GI lymphomaSHANKAR ZANWAR
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 lymphomaBautista J gastro-onco 2012
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
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
Distribution
Papaxoinis, Leuk Lymphoma 2006
Stomach68%
SI9%
Ilececal7%
More than 1
site13%
Rectum2%
Diffuse colonic1%
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
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
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
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
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
Genetic aberrations in gastric MALToma
Four main chromosomal translocations1. 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
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
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
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
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
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)
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
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 studyStathis, 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
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
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
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
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.
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
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 PETAdams, Eur J Nucl Med 2014
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%
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
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
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
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 spreadLee, Leuk Res 2007
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
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
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
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
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
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
WHOa. Diffuse, dense, compact & benign Lymphoproliferative mucosal infiltrationb. A + circumscribed immunoblastic in SI/ mesenteric LNc. Diffuse immunoblastic lymphoma
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
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
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 trialsSaghir J Clin Onco 1995
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%
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
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
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)
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
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
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
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
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
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
Concluded that chemo alone was non inferior to chemo+surgery
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