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GI Lymphoma Overview: Types, Diagnosis and Treatment
- 2. Overview Lymphoma are solid malignancies of lymphoid system – Hodgkins(HL) and non hodgkins(NHL) HL is rare in GI tract Of all GI malignancy lymphomas – 1-4% GI tract is most common site of lymphomas after LN Majority of the GI lymphomas are B cell lymphoma Bautista J gastro-onco 2012
- 3. Lymphoid cells array Lymphoid tissue in gut is near the mucosa and named as Mucosa Associated Lymphoid Tissue(MALT) e.g. Peyer’s patches Germinal center – Ag exposed B cells – somatic mutation center become more Ag specific Marginal zone – memory cells’ residence Mantle – Naïve(unexposed) B cells zone
- 4. Family of GI lymphomas Gastric – Marginal Zone B cell lymphoma/ MALToma Diffuse large B cell lymphoma(DLBCL) Uncommon types Small intestinal B-cell IPSID Non-IPSID MALToma DLBCL Mantle Follicular Burkitt’s T-cell Enteropathy associated T cell lymphoma Other sites Walyder’s ring Esophagus Liver and biliary tree Pancreas Colon, rectum and anus Immunodeficiency – related Post transplant HIV associated
- 5. Distribution Papaxoinis, Leuk Lymphoma 2006 Stomach 68% SI 9% Ilececal 7% More than 1 site 13% Rectum 2% Diffuse colonic 1%
- 6. Predisposing factors H. pylori infection Autoimmune diseases Sjogren’s RA SLE, Wegners in all these immunosuppressive Rx culprit Immunodeficiency/suppression Wiscot Aldrich SCID – severe combined immunodeficiency syndrome HIV Celiac disease Inflammatory bowel disease – controversial Nodular lymphoid hyperplasia
- 7. Staging Ann arbor staging for HL is inadequate for GI lymphoma Several alternatives available Paris staging Lugano Paris T1-T4 – mucosal to adjacent organ invasion N1-N3 – regional to extra abdominal spread M – mets non contiguous involvement B – bone marrow infiltration
- 9. Gastric lymphomas These are 5% of all gastric neoplasms Most of these (90%) are either MALToma or DLBCL Most common presenting symptoms Epigastric pain – 78-93% Anorexia – 47% Weight loss – 25% Nausea and vomiting - 18% Occult GI bleeding – 19% Early satiety B symptoms – fever, weight and loss night sweats Hematemesis and melena are uncommon Koch P J Clin Onco 2001
- 10. Gastric MALToma Gastric MALToma a.k.a marginal zone B cell lymphoma Gastric mucosa does not contain lymphoid tissue normally, MALT is acquired in response to infection or autoimmune process Malignant transformation of B cells in these MALT results this MALToma Majority of cases the inciting cause is H pylori – lymphoma regression in 50-80% on Hp eradiction Nakamura, Gut 2012
- 11. Pathogenesis Hp infection Immune response and MALT formation Hp specific T cell Growth signals to B cells B cell proliferation Somatic hypermutation in Ig to increase Ag affinity Continued B cell proliferation for prolonged time Accumulation of genetic aberrations Autonomy - Independence from T cell for growth factors
- 12. Genetic aberrations in gastric MALToma Four main chromosomal translocations 1. t(11:18) – 30% API – 2 gene apoptosis inhibition gene MALT-1 – NFķB gene Less aggressive form, But less responsive to antibiotics 2. t(14:18) – 20% MALT -1 gene to Ig heavy chain gene More common in eye rare in GI 3. t(1:14) – bcl-10 gene – to Ig heavy chain gene – 5% 4. t(3:14) in rare cases
- 13. Pathology Histologically – Characteristic feature – lympho-epithelial lesion Defined as un-doubtful invasion and partial destruction of gastric glands or pits by tumor cells Tumour cells are small to medium lymphocytes. Cytological atypia, presence of plasma cells with dutcher bodies differentiate from gastritis Ruskone Gut 2011
- 14. Immuno-histochemistry and molecular tests MALToma express pan B antigens CD 19, CD 20, CD 79a +ve CD 5, CD 10, CD23 cyclin D are absent Differentiation from B cells – MALToma are CD 43 +ve Molecular test PCR assay of immunoglobulin heavy chain assist in documentation of monoclonality But monoclonality may also be seen in gastritis Not for practical purposes - reserved for research
- 15. Diagnosis Clinical features as described earlier Median age 60 years Nearly 40 % of gastric lymphomas Endoscopy findings Erythema Erosions Ulcers Most common in body, antrum and cardia
- 16. Biopsies Bx from both suspicious appearing and normal lesion – since lymphoma can be multifocal with intervening normal appearing mucosa, including D2 and OGJ Aim for largest biopsy specimen as possible Conventional pinch biopsy may miss diagnosis, since lymphoma may infiltrate s/mucosa without involving mucosa – more so when no obvious mass Jumbo biopsy, snare biopsies, well technique and needle aspiration can increase yield in suspected cases EUS guided Bx increase outcome
- 17. Additional work up Hp should be tested – HPE, fecal Ag test or breath test EUS for depth of infiltration and assessment of perigastric lymphnodes Additional staging CT – chest, abdomen and pelvis Bone marrow aspiration and Bx LDH and B2 microglobulin levels PET is not useful since MALToma have low uptake on FDG Optional pretreatment test – FISH/PCR for t(11:18)
- 18. Treatment Large RCTs to prove the best treatment are not available Trial of antibiotics for Hp eradication should be offered to all even advanced disease can show regression When early stage disease fails [(or those with t(11:18)] on antibiotic therapy, CT/ RT should be planned Nearly 75% respond over median of 5 months
- 19. Early MALToma H pylori eradication – Nearly 20 % will require second course of Hp therapy After a median follow up of 6.8 years ~22% relapsed in a study Stathis, Ann Onco 2009 Response evaluation – 4-8 wks after completion of Rx urease breath test After successful eradication – OGD with Bx, every 3 mon after Rx until histological response(absence/sparse l’cytes in lamina propria) & every 6 mon X 2yr and then yearly Copie – Bergman Gut 2003 Treatment failures (no response after 12 – 18 months) should go for RT
- 20. Locally advanced disease T2 disease is a grey area best treatment as to surgery/CT/RT is under debate All should receive antibiotics along with either of the theapies Modality Cure rate Comment Event free survival - 7.5y Overvall survival Surgery – gastrectomy 80% ↓ QOL 52% 80% Chemotherapy – Cyclophos/chlorambucil +fludarabine +/- rituximab 80- 100% Acceptable S/E 52% 75% Radiation – 30-40 Gy 90- 100% Preserve gastric function 87% 87% Avlies, Med Onco, 2005
- 21. Advanced MALToma Lugano IV/ Paris stage with N1-N3 Worst prognosis of all stages Antibiotics if Hp is +ve, chemotherapy is started when they become overtly symptomatic Local management is with radiation Surgery in cases to case basis Those who have failed on multiple Rx regimen, radio-immunotherapy with ibritumomab can be tried(Rituximab linked to radioisotope) Hoffman, Leuk – lymphoma 2011
- 22. Diffuse large B cell lymphoma Most common lymphoma of stomach – nearly 50% of all lymphomas Higher in developing countries, mean age 60 y, M>F Etiology is poorly understood Many large cell tumours(20-40%) are suspected to arise from MALTomas But rest of the DLBCL have no e/o of low grade MALToma tissue Role of Hp is thus suggested in few cases
- 23. Pathology Microscopic examination Compact clusters, confluent aggregates or sheets of large cells (immunoblasts like cells) and centroblasts IHC- CD 19,20,22 and CD79a positive and also CD45 Differentiation from MALToma – BCL2 negative in DLBCL.
- 24. Clinical findings They may occur as large tumours and may present with GOO Common sites are – antrum and body Appear as large ulcers, multiple shallow ulcers May present as adenoca. like features
- 25. Other work up Hp detected in 35% more often in those which have evolved from MALToma EUS for depth assessment Unlike MALToma PET-CT has special role in DLBCL, more sensitive than BM biopsy Sns – 88.7% and Sps – 99.8% for detection of BM involvement BM negative - 13% patients detected +ve by PET Adams, Eur J Nucl Med 2014
- 26. Treatment of DLBCL Current consensus – chemoimmunotherapy +/- RT Traditionally surgery was 1st choice – 70% stage 1 disease free for 5 years but 5% -10% risk mortality Aviles Ann Surg 2004 Modality for localized dis 10 year event free survival 10 overall survival Surgery 28% 54% Surgery+RT 23% 53% Surgery+CT 82% 92% Chemotherapy 92% 96%
- 27. Chemotherapy DLBCL CHOP - R – Cyclophosphamide, Hydroxidoxorubicin, Oncovin, Prednisone and Rituximab Standard regimen – for Lugano I and II for 3-4 cycles. For stage IV 6-8 cycles With any Hp evidence – antibiotics but alone not as treatment. Persky J clini Onco 2008 Previously feared concept of perforation with CT is seen in <5% of patients. Vaidya R, Ann Onco, 2013
- 28. Small intestinal lymphoma Approx – 30% occur in small intestine Most common site of occurrence – ileocecal area Marginal zone and follicular are considered indolent – incurable but controllable by chemo DLBCL, mantle and Burkitt’s – more aggressive ones
- 29. MALToma of small intestine Most cases seen in elderlies May present as annular and exophytic tumours Usually confined to SI or regional LN Histological and immunophenotypic features same as gastric MALToma, if a/w large cells –poor progn. Hp association not commonly documented. Treatment is generally surgical, data regarding CT insufficient Five yr survival – ~75% Ishii Y Hemat Onco 2012
- 30. Diffuse large B cell lymphoma of SI DLBCL similar to gastric in histology and clinical behavior C/f – abdominal pain, wt. loss, obstruction, abdominal mass, bleeding and perforation Half have localized and half have distant spread Surgery for obstruction and perforation CHOP- R +/- RT is treatment of choice Prognosis depends on age and disease spread Lee, Leuk Res 2007
- 31. Mantle cell lymphoma Presents as widespread adenopathy, BM and extranodal involvement C/f pain, obs, diarrhea and hematochezia Endoscopy multiple polyps seen – lymphomatous polyposis(also be seen in follicular and MALToma) HPE – small atypical lymphocytes surrounding GC. Mesentric nodal masses on CT - Hamburger sign, nodal mass surrounding the mesenteric vessel
- 32. IHC pan B markers and T cells marker CD5 Pathogenesis - t(11:14) & cyclinD1 overexpression Obstructive masses – surgery, mainstay of Rx chemo. Initial responds to chemo – later refractory, median survival 3-5 yr. refractory cases – Ibrutinib trial. Dreyling Ann Onco - 2013
- 33. Follicular Lymphoma These are rare in GIT Most common – obstructing lesion at IC region May also present as multiple polyposis Pathogenesis – t(14:18) over expression of bcl-2 Management – wait and watch if incidentally detected Standard chemo radio therapy if symptomatic
- 34. Burkitt’s Lymphoma Highly aggressive tumour in HIV negative pts. Common sites – ileum, cecum and mesentry Medium sized cells with round nuclei, multiple nucleoli – interspersed macrophages – starry sky appearance Rapidly fatal if untreated, dramatic response with chemo Cure rates 50-90%, High risk of tumour lysis
- 35. Immunoproliferative small intestinal disease Also known as – α – heavy chain disease / Mediterranean disease Usually in 2nd or 3rd decade Usually seen in developing countries Pathogenesis of this is similar to MALToma stomach and Hp association B lymphocytes in intestine are stimulated in response to infectious agents(esp C.jejuni) proliferate initial need of stimulation by growth run amok
- 36. Associated with production of α heavy chain Gross lesion commonly in proximally in SI Though histological disease is widespread Various staging system based on extent of disease WHO a. Diffuse, dense, compact & benign Lymphoproliferative mucosal infiltration b. A + circumscribed immunoblastic in SI/ mesenteric LN c. Diffuse immunoblastic lymphoma
- 37. IPSID – clinical features Symptoms may be present for months to years Chronic diarrhea – initially intermittent voluminous and foul smelling – malabsorption, anorexia and significant wt. loss, fever(50%) O/e – Musc. wasting, clubbing, edema, late ascites H/Smegaly, abd. mass and peripheral l’denopathy Endoscopy – thickened folds, nodules, ulcers and s/mucosal infilteration non-destensible
- 38. Tests Hematology – anemia (B vit def.), ↑ESR(30%) Circulating lymphocyte count is low Stool examination – Giardia +ve C. jejuni – high incidence – detection by DNA PCR/ FISH or IHC studies on HPE of SI Serum Ig A levels are low Unique lab finding – presence of α chain prt. On electrophoresis
- 39. Diagnosis and treatment Endoscopic biopsy alone insufficient since deeper layers also involved staging laparoscopy, FNA of larger LN Treatment – no large trials Intensive nutritional supplementation Early disease – Antibiotics for 6/more months Tetracycline alone or ampi+metro Response rates 33-71% disease free survival – 43% @ 5y No response by 6m or advanced CHOP-R – complete response 67% and 58% surviaval @ 3.5 yr Total abdominal RT under is under trials Saghir J Clin Onco 1995
- 40. Enteropathy Asso. T cell Lymphoma EATL occurs as complication of celiac disease Rare malignancy – 0.016per 1 lakh Mean age 60, strict gluten free diet ↓ risk Normal intraepithelial lymphocytes – CD3/CD8 are polyclonal monoclonality leads to malignancy Evolves as spectrum – refractory celiac disease ulcerative jejunitis EATL Genetic rearrangements – gains in long arms of chr 1,5,7 and 9, 9q is most common – 58%
- 41. Pathology Gross – ulcerating, circumferential, nodules, plaques, strictures uncommonly large masses HPE - Large pleomorphic T cells background inflammation Variant type –II - monomorphic T cells, occurs in non- celiac pts. IHC – CD2, CD3, CD5, CD8 and CD 103 +ve Type I variant CD 56 –ve , type II CD 56 & MYC +ve
- 42. Clinical features and diagnosis Documented CD in past, but ~50% are ∆ed to have CD at presentation. S/s – abd. pain, wt. loss diarrhea or vomiting, fever night sweats, obs. or perforation Rarely palpable masses or lymphadenopathy ↑ ß2 microglobulin – 86% and LDH – 62%, Anemia – 91% and hypoalbuminemia 88% ∆ - endoscopy & duodenal Bx, FDG-PET may aid in identifying malignant nature of disease Nakamura, Gut 2012
- 43. Treatment No large trials Surgery if feasible for large masses Chemo- CHOP-R, but only <50% are fit for chemo since nutritionally deprived and <50% of this complete Rx Relapse in 80% after 6 months of diagnosis Other options autologous stem cell transplant 44 pts. tried 4 year survival – 59% Jantunen – Blood 2013 Newer under trials – Alemtuzumab(anti CD52) and Brentuximab(anti CD 30)
- 44. Other GI sites Primary hepatic lymphoma – M>F, median age 50 Multilobulated mass or single or multiple nodules ∆ - Bx, to check Hep C if marginal zone lymphoma – response to Hep C Rx documented also in splenic lymphoma Salmon, Clin Lymphoma myeloma 2008 Long term survival – after surgery Chemo if DLBCL
- 45. Primary pancreatic lymphoma – presentation similar to adenoca – pain, obs jaundice, chylous ascites HPE usually – DLBCL Rx – CHOP-R When Bil is high, stenting to ease chemo Colorectal lymphoma – MC site – cecum, most are early stages Treatment - Resection followed by chemo Gonzales, Am Surg 2008
- 46. Immunodeficency related lymphoma Post transplant lympho-proliferative disease(PTLD) Seen in 0.8 – 20% pts. post transplant Highest after heart-lung, also seen in BMTs Usually results from EBV transformed B cell proliferation HPE – polymorphic/ monomorphic May have symptoms like lymphoma depending on site Treatment – withdrawal of immunosuppression, CHOP regimen for nonresponders, RT/Surg for localized disease Other modalities – EBV Rx – acyclovir, IFN- α, donor WBC infusions
- 47. HIV associated NHL Risk of B cell NHL high in HIV Presence of lymphoma is AIDS defining condition MC - DLBCL, HIV asso. NHL are typically aggressive Unusual site presentation – anus and rectum With low CD4 count chemo tolerance poor Malignant ascites may be due to body cavity lymphoma caused by HHV-8 – kaposis Sa asso virus Disease progression rapid – survival few weeks- months Brimo Cancer 2007
- 48. Indian scenario Two recent studies one from south and another from north CMC study from south Neeraj Arora, Ashok Chacko , Ind J of pathology 2011 Total of 361 patients studied, over 10 years 336 primary GI lymphoma Rest were secondary
- 52. Another study from AIIMS Total of 77 patients enrolled. Aim – comparison of chemo vs chemo + Surg All pts. given chemo irrespective of stages - CHOP Vinod Raina, Ind Journal of cancer 2006
- 54. Concluded that chemo alone was non inferior to chemo+surgery
- 55. Thank You