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Gastrointestinal Tract
Lymphoma
Dr. Shad Salim Akhtar
MBBS, MD, MRCP(UK), FRCP(Edin), FACP(USA),
Member AUICC Fellows
Cons...
Non Hodgkin's Lymphoma
 Heterogeneous collection of lympho-proliferative
diseases
 Is it the same disease at all sites??...
Extra nodal NHL
 Clinically dominant (>75%) extra nodal
component with
 No or Minor nodal involvement (25%)
 Tonsils / ...
GI NHL-Definition
 Localized disease to the GIT
 Stage IE, IIE disease
 Lymphoma patients exhibiting GI symptoms
or hav...
All patients who present with
NHL that apparently originated
at an extra nodal site even in
the presence of disseminated
...
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%/...
GI NHL-Sites of involvement
Author Total Gastric Intest
Koch P 371 277 70
Liang R 442 238 184
Radaszkiewicz T 307 264 59
M...
GI NHL-Major symptoms
Pain
Nausea vomiting
Bleeding
Weight loss
Diarrhea
Acute abdomen
GI NHL-Symptoms versus site
Stomach Small
intestine
Colorectal
Pain Pain Pain
Nausea &
Vomiting
Obstruction Bleeding
Weigh...
GI NHL-Staging system TNM
I Single nodal region
Localized single extra lymphatic organ/site IE
II 2 or more node regions s...
GI NHL-Staging system
Stage I
 Tumor confined to the GI tract
 Single primary site or multiple non contiguous
lesions
...
Stage IIE
 Penetration of serosa to involve adjacent
organs or tissues
Stage IV
 Disseminated extra nodal involvement ...
 ? X to denote the organ of origin
 X [stomach] II (gastric NHL with local nodes
involved)
 X [stomach, colon] II
 Add...
GI NHL-Work up
 History & physical examination
 Weight loss not recorded as a B symptom
 Waldeyer’s ring assessment esp...
GI NHL-Do they need
laparotomy for diagnosis?
In 30-50% of intestinal NHL who may
present as an emergency
Endoscopic bio...
FNAC
Laparoscopic biopsy
 Frozen section facility
 Bone marrow in the same sitting
All tissues must be sent for
 His...
GI NHL-Histological types
 Diffuse B cell large cell
 Secondary DLBCL
 Extra nodal marginal zone lymphoma (MALT)
 Foll...
Risk of relapse from complete response according to the primary
site of the lymphoma. GI, gastrointestinal.
J Clin Oncol 2...
Overall survival of 382 patients with diffuse large B-cell lymphoma
according to the primary site of the lymphoma. GI, gas...
OS and EFS of
nodal vs extra
nodal lymphoma
in 1168 patients
including 216 GI
lymphomas
defined as per
Krol ADG et al.
Kro...
Extra nodal lymphomas-Why
do these do better
 Gene expression of typical germinal center
type B cell rather than activate...
Is surgical resection important
for?
Definitive diagnosis
Improving survival (stage I & II)
Preventing complications
G...
Role of radiotherapy
Role of chemotherapy
Which chemotherapy
Gastric DBCLC NHL-Therapy
questions?
Gastrectomy – Points in favor
 Multiple studies
 Stage I surgical resection may be curative
 ? The number of MALT lymph...
Role of radiotherapy
Multiple retrospective studies positive for
multimodality therapy
Has been used as the sole modalit...
Adjuvant RT in Early Stage NHL
Miller TP et al NEJM 1998;339:21
Comp surg excision
Complete response
5 yrs surv RFS
5 yrs ...
What therapy?
Stage IPI Rx 5yr
MSur
Limited
stage
Proposed
description
I, IE 0 CHOP(3)
+ RT
>90% Yes Very
limited
I, IE,
I...
German multi-center study
 Prospective non randomized
 Surgery left to the treating physician
 Post operative therapy s...
 277 patients accrued and 185 analyzed
 IE 96; II1E 58; II2 E 31
 High grade 101 pts (54.6%)
 70% without low grade co...
Gastric Lymphoma Therapy-
German MC Study
Type Stage CT RT
LG resected IE X EFRT
IIE COP 6 EFRT
LG unresec IE EFRT+boost
I...
Gastric Lymphoma Therapy-
German MC Study
High grade No surgery Surgery+CRT
Number 54 47
EFS 69.6% 76.6% NS
OS 77.9% 78.9%...
No Surgery
Surgery
Event free
survival
surgical
intervention
&
conservative
therapy only
Koch Petal:JClinOncol 2001;19:3874
nonrandomized comparison; all histologic subtypes
Koch P et al: J Clin Oncol 2001; 19:3874
EFS
EFS of gastric lymphoma resected completely vs
partial or incomplete resection
Koch P et al: J Clin Oncol 2001; 19:3874
Gastrectomy present status
 Organ preservation is an important quality of
life issue
 Resectabilty rates range from 60-8...
Gastrectomy ideal approach
“in between the
extremes of never
and always”
Which chemotherapy
CHOP
Variations
Additional 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...
DLBCL Gastric origin
Algorithm for therapy
Localized (stage I, II)
Advanced disease
Complications
Complete resectionPossib...
GI NHL-Site of disease-
Geographical Variation
Site USA Ger Fra KSA NGui Nigeria Jord
Gast 77 277 43 185 24 19 23
Small
In...
Intestinal DLBCL
 Surgical intervention is less controversial
 Acute presentation more common
 Completely resected pati...
Marginal Zone
Mantle Zone
Germinal Centre
(Contains post germinal centre B cells, monocytoid
B cells, plasma cells and cen...
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 studi...
Gastric MALT lymphoma
 MALT reacts with the antigen
present within the lumen
 An Pr Cells +H pyhlori
antigen+CD4+ T cell...
Rooney N et al: Curr Diag Pathol 2004; 10:69
Rooney N et al: Curr Diag Pathol 2004; 10:69
Gastric MALT types
A low grade classical
 <5% blasts and clusters of <10 cells
B
 10-20% transformed cells
 Clusters ...
MALT lymphoma management
 Careful imaging
 CT scan
 Endoscopic ultrasonography
 Sufficient tissue to
 Differentiate f...
Gastric MALT management
 Antibiotic therapy
 Regression in approximately 75% cases
 Time to regression may be as long a...
 Surgical resection
 Antrectomy usually adequate
 Radiotherapy
 Chemotherapy
 Alone or in combinations
 5 yr DFS
 >...
IPSID
 MALT type B cell lymphoma
 Proximal small intestine involved
 Geographical distribution
 Mediterranean Middle E...
IPSID
 Campylobacter jejuni
 Small group of patients (4/6)
 FISH, PCR, DNA sequencing and
immunohistochemistry
 Early ...
Gastrointestinal tract lymphoma
Gastrointestinal tract lymphoma
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Gastrointestinal tract lymphoma

Lymphoma of GIT, NHL, Lymphoreticular malignancy

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Gastrointestinal tract lymphoma

  1. 1. Gastrointestinal Tract Lymphoma Dr. Shad Salim Akhtar MBBS, MD, MRCP(UK), FRCP(Edin), FACP(USA), Member AUICC Fellows Consultant Medical Oncologist Medical Director Prince Faisal Oncology Center & KFSH Prof. of Clinical Medicine, Qassim Medical University Buraidah, Al-Qassim, KSA
  2. 2. 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
  3. 3. 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
  4. 4. 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
  5. 5. 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
  6. 6. 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`
  7. 7. GI NHL-Sites of involvement Author Total Gastric Intest Koch P 371 277 70 Liang R 442 238 184 Radaszkiewicz T 307 264 59 Morton JE 175 78 95 Azab MB 106 55 43 Amer MH 185 94 91 El Foudeh M 215 185 66 Nakamura S 455 342 96 Ducreux M 78 42 13
  8. 8. GI NHL-Major symptoms Pain Nausea vomiting Bleeding Weight loss Diarrhea Acute abdomen
  9. 9. GI NHL-Symptoms versus site Stomach Small intestine Colorectal Pain Pain Pain Nausea & Vomiting Obstruction Bleeding Weight loss Weight loss Diarrhea Bleeding Malabsorption Crump M et al: Semin Oncol 1999; 26:324
  10. 10. GI NHL-Staging system TNM I Single nodal region Localized single extra lymphatic organ/site IE II 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/site Spleen / Both IIIE IIIS IIIES 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
  11. 11. GI NHL-Staging system Stage I  Tumor confined to the GI tract  Single primary site or multiple non contiguous lesions Stage II  Tumor extending into abdomen from a primary GI site  Nodal involvement  II1 local (paragastric / paraintestinal)  II2 distant (mesenteric, para-aortic, paracaval, pelvic, inguinal) Rohatiner A et al: Ann Oncol 1994; 5:397
  12. 12. Stage IIE  Penetration of serosa to involve adjacent organs or tissues Stage 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
  13. 13.  ? 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- Staging Suggested modifications Armitage JO; N Engl J Med 2005; 352:1250 Grothus-Pinke B et al: Ann Oncol 1996; 7:S126
  14. 14. 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
  15. 15. 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
  16. 16. 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; 115:136 Koniaris LG et al: J Am Coll Surg 2003; 197:127
  17. 17. 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
  18. 18. Risk of relapse from complete response according to the primary site of the lymphoma. GI, gastrointestinal. J Clin Oncol 23. © 2005Lo´ pez-Guillermo et al DOI: 10.1200/JCO.2005.07.155
  19. 19. Overall survival of 382 patients with diffuse large B-cell lymphoma according 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
  20. 20. 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
  21. 21. 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
  22. 22. Is surgical resection important for? Definitive diagnosis Improving survival (stage I & II) Preventing complications Gastric DBCLC NHL-Therapy questions?
  23. 23. Role of radiotherapy Role of chemotherapy Which chemotherapy Gastric DBCLC NHL-Therapy questions?
  24. 24. 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
  25. 25. Role of radiotherapy Multiple retrospective studies positive for multimodality therapy Has been used as the sole modality of therapy especially in MALT Post operative adjuvant 88% OS rate Problems of late toxicity Reserve for residual disease, elderly or inoperable patients Koniaris LG et al: J Am Coll Surg 2003; 197:127
  26. 26. Adjuvant RT in Early Stage NHL Miller TP et al NEJM 1998;339:21 Comp surg excision Complete response 5 yrs surv RFS 5 yrs surv OS Life threat toxic 58 104/243(73%) 64% 72% 40% 58 106/142(75%) 77% 82% 30% 0.03 0.02 0.06 CHOP 8 CHOP3+RT Stage I/II lymphoblastic NHL excluded
  27. 27. What therapy? Stage IPI Rx 5yr MSur Limited 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
  28. 28. German multi-center study  Prospective non randomized  Surgery left to the treating physician  Post operative therapy standardized
  29. 29.  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 RT HG IE CHOP 4 EFRT (30G) + boost IIE COP 6 IFRT (40G) Gastric Lymphoma Therapy- German MC Study Koch P et al: J Clin Oncol 2001; 19:3874
  30. 30. 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 Koch P et al: J Clin Oncol 2001; 19:3874
  31. 31. Gastric Lymphoma Therapy- German MC Study High grade No surgery Surgery+CRT Number 54 47 EFS 69.6% 76.6% NS OS 77.9% 78.9% NS Low grade Number 52 32 EFS 87.6% 82.2% NS OS 90.2 87.2 NS Koch P et al: J Clin Oncol 2001; 19:3874
  32. 32. No Surgery Surgery Event free survival surgical intervention & conservative therapy only Koch Petal:JClinOncol 2001;19:3874
  33. 33. nonrandomized comparison; all histologic subtypes Koch P et al: J Clin Oncol 2001; 19:3874
  34. 34. EFS EFS of gastric lymphoma resected completely vs partial or incomplete resection Koch P et al: J Clin Oncol 2001; 19:3874
  35. 35. 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
  36. 36. Gastrectomy ideal approach “in between the extremes of never and always”
  37. 37. Which chemotherapy CHOP Variations Additional immunotherapy Gastric NHL-Chemotherapy
  38. 38. 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
  39. 39. DLBCL Gastric origin Algorithm for therapy Localized (stage I, II) Advanced disease Complications Complete resectionPossible Not possible CHOP X 6-8 +Ritux CHOPX3+Ritux IFRT (avoid in young) Residual disease EFRT (avoid in young) Resection CR
  40. 40. GI NHL-Site of disease- Geographical Variation Site USA Ger Fra KSA NGui Nigeria Jord Gast 77 277 43 185 24 19 23 Small Intest 36 35 39 66* 55 62 59 Ileo- cecal 26 13 Colon 17 3 10 21 19 15 Rect 6 6 Panc 10 5 0 0 Diffu 5 24 16 10 0 2 Kniaris LG :J Am Coll Surg2003;197:127 Koch P :JCO 2001;19:3861
  41. 41. 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; 197:127 Daum S et al: J Clin Oncol 2003; 21:2740
  42. 42. Marginal Zone Mantle Zone Germinal 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
  43. 43. Calam J etal. BMJ 2001;323:980 Relation of H pylori infection to UGI conditions
  44. 44. H pylori and Malt lymphoma  ~90% have H pylori in gastric mucosa~90% have H pylori in gastric mucosa  Case control studies confirm relationshipCase control studies confirm relationship between previous infection and lymphomabetween previous infection and lymphoma  Clonal B cell detection in chronic gastritisClonal B cell detection in chronic gastritis which precedes lymphomawhich precedes lymphoma  H pylori strain specific T cells promoteH pylori strain specific T cells promote lymphoma growth in culturelymphoma growth in culture  Eradication of H pylori causes regression inEradication of H pylori causes regression in 75% of caces75% of caces
  45. 45. 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
  46. 46. Rooney N et al: Curr Diag Pathol 2004; 10:69
  47. 47. Rooney N et al: Curr Diag Pathol 2004; 10:69
  48. 48. Gastric MALT types A 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 recognizable Isaacson PG: Hematology 2001; 241
  49. 49. 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)
  50. 50. 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 disappear Isaacson PG; Best Prac & Res 2005; 18:57 Cavalli F et al: Hematology 2001; 241
  51. 51.  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
  52. 52. 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 chain Lecuit M et al: N Engl J Med 2004; 350:239
  53. 53. 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

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