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

Thank You