the most prevalent malignant neoplasm followed by NETs

3. Risk factors for Small Bowel Neoplasia FAP HNPCC PJS CD Gluten sensitive enteropathy PUD CF Biliary diversion Smoking Heavy alcohol Consumption of red meat Salty food

4. Genetics for causing small bowel neoplasia KRAS gene Allelic losses at chromosomes 5q (APC), 17q (p53 gene) and 18q (DCC) and DPC 4 Inactivated DNA mismatch gene repair and Microsatellite instability are seen in 15% of population MSI-H is typical of small bowel carcinomas associated with celiac disease linked by CpG island methylation. Microarray analysis shows small bowel tumors expressing EGFR and VEGF which may contribute to carcinogenesis

5. Clinical features Vague and nonspecific Include  dyspepsia, anorexia, malaise and dull abdominal pain (intermittent and colicky) May be present for months or years before diagnosis. Most patients with benign neoplasms remain asymptomatic Sometimes the symptoms may be in the form of obstruction, intussusception and hemorrhage. Hemorrhage may be Hematochezia, Hematemesis or Occult GI bleeding

6. Diagnosis Mostly diagnosed due to suspicion. Pre-operative diagnosis is made only in 50% of symptomatic patients Plain films  Obstruction features may be present UGI series with small bowel follow through Accurate diagnosis in 53-83% of patients CT abdomen Extraluminal tumors (GIST) CT and MRI enteroclysis sensitivity and specificity reaching up to 97-98% Flexible Endoscopy visualization and biopsy of ileal neoplasms Capsule endoscopy variable sensitivity and specificity

7. Benign neoplasms of small intestine

8. Benign neoplasms MC benign neoplasm of small intestine include stromal tumors (mc tumors producing symptoms) Adenomas (mc tumors in autopsy) Lipomas When benign tumor is identified at operation, resection MUST be done Once the tumor is identified, thorough search of the bowel must be done because other tumors may also be present

9. Adenomas Account for almost 15% of all benign tumors of the small bowel Types Brunner gland adenoma Villous adenoma True adenoma Location wise Duodenal adenoma (20%) Jejunal adenoma (30%) Ileal adenoma (50%) Most are found singly and incidentally and are asymptomatic MC presentation  BLEEDING and OBSTRUCTION True and villous adenomas proceed through the same Adenoma-Carcinoma sequence as CRC and should be considered pre-malignant

10. Malignant potential of villous adenoma is from 35-55%. Treatment is both endoscopic and surgical Jejunal and ileal tumors  Surgical resection is treatment of choice In duodenum Decisions about surgical management must be carefully planned because of potential morbidity associated with duodenal resection by pancreaticoduodenectomy OR pancreas-preserving duodenectomy Before surgery pre-operative EUS has recently emerged as a useful modality Helps guide management Endoscopic submucosal resection is a safe alternative ( yet risk for recurrence is 50%). Especially duodenal adenomas and Brunner gland tumors are managed using ESmR . If the tumor is invasive OR evidence of recurrence is seen, definitive approach (Pancreaticoduodenectomy) is done.

11. FAP in small intestine Familial adenomas are present in patients with FAP syndrome. Most FAP neoplasms occur in duodenum. Extracolonic manifestations are usually present and also have different algorithm in management. Adenomas in duodenum can be found in 50-90% of cases. FAP Neoplasms grow very slowly, there is 5% risk of duodenal adenocarcinoma Life long surveillance is a priority in patients with duodenal FAP Any adenoma > 3 cm should be biopsied Additional duodenal biopsy must also be done Spigelman classification is used to guide the surveillance for patients with FAP adenoma

12. FAP in small intestine (duodenum)-Management Spigelman Stage I-III Large adenomas  EMR, surgical polypectomy Ablative therapy Argon beam coagulation, Photodynamic therapy Spigelman Stage IV Carcinoma in-situ OR High grade dysplasia Pancreaticoduodenectomy Or pancreas-preserving duodenectomy

13. Lipomas Most common in the ileum and manifested as single intramural lesion in submucosa Occur in 6-7 th decade Men>> Women Features may be obstruction and bleeding from superficial ulceration Symptomatic lesions  Excision

14. Hemangiomas Developmental malformations consisting of submucosal proliferation of blood vessels Jejunum mostly affected Hemangiomas account for 3-4 % of all benign tumors of small bowel and is multifocal May occur as a part of inherited disorder known as Osler-Weber- Rendu disease, Turner syndrome

15. Malignant neoplasms of small intestine

16. Introduction Incidence of malignant neoplasms have increased during past three decades Increased up to as much as four fold. SEER database  5 year survival rate of 34.9 % Chemotherapy for small bowel adenocarcinomas has not improved overall survival Malignant neoplasms almost always produce symptoms, most of which includes pain and weight loss. Intussusception in malignancy suggests tumor infiltration and adhesion . Other symptoms may be  Diarrhoea, Tenesmus, GI bleeding, palpable mass, perforation ( sarcomas, lymphomas)

17. Neuroendocrine Neoplasms (NENs) Arise from Kulchitsky cells ( enterochromaffin cells ) situated at the base of the crypts of Lieberkühn Also called argentaffin cell tumors (affinity to silver stains) Lubarsch (1888) identified the tumor for the first time Oberndorfer coined the term Karzinoide to indicate carcinoma like appearance and the lack of malignant potential Term “Carcinoid” is misnomer now and is not used as all NENs have some intrinsic malignant potential. NENs may occur in Lungs Bronchi GI tract Age at diagnosis  7 th decade of life, median age of 63 years Classification of NENs based on tumor grade and differentiation.

18. Classification of NENs May be benign or well differentiated malignant type Malignant type may be Low grade Intermediate grade High grade Classification based on appearance, mitotic rates, behavior and Ki-67 proliferation index . All neuroendocrine carcinomas are G3, poorly differentiated malignant neoplasms. Based on embryologic site of origin and secretory product Origin Secreted product Foregut Low serotonin High ACTH High 5 Hydroxytryptophan Midgut High serotonin Hindgut Somatostatin Neuropeptide YY

19. NENs are usually located in appendix. Small intestine is the second most common site. In small intestine, NETs is almost always located within last 2 feet of the ileum. Why are we worried about NENs ? Inherent malignant potential Carcinoid syndrome (cutaneous flushing, bronchospasm, diarrhoea, vasomotor collapse) Primary tumors that secrete directly into the venous system, bypassing portal system give rise to carcinoid syndrome without metastasis.

20. Pathology 80% of NETs are asymptomatic and found incidentally at the time of surgery 90% of NETs are found in 5 typical sites Small intestine Rectum Colon Stomach Unknown sites Malignant potential of the tumor is related to LOCATION (ileal ) DEPTH OF INVASION SIZE (> 2cm) GROWTH PATTERN OF TUMOR

21. 3% appendiceal NET metastasize, 35% ileal NETs are associated with metastasis Approximately 75% GIT NET are < 1cm in size NETs of size > 2cm are metastatic in 80-90% of cases. Gross appearance Small, firm, submucosal, yellowish, usually along the antimesenteric border of small intestine Histological appearance Slow growing tumors However after invasion into the serosa, tumors have intense desmoplastic reaction Mesenteric fibrosis, intestinal kinking, intermittent obstruction are seen Multicentric tumors Frequent co-existence of the tumor with second primary tumor of different histologic subtype (synchronous adenocarcinoma). MC seen in large intestine May be associated with MEN 1

22. Clinical features MC symptom  Abdominal pain a/w partial or complete small bowel obstruction Intussusception  Note this a/w Diarrhoea (due to obstruction) Weight loss As mesenteric and nodal extension progresses Local venous engorgement, ischemia of affected segment may occur Malignant carcinoid syndrome Rare (<10% of patients with NET) Usually seen in gastrointestinal NET (small bowel) Features include Vasomotor, cardiac and GIT manifestations Hormones responsible: Serotonin, 5HT, histamine, dopamine, tachykinin, kallikrein, substance P, prostaglandin, neuropeptide K Most patients who have symptoms have massive hepatic metastasis Ovarian and retroperitoneal NETs may bypass liver and produce symptoms. Symptoms  See next slide

23. Symptoms include: Cutaneous flushing Diarrhoea Hepatomegaly Cardiac lesions (Right sided valvular heart disease) Asthma

24. Diarrhoea Episodic Usually occurring after meal Watery Explosive Cardiac lesion Right heart involved Can lead to congestive heart failure Pulmonary stenosis Tricuspid insufficiency Tricuspid stenosis

25. Asthma Observed during flushing Due to serotonin and bradykinin Malnutrition Pellagra due to tryptophan use for making serotonin

26. Diagnosis Elevated levels of 5-HIAA in urine during 24 hours with high performance liquid chromatography Chromogranin A (CgA) (in more than 80% cases) A combination of serum CgA and 24-hour urinary 5-HIAA is more diagnostic Serum CgA and N-terminal pro-brain natriuretic peptide may also be used For surveillance, CgA levels have proven efficacy over urinary 5-HIAA Plasma serotonin, substance P, neurotensin, neurokinin Am neuropeptide K levels can be measured Provocative tests  Penta gastrin, calcium, epinephrine may be used to reproduce symptoms of NETs. (but rarely used at present)

27. 5-HIAA, CgA and N-terminal pro BNP together increase overall diagnostic reliability of the condition.

28. NETs of small intestine are rarely diagnosed preoperatively Barium radiographic studies of small may exhibit multiple filling defects as a result of kinking and fibrosis of the bowel. A combination of anatomic and functional imaging techniques is routinely performed to optimize sensitivity and specificity.

29. Radiological investigation CT scan Depends upon size, degree of mesenteric invasion, desmoplastic reaction and regional LN invasion If these are not well defined, CT scan may not fully diagnose the condition CT thus has limited diagnostic capability CT scan reveals solid mass with spiculated borders and radiating surrounding strands that is associated with linear strands within mesenteric fat and kinking of the bowel

30. Other diagnostic tools CT angiography MRI  T1-weighted (low signal intensity) and T2-weighted (high signal intensity) help in identifying liver metastasis Peripheral enhancement in hepatic arterial phase Hypointense defects in portal venous phase. Functional nuclear imaging studies  Indium labeled pentetriotide which binds to somatostatin receptors Helps in diagnosing extra abdominal metastatic disease 18FDG-PET scan, 18F-DOPA scan, Somatostatin receptor imaging with Gadolinium 68 (68 Ga-DOTATATE PET-CT)

31. Somatostatin receptor imaging with Gadolinium 68 (68 Ga-DOTATATE PET-CT) Helps localize primary tumor in patients with NETs of unknown origin Define the existence of disease and extent of metastasis 64 Cu-DOTATATE has also been recently FDA approved

32. Management of NETs Surgical therapy Based upon the tumor size, location, and presence of metastatic disease For lesions < 1 cm in diameter Segmental resection of intestine is enough There should be no evidence of regional LN metastasis For lesions > 1cm in diameter or multiple tumors or with regional LN metastasis Wide excision of bowel and mesentery

33. Precautions for surgery Carcinoid crisis Featured by Hypotension Bronchospasm Flushing Tachyarrhythmia Often caused prior OT secondary to anesthetic agents Managed using IV Octreotide 50-100 mcg bolus followed by infusion at 50 mcg/hr.

34. Examination of abdomen to look for multicentric lesions In cases where mesentery is involved, dissection of the tumor off the mesenteric vessels with preservation of blood supply to unaffected bowel is appropriate. Patients with NETs and widespread metastatic disease: Role of surgical debulking is definite Limited hepatic metastasis  Metastasectomy Extensive hepatic metastasis Surgical resection if there is no extrahepatic metastases, LFT not compromised, no diffuse bilobar hepatic involvement Recurrence is >75% In recurrent cases Trans arterial chemoembolization OR radioembolization can be an option

35. Medical management of NETs Basis: Relief of symptoms produced by increased production of humoral factors Drug classes: Somatostatin analogs (SSAs ): Octreotide/ Lanreotide Helps to delay cancer progression as well PROMID trial  Octreotide utility CLARINET trial  Lanreotide utility for management of non functioning pancreatic NETs Follow up diagnostic imaging is required after 3-6 months. Second generation SSAs (Pasireotide) as well as chimeric dimers are currently being developed for current use

36. b. mTOR inhibitor  Everolimus Non-functional gastrointestinal NET RADIANT-4 trial  Tumor PFS for 4-11 months c. Peptide receptor radionuclides NETTER 1 trial  177-Lu-DOTATATE (Lu-DOTA) was shown to increase tumor PFS by 79% compared to high-dose Octreotide. d. Interferon- α (no longer recommended due to adverse effects) e. For somatostatin refractory diarrhoea TELESTAR trial telotristat f. For metastatic NETs  combination cytotoxic therapy Streptozocin , 5-FU, Cyclophosphamide Used for patients with G2 metastatic disease. Duration of response is however short lived. Other investigational therapy Temozolomide (monotherapy), Temozolomide + Capecitabine (combination) therapy, etoposide+cisplatin (combination therapy for poorly differentiated NETs)

37. Management of metastatic NETs Multidisciplinary approach Combined modalities using Surgical debulking Hepatic artery embolization Chemoembolization or radioembolization Medical therapy Targeted therapy (Sunitinib  PDGFR and VEGF receptor inhibitor)

38. Prognosis Best prognosis of all small bowel tumors Resection of localized primary  almost 100% survival rate 5-year survival rate Regional  65% Distant 25-35% Tumor metastasis 20-50% Tumor recurrence 40-60% An elevated level of CgA is an independent predictor of an adverse prognosis