Small bowel adenocarcinoma Tumor Board Englewood Hospital and Medical Center

1. Small bowel adenocarcinomaTumor BoardEnglewood Hospital and Medical Center Donald Baril Department of Surgery Mount Sinai School of Medicine December 10, 2004

2. Case presentation – R.H. 79 yo F presented with progressive fatigue and shortness of breath PMHx: Esophageal cancer, papillary bladder cancer, endocarditis, hypertension, atrial fibrillation, CAD, hypothyroidism, CVA PSurgHx: Esophagogastrectomy/Splenectomy (6/03), CABG/MVR (5/03)

3. Case presentation – R.H. Found to be markedly anemic with a hematocrit of 18 October 2004 – negative endoscopy and colonoscopy; capsule endoscopy showed two small bowel ulcers CT scan – lumen constricting lesion of mid-small bowel Planned exploratory laparoscopy in mid-November November 2004 – right hemispheric stroke

4. Case presentation – R.H. November 23 – Exploratory laparoscopy converted to open lysis of adhesions, small bowel resection Returned emergently to the OR immediately post-operatively for intraabdominal bleeding

5. Case presentation – R.H.: Pathology Moderately differentiated invasive adenocarcinoma with focal adenosquamous features and minor mucinous component Transmural invasion Lymphovascular invasion Lymph node metastasis (1/7 lymph nodes)

6. Epidemiology of small bowel adenocarcinoma Small intestine accounts for approximately 75% of the length of the GI tract and more than 90% of the mucosal surface Fewer than 2% of GI malignancies arise in the small intestine Incidence of small bowel malignancies is 1 per 100,000 Estimated to be less than 5000 cases per year diagnosed in the U.S.

7. Small bowel tumors

8. Small bowel malignancies 30-50% are adenocarcinomas 25-30% are carcinoids 15-20% are lymphomas 10-20% are gastrointestinal stromal tumors

9. Anti-neoplastic environment of the small intestine Liquid contents cause less irritation than more solid contents of large bowel Rapid transit of intestinal contents provides shorter exposure of mucosa to carcinogens Lower bacterial load may result in decreased conversion of bile acids into potential carcinogens Benzopyrene hydroxylase, enzyme responsible for the conversion of the known carcinogen benzopyrene, is present in higher concentrations in the small bowel Increased lymphoid tissue and higher levels of IgA

10. Clinical presentation Abdominal pain Nausea and vomiting Bleeding/Anemia Weight loss Gastric outlet obstruction Diarrhea Mean time to diagnosis from the onset of the initial complaint is 7 months 50% of patients present emergently with obstruction or bleeding

11. Diagnosis of small bowel malignancies Plain abdominal radiographs Obstruction Calcified mass UGI/SBFT Mass Mucosal defect Intussusception

12. Diagnosis of small bowel malignancies Enteroclysis NGT directed to the jejunum and a combination of barium and methylcellulose is instilled Reported sensitivity of 90% for detecting small bowel tumors vs. 50% for SBFT

13. Diagnosis of small bowel malignancies CT Study of choice for preoperative staging and evaluation of metastases CT enteroclysis MRI Ultrasound

14. Diagnosis of small bowel malignancies Endoscopy/Enteroscopy Push enteroscopy allows for visualization of 40-60 cm of small bowel beyond the ligament of Treitz Intraoperative endoscopy EUS Useful in the evaluation of ampullary tumors

15. Diagnosis of small bowel malignancies Capsule endosocopy

16. Diagnosis of small bowel malignancies Exploratory laparotomy/laparoscopy Most sensitive diagnostic modality Preoperative diagnosis of small bowel malignancy is made in only 50% of cases Should be considered for all cases in patients with occult GI bleeding, weight loss, unexplained abdominal pain

17. Clinical features of small bowel adenocarcinoma Majority arise in the duodenum and jejunum Increased exposure to pancreatic and biliary secretions Exception is in patients with Crohn’s, in whom the most common site is the terminal ileum Peak incidence is in the 7th decade Male: Female ratio of 2.4:1

18. Risk factors for small bowel adenocarcinoma Pre-existing adenoma, either single or multiple 300-fold increased risk in patients with FAP Crohn’s Celiac disease IgA deficiency Alcohol abuse Neurofibromatosis Urinary diversion procedures ? Red meat

19. Crohn’s disease and adenocarcinoma 12-fold increased risk of small bowel cancer Symptoms often mimic symptoms of Crohn’s Risk factors Long duration of disease Male gender Fistulas Surgically excluded loops of small bowel Strictures Immunosuppressive drugs

20. Staging of adenocarcinoma of the small intestine Stage I – tumor confined to the lamina propria, submucosa, or muscularis propria Stage II – tumor extending beyond the muscularis propria or invading adjacent structures Stage III – tumors with any bowel wall extension and positive lymph nodes Stage IV – tumor with any degree of bowel wall invasion, with or without lymph node metastases, and with distant disease

22. Adenocarcinoma of the small intestine

23. Adenocarcinoma and therapy Surgery is the treatment of choice Procedure of choice is determined by location of tumor: 1st and 2nd portion of the duodenum –pancreaticoduodenectomy Distal duodenum – resection and duodenojejunostomy Jejunum and ileum – segmental resection including wide mesentery resection (6 inches) Terminal ileum – right hemicolectomy

24. Surgical pearls Resection of adequate mesentery is often limited by proximity of nodes or tumor to the SMA Margin-status must be confirmed by frozen-section if in question Patients with metastatic disease should undergo resection in most cases to prevent later complications

25. Adjuvant therapy Patients who undergo radical surgery often later die from distant disease recurrence No proven survival benefit No prospective studies 5-fluorouracil has shown the most promise

26. Adenocarcinoma of the small bowelDabaja SD et al. Cancer June 2004

28. Survival

29. Aggressive treatment and increased survival

31. Prognosis Overall 5-year survival of 30% 40-60% for resected tumors 15-30% for non-resected tumors Stage I – 100% Stage II – 52% Stage III – 45% Stage IV – 0%

32. Prognosis

33. Prognosis Poor prognosis correlated with: Mural penetration Nodal involvement Distant metastasis Perineural involvement Large tumor size Poor histologic grade

34. Metastatic disease involving small bowel Secondary neoplastic involvement of small intestine is more frequent than primary small bowel neoplasia Primary tumors of the colon, ovary, uterus, and stomach typically involve the colon by direct invasion or intraperitoneal spread Primary tumors from breast, lung, and melanoma metastasize to small bowel hematogenously

35. Metastatic disease involving small bowel Treatment is palliative Limited resection Intestinal bypass Melanoma Metastatic focus may further disseminate to small bowel mesentery and draining lymph nodes Aggressive resection may improve disease-free survival

36. Esophageal cancer and metastases Patients with esophageal cancer usually present with recurrence within 2 years Treatment of solitary metastasis appropriate when: Contained with a single organ that can be easily resected Good overall patient function No local recurrence of primary tumor > 1 year after the initial treatment

39. Gastrointestinal stromal tumors Visceral sarcomas, previously classified as leiyomyomas and leiyomyosarcomas Now classified as GISTs with a range of biological behaviors from low grade to high grade malignancies Traditionally, microscopic findings were used to define malignancy including: Increased cell size Increased cell irregularity Lack of cell differentiation Presence of cells with hyperchromic and multiple nuclei

40. GISTs – Tumor biology Proposed to arise from the interstitial cell of Cajal, an intestinal pacemaker cell of mesodermal origin Similar cell markers to those of normal Cajal cells 1) myeloid stem cell antigen CD34 2) KIT receptor tyrosine kinase 3) variably positive for smooth-muscle actin 4) usually negative for desmin Previously thought to be smooth muscle neoplasms but now accepted to have: 1) myogenic features (smooth muscle GIST) 2) neural features (GI autonomic nerve tumor) 3) myogenic and neural features (mixed GIST)

41. Clinical features of GISTs Most commonly present with pain and weight loss Most commonly present in the 6th and 7th decades but may occur at any age Distribution of occurrence is proportional to the length of the segments of the small bowel Lesions occur in extraluminal, subserosal locations Often develop central ischemia and necrosis that leads to bleeding

42. GISTs of the small intestine

43. GISTs of the small intestine

44. Prognostic factors and therapy of GISTs Only complete resection has been found to be a significant favorable prognostic factor Surgical resection is therefore the mainstay of therapy and should include any involved adjacent organs Complete resection results in 3 and 5-year survival rates of 54% and 42% compared to 13% and 9% after incomplete resection No added benefit to wide resections or extensive lymphadenectomies

45. Prognostic factors and therapy of GISTs Poor prognostic factors include tumors greater than 5 cm, non-smooth muscle cell differentiation, and those classified as high grade Metastases present in 30%; most commonly hepatic Recurrence rates of 25-50% reported No demonstrable benefit of adjuvant therapy

46. GISTs and STI-571 – Molecular therapeutic options Most GISTs (52-85%) have a gain-of-function mutation in the c-kit proto-oncogene Results in ligand-independent activation of the KIT receptor tyrosine kinase Unopposed stimulus for cell growth STI-571 molecule which inhibits: Enzymatic activity of the KIT tyrosine kinases, Platelet-derived growth factor receptor BCR-ABL fusion protein

47. GISTs and STI-571 – Molecular therapeutic options Initial phase II trial of STI-571 in patients with metastatic GISTs (follow-up of three months) Partial response rate in 59% Stable disease in 27% Progression of disease in 13% 86% had a mutation in c-kit and were more likely to respond EORTC study showed similar results Partial response rate in 69% Stable disease in 19% Progression of disease in 11% Dematteo et al. Human Pathology. May 2002

48. Carcinoid Tumors of the Small Intestine Originally described by Oberndorfer in 1907 Arise from Kulchitsky cells Type of enterochromaffin cell Cells of the amine precursor uptake decarboxylase (APUD) system which have the ability to synthesize biologically active substances

49. Clinical features of carcinoid tumors Most commonly present in the 7th decade Often present with nonspecific complaints Up to 50% of patients present with obstruction Carcinoid syndrome, marked by flushing and diarrhea, is rare and occurs in only 5-7% of patients Right sided valvular fibrosis occurs late in the disease Increasing frequency from the duodenum to the ileum

50. Pathological features of carcinoid tumors Carcinoid invasion into the mesentery leads to fibrosis and often kinking of the small intestine Thickening of the vessel wall is also present and may lead to ischemic changes in the gut Serotonin is postulated to be responsible for these features

51. Diagnosis of Carcinoid Tumors Traditional studies may fail to demonstrate the primary tumor Indium-labeled octreotide scan is the most accurate (sensitivity of 90%) means of localizing a carcinoid tumor Tumor cells express somatostatin receptors which take up octreotide 24-hour urine levels of 5-hydroxyindoleacetic acid (5-HIAA) may alone be diagnostic Serotonin is metabolized in the liver to 5-HIAA and excreted in the urine

52. Carcinoid tumors of the small intestine

53. Carcinoid tumors of the small intestine

54. Surgical therapy of carcinoid tumors Surgical excision is the mainstay of therapy Isolated disease is widely resected Synchronous tumors are found in 33-40% of patients and should all be excised if feasible Noncarcinoid synchronous tumors are found in up to 25% of patients Typically tumors of the breast, lung, stomach, or colon

55. Surgical therapy of carcinoid tumors Tumor size is an unreliable predictor of metastatic disease Aggressive attempts should be made to resect metastatic disease Decreases the need for medical therapy Prolongs survival Hepatic metastases Surgical resection Hepatic artery embolization Cryosugery Radiofrequency ablation Transplantation

56. Medical therapy of small bowel carcinoid tumors Octreotide inhibits tumor secretion of hormones May have a direct tumor control effect on carcinoid tumors Relieves flushing in 76% of patients Improves diarrhea in 83% Decreases the urinary 5-HIAA levels in 80% Interferes with endo-and exocrine pancreas function

57. Medical therapy of small bowel carcinoid tumors Interferon-alpha has shown improvement in symptoms in 68% and a biochemical response in 42% Use limited by high incidence of side effects Response to chemotherapy has been variable and short lived Combination of streptozocin and 5-fluorouracil has shown a 20-30% response rate No proven benefit of radiotherapy

58. Conclusions Small bowel malignancies although rare are associated with relatively poor 5-year survival rates Abdominal pain of unknown origin should prompt a limited investigation for these tumors Surgical therapy remains the mainstay of therapy Future directions in the therapy of these tumors include the use of direct molecular modification and immunotherapy