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.

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

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

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

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

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

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

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):253-258 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

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

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):839-846., Endoscopy 1993;25(8):531-533 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.

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 1408 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%

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

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

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, 145-152 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

Optimal Treatment for Early Stage High Grade Gastric Lymphoma Brands et al reviewed 100 papers analyzing over 3000 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

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

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.

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. 1751-1757. American Journal of Medicine, Vol. 90, No. 1, 1991, pp. 77-84.

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

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):237-241, J Clin Oncol 2001;19(18):3874-3883. Rev Esp Enferm Dig 2006; 98(3): 180-188 Gastroenterology Research 2009;2(5):253-258 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

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

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

Thank you

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

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; 48:297-303) 33% LN +ve vs. 76% LN –ve (Am J Gastroenterology 2002; 97:292-297) t (11:18) chromosomal translocation review of 111 patients by Liu et al: 73% vs. 4% (Gastroenterology 2002; 122: 1286-1294) 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