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September 15, 2011 UB Department of Surgery Grand Rounds Craig Collins MD.

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Presentation on theme: "September 15, 2011 UB Department of Surgery Grand Rounds Craig Collins MD."— Presentation transcript:

1 September 15, 2011 UB Department of Surgery Grand Rounds Craig Collins MD

2 Anatomy/Physiology Pathogenesis Background Incidence Risk Factors Diagnosis Management Prognosis Take Home Points Future

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4 Small Bowel ~3m Duodenum ~20-30cm Jejunum ~100-110cm Ileum ~ 150cm Blood supply based upon celiac axis and superior mesenteric artery (SMA). Venous return via superior mesenteric vein (SMV).

5 Layers of Small Bowel Mucosa Submucosa Muscularis Serosa

6 Spiral folds of mucosa and submucosa (plicae circularis) are more prominent proximally. Jejunum is larger in diameter, is generally thicker, and has more prominent mucosal folds. Peyer’s Patches (lymphoid tissue) found in submucosal layer and become more prominent distally in the Ileum.

7 Primary functions are digestion, absorption, and motility. Endocrine function (CCK, secretin, other peptides) Immune function via secretion of IgA from Peyer's patches.

8 Small bowel accounts for 75% of GI tract length and 90% of mucosal surface. Accounts for 3-6% of GI tract tumors and 1-3% of all malignant GI tumors. 2/3 of symptomatic GI tract tumors are malignant. Majority of benign lesions are asymptomatic and are discovered at autopsy.

9 Several factors thought to account for rarity of small bowel neoplasms. Rapid transit time Liquid contents Neutral pH and high levels of benzopyrene hydroxylase Bacterial flora/load Increased lymphoid tissue and IgA- Immunoprotective role.

10 Hodgkin’s Lymphoma first described in 1832 by Dr. Thomas Hodgkin. Orderly spread of disease from one lymph node group to another, pathologically characterized by presence of Reed Sternberg cells. One of the first cancers to be cured by XRT and subsequently by combination chemotherapy. ~93% cure rate.

11 Classified into 4 pathologic subtypes based upon Reed- Sternberg cell morphology. Nodular Sclerosing Mixed Cellularity Lymphocyte rich Lymphocyte depleted

12 Non-Hodgkin’s Lymphoma B-Cell* diffuse large cell* Small cell (Mantle cell and follicular) mixed small and large cell MALT Lymphoma Burkitt’s EATL (Enteropathy Associated T-Cell Lymphoma) Immunoproliferative small intestinal disease (IPSID) * Most common (2/3), 70-80% High grade, 20-30% low grade

13 Lymphomas can affect any lymph node station and nearly every organ. Primary GI (extra-nodal) lymphomas represent ~30% of all lymphomas. Gastric- 75% Small Bowel (including duodenum)- 9% Ileo-cecal region- 7% >1 GI site- 6% Rectum- 2% Colon- 1%

14 All sub-types of nodal lymphomas may also arise in GI tract but NHL are most common. Ulcerating or infiltrating.

15 Colon cancer 50-60x more common than small bowel cancers. Primary small bowel cancer: Adenocarcinoma (40%) > NET (30%) > Lymphoma (20%) > Sarcoma/other (~10%) ~ 50% of small bowel neoplasms are secondary (metastasis)*. Colon, stomach, pancreas, melanoma, breast, & lung. *Direct extension, intraperitoneal seeding, hematogenous/lymphatic spread

16 1.6 cases/million/year Steep rise in the 1980’s in correlation to AIDS Bimodal age distribution, 20’s-30’s and >50.

17 Celiac disease IBD RA Chronic infection, poor sanitation HIV/AIDS with low CD4 count Post transplant Inflammation Immunosuppression

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20 Data taken as a whole do not support the hypothesis that IBD alone is a risk factor for lymphoma. Suggests IBD pts. Treated with AZA and 6-MP are at greater risk of lymphoma than general population. ? Regarding risk of severe or prolonged IBD compared with less severe disease.

21 Small but real increase in the risk of lymphoma in IBD patients receiving anti-TNF-α therapy, but risk yet to be clearly quantified.

22 Undoubtedly an increased risk of malignancy in celiac disease with regard to small bowel lymphoma and adenocarcinoma. Risk of NHL may be increased 3-9 fold, but the overall risk to celiac population is < 1 %. Risk diminishes over time if compliant with gluten free diet and is equal to general population 15 years after diagnosis.

23 Prospective cohort study of 637 pts with treated celiac disease in the UK from 1978-2001. Malignancy rates recorded. Risk to general population was estimated from cancer registries. Median follow up was 6.6 years (2.2-14.5 yrs). Cancer diagnosis within 2 years of celiac disease excluded.

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25 No increase in overall malignancy rate in diagnosed celiac disease in the post-diagnosis period when compared with the general population. 5x greater rate of NHL and 40x greater rate of small bowel lymphoma compared with general population in the post- diagnosis period.

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27 Abdominal pain, weight loss, nausea, emesis, GIB, chronic anemia. Median duration of symptoms- 6 months. Normal PE in 24%, abdominal mass in 46%. Often present with perforation, bleeding, or obstruction necessitating emergent surgery (~25-50%)

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29 Criteria: Lack of peripheral or mediastinal lymphadenopathy. Normal WBC count and differential on peripheral smear. Tumor involvement primarily in GI tract. No involvement of liver or spleen. No history of previously treated nodal lymphoma.

30 SBFT/Enteroclysis Barium Enema EGD/Colonoscopy Push Enteroscopy, Double Balloon Endoscopy Capsule endoscopy CT MRI PET/ PET CT Exploratory Laparotomy/Laparoscopy* * Diagnosis in ~50% of patients

31 Wide variety of radiologic manifestations- ulceration, stricture, polypoid mass, mechanical obstruction, intussusception, fistulas, aneurysmal bowel dilatation, thick mucosal folds, separation of adjacent loops, mesenteric adenopathy and mesenteric thickening. Clinical and radiographic challenge due to vague symptoms, rarity of disease, and relative inaccessibility of the small bowel.

32 Physical Exam with performance status CBC with differential, platelets LDH Hep B testing if Rituximab contemplated CT Chest/Abdomen/Pelvis for staging Pregnancy testing in women of childbearing age if chemo planned. Select cases- Bone marrow biopsy with aspirate for multifocal disease. PET-CT, MRI, Hep C testing

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37 Diagnosis- CT

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41 Endoscope introduced, balloon inflated, scope advanced. Performed via oral and anal routes. Depth range from 1- 8.8m. Allows for visualization and tissue diagnosis.

42 Retrospective review of 29 pts with GI lymphoma, further examined by double balloon endoscopy. Sought to determine prevalence of additional GI lymphomas.

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44 50% of their pts had additional GI lymphomas. Recommends complete evaluation of the small bowel in any patient with GI lymphoma.

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48 Low yield but superior test for small bowel Diagnostic impact in 57%, exclusive therapeutic decisions in 12% Overall diagnostic yield for obscure GIB 58-80% 6% were SB tumors

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50 Stage I- limited to intestine Stage II- Extension into regional nodes or infiltration of surrounding organ Stage III- Involvement of lymph nodes on both sides of diaphragm Stage IV- Involvement of distant organs or extra abdominal lymph nodes

51 Optimal treatment remains poorly defined but remains surgical as a primary therapy followed by adjuvant chemotherapy. Rarity of tumors, paucity of data on mgmt and prognosis…info usually from small case series and extrapolated from nodal lymphomas. Two most important factors regarding management Histology Staging

52 For localized, early stage disease, surgical resection with wide margins including node bearing mesentery is the standard. For advanced, disseminated tumors which are not resectable, surgical treatment is limited to obtaining tissue for diagnosis and palliating complications. Radiation and chemotherapy.

53 Stage I/II- Resection +/- chemotherapy Negative margins- clinical f/u Q3-6mos for 5 years then annually thereafter Positive margins- chemotherapy, possible reoperation Multiple lymphomatous polyposis- chemo only Stage III/IV- Resection + Chemotherapy Observation Close clinical follow up Re-staging- which imaging to use? Neoadjuvant therapy?

54 The best chemotherapy regimen depends on the histology of the tumor. diffuse large B-cell lymphoma-CHOP is still the gold standard. +/- Rituximab- primary therapy, combination, maintenence Low-grade lymphomas- indolent course- Fludarabine alone or in combination with cyclophosphamide. Rituximab as monotherapy.

55 First Line- R+CHOP, RCVP x 6 cycles First line for elderly or Infirm- Rituximab + single agent alkylator (cyclophosphamide, chlorambucil) Extended therapy- Rituximab maintenance x 2 years Fludarabine, cyclo, mitoxantrone

56 Extent of therapy based upon age, performance status, previous therapies, and extent of relapse. No role for radiation of the small bowel.

57 Bovine and shark cartilage Echinacea Garlic Ginseng Ginger

58 Perforation- median survival of 8 months AIDS related lymphomas Median survival 5-11 months B cell stage I/II- ~60-75% 5 year survival Stage III/IV- ~ 20-40% 5 year survival EATL 5 year survival 10-20%

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62 Small bowel lymphoma is a rare disease with vague symptoms initially, making timely diagnosis difficult. Risk factors include RA, CD, ?IBD, & immunosuppression. Imaging plays an integral role in diagnosis but studies remain difficult to obtain/interpret. Majority of cases diagnosed at laparotomy, many present emergently

63 >50% of patients have nodal/distant mets at presentation. Primary therapy is surgery followed by adjuvant chemotherapy depending on the stage and histology. Minimal progress in overall survival over the last 2 decades.

64 Significant improvement in diagnostic modalities and surgical care over the past 20 years but no significant change in survival. Need better medical therapy Immunotherapy Gene therapy Chemotherapy Neoadjuvant therapy?

65 1. Balthazar EJ, et al. "CT of small-bowel lymphoma in immunocompetent patients and patients with AIDS: comparison of findings." AJR. American Journal of Roentgenology 168.3 (1997): 675-80. 2. Berkelhammer C, et al. "Ileocecal intussusception of small-bowel lymphoma: diagnosis by colonoscopy." Journal of Clinical Gastroenterology 25.1 (1997): 358-61. 3. Boudiaf M, et al. "Small-bowel diseases: prospective evaluation of multi-detector row helical CT enteroclysis in 107 consecutive patients." Radiology 233.2 (2004): 338-44. 4. Chao TC, et al. "Perforation through small bowel malignant tumors." Journal of Gastrointestinal Surgery 9.3 (2005): 430-5. 5. Freeman HJ. "Free perforation due to intestinal lymphoma in biopsy-defined or suspected celiac disease." Journal of Clinical Gastroenterology 37.4 (2003): 299-302. 6. Johnston SD and Watson RG. "Small bowel lymphoma in unrecognized coeliac disease: a cause for concern?." European Journal of Gastroenterology & Hepatology 12.6 (2000): 7. Loberant N, et al. "Enteropathy-associated T-cell lymphoma: a case report with radiographic and computed tomography appearance." Journal of Surgical Oncology 65.1 (1997): 8. Matsumoto T, et al. "Double-balloon endoscopy depicts diminutive small bowel lesions in gastrointestinal lymphoma." Digestive Diseases & Sciences 55.1 (2010): 158-65. 9. Neugut AI, et al. "The epidemiology of cancer of the small bowel." Cancer Epidemiology, Biomarkers & Prevention 7.3 (1998): 243-51 10. Nguyen AT, et al. "A new subtype of Hodgkin's lymphoma, syncytial nodular sclerosing: first case report of primary small bowel lymphoma." Journal of Gastrointestinal Cancer 40.1-2 (2009): 38-40. 11. O'Boyle CJ, et al. "Primary small intestinal tumours: increased incidence of lymphoma and improved survival." Annals of the Royal College of Surgeons of England 80.5 (1998): 12. Pandey M, et al. "Malignant lymphoma of the gastrointestinal tract." European Journal of Surgical Oncology 25.2 (1999): 164-7 13.Pasta V, et al. "[Small bowel lymphomas: a case report]." [in Italian] Giornale di Chirurgia 25.3 (2004): 89-94.

66 14. Ullerich H, et al. "18F-Fluorodeoxyglucose PET in a patient with primary small bowel lymphoma: the only sensitive method of imaging." American Journal of Gastroenterology 96.8 (2001): 2497-9 15. Washington K, et al. "Gastrointestinal pathology in patients with common variable immunodeficiency and X-linked agammaglobulinemia." American Journal of Surgical Pathology 20.10 (1996): 1240- 52. 16.Woodley HE, Spencer JA and MacLennan KA. "Small-bowel lymphoma complicating long-standing Crohn's disease." AJR. American Journal of Roentgenology 9.5 (1997): 17. Liu PP, et al. "Lymphoproliferative disorder after liver transplantation." Journal of the Formosan Medical Association 97.1 (1998): 59-62.. 18. Lohan DG, et al. "MR enterography of small-bowel lymphoma: potential for suggestion of histologic subtype and the presence of underlying celiac disease." AJR. American Journal of Roentgenology 190.2 (2008): 287-93. 19. McGough N and Cummings JH. "Coeliac disease: a diverse clinical syndrome caused by intolerance of wheat, barley and rye." Proceedings of the Nutrition Society 64.4 (2005): 20. Ang YS and Farrell RJ. "Risk of lymphoma: inflammatory bowel disease and immunomodulators." Gut 55.4 (2006): 580-1. 21. Barrington SF and O'Doherty MJ. "Limitations of PET for imaging lymphoma." European Journal of Nuclear Medicine & Molecular Imaging 30 Suppl 1.(2003): S117-27. 22. Buckley JA and Fishman EK. "CT evaluation of small bowel neoplasms: spectrum of disease." Radiographics 18.2 (1998): 379-92. 23. Card TR, West J and Holmes GK. "Risk of malignancy in diagnosed coeliac disease: a 24-year prospective, population-based, cohort study." Alimentary Pharmacology & Therapeutics 20.7 (2004): 769-75. 24. Catena F, et al. "Small bowel tumours in emergency surgery: specificity of clinical presentation." ANZ Journal of Surgery 75.11 (2005): 997-9. 25. Cheung DY, et al. "Capsule endoscopy in small bowel tumors: a multicenter Korean study." Journal of Gastroenterology & Hepatology 25.6 (2010): 1079-86. 26. Gore RM, et al. "Diagnosis and staging of small bowel tumours." Cancer Imaging 6.(2006): 209-12.

67 27. Jones JL and Loftus EV Jr. "Lymphoma risk in inflammatory bowel disease: is it the disease or its treatment?." Inflammatory Bowel Diseases 13.10 (2007): 1299-307. 28 Kam MH, et al. "Small bowel malignancies: a review of 29 patients at a single centre." 29..Lepage C, et al. "Incidence and management of primary malignant small bowel cancers: a well-defined French population study." American Journal of Gastroenterology 101.12 (2006): 2826-32. 30. Lewis JD, et al. "Inflammatory bowel disease is not associated with an increased risk of lymphoma." Gastroenterology 121.5 (2001): 1080-7. 31. Loftus EV Jr and Sandborn WJ. "Lymphoma risk in inflammatory bowel disease: influences of referral bias and therapy." Gastroenterology 121.5 (2001): 1239-42. 32. O'Riordan BG, Vilor M and Herrera L. "Small bowel tumors: an overview." Digestive Diseases 14.4 (1996): 245-57. 33.Psyrri A, Papageorgiou S and Economopoulos T. "Primary extranodal lymphomas of stomach: clinical presentation, diagnostic pitfalls and management." Annals of Oncology 19.12 (2008): 1992-9. 34. Rawis RA, Vega KJ, Trotman BW. “Small Bowel Lymphoma.” Curr treat Options Gastroenterol. 2003. Feb; (1):27-34. 35. Daum S, Ullrich R, Heise W, et al. Intestinal non-Hodgkin’s lymphoma: a multicenter prospective clinical study from the German Study Group on Intestinal non-Hodgkin’s Lymphoma. J Clin Oncol 2003; 21:2740. 36. Sabiston. “Textbook of Surgery.” 17th Edition.2004. 37. Cameron. “Current Surgical Management. 10th Edition. 2011.

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