gastrointestinal tract lymphoma

Gastrointestinal Tract Lymphoma

Dr. Shad Salim AkhtarMBBS, MD, MRCP(UK), FRCP(Edin), FACP(USA), Member AUICC Fellows

Consultant Medical OncologistMedical DirectorPrince Faisal Oncology Center & KFSHProf. of Clinical Medicine, Qassim Medical UniversityBuraidah, Al-Qassim, KSA

Non Hodgkin's Lymphoma Heterogeneous collection of lympho-proliferative

diseases Is it the same disease at all sites??? Major divisions

Nodal Extra nodal

Around 33-40% are extra nodal GIT is the commonest extra- nodal site

Around 50%

Henessey BT et al. Lancet Oncol 2004;5:341

Extra nodal NHL Clinically dominant (>75%) extra nodal

component with No or Minor nodal involvement (25%) Tonsils / Waldeyer’s ring??

Zucca E et al: Ann Oncol 1997; 8:727

GI NHL-Definition Localized disease to the GIT

Stage IE, IIE disease

Lymphoma patients exhibiting GI symptoms or have a predominant lesion in GI

Dawson IMP et al: Br. J Surg 1961; 49:80

Lewin KJ et al: Cancer 1978; 42:693

Haber DA et al: Semin Oncol 1988; 15:154

All patients who present with NHL that apparently originated at an extra nodal site even in the presence of disseminated disease, as long as the extra nodal component is dominant”

GI NHL-Definition

Krol ADG et al: Ann Oncol 2003; 14:131

NHL-Increasing incidence 1970 10.2/100,000 1990 18.5/100,000 81% increase or 3.6% per year Extra nodal NHL 3-6.9%/year Nodal NHL 1.7-2.5%/year

Vose JM et al: Hematology 2002; 242

Ries LAG et al: National Cancer Institute 2002`

GI NHL-Sites of involvementAuthor Total Gastric IntestKoch P 371 277 70Liang R 442 238 184Radaszkiewicz T 307 264 59Morton JE 175 78 95Azab MB 106 55 43Amer MH 185 94 91El Foudeh M 215 185 66Nakamura S 455 342 96Ducreux M 78 42 13

GI NHL-Major symptomsPainNausea vomitingBleedingWeight lossDiarrheaAcute abdomen

GI NHL-Symptoms versus site

Stomach Small intestine

Colorectal

Pain Pain PainNausea & Vomiting

Obstruction Bleeding

Weight loss Weight loss DiarrheaBleeding Malabsorption

Crump M et al: Semin Oncol 1999; 26:324

GI NHL-Staging system TNMI Single nodal region

Localized single extra lymphatic organ/site IEII 2 or more node regions same side of diaphragm

Localized single extra lymphatic organ/site with its regional nodes+/- other nodes on the same side of diaphragm

IIE

III Node regions both sides of diaphragm+/- localized single extra lymphatic organ/siteSpleen / Both

IIIEIIISIIIES

IV Diffuse or multi focal involvement of extra lymphatic organs+/- regional nodes; isolated extra lymphatic organ and non regional lymph nodes

Sobin LH et al: TNM Manual 6th Edition 2002; 238

GI NHL-Staging systemStage I

Tumor confined to the GI tract Single primary site or multiple non contiguous

lesionsStage II

Tumor extending into abdomen from a primary GI siteNodal involvement

II1 local (paragastric / paraintestinal) II2 distant (mesenteric, para-aortic, paracaval, pelvic,

inguinal)Rohatiner A et al: Ann Oncol 1994; 5:397

Stage IIE Penetration of serosa to involve adjacent

organs or tissuesStage IV

Disseminated extra nodal involvement or GIT lesion with supradiaphragmatic nodal

involvement

GI NHL-Staging system

Rohatiner A et al: Ann Oncol 1994; 5:397

? X to denote the organ of origin X [stomach] II (gastric NHL with local nodes

involved) X [stomach, colon] II

Addition of IP index as in AJCC Cancer Staging Manual 6th Edition?

GI NHL- StagingSuggested modifications

Armitage JO; N Engl J Med 2005; 352:1250Grothus-Pinke B et al: Ann Oncol 1996; 7:S126

GI NHL-Work up History & physical examination Weight loss not recorded as a B symptom Waldeyer’s ring assessment especially with

limited GI involvement Routine bloods Endoscopic examination CT Barium studies Bone marrow examination!!! Endoscopic USG

GI NHL-Do they need laparotomy for diagnosis?

In 30-50% of intestinal NHL who may present as an emergency

Endoscopic biopsy from accessible lesions Diagnostic accuracy 62% to 98.5% First attempt diagnosis 80% of

above May miss areas of transformation

Al Akwaa AM et al: Worl J Gastroenterol 2004; 10:5

FNAC Laparoscopic biopsy

Frozen section facility Bone marrow in the same sitting

All tissues must be sent for Histological Immunohistochemistry Cytogenetic studies

GI NHL-Diagnosis?

Kaleem Z et al: Am J Clin Pathol 2001; 115:136Koniaris LG et al: J Am Coll Surg 2003; 197:127

GI NHL-Histological types Diffuse B cell large cell

Secondary DLBCL Extra nodal marginal zone lymphoma (MALT) Follicular lymphoma Mantle cell lymphoma Burkitt’s lymphoma Enteropathy type T cell lymphoma Peripheral T cell lymphoma NOS Majority of cases seen in KSA are DLBCL type

Risk of relapse from complete response according to the primarysite of the lymphoma. GI, gastrointestinal.

J Clin Oncol 23. © 2005Lo´ pez-Guillermo et al

DOI: 10.1200/JCO.2005.07.155

Overall survival of 382 patients with diffuse large B-cell lymphomaaccording to the primary site of the lymphoma. GI, gastrointestinal.

J Clin Oncol 23. © 2005 in pressLo´ pez-Guillermo et al

DOI: 10.1200/JCO.2005.07.155

OS and EFS of nodal vs extra nodal lymphoma in 1168 patients including 216 GI lymphomas defined as per Krol ADG et al.

Krol ADG et al: Ann Oncol 2003; 14:131

Extra nodal lymphomas-Why do these do better Gene expression of typical germinal center

type B cell rather than activated circulating B cell. Former better prognosis

Additionally bcl2 protein expression in the absence of t(14:18)

translocation are susceptible to rituximab. ??Significance in GI lymphomas

Armitage JO: N Engl J Med 2004; 325:1250

J Clin Oncol 23. © 2005 in pressLo´ pez-Guillermo et al

Is surgical resection important for?Definitive diagnosisImproving survival (stage I & II)Preventing complications

Gastric DBCLC NHL-Therapy questions?

Role of radiotherapyRole of chemotherapyWhich chemotherapy

Gastric DBCLC NHL-Therapy questions?

Gastrectomy – Points in favor Multiple studies

Stage I surgical resection may be curative ? The number of MALT lymphomas in these series

Patients undergoing radical excision have a superior outcome ? Inidicator of low burden disease

Multimodality treatment better survival Small non randomized retrospective studies Data collected is of many years

Crump M et al: Semin Oncol 1999; 26:324

Role of radiotherapyMultiple retrospective studies positive for

multimodality therapyHas been used as the sole modality of

therapy especially in MALTPost operative adjuvant 88% OS rateProblems of late toxicityReserve for residual disease, elderly or

inoperable patientsKoniaris LG et al: J Am Coll Surg 2003; 197:127

Adjuvant RT in Early Stage NHL

Miller TP et al NEJM 1998;339:21

Comp surg excisionComplete response5 yrs surv RFS5 yrs surv OSLife threat toxic

58104/243(73%)64%72%40%

58106/142(75%)77%82%30%

0.030.020.06

CHOP 8 CHOP3+RT

Stage I/II lymphoblastic NHL excluded

What therapy?Stage IPI Rx 5yr

MSurLimited stage

Proposed description

I, IE 0 CHOP(3) + RT

>90% Yes Very limited

I, IE, II, IIE (non bulky)

>=1 CHOP(3) + RT

70% Yes Limited

Bulky II, IIE

>=1 CHOP(8) 50% No Advanced

Fisher RI et al: Hematology 2004; 221

German multi-center study Prospective non randomized Surgery left to the treating physician Post operative therapy standardized

277 patients accrued and 185 analyzed IE 96; II1E 58; II2 E 31 High grade 101 pts (54.6%)

70% without low grade component

Type Stage CT RTHG IE CHOP 4 EFRT (30G) +

boostIIE COP 6 IFRT (40G)

Gastric Lymphoma Therapy- German MC Study

Koch P et al: J Clin Oncol 2001; 19:3874

Gastric Lymphoma Therapy- German MC Study

Type Stage CT RT

LG resected IE X EFRT

IIE COP 6 EFRT

LG unresec IE EFRT+boost

IIE COP 6 EFRT+boost


Gastric Lymphoma Therapy- German MC StudyHigh grade No surgery Surgery+CRTNumber 54 47EFS 69.6% 76.6% NSOS 77.9% 78.9% NSLow gradeNumber 52 32EFS 87.6% 82.2% NSOS 90.2 87.2 NS


No Surgery

Surgery

Event free survival surgical intervention & conservative therapy only

Koch Petal:JClinOncol 2001;19:3874

nonrandomized comparison; all histologic subtypes


EFS

EFS of gastric lymphoma resected completely vs partial or incomplete resection


Gastrectomy present status Organ preservation is an important quality of

life issue Resectabilty rates range from 60-80% Operative mortality and morbidity rates range

from 3-25% Patient preference, tumor size, stage and

resectability should be considered

Gastrectomy ideal approach

“in between the extremes of never and always”

Which chemotherapyCHOPVariationsAdditional immunotherapy

Gastric NHL-Chemotherapy

Binds CD20, which is present on normal and malignant pre-B and mature B cells; >90% of B-cell NHL express CD20

May induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity, based on in vitro data

Also triggers apoptosis (programmed cell death) in vitro

No apparent dependence on cell cycle for activity

Rituximab

DLBCL Gastric origin Algorithm for therapy

Localized (stage I, II)

Advanced diseaseComplications

Complete resectionPossible

Not possible

CHOP X 6-8 +RituxCHOPX3+Ritux

IFRT (avoid in young)

Residual disease

EFRT (avoid in young)

Resection

CR

GI NHL-Site of disease-Geographical VariationSite USA Ger Fra KSA NGui Nigeria JordGast 77 277 43 185 24 19 23SmallIntest

36 35 39 66* 55 62 59

Ileo-cecal

26 13

Colon 17 3 10 21 19 15Rect 6 6Panc 10 5 0 0Diffu 5 24 16 10 0 2

Kniaris LG :J Am Coll Surg2003;197:127 Koch P :JCO 2001;19:3861

Intestinal DLBCL Surgical intervention is less controversial

Acute presentation more common Completely resected patients do better Generally poorer prognosis as compared to

gastric Survival

Early stage disease better Surgery+CT+RT 50-70% Single modality 30-50%

Koniaris LG et al: J Am Coll Surg 2003; 197:127Daum S et al: J Clin Oncol 2003; 21:2740

Marginal Zone

Mantle ZoneGerminal Centre

(Contains post germinal centre B cells, monocytoid B cells, plasma cells and centrocyte like cells)

Normal MALT

Rooney N et al: Curr Diag Pathol 2004; 10:69

Calam J etal. BMJ 2001;323:980

Relation of H pylori infection to UGI conditions

H pylori and Malt lymphoma ~90% have H pylori in gastric mucosa~90% have H pylori in gastric mucosa Case control studies confirm relationship Case control studies confirm relationship

between previous infection and lymphomabetween previous infection and lymphoma Clonal B cell detection in chronic gastritis Clonal B cell detection in chronic gastritis

which precedes lymphomawhich precedes lymphoma H pylori strain specific T cells promote H pylori strain specific T cells promote

lymphoma growth in culturelymphoma growth in culture Eradication of H pylori causes regression in Eradication of H pylori causes regression in

75% of caces75% of caces

Gastric MALT lymphoma MALT reacts with the antigen

present within the lumen An Pr Cells +H pyhlori

antigen+CD4+ T cells stimulate peoliferation of B cells

B cells synthesize immunoglobulins

Immunoglobulins react with autoantigens

Parsonnet J et al: N Engl J Med 2004; 350:213

Rooney N et al: Curr Diag Pathol 2004; 10:69

Gastric MALT typesA low grade classical

<5% blasts and clusters of <10 cells

B 10-20% transformed cells Clusters of >20 cells

C high grade transformation with sheets of transformed cells

D no MALT component is recognizableIsaacson PG: Hematology 2001; 241

MALT lymphoma management Careful imaging

CT scan Endoscopic ultrasonography

Sufficient tissue to Differentiate from

Mantle cell lymphoma Follicular lymphoma

Confirm presence of more transformed clone Immunohistochemical studies (bcl2 expression)

Gastric MALT management Antibiotic therapy

Regression in approximately 75% cases Time to regression may be as long as 18 months Predictors of failure of antibiotic therapy

t(14:18) do not respond to antibiotics Node positive disease Depth of invasion muscularis mucosa

Lymphoma clone persists Therefore it becomes dormant rather than disappearIsaacson PG; Best Prac & Res 2005; 18:57

Cavalli F et al: Hematology 2001; 241

Surgical resection Antrectomy usually adequate

Radiotherapy Chemotherapy Alone or in combinations 5 yr DFS

>95% in IE 75% in IIE

Gastric MALT management antibiotic failure or advanced

Koniaris LG: J Am Coll Surg 2003; 197:127

IPSID MALT type B cell lymphoma Proximal small intestine involved Geographical distribution

Mediterranean Middle East Africa Far East

Children & young adults Monotypic truncated immunoglobulin α heavy

chainLecuit M et al: N Engl J Med 2004; 350:239

IPSID Campylobacter jejuni

Small group of patients (4/6) FISH, PCR, DNA sequencing and

immunohistochemistry Early stages respond to antibiotics Non responsive pts progress to lymphoma

Lymphoplasmacytic & immunoblastic Locally invasive and metastatic

Poor prognosis

gastrointestinal tract lymphoma

Health & Medicine