1. Dr. CC Chan Kwong Wah Hospital
Role of Surgeon in Management of Gastric Lymphoma
Dr. CC Chan
Kwong Wah Hospital
Good morning consultants, seniors and fellow colleagues.
Today, it is my pleasure to present my topic of review on the Role of Surgeon in Management of Gastric Lymphoma.

2. Introduction Primary gastric lymphoma
Uncommon disease
5% of all gastric malignancy
10% of all malignant lymphoma
Stomach is by far the most common site of extra-nodal non-Hodgkin lymphoma (NHL)
Accounting for 60% of cases
Primary gastric lymphoma is an uncommon disease, accounting for only about 5% of all gastric malignancy and 10% of all lymphoma
Although primary gastric lymphoma is rare, stomach is still, by far, the most common site of extra-nodal non-Hodgkin lymphoma (NHL), accounting for 60% of cases

3. Revised European-American Lymphoma (REAL) (WHO 1993)
B-cell lymphoma
Diffuse Large B-cell
Marginal-zone (Extranodal, Nodal, splenic)
Lymphoblastic
Small lymphocytic
Lymphoplasmacytoid
Mantle-cell
Follicular center (follicular, diffuse, small)
T cell lymphoma
Lymphoblastic
Mycosis fungoides/ sezary syndrome
Peripheral T-cell
Burkitt’s / Burkitt-like
Lymphoma can be classified according to the WHO REAL classification, into B-cell, T cell and Burkitts lymphoma
Nearly all primary gastric lymphomas are of B-cell origin
And today we would concentrate our discussion on B-cell gastric lymphoma

4. Classification by Histology
Among all B-cell gastric lymphoma, two histological subtypes, namely the Diffuse Large B Cell Lymphoma & Marginal zone B-cell lymphoma
, already accounted for over 90% of gastric lymphoma
Two histological subtypes accounted for over 90% of cases:
Diffuse large B-cell (DLBC) Lymphoma
Marginal zone B-cell lymphoma

5. Classification by Grading
Low-grade (Indolent NHL)
Derived from Mucosa Associated lymphoid tissue (MALT)
Remained localized for extended period of time
High-grade (Aggressive NHL)
One third contained low-grade component
Progress from low grade lesion
Includes diffuse large B cell lymphoma (DLBCL)
Disseminate more rapidly
Beside histology, gastric lymphoma is also classified according to grading.
Low-grade lymphoma, referred to as indolent lymphoma according to new WHO classification, is derived from Muscosa Associated Lymphoid Tissue. It remained localized for extended period of time.
High-grade lymphoma also known as aggressive lymphoma. One third of these lesion contained low-grade component, representing progression from low grade lesion. Diffuse large B cell lymphoma & High grade MALToma are under the category of high grade lymphoma. They ususlly disseminates more rapidly

6. Presentation of Gastric Lymphoma
Presenting symptoms are non-specific
Abdominal pain (80%)
Weight loss (40%)
Gastrointestinal bleeding (36%)
Vomiting (32%)
Delay in diagnosis
Median time from onset of symptoms to diagnosis is about 3 months
Gastric Lymphoma affects equal number of men and women.
The median age of diagnosis is around 60
Presenting symptoms are rather non-specific. Abdominal pain being the most common symptom, followed by Weight loss, Gastrointestinal bleeding and Vomiting
Because of the vague symptoms, there is usually a delay in diagnosis. The median time from onset of symptoms to diagnosis is about 3 months

7. Historically, laparotomy and biopsy is required for diagnosis and accurate staging of the disease

8. Diagnosis of Gastric Lymphoma
Upper endoscopy
Three main patterns: ulcerative, diffuse infiltrative, polypoid mass
Multiple biopsies from macroscopic lesions
Antrum biopsy
Assess for H. pylori infection
Achieved 90% efficacy in diagnosing gastric lymphoma
Gastroenterology Research • 2009;2(5):
Today, the diagnosis of lymphoma mostly relies on Upper Endoscopy
An ulcerative growth, diffuse infiltrative & polypoid mass are the three main endoscopic findings.
During endoscopy, Gastric mapping procedure which involves multiple biopsies from macroscopic lesions and normal mucosa should be performed
be performed in the case of suspected or diagnosed gastric
Achieved 90% efficacy in diagnosing gastric lymphoma

9. Staging of Gastric Lymphoma
Musshoffs modification of Ann Arbor system
Stage
Definition IE
Lymphoma limited to the stomach
IIE₁
Involvement of stomach and contiguous LN
IIE₂
Involvement of stomach and non-contiguous sub-diaphragmatic LN
III
Involvement of stomach and LN on both sides of diaphragm IV
Hematogenous spread (stomach and one or more extra-lymphatic organs or tissues)
Modified Ann Arbor system is used for staging of gastric lymphoma
The letter E stands for Extra-nodal involvement
Stage I &II disease are regarded as early stage while Stage III & IV are treated as advanced stage

10. Staging of Gastric Lymphoma
Endoscopic ultrasound
Determine depth of tumor invasion
Detect any enlarged peri-gastric lymph nodes
Sensitivity
T staging: 80–92%
N staging: 77–90%
Ann Oncol 1993;4(10): ,
Endoscopy 1993;25(8):
Look for distant spread of disease
Bone marrow biopsy
CT scan of thorax, abdomen and pelvis
Positron emission tomography (PET) scan
Diagnostic value only for DLBCLs but controversial for MALT lymphomas
For the Staging process of gastric lymphoma,
Endoscopic ultrasound can determine the depth of tumor invasion & detected any enlarged perigastric lymph nodes.
Sensitivity of EUS for the T and the N stage were reported to be approaching 90%
Bone marrow biopsy and CT scan of thorax, abdomen & pelvis should be performed to look for distant spread of disease.
PET scan has its diagnostic value for diffuse large B cell lymphoma only but remained controversial for MALToma.

11. Treatment of Low Grade MALToma
Low-grade MALT lymphoma
Presented as stage I or II disease with slow progression
Helicobacter pylori identified in 90% of cases
Systematic review in 2010 of 32 studies including patients
Remission rate after HP eradication up to 77.5%
Prognosis
10-year survival 80-90%
Gastroenterol Hepatol 2010;8:105e10.
There is little debate about the treatment for low grade MALToma
Low-grade MALT lymphoma usually presented with stage I or II disease with slow progression
Helicobacter pylori identified in 90% of gastric MALT lymphoma
Over 70% of low grade MALToma regresses after HP eradication by triple therapy
Prognosis is good, with 10-year survival 80-90%

12. Treatment of Low Grade MALToma
Complete remission
Within 6 to12 months from eradication
Follow-up (EGILS consensus report 2011)
First endoscopy 3-6 months after triple therapy
Check for H pylori status
Subsequent follow-up endoscopy every 4-6 months until complete remission
Complete remission is obtained usually within 6-12 months from eradication
According to EGILS consensus report 2011
First endoscopy is performed 3-6 months after triple therapy completion for checking of the H pylori status
Subsequent follow-up endoscopy should be performed every 4-6 months until complete remission of lymphoma

13. Treatment of Advanced Disease
Stage III & IV disease
Primary treatment with chemotherapy and monoclonal antibody (R-CHOP)
Surgery indicated in:
Patient with localized residual disease in stomach alone after chemoRT
To Palliate symptoms of bleeding and obstruction that do not resolve with non-operative therapies
There is also little debate about the treatment for advanced gastric lymphoma
For Stage III & IV disease, Primary treatment would be chemotherapy and monoclonal antibody (R-CHOP)
Ann Surg 2004;240: 28–37

14. Controversies in Treatment of Gastric Lymphoma
Optimal Treatment for Early Stage High Grade Gastric Lymphoma
Radicality of Gastrectomy
Management of Complications
Bleeding & Perforation during Chemotherapy
Obstruction
Journal of Cancer Therapy, 2013, 4,
Since gastric lymphoma is a rather infrequent disease, there are still controversies in some aspect of management
First one is the Optimal Treatment for Early Stage High Grade Gastric Lymphoma
Second one is about the Radicality of Gastrectomy
Third one is about the Management of Complication including Bleeding & Perforation during Chemotherapy / Obstruction

15. Optimal Treatment for Early Stage High Grade Gastric Lymphoma
Brands et al reviewed 100 papers analyzing over patients of gastric lymphoma treated from 1974 to 1995
For early stage disease
80% of studies recommended treatment with surgery
Brands et al reviewed 100 papers analyzing over 3000 patients with all stages of gastric lymphoma treated from 1970s to 1990s
At that time, for early stage disease, 80% of studies recommended treatment including surgery
Eur J Surg. 1997;163:803–813

16. Optimal Treatment for Early Stage High Grade Gastric Lymphoma
Results of combined modality (Surgery + chemotherapy) and chemotherapy compared
No significant difference in survival rate in both groups
5 year survival rate ranged from 75% to 84%
Aviles et al in 1991
German Multicenter Study Group by Koch et al in 2001
In the era of chemotherapy, the need of surgery in treating gastric lymphoma is being questioned
The results of combined modality and chemotherapy alone are compared
In several small scale studies, there is No significant difference in survival rate in both groups

17. Chemotherapy in Managing Gastric Lymphoma
Aveiles et al in Ann Surg 2004
Prospective Randomized Control Study
589 patients of Stage I & II Diffuse Large B cell Lymphoma
Four groups:
Surgery alone
Surgery + Radiotherapy
Surgery + Chemotherapy
Chemotherapy (CHOP: Cyclophamide, vincristine, doxorubicin, prednisolone)
In year 2004, a prospective randomized control study was published.
It included over 500 patients of stage I&II diffuse large B cell lymphoma.
Patients were randomized into four arms: surgery alone, surgery with radiotherapy, surgery with chemotherapy & chemotherapy alone
Ann Surg 2004;240:44–50.

18. Overall Survival Rate at 10 years
Surgery alone: 52% [46% to 64%]
Surgery + Radiotherapy: 53% [45% to 65%]
Surgery + Chemotherapy: 91% [85% to 99%]
Chemotherapy: 96% [90% to 100%]
No difference observed between chemotherapy alone & Surgery + Chemotherapy
Surgical resection before chemotherapy
Not affect complete response rate, survival rate and disease free survival
No difference in 10 year survival rate is observed among patient treated with chemotherapy alone or Surgery + Chemotherapy, which is over 90% in both groups
Ann Surg 2004;240:44–50.
Annals of Oncology, Vol. 14, No. 12, 2003, pp
American Journal of Medicine, Vol. 90, No. 1, 1991, pp

19. Risk of Gastrectomy
Mortality: 5%
Complication Rate: 30%
Better Quality of Life in patient with gastric preservation
Dumping syndrome
Nutrition malabsorption
Chemotherapy recommended as first line treatment for early stage high grade gastric lymphoma
Furthermore, gastrectomy itself carries 5% mortality and 30% risk of complication
Better Quality of Life is observed in patient with gastric preservation which can avoid post-gastrectomy dumping syndrome & nutrition malabsorption
Therefore, Chemotherapy has already replaced surgery in treatment for early stage high grade gastric lymphoma

20. Radicality of Gastrectomy
Better outcome in radical resection compared with incomplete resection or biopsy alone
More recent studies
Positive margin has no impact on outcome
? Related to lower tumor burden which allow complete resection
Role of Chemotherapy
J Surg Oncol 1997;64(3): ,
J Clin Oncol 2001;19(18):
Rev Esp Enferm Dig 2006; 98(3):
Gastroenterology Research 2009;2(5):
Second controversies is about the Radicality of Gastrectomy
The current debate on the margin of surgery is not yet settled
If surgery is really to be performed
Previously some authors observed a better outcome in radical resection compared with those having incomplete resection or biopsy alone
Others studies showed no impact on outcome, which suggested that complete resection reflected lower tumor burden
Given the effectiveness of chemotherapy, positive resection margin could probably be managed by chemo nowadays

21. Management of Complication
Risk of perforation
Low: 1.7% without surgery
Risk of bleeding
2.1% (without surgery) vs 2.2% (with surgery)
Not significant different
Obstruction
High dose steroid
Non-responder: Surgical resection
The third controversies is about the management of complication
Oncologist always concerned about the risk of perforation and bleeding in gastric lymphoma patient undergone chemotherapy
However, the rate of complication might be exaggerated.
On literature revidw, Risk of perforation was observed to be 1.7% only when the risk of bleeding is around 2% only. No significant difference was observed in surgery group and non-surgery group for bleeding
For obstruction, a trial of high dose steroid may solve the problem. For non-responder, surgical resection can be considered
Ann Surg 2004;240: 28–37

22. Summary
Management of primary gastric lymphoma should involve a multidisciplinary approach
Treatment for primary gastric lymphoma
For low-grade MALToma: HP eradication therapy
Chemotherapy for early stage high grade lymphoma and advanced disease
Controversy still exists in the radicality of surgery
Risk of bleeding and perforation during chemotherapy is extremely low
Surgeons still play a role in diagnosing and accurate staging of gastric lymphoma as well as management of complication
No recent update in the surgical management of gastric lymphoma in the recent 10 years
Surgeon still play a role in diagnosing and staging

23. Thank you

24. This slide showed the relationship between Helicobacter Pylorus infection and gastric lymphoma
Nowadays, we know that gastric lymphoma was caused by chronic infection with H. pylori
H. pylori produces specific antigens that initiate an inflammatory response, inducing proliferation of B cells, initially it is oligoclonal followed by monoclonal proliferation and subsequent malignant transformation to marginal zone B-cell lymphoma
For DLBCL, it can arise de novo or transformed from low grade MALToma

25. Predictive factors for poor response to H pylori eradication therapy
Perigastric LN involvement (stage II₁)
0% with stage II vs. 79% with stage I
(Multicentre French study, Gut 2001; 48: )
33% LN +ve vs. 76% LN –ve
(Am J Gastroenterology 2002; 97: )
t (11:18) chromosomal translocation
review of 111 patients by Liu et al: 73% vs. 4% (Gastroenterology 2002; 122: )
H pylori –ve
H pylori may have been missed by the diagnostic tests
Another Helicobacter, H heilmannii, may be the cause
H pylori-negative patients with gastric MALT lymphoma can also undergo anti-H pylori treatment