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Gastrointestinal Lymphoma.pptx

  1. Gastrointestinal Lymphoma Dr Kartik Kadia MMIMSR, Ambala
  2. • The term LYMPHOMA identifies a heterogeneous group of biologically and clinically distinct neoplasms that originate from cells in the lymphoid organs and have been historically divided into : • Non-Hodgkin lymphoma (NHL) and • Hodgkin lymphoma (HL)
  3. Introduction to Lymphoma • Although NHLs and Hodgkin lymphoma (HL) both frequently involve lymphohematopoietic tissues, their biologic and clinical behaviors are distinct.
  4. Hodgkin’s Lymphoma NHL Cells of origin B cells B cells, T cells, NK cells Classification Nodular sclerosing, Mixed celluarity, Lymphocyte predominant, Lymphocyte depleted DLBC, Follicular mixed, Burkitt, Small Lymphocytic Epidemiology Bimodal : 20-25 years >60 years <65 years, HIV,EBV, Congenital immunodeficiencies H/P Painless Cervical Lymphadenopathy, B symptoms (Fever, Night sweats, weight loss) Painless Disseminated Lymphadenopathy, B symptoms LN More often localized to single axial group of nodes More frequent involvement of multiple peripheral nodes Cure rates High (80%) Low (<50%)
  5. • Current lymphoma classification systems divide the lymphomas into different entities based on their perceived cell of origin • During embryogenesis, hematopoietic stem cells from the liver and the placenta give rise to progenitor cells that migrate to the Bone marrow and the Thymus where they undergo a program of antigen-independent differentiation into B- and T-cell lineage precursor cells, respectively Introduction to Lymphoma
  6. Immunophenotyping of Lymphoid Cells • Lymphocytes at various stages in development can be defined and differentiated by the detection of certain antigens on the cell surface (CD) • This antigen fingerprint is referred to as the immunophenotype of the cell.
  7. • It can be detected by flow cytometric analysis of single cell suspensions of o whole blood, o bone marrow, o body fluids, or o disaggregated tissue • using fluorescently labeled antibodies against these antigens or by immunohistochemistry Immunophenotyping of Lymphoid Cells
  8. Primary gastrointestinal lymphoma • Gastrointestinal tract is the most common extranodal site involved by lymphoma accounting for 5%-20% of all cases* • Primary gastrointestinal lymphoma, however, is very rare, constituting only about 1%-4% of all gastrointestinal malignancies. • Gastrointestinal lymphoma is usually secondary to the widespread nodal diseases. *Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal lymphomas. Cancer 1972; 29: 252-260
  9. • The most commonly involved sites are as follows*: ostomach (60–75%), osmall intestine (9%), oileocecal region (7%), and ocolorectal region (<1%). *Herrmann R, Panahon AM, Barcos MP, Walsh D, Stutzman L. Gastrointestinal involvement in non- Hodgkin's lymphoma. Cancer 1980; 46: 215-222
  10. • Histopathologically, almost 90% of the primary gastrointestinal lymphomas are of B cell type with very few T-cell lymphomas and Hodgkin lymphoma. *Herrmann R, Panahon AM, Barcos MP, Walsh D, Stutzman L. Gastrointestinal involvement in non- Hodgkin's lymphoma. Cancer 1980; 46: 215-222
  11. • Certain histological subtypes have been noted to have a relative predilection site as – *Rizvi MA, Evens AM, Tallman MS, Nelson BP, Rosen ST. T-cell non-Hodgkin lymphoma. Blood 2006; 107: 1255-1264
  12. • Certain risk factors have been implicated in the pathogenesis of gastrointestinal lymphoma including – oViral Infection oBacterial Infection oImmunosuppression oCeliac disease oInflammatory bowel disease
  13. Bacteria - • Helicobacter pylori (H. pylori) • Campylobacter jejuni (C. jejuni), H. pylori C. jejuni
  14. Virus - • Human immunodeficiency virus (HIV), • Epstein-Barr virus (EBV), • hepatitis B virus (HBV), • human T-cell lymphotropic virus-1 (HTLV-1)
  15. • Dawson’s criteria are used for labeling primary gastrointestinal lymphoma – (1) absence of peripheral lymphadenopathy at the time of presentation; (2) lack of enlarged mediastinal lymph nodes; (3) normal total and differential white blood cell count; (4) predominance of bowel lesion at the time of laparotomy with only lymph nodes obviously affected in the immediate vicinity; and (5) no lymphomatous involvement of liver and spleen *Dawson IM, Cornes JS, Morson BC. Primary malignant lymphoid tumours of the intestinal tract. Report of 37 cases with a study of factors influencing prognosis. Br J Surg 1961; 49: 80-89
  16. Pretreatment evaluation of primary gastrointestinal lymphomas
  17. Staging of Primary GI Lymphoma
  18. A proper staging for GI lymphomas will include • Physical examination: oevaluation of superficial lymph nodes; oabdomen palpation to detect liver enlargement, osplenomegaly, and oabdominal masses.
  19. • Endoscopic ultrasonography, which is the gold standard in defining the locoregional GI involvement A proper staging for GI lymphomas will include
  20. • Computed tomography of the neck, chest, and abdomen in order to detect involvement of nodes above and below the diaphragm and also other extranodal involvement not pertaining to the GI tract. A proper staging for GI lymphomas will include
  21. • Positron emission tomography is not generally indicated as a staging procedure, but it retains a role in defining the pretreatment lymphomatous involvement and response to treatment A proper staging for GI lymphomas will include
  22. • Bone marrow biopsy: bone marrow biopsy should be performed in order to exclude a marrow involvement that could influence treatment and follow-up management A proper staging for GI lymphomas will include
  23. • Ann Arbor staging is commonly employed to stage lymphoma and the international prognostic index has been used to define the prognostic subgroups, but Paris staging has increasingly gained its significance.
  24. • The spreading patterns of extranodal lymphomas are different from primary nodal lymphomas. • Because of this, the use of Ann Arbor staging is not suitable, especially for primary gastric lymphomas.
  25. Several adaptations and modifications have been done for gastrointestinal lymphomas by Musshoff
  26. • The Lugano staging system is a modification of the original Ann Arbor staging system designed for the staging of primary gastrointestinal lymphomas. • It was developed to incorporate measures of depth of invasion and distant nodal involvement
  27. • A modified TNM staging system, also called the Paris staging system, suggested by European Gastro-Intestinal Lymphoma Study Group modeled after the staging of gastric adenocarcinoma, is commonly used
  28. Esophageal lymphoma • The esophagus is a rarely involved site, accounting for < 1% of all gastrointestinal lymphomas. • Esophageal involvement usually results from metastasis from cervical or mediastinal lymph nodes or extension from gastric lymphoma. • Primary esophageal lymphoma is extremely rare, with less than 30 cases reported in the literature* * Coppens E, El Nakadi I, Nagy N, Zalcman M. Primary Hodgkin's lymphoma of the esophagus. AJR Am J Roentgenol 2003; 180: 1335-1337
  29. • The majority are the DLBCL type of NHL. • Only few cases of MALT lymphoma, MCL, T-cell lymphoma and HL involving the esophagus have been reported • The etiology of esophageal lymphoma is unknown and the role of EBV in its pathogenesis is controversial. • It has been shown that esophageal lymphoma is most common in immunocompromised patients, with HIV infection as a probable risk factor* *Weeratunge CN, Bolivar HH, Anstead GM, Lu DH. Primary esophageal lymphoma: a diagnostic challenge in acquired immunodeficiency syndrome--two case reports and review. South Med J 2004; 97: 383-387
  30. • The age of presentation is variable The common symptoms of patients with esophageal lymphoma include – • dysphagia, • odynophagia, • weight loss, • chest pain or • present as a result of complications such as hemorrhage, obstruction or perforation with a tracheoesophageal fistula. • Constitutional B symptoms (fever, night sweats) are not typically present.
  31. • The morphological features seen by endoscopy* are onodular, opolypoidal, oulcerated or ostenosis *Zhu Q, Xu B, Xu K, Li J, Jin XL. Primary non-Hodgkin's lymphoma in the esophagus. J Dig Dis 2008; 9: 241-244
  32. • EUS has gained clinical acceptance for the assessment of lymphoma and preoperative staging, because it can accurately depict the structural abnormalities and depth of invasion of the lesions. • EUS findings, however, are not pathognomonic, with presentation varied as anechoic, hypoechoic or even hyperechoic masses
  33. • CT findings in esophageal lymphoma are nonspecific and not diagnostic, with features such as thickening of the wall mimicking other common tumors, such as esophageal carcinoma. • CT, however, they are valuable for the evaluation of – o extraluminal component of esophageal mass, o its mediastinal extension, and o status of lymph nodes, • thus playing a role in staging disease, assisting in stratification of available treatment modalities, evaluating treatment responses, monitoring disease progression, and detecting relapses *Paes FM, Kalkanis DG, Sideras PA, Serafini AN. FDG PET/ CT of extranodal involvement in non-Hodgkin lymphoma and Hodgkin disease. Radiographics 2010; 30: 269-291
  34. • Radiological findings in esophageal lymphoma vary greatly and are nonspecific, which poses diagnostic challenges when it is differentiated from other benign and malignant lesions. • Radiographic patterns* of esophageal lymphoma include – o stricture, o ulcerated mass, o multiple submucosal nodules, o varicoid pattern, o progressive aneurysmal dilatation, and o tracheoesophageal fistula formation, but none of them is diagnostic. *Carnovale RL, Goldstein HM, Zornoza J, Dodd GD. Radiologic manifestations of esophageal lymphoma. AJR Am J Roentgenol 1977; 128: 751-754
  35. • Incorporation of PET/CT has emerged as an indispensable tool in staging the disease and following up the patients with extranodal involvement of Hodgkin’s and non-Hodgkin’s lymphoma* • Intensity of FDG uptake in lymphoma is influenced by various intrinsic tumor factors such as histological features and grade • FDG PET/CT can also detect the indolent lesions that are undetectable on conventional cross-sectional imaging *Paes FM, Kalkanis DG, Sideras PA, Serafini AN. FDG PET/ CT of extranodal involvement in non-Hodgkin lymphoma and Hodgkin disease. Radiographics 2010; 30: 269-291
  36. Treatment of Esophageal lymphoma • Due to the rarity of esophageal lymphoma, no standardized approaches to its management have been formulated. • Secondary lymphoma involving the esophagus can be treated with chemotherapy, while primary esophageal lymphoma can be managed with surgery, chemotherapy and radiotherapy or their combination. • Treatment protocols vary depending on its histological subtypes and extent.
  37. • Although surgery is the initial treatment modality, it has been recently reserved for cases with their diagnosis not possibly made at endoscopic biopsy or for those who warrant surgical intervention due to complications such as perforations
  38. • Chemotherapy or radiotherapy alone can be used as its initial therapy. • The commonly employed chemotherapy regimen is CHOP in combination with Rituximab. • It was reported that external beam radiation at the dose of 40 Gy can also be used* *Chadha KS, Hernandez-Ilizaliturri FJ, Javle M. Primary Ghimire P et al. Primary GI lymphoma WJG| 707 February 14, 2011|Volume 17|Issue 6| esophageal lymphoma: case series and review of the literature. Dig Dis Sci 2006; 51: 77-83
  39. Gastric lymphoma
  40. Epidemiology • Stomach is the most commonly involved site (60%-75%) in gastrointestinal tract followed by small bowel, ileocecal region and rectum* • Gastric lymphoma accounts for 3%-5% of all malignant tumors of the stomach *Ferrucci PF, Zucca E. Primary gastric lymphoma pathogenesis and treatment: what has changed over the past 10 years? Br J Haematol 2007; 136: 521-538
  41. • Primary gastric lymphoma can arise from mainly 2 different sources: o extranodal marginal B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type and o diffuse large B-cell lymphoma (DLBCL) The majority of primary lymphomas of the stomach are MALT type (40–50%), of which 70–80% are confined to the stomach (stage IE)* *Cogliatti SB, Schmid U, Schumacher U, Eckert F, Hansmann ML, Hedderich J, Takahashi H, Lennert K. Primary B-cell gastric lymphoma: a clinicopathological study of 145 patients. Gastroenterology 1991; 101: 1159-1170
  42. • MALT lymphoma can be divided into • H. pylori positive or negative based on the presence of Helicobacter pylori. • Most patients (>90%) with gastric MALT lymphoma are H. pylori positive • H. pylori negative MALT lymphoma tends to have a higher frequency for t(11;18) (q21;q21) translocation compared to H. pylori positive MALT lymphoma
  43. The development of MALT lymphomas is linked to the clonal expansion of B cells that accompanies chronic gastritis in the presence of H. pylori H. pylori-induced gastritis first leads to the accumulation of CD4+ lymphocytes and mature B cells in the gastric lamina propria Antigens derived from H. pylori drive the activation of T cells, B-cell proliferation, and lymphoid follicle formation, which if persistent can evolve into a monoclonal lymphoma
  44. • Extranodal marginal zone B-cell lymphoma (MZL), also called low-grade B-cell lymphoma of mucosa-associated lymphoid tissue, is an extranodal lymphoma that arises in a number of epithelial tissues, including – • stomach, • salivary gland, • lung, • small bowel, • thyroid, and elsewhere. • It was originally referred to as a “pseudo-lymphoma” because of its tendency to remain localized, but it is now recognized that it is a clonal B-cell neoplasm that frequently recurs locally and has the potential for systemic spread and transformation to a high- grade B-cell lymphoma.
  45. • It has been shown that individuals with positive HBsAg have an increased risk of developing Gastric Lymphoma* • It was reported that HBV plays a role in the development of B-cell NHL* *Engels EA, Cho ER, Jee SH. Hepatitis B virus infection and risk of non-Hodgkin lymphoma in South Korea: a cohort study. Lancet Oncol 2010; 11: 827-834
  46. • In contrast, primary gastric lymphoma with a T-cell phenotype is relatively rare, accounting for only 7% of primary gastric lymphomas in HTLV-1 infected endemic areas • Primary gastric T-cell lymphoma without HTLV-1 infection is rare, and sporadic cases have been reported* *Sugita S, Iijima T, Furuya S, Kano J, Yanaka A, Ohta K, Kojima H, Noguchi M. Gastric T-cell lymphoma with cytotoxic phenotype. Pathol Int 2007; 57: 108-114
  47. Clinical symptoms - Gastric lymphoma
  48. • Clinical symptoms of gastric lymphoma are nonspecific and indistinguishable from other benign and malignant conditions. • The most common complaints of gastric lymphoma patients are o epigastric pain, o weight loss, o nausea and vomiting. • Occasionally, an abdominal mass is palpable. • Lymphadenopathy is rare and its patients often have no physical signs. • Unlike nodal lymphoma, B constitutional symptom is not common.
  49. • Endoscopy cannot distinguish* gastric lymphoma from the more common gastric carcinoma. • The three main patterns that can be recognized at endoscopy include – o ulceration, o diffuse infiltration, and o polypoid mass • Endoscopy, however, is an indispensable tool for the initial diagnosis and follow-up of cases as well as for obtaining biopsy specimens. *Taal BG, Burgers JM. Primary non-Hodgkin's lymphoma of the stomach: endoscopic diagnosis and the role of surgery. Scand J Gastroenterol Suppl 1991; 188: 33-37
  50. • EUS can assess the extent of lesion and its invasion. • Lesions are usually hypoechoic although few hyperechoic cases have been reported* *Taal BG, Burgers JM. Primary non-Hodgkin's lymphoma of the stomach: endoscopic diagnosis and the role of surgery. Scand J Gastroenterol Suppl 1991; 188: 33-37
  51. • Infiltrative carcinoma tends to have a vertical growth in gastric wall, while lymphoma tends to show mainly a horizontal extension and more involvement of perigastric lymph nodes* • EUS is highly accurate in detecting the o depth of lymphomatous infiltration and the o presence of perigastric lymph nodes, thus providing additional information for treatment planning, and can differentiate lymphoma from carcinoma *Püspök A, Raderer M, Chott A, Dragosics B, Gangl A, Schöfl R. Endoscopic ultrasound in the follow up and response assessment of patients with primary gastric lymphoma. Gut 2002; 51: 691-694
  52. • Radiographic patterns of gastric lymphoma observed in double-contrast UGI studies include – o ulcers, o polypoid mass, o thickened fold, o mucosal nodularities or o infiltrating lesions, which are not conclusive, thus posing a diagnostic challenge while differentiating from other malignant and benign lesions, hence requiring pathological confirmation
  53. • Preservation of gastric distensibility and pliability, with gastric fold thickening, is a finding more suggestive of lymphoma. • Gastric wall thickening is much less severe in low-grade lymphoma than in high- grade lymphoma on CT images, and abdominal lymphadenopathy is less common in low-grade lymphoma.
  54. The MRI features include – • irregularly thickened mucosal folds, • irregular submucosal infiltration, • annular constricting lesion, • exophytic tumor growth, • mesenteric masses and • mesenteric/retroperitoneal lymphadenopathy. MRI – Gastric Lymphoma
  55. • Application of 18F-FDG PET/CT in diagnosis of gastric lymphoma is challenging due to the physiologic FDG activity in the stomach and variability in the degree of uptake in various histologic subtypes • It was reported that aggressive gastric lymphoma has more intense uptake than low grade MALT lymphoma* *Radan L, Fischer D, Bar-Shalom R, Dann EJ, Epelbaum R, Haim N, Gaitini D, Israel O. FDG avidity and PET/CT patterns in primary gastric lymphoma. Eur J Nucl Med Mol Imaging 2008; 35: 1424-1430
  56. Treatment - Gastric lymphoma
  57. Treatment - Gastric lymphoma • Gastric lymphoma has better prognosis than o intestinal lymphoma and o gastric adenocarcinoma, perhaps because of the tendency of gastric lymphomas to remain localized in the stomach for a long time
  58. • Antibiotic therapy can achieve a long-term remission in 60%-100% patients with localized H. pylori-positive MALT lymphoma without t (11;18) chromosomal translocation. • Histological assessment of treatment response, however, faces the problem of standardization, thus mandating serial followup.
  59. • The GELA histologic evaluation system is commonly employed at certain centers. It has been shown that monoclonal B-cells still exist in almost half of the patients despite histological and endoscopic remission following antibiotic therapy* *Stathis A, Chini C, Bertoni F, Proserpio I, Capella C, Mazzucchelli L, Pedrinis E, Cavalli F, Pinotti G, Zucca E. Long- term outcome following Helicobacter pylori eradication in a retrospective study of 105 patients with localized gastric marginal zone B-cell lymphoma of MALT type. Ann Oncol 2009; 20: 1086-1093
  60. • No definite guidelines have been advocated for the treatment of advanced or H. pylori negative MALT-type of gastric lymphoma. • Although surgery has been used as its initial treatment, recent studies showed that radiotherapy alone can achieve a complete remission with a 5-year disease free period • Thus, “involved-field” irradiation at the total dose of 30 Gy has become the treatment of choice for stagesⅠand Ⅱ MALT lymphoma without H. pylori or with persistent lymphoma following therapy.
  61. • Surgery is, at present, reserved only for those with complications such as perforation, hemorrhage or obstruction that cannot be treated with other alternative therapies. • Systemic therapy similar to that for indolent and advanced lymphoma must be taken into consideration in patients with their disease spread.
  62. • Diffuse large B-cell lymphoma of the stomach is treated with aggressive poly- chemotherapy, which is usually combined with Rituximab. • Thus, gastric lymphoma should be treated with the front-line chemoimmunotherapy with 3-4 cycles of standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) followed by “involved-field” radiotherapy.
  63. Follow up – Gastric Lymphoma oGood clinical judgment, oa careful history, and ophysical examination are the cornerstones of patient follow-up.
  64. • Patients initially treated with H. pylori eradication therapy need to be evaluated 4–8 weeks after the completion of treatment to determine whether the H. pylori was successfully eradicated and whether there has been a tumor response
  65. • Following the documentation of the achieved H. pylori eradication, a strict endoscopic follow-up is recommended, with multiple biopsies taken 2–3 months after treatment to rule out tumor progression, and subsequently (twice per year for 2 years) to monitor the histological regression of the lymphoma
  66. • Because of high recurrence rate in Gastric lymphomas, monitoring is necessary. • A long-term careful endoscopic and systemic follow-up (clinical examination, blood counts and adequate radiological or ultrasound examinations every 12–18 months) is recommended for all patients
  67. Small intestine lymphoma
  68. Small intestine lymphoma • Primary malignant tumors of the small intestine are very rare, accounting for less than 2% of all gastrointestinal malignancies* o Ileum is the most common site (60%-65%) involving small intestine lymphoma followed by o jejunum (20%-25%), o duodenum (6%-8%) *Schottenfeld D, Beebe-Dimmer JL, Vigneau FD. The epidemiology and pathogenesis of neoplasia in the small intestine. Ann Epidemiol 2009; 19: 58-69
  69. The clinical presentation of small intestinal lymphoma is non specific and the patients have symptoms, such as – • colicky abdominal pain, • nausea, • vomiting, • weight loss and • rarely acute obstructive symptoms, • Intussusception or • perforation
  70. The World Health Organization (WHO) classification system • Most small intestinal lymphomas are of B-cell origin and Non-Hodgkin’s lymphomas • Lymphomas of T-cell origin constitute only 20%; and Hodgkin lymphomas of the gastrointestinal tract, either primary or secondary, are extremely rare
  71. • Small intestinal lymphomas are mainly divided into three groups: o MALT lymphomas, o Other B-cell lymphomas except MALT lymphoma (e.g., diffuse large B-cell lymphoma, mantle cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, etc.), and o T-cell lymphomas. The World Health Organization (WHO) classification system
  72. • MALT lymphomas are also subdivided into two groups: oimmunoproliferative small intestinal disease (IPSID) and o non-IPSID MALT lymphomas. • There are two main types of T-cell intestinal lymphomas: o Enteropathy associated T-cell lymphoma (EATL) and o extranodal NK-/ T cell lymphoma The World Health Organization (WHO) classification system
  73. • IPSID, also known as alpha chain disease, is a MALT associated lymphoma due to C. jejuni infection and characterized by “centrocyte like” mucosal infiltration with plasma cells that secrete monotypic and truncated immunoglobulin, a heavy chain lacking of an associated light chain.
  74. • IPSID mainly affects older children and younger adults with a predominant involvement of proximal small intestine, the symptoms of its patients are diarrhea and abdominal pain
  75. • MCL primarily affects individuals at the age of over 50 years, and involves terminal ileum and jejunum appearing as numerous polyps, hence called multiple lymphomatous polyposis
  76. • The prototype MCL is positive for pan B-cell antigens, although few cases of CD5- MCL have been reported • Cytogenetic analysis of MCL has shown the rearrangement of bcl-1 locus on chromosome 11 due to t (11;14) (q13;q32) translocation, accompanying cyclin D1 antigen overexpression. • Few cases of cyclin D1-negative MCL, however, have been reported with up- regulated cyclin D2 or D3
  77. • Burkitt’s lymphoma mainly affects children and is associated with EBV and HIV/AIDS* • T cell lymphoma of the small intestine accounts for approximately 10%-25% of all primary intestinal lymphomas primarily occurring as enteropathy associated T cell lymphoma, and most of them are often complicated by Crohn’s disease * Biko DM, Anupindi SA, Hernandez A, Kersun L, Bellah R. Childhood Burkitt lymphoma: abdominal and pelvic imaging findings. AJR Am J Roentgenol 2009; 192: 1304-1315
  78. Diagnosis – Small Intestinal Lymphoma
  79. • Evaluation of the small intestinal lymphoma has been revolutionized since the introduction of capsule endoscopy (CE) and double-balloon technique of push-and pull enteroscopy which is capable of enabling biopsies as well as performing interventions, and limiting major surgical interventions.
  80. • Small intestine lymphoma appears as a mass, polyp and ulcer on CE which cannot be distinguished from other lesions
  81. • The common features of small intestine lymphoma seen in CT include- opolypoid form, omultiple nodules, oinfiltrative form Small intestine lymphoma seen in CT
  82. Treatment - Intestinal lymphoma • The treatment outcome of intestinal lymphoma is relatively poorer than that of gastric lymphoma depending on their histologic subtypes. • Lymphoma primarily located in the small intestine usually warrants laparotomy with the affected segment removed both for its diagnosis and further treatment.
  83. • Low-grade B-cell lymphoma of the small intestine (stage IE) only requires surgical resection. • Although few studies have reported its benefit for localized intestinal lymphoma particularly that of the duodenum and rectum, radiotherapy in particular is not beneficial for intestinal lymphoma due to the multifocal involvement and its spread.
  84. • No therapeutic guidelines are available for MALT lymphoma involving the small intestine with various modalities depending on the disease burden and other clinical parameters. • Local intestinal lymphoma can be managed with surgical or endoscopic resection, while some cases of colonic MALT lymphoma can benefit from H. pylori therapy alone
  85. • Multi-agent chemotherapeutic strategy is warranted for advanced stage intestinal lymphoma with multifocal presentation of MALT lymphoma. • A wait and watch policy for indolent FL at stage IE is advocated by some authors until they are symptomatic or show evidence of its progression * *Yamamoto S, Nakase H, Yamashita K, Matsuura M, Takada M, Kawanami C, Chiba T. Gastrointestinal follicular lymphoma: review of the literature. J Gastroenterol 2010; 45: 370-388
  86. • Symptomatic cases, or advanced disease of FL necessitates surgery, chemotherapy (CHOP) and/or irradiation intervention. • Although Rituximab is beneficial for FL, its true value has not been well ascertained* *Dickson BC, Serra S, Chetty R. Primary gastrointestinal tract lymphoma: diagnosis and management of common neoplasms. Expert Rev Anticancer Ther 2006; 6: 1609-1628
  87. • MCL treatment response and prognosis are poor with a short unmaintained remission after chemotherapy. • Treatment is stratified based on the eligibility of patients for stem cell transplantation • Those who are eligible for grafting are previously induced with R-CHOP or R- HyperCVAD (Rituximab, cyclophosphamide, vincristine, doxorubicin and dexamethasone).
  88. • The mammalian target of rapamycin inhibitors, antibodies, bendamustine or radioimmuno conjugates, can achieve a promising outcome in patients with relapse or refractory setting single-agent* - o bortezomib, o temsirolimus and o ibritumomab tiuxetan *Ogura M. Current treatment strategy and new agents in mantle cell lymphoma. Int J Hematol 2010; 92: 25-32
  89. • IPSID (immunoproliferative small intestinal disease) in early stage responds to antibiotics such as tetracycline or combined metronidazole and ampicillin • IPSID at intermediate or advanced stage responds to anthracycline-based chemotherapy, with added antibiotics such as tetracycline.
  90. • High grade lymphoma frequently presents with complications, thus mandating surgical intervention. • No optimized therapeutic protocol is available for Burkitt lymphoma which usually requires an aggressive approach.
  91. • High dose chemoradiotherapy and hematopoietic SCT are beneficial for almost 50% of Burkitt lymphoma patients* *Song KW, Barnett MJ, Gascoyne RD, Horsman DE, Forrest DL, Hogge DE, Lavoie JC, Nantel SH, Nevill TJ, Shepherd JD, Smith CA, Sutherland HJ, Voss NJ, Toze CL, Connors JM. Haematopoietic stem cell transplantation as primary therapy of sporadic adult Burkitt lymphoma. Br J Haematol 2006; 133: 634-637
  92. • Radiotherapy is not beneficial for DLBCL involving the small intestine* • Systemic treatment with anthracycline-based chemotherapy followed by radiotherapy is proposed for wide spread advanced intestinal lymphoma which cannot be removed. *Aleman BM, Haas RL, van der Maazen RW. Role of radiotherapy in the treatment of lymphomas of the gastrointestinal tract. Best Pract Res Clin Gastroenterol 2010; 24: 27-34
  93. Treatment of intestinal T-cell lymphomas • No guidelines are available for the management of EATL (Enteropathy associated T-cell lymphoma) although anthracyclin-based chemotherapy is a mainstay treatment modality for overt EATL with a poor response* *Babel N, Paragi P, Chamberlain RS. Management of Enteropathy-Associated T-Cell Lymphoma: An Algorithmic Approach. Case Rep Oncol 2009; 2: 36-43
  94. • Treatment of either EATL or extranodal NK-/T-cell lymphoma, must be aggressive. • Historical data with standard CHOP show poor response in all T-cell lymphomas. Treatment of intestinal T-cell lymphomas
  95. • Based on these unsatisfactory outcomes in extranodal NK-/T-cell lymphomas, a novel regimen called SMILE (steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide) was developed. Treatment of intestinal T-cell lymphomas
  96. • This regimen consists of – o methotrexate 2 g/m2 on day 1; o ifosfamide 1500 mg/m2 on day 1, o etoposide 100 mg/m2 on day 1, and o dexamethasone 40 mg/body from days 2 to 4; and o L-asparaginase a total of 7 doses 6000 U/m2 every other day from day 8 to day 20. • SMILE appeared to be more effective than CHOP* Treatment of intestinal T-cell lymphomas *Yamaguchi M, Suzuki R, Kwong YL, Kim WS, Hasegawa Y, Izutsu K, et al. Phase I study of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy for advanced-stage, relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma and leukemia. Cancer Sci. 2008;99(5):1016–20
  97. • It was reported that 66% of EATL patients undergoing surgical resection followed by combination chemotherapy and autologous stem cell transplantation can achieve a sustained complete response* *Bishton MJ, Haynes AP. Combination chemotherapy followed by autologous stem cell transplant for enteropathyassociated T cell lymphoma. Br J Haematol 2007; 136: 111-113
  98. Colorectal lymphoma
  99. Colorectal lymphoma • Colorectal lymphoma constitutes 6%-12% of all gastrointestinal lymphomas. • Most colorectal lymphomas are secondary involvement of the wide spread diseases.
  100. • Primary colorectal lymphoma is very rare, constituting only 0.2% of all malignant tumors arising from the colorectal region with caecum, ascending colon and rectum more often affected
  101. • The disease predominantly affects males in the fifth-seventh decade of life with main complaints of – o abdominal pain, o loss of weight, o palpable abdominal mass or o lower gastrointestinal bleeding.
  102. • Obstruction and perforation are relatively rare in patients with colorectal lymphoma • Lymphoma of the colorectal region is mostly the B-cell lineage as other sites of the gastrointestinal tract. • Primary colorectal lymphoma comprises low grade B-cell lymphoma arising from MALT, MCL and T-cell lymphoma besides large B cell lymphoma.
  103. • The role of H. pylori in the pathogenesis of colorectal lymphoma has not been fully established* • Colorectal MALT-lymphoma is less common in colon and rectum than in small intestine. • MCL in the colorectal region presents usually in the setting of diffuse systemic diseases. *Niino D, Yamamoto K, Tsuruta O, Maeda T, Yakushijin Y, Aoki R, Kimura Y, Hashikawa K, Kiyasu J, Takeuchi M, Sugita Y, Ohshima K. Regression of rectal mucosa-associated lymphoid tissue (MALT) lymphoma after antibiotic treatments. Pathol Int 2010; 60: 438-442
  104. • The radiologic appearances of colorectal lymphoma are variable and significantly overlapped with other benign and malignant condition of the colorectal region.
  105. • Peripheral T-cell lymphoma presents as a diffuse or focal segmental lesion with extensive mucosal ulceration similar to that observed in granulomatous conditions as Crohn’s disease or tuberculosis.
  106. Treatment – Colorectal Lymphoma
  107. Treatment – Colorectal Lymphoma • Although chemotherapy remains the mainstay of management of aggressive lymphomas, the vast majority of patients undergo surgery • The regimens containing cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or addition of rituximab to CHOP are first-line therapies according to the cell of origin
  108. • Curative approach to MCL, which is primarily seen in elderly men, consists of chemotherapy followed by radiation of 30 Gy to the involved site • Radiotherapy with lower doses may also play a role in a palliative setting, especially in bleeding in colorectal lymphomas.
  109. Extranodal Involvement of Gastrointestinal Tract by Systemic Lymphomas
  110. • 40% of NHL cases will present with a primary or secondary extranodal involvement* • Secondary involvement of extranodal tissue as part of generalized lymphoma is more common than primary extranodal disease in which there is a dominant extranodal component without or with minor nodal involvement. Extranodal Involvement of Gastrointestinal Tract by Systemic Lymphomas *Koniaris LG, Drugas G, Katzman PJ, Salloum R. Management of gastrointestinal lymphoma. J Am Coll Surg. 2003;197(1):127–41.
  111. • The GI tract is the most common extranodal site involved, with lymphoma accounting for 5–20% of all cases* *Ghimire P, Wu GY, Zhu L. Primary gastrointestinal lymphoma. World J Gastroenterol. 2011;17:697–707.
  112. • The clinical manifestations of secondary GI lymphomas depend principally on the involved site and can be lymphoma-related “B-symptoms” • Site-related symptoms are mainly - o dyspepsia, o abdominal pain, o nausea or vomiting, and o anorexia. • Symptoms such as weight loss, vomiting, hematemesis/ melena, and perforation are alarming and are more frequent in aggressive lymphomas
  113. • Diffuse large B-cell lymphoma (DLBCL), • follicular lymphoma (FL), • mantle cell lymphoma (MCL), and • Burkett’s lymphoma (BL) are the dominant systemic histological subtypes in extranodal lymphomas, especially in the gastrointestinal tract.
  114. • The diagnosis of systemic lymphomas is best made by examining the excisional tissue biopsy, most commonly a lymph node. • This allows assessment of nodal architecture and provides adequate material for molecular studies.
  115. Treatment – Secondary GI Lymphoma
  116. Treatment – Secondary GI Lymphoma • Secondary GI lymphomas are generally in advanced stage at the time of presentation • Rituximab-based chemotherapy is the cornerstone of the treatment in secondary GI lymphomas
  117. • The nodal DLBCL with non-bulky limited stage are treated with combined modality therapy consisting of abbreviated systemic chemotherapy (i.e., three cycles of R-CHOP) and involved field radiation therapy • An acceptable alternative is the administration of full course (6–8 cycles) systemic chemotherapy plus rituximab without radiation
  118. • Multiple regimens used in other B-cell lymphomas have demonstrated activity in FL, including o CHOP and o CVP (cyclophosphamide, vincristine, and prednisone) as well as o Fludarabine based regimens (fludarabine and cyclophosphamide [FC]; fludarabine, cyclophosphamide, and mitoxantrone [FCM]), o Chlorambucil, and o Bendamustine in combination with rituximab
  119. • MCL is usually responsive to a variety of initial therapies, but relatively short-term remissions are obtained with conventional chemotherapy regimen • When the patients become symptomatic, first-line therapy choices include o R-CHOP, o R-Bendamustine
  120. • Chemotherapy for BL has traditionally involved intensive therapy with regimens such as - o R-HyperCVAD, o CODOX-M/ IVAC (cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high dose cytarabine)
  122. FUTURE PERSPECTIVE • There has been a tremendous leap in the diagnosis, staging and management of gastrointestinal lymphoma in the last two decades • With a better insight into its etiology and molecular aspect, various critical signaling pathways provide an impetus with greater benefits. • Identification of the cell surface antigens has led to the introduction of monoclonal antibodies like Rituximab and radioimmunotherapy that can result in a more targeted approach with a significant impact for the overall management of lymphoma.
  123. • A deep understanding of the role of monoclonal antibodies* in the pathogenesis of gastrointestinal lymphoma has led to development of – o the second and third generations of anti CD-20 antibodies (ofatumumab, veltuzumab, ocrelizumab), o anti CD-22 antibodies such a Epratuzumab, o anti CD-30 antibodies such as SGN-30, o anti CD-40 antibody SGN-40, and o anti vascular endothelial growth factor (VEGF) antibody bevacizumab *Elstrom RL, Martin P, Leonard JP. New biologic agents and immunologic strategies. Hematol Oncol Clin North Am 2008; 22: 1037-1049, x-xi
  124. • Furthermore, addition of cytokines and other immune modulators has a boon resulting from a better understanding of the antibody activities at targeted tissues. • Agents targeting the Bcl-2, Syk and the PI3K/AKT/mTOR pathways have emerged as a more biologically- focused management with further development in treatment of GI Lymphoma
  125. Thank You

Editor's Notes

  1. anaplastic large cell lymphoma 
  2. Human T-cell lymphotropic virus type 1
  3. The use of the 2 substances, barium and gas, is called a double contrast study.
  4. Involved-field radiation therapy (IFRT) is a term used for delivering radiation to only those areas of the body involved by lymphoma. For example, if lymphoma affects the left side of the neck, IFRT will deliver radiation to the entire left side of the neck.
  5. immunoproliferative small intestinal disease
  6. Systemic lymphomas may secondarily involve the GI tract.