Gastric Lymphoma Treatment: Medical Versus Surgical

0039-6109/92 $0.00

GASTRIC SURGERY

+

.20

GASTRIC LYMPHOMA TREATMENT Medical Versus Surgical Richard C. Frazee, MO, and John Roberts, MO

Gastric lymphoma is the most frequent type of extranodal nonHodgkin's lymphomay,21 There is an increasing frequency of gastric lymphoma, while the incidence of gastric adenocarcinoma has declined in the past decade. 27 In spite of this, gastric lymphoma is an uncommon malignancy and accounts for less than 2% of primary gastric cancers. 8 Because of its rarity, it is difficult for one institution to accumulate sufficient experience to determine the optimal treatment approach. Traditionally, this condition has been treated by aggressive surgical resection, but more recently, some authors have advocated primary or adjuvant radiotherapy and chemotherapy because of the known responsiveness of lymphomas in general to these regimens. A review of the treatment options is presented here. CLINICAL PRESENTATION AND PATHOLOGIC FEATURES

Gastric lymphoma can occur in any age group, but most patients are over age 50 at the time of presentation.4-7, 10, 26, 28, 30 This malignancy predominates in males by a ratio of about 2:1. Upper abdominal pain, nausea and vomiting, and weight loss are the most common presenting symptoms. Other symptoms include weakness, gastrointestinal bleeding, appetite loss, and symptoms of gastric perforation. 28 From the Scott & White Clinic and Memorial Hospital, Scott, Sherwood and Brindley Foundation, Texas A&M University College of Medicine, Temple, Texas

SURGICAL CLINICS OF NORTH AMERICA VOLUME 72· NUMBER 2· APRIL 1992

423

=

'f 424

FRAZEE & ROBERTS

Because of the vague symptoms associated with gastric lymphoma, many patients do not present until after they have developed large bulky tumors. Dworkin et aP1 reported a median duration of symptoms of 10.3 months prior to treatment. Early lesions can be mistaken for benign ulcers, and Adkins and associates 1 saw partial "healing" of gastric lymphoma by endoscopy after H2 blocker therapy. Jung and coworkers20 reported 6 of 15 endoscopic biopsies of gastric lymphoma were nondiagnostic. The reported yield of positive material on gastroscopic biopsy ranges from 50% to 90% for gastric lymphoma. Many centers utilize a combination of biopsy and brush cytology to improve the diagnostic yield. 27, 29, 37 This practice reinforces the importance of aggressive endoscopic biopsy of gastric lesions but in addition mandates follow-up of all gastric pathology to complete healing. Gastric lymphoma tends to spread locally by submucosal infiltration, and the size of the tumor is often underestimated by endoscopic examination. As opposed to other lymphomas, gastric lymphoma has a pattern of metastasis similar to that of gastric adenocarcinoma. Local extension to adjacent organs and regional node metastases tend to precede distant metastases. This pattern of spread has implications for optimal treatment. Gastric lymphoma is universally the non-Hodgkin's type, The working formulation,12 Rappaport,31 Kiel,12 and Lukes and Collins22 classifications have all been utilized to describe gastric lymphoma. The majority of tumors are the diffuse histiocytic or mixed lymphocytic and histiocytic type. Nodular pattern and low nuclear grade carry a better prognosis than the diffuse and high-grade patterns. 2,4, 18 Tumor size greater than 5 cm, serosal involvement, regional lymph node metastases, and distant metastases have been associated with a poorer prognosis. ]], 19, 27, 32, 34, 35 In an attempt to delineate the prognosis of patients with gastric lymphoma, Villar et al40 performed immunophenotyping of patients with gastric lymphoma. They found that levels of Ki-67, a nuclear marker of tumor proliferation, of greater than 45% carried a poorer prognosis, whereas lower proliferation indices were associated with a better survival rate. Once the diagnosis of primary gastric lymphoma has been established, every effort should be made to rule out the presence of systemic lymphoma. Bone marrow biopsy, chest radiography, lymphangiography, and CT scanning of the abdomen have been advocated for the preoperative evaluation. The accuracy of CT scan for preoperative staging has been questioned, however, with a high rate of false-negative studies reported. 25 Regional gastric nodes are difficult to image by CT, and undetected involvement leads to pathologic upstaging of patients postoperatively.7 Endoscopic ultrasonography has been promoted as a new modality to assess gastric lymphoma more accurately. It is reported to be useful in differentiating lymphoma from carcinoma and in determining the depth of penetration and the presence of pedgastric nodes. 38 Our approach has consisted of chest radiography, abdominal CT, and bone marrow biopsy for the preoperative evaluation of patients with

¥

GASTRIC LYMPHOMA TREATMENT

425

newly diagnosed gastric lymphoma. This protocol identifies the patient with diffuse disease who will benefit from systemic therapy.

TREATMENT Until recently, it has been difficult to draw significant conclusions regarding the treatment of gastric lymphoma. In the past, lymphoma and pseudolymphoma were reported as one entity. Other series have included sarcomatous lesions with their results. Some authors report all gastrointestinal lymphomas as a whole, and because gastric lymphoma tends to have a better prognosis than other intestinal lymphomas, it will alter survival statistics. In addition, there has been no universally accepted staging system for gastric lymphoma. The Ann Arbor system is utilized by several authors and may include Musshoff's modification for stage 11.29 Other authors prefer the gastric carcinoma staging system37 or have proposed their own staging classifications. 14 Following the development of classification systems (Rappaport, Kiel, Lukes Collins, and the Working Formulation), more meaningful analysis of results specific to gastric lymphoma has become possible. The treatment of gastric lymphoma has varied from institution to institution, with some centers utilizing surgery alone, while others promote nonoperative treatment by endoscopic biopsy followed by radiation. Surgery

Historically, surgery has been the treatment of choice for gastric lymphoma. In addition to an attempt at curative resection, accurate staging of the disease can be performed. During abdominal exploration, tumor size, depth of penetration, and intra-abdominal spread can be assessed. Although CT scanning can demonstrate regionallymphadenopathy, only node dissection will allow pathologic confirmation of metastatic involvement. Traditionally, radical total gastrectomy with splenectomy and en bloc lymph node dissection was performed to assure adequate margins of resection. More recent reports indicate that lesser gastric resections are sufficient. The goal of curative resection should be removal of all gross disease along with regional lymph nodes. The role of splenectomy has been questioned in recent years. Rosen et aP2 reported splenic involvement only by direct extension in their series of 84 patients: no patient had metastatic involvement of the spleen. Resectability rates for gastric lymphoma range from 66% to 88% .16, 17, 21 Operative mortality rates for gastric resection range from 2.3% to 23.5%5,32 and tend to be higher in the group of patients undergoing palliative procedures. The 5-year survival rate after curative resection ranges from 50% to 90%. This compares with a 5-year survival rate of 25% when palliative procedures are performed. These differences reflect a selection bias,

426

FRAZEE & ROBERTS

with patients undergoing curative resection having earlier-stage disease. Hockey et aP6 found that of 32 long-term survivors, 29 had curative resection as their initial therapy. Those investigators concluded that surgical resection is the only proven treatment of benefit. Although the goal of surgical therapy should be complete resection of the tumor, if the lymphoma extends into the duodenum distally or the esophagus proximally, more extensive procedures in an attempt to achieve clear margins are not indicated. Splenectomy or liver biopsy is indicated for direct extension but is not necessary for the evaluation of metastatic disease unless these organs are grossly abnormal by inspection or palpation. En bloc excision of adjacent organs involved by direct extension has been reported with long-term survivors.9, 27 For example, Orlando et aF8 reported a patient free of disease 11 years after a resection that included a distal pancreatectomy. Connors and Wise reported a series of 11 patients treated by extended resection of contiguous organs,9 9 of whom also received postoperative radiation therapy. Six patients died 1 to 32 months postoperatively, but five survived 5 to 24 years. The authors concluded that direct invasion portended a general poor outcome but did not preclude an attempt at curative therapy. In the event of diffuse metastases are discovered at the time of exploration, palliative resection of the main tumor mass can be of benefit by relieving potential problems with gastrointestinal bleeding and obstruction. It will also decrease the risk of perforation if postoperative radiotherapy or chemotherapy is given. Recurrent disease after surgical excision of gastric lymphoma is usually evident within 2 years and frequently occurs in extra-abdominal sites. Late recurrence is rare but has been reported as late as 14 years after initial presentation. Salvage radiotherapy for local recurrence has led to long-term survival in some patients. II, 13

Radiation

Radiation therapy has been proposed in two settings: as primary therapy for eradication of local disease and as an adjuvant to complete or palliative surgical resection to decrease the risk of local recurrence. Herrmann et aP4 reviewed 71 patients with primary gastrointestinal lymphoma admitted to Roswell Park Memorial Institute from 1963 to 1972. The majority of these patients were treated surgically at other institutions and referred for adjuvant therapy. Those authors concluded that radiotherapy alone is the treatment of choice, particularly for stages I and II disease, and reported a 5-year survival rate of 75% with radiation therapy versus 25% with surgery alone. Unfortunately, survival comparisons in their series are difficult, because the majority of patients treated with radiotherapy had gastric lymphoma, whereas the majority of the surgically treated patients had other intestinal lymphomas, which have a poorer prognosis. Shiu et aps retrospectively reviewed 51 patients treated by either

GASTRIC LYMPHOMA TREATMENT

427

surgery alone or surgery with radiotherapy. In their early experience, the radiation dose was relatively low using cobalt-60 teletherapy or 250kV peak X-rays administered to an area limited to the left upper quadrant. In their more recent experience, the radiation therapy was administered using supervoltage machines with higher doses and larger portals. Excluding the early deaths, 36 patients were available for follow-up. Fifteen patients were treated by surgery alone and demonstrated a 5-year survival rate of 33%. Adjuvant radiation was given to 21 additional patients with a 5-year survival rate of 67%. An interesting subset was the 13 patients who received higher-dose radiation therapy, in excess of 2000 cGy. Eleven of these patients survived 5 years or more after treatment. Shiu et al concluded that combined therapy by surgical resection and radiation after operation should be regarded as the optimal method of treatment for the majority of patients with gastric lymphoma. They also emphasized the importance of dosages over 2000 cGy and extended radiation portals for the best survival. Shimm et aP4 analyzed 26 patients with gastric lymphoma, of whom 25 had total or partial gastrectomy. In addition, 19 patients received a mean 3600 cGy administered to the area of tumor resection. Survival was not affected by positive margins of resection as long as radiation therapy was administered. In spite of this, there was no statistically significant improvement in the overall survival rate in those patients receiving radiation therapy versus surgery alone. In a subgroup of patients with poor prognostic factors such as regional node involvement, penetration of the serosa, or involved surgical margins, radiation therapy increased the survival rate from 25% to 35%. The authors concluded that dosages in excess of 4000 cGy will achieve better local control and recommend treatment fields of the gastric bed and periaortic nodes alone, because their results with this approach were similar to those in other reports using whole-abdominal radiation. The majority of patients in their series who developed recurrence were systemic rather than local failures, and because of this, the authors suggested the addition of chemotherapy for high-risk patients to reduce the risk of metastatic disease. Talamonti et al, 39 on the other hand, were able to achieve a 5-year survival rate of 82% with surgical resection in stage I and II tumors, whereas radiotherapy for patients with similar-stage disease produced a 50% 5-year survival rate. Even in patients with disseminated disease, the 5-year survival rate with surgery and chemotherapy was 81 % compared with 6% for radiation and chemotherapy. In addition, 19 of the patients (78%) in their series who were treated with radiation or chemotherapy without surgical resection suffered complications of therapy. Dworkin et aP! found that among 50 patients treated for gastric lymphoma, postoperative radiation added no benefit. The 5-year survival rate for stage I disease was 88% with surgery alone and 83% with surgery and radiation. For stage II disease, the 5-year survival rates dropped to 28% and 38% respectively. Hockey et aP6 reported similar findings in 153 patients with primary gastric lymphoma. The only

428

FRAZEE & ROBERTS

patients who experienced long-term survival in their series had been treated by surgical resection. Brooks and Enterline6 reported as-year survival rate of 65% with surgery alone compared with 67% with surgery and radiation for stages I and II disease. Although this remains an area of controversy, the majority of reports in the literature show no benefit for adjuvant radiation therapy in the absence of residual disease. It is our practice to utilize postoperative radiation therapy only in patients with positive surgical margins, patients who have gross residual disease after attempted resection, or as a salvage after local recurrence. Chemotherapy

In spite of the good results seen with local treatment of gastric lymphoma, a significant proportion of patients either present with or develop systemic disease. To address this problem, several centers advise the use of chemotherapy after local therapy or as a primary treatment. Maor et aP reviewed 61 patients with gastric lymphoma treated by various combinations of surgery, radiation therapy, and chemotherapy from 1953 through 1980. They found an overall survival rate of 56% and a corresponding disease-free survival rate of 54%. Most relapses occurred within 2 years of therapy. The 5-year survival rate was significantly better for patients with stage IE (disease limited to the stomach) disease (76%) than for patients with stage lIE (disease extending to regional lymph nodes) disease (42%). Thirteen patients in their series with stages IE and lIE disease were treated without surgery by alternating Cytoxan, Adriamycin, vincristine, prednisone, bleomycin (CHOP-BLEO), and radiotherapy. With an average follow-up of 53 months, only one patient had developed recurrence. Maor and associates24 recently updated their experience with 34 patients with stages IE and II gastric lymphoma treated by endoscopic or open biopsy followed by alternating chemotherapy and radiation therapy. Four cycles of CHOP-BLEO were given every 28 days followed by radiation therapy of 3000 to 5000 cGy (mean 3946 cGy). Subsequently, as many as eight additional cycles of chemotherapy were administered. The 5-year survival rate was 73% and the disease-free survival rate was 62%. Two treatment-related deaths occurred, for a treatment-related mortality rate of 6%. Five additional patients experienced serious treatment-related morbidity. Ninety-two percent of the patients did not require stomach resection and maintained good functional results. Those investigators conclude that with the improved results of diagnostic endoscopic biopsy and long-term survival achieved by a combination of chemotherapy and radiation, surgery can be eliminated in the treatment of gastric lymphoma. Solidoro et aP6 reported on 21 patients with stage III or IV disease treated by CHOP or CHOP-BLEO alone (17 patients) or by surgical resection with chemotherapy (four patients). Of the 18 patients with stage IV disease who were treated with combined chemotherapy, 14

r

GASTRIC LYMPHOMA TREATMENT

429

were alive with no evidence of disease with a mean follow-up of 3.85 years. Patients with stage IV disease who refused chemotherapy had a median survival of only 5 months. These results reflect a marked improvement over other series for patients with advanced disease. Sheridan et aP3 undertook a prospective study of surgery and CHOP or cyclophosphamide, vincristine, and prednisone (CVP) in 18 patients. Ten patients had stage IE, four had stage lIE, and four had stage IV disease. Surgical resection ranged from partial to total gastrectomy, depending on the tumor size. One patient died postoperatively from a pulmonary embolism and myocardial infarction. With a mean follow-up of 40 months, the actuarial disease-free survival rate was 94%. No significant survival differences were noted between early and advanced stages. Those authors attributed their success in early-stage disease to surgical eradication of local disease and elimination of occult metastatic lymphoma by adjuvant chemotherapy. They found that good results could be obtained with CVP alone if there was no macroscopic disease after surgery, thus eliminating the necessity and potential toxicity of doxorubicin (Adriamycin).

COMPARISON OF THERAPY

It is difficult to determine from a review of the literature which treatment leads to improved outcome as opposed to improved survival because of the selection bias of patients treated. Few prospective trials have been performed, and all have small numbers. Three series have utilized the Cox regression analysis in an attempt to remove the variables that affect prognosis. 3, 32, 41 In each of these studies, surgical resection was the only treatment modality in which the improvement reached statistical significance. This finding does not exclude the benefits that can be achieved by radiation therapy and chemotherapy, however. Our current approach to the patient with gastric lymphoma is an initial attempt at surgical resection. If complete resection is not feasible, then radiation therapy will assist with local control. Chemotherapy is clearly indicated for diffuse disease and appears promising as an adjuvant following curative resection for patients with poor prognostic factors. Newer techniques are being developed to define the patient with early disease pathologically who may benefit from adjuvant therapy.

References 1. Adkins RB, Scott HW, Sawyers JL: Gastrointestinal lymphoma and sarcoma. Ann Surg 205:625--633, 1987 2. Aozasa K, Veda T, Kuruta A, et al: Prognostic value of histologic and clinical factors in 56 patients with gastrointestinal lymphomas. Cancer 61:309-315, 1988

430

FRAZEE

&

ROBERTS

3. Azab MB, Henry-Amar M, Rougier P, et al: Prognostic factors in primary gastrointestinal non-Hodgkin's lymphoma. Cancer 64:1208-1217, 1989 4. Azzopardi JG Menzies T: Primary malignant lymphoma of the alimentary tract. Br J Surg 47:358-366, 1960 5. Bailey RL, Laws HL: Lymphoma of the stomach. Am Surg 55:665-668, 1989 6. Brooks JI, Enterline HT: Primary gastric lymphomas. Cancer 51:701-711, 1983 7. Burgers JMV, Taul BG, Van Heerde P, et al: Treatment results of primary stage I and II non-Hodgkin's lymphoma of the stomach. Radiother Oncol 11:319-326, 1988 8. Burgess HN, Dockerty MB, ReMine WH: Sarcomatous lesions of the stomach. Ann Surg 173:758-766, 1971 9. Connors I, Wise L: Management of gastric lymphomas. Am J Surg 127:100-108, 1974 10. Contreary K, Nance Fe, Becker WF: Primary lymphoma of the gastrointestinal tract. Ann Surg 191:593-598, 1980 11. Dworkin B, Lightdale q, Weingrad ON, et al: Primary gastric lymphoma: A review of 50 cases. Dig Dis Sci 27:986-992, 1982 12. Ersboll I, Schultz HB, Hougaard P, et al: Comparison of the working formulation of non-Hodgkin's lymphoma with the Rappaport, Kiel, and Lukes Collins classifications. Cancer 55:2442-2458, 1985 13. Green JA, Dawson AA, Jones PF, et al: The presentation of gastrointestinal lymphoma: Study of a population. Br J Surg 66:748-801, 1979 14. Herrmann R, Panahon AM, Barcos MP: Gastrointestinal involvement in non-Hodgkin's lymphoma. Cancer 46:215-222, 1980 15. Hertzer NR, Honer SO: An interpretative review of lymphoma of the stomach. Surg Gynecol Obstet 143:113-124, 1976 16. Hockey MS, Powell I, Crocker I, et al: Primary gastric lymphoma. Br J Surg 74:483487, 1987 17. Jones RE, Willis S, Innes OS, et al: Primary gastric lymphoma. Am J Surg 155:118123, 1988 18. Jones SE, Fuks Z, Bull M, et al: Non-Hodgkin's lymphomas: Clinicopathological correlation in 405 cases. Cancer 31:806-823, 1973 19. Joseph JI, Lattes R: Gastric lymphosarcoma: Clinicopathologic analysis of 71 cases and its relation to disseminated lymphosarcoma. Am J Clin Pathol 45:653--669, 1966 20. Jung SS, Wieman TI, Lindberg RD: Primary gastric lymphoma and pseudolymphoma. Am Surg 54:594-597, 1988 21. Lim FE, Hartman AS, Tan EGe, et al: Factors in the prognosis of gastric lymphoma. Cancer 39:1715-1720, 1977 22. Lukes RI, Collins RD: New approaches to the classification of lymphoma. Br J Cancer 21 (suppl 3):1-28, 1975 23. Maor MH, Maddux B, Osborne BM, et al: Stages IE and liE non-Hodgkin's lymphomas of the stomach. Cancer 54:2330-2337, 1984 24. Maor MH, Velasquez WS, Fuller LM, et al: Stomach conservation in stages IE and liE gastric non-Hodgkin's lymphoma. J Clin Oncol 8:266-271, 1990 25. Mentzer SS, Osteen RT, Rosenthal OS, et al: Surgical therapy of localized abdominal non-Hodgkin's lymphomas. Surgery 103:609-614, 1988 26. Naqvi MS, Burrows L, Kark AE: Lymphoma of the gastrointestinal tract: Prognostic guides based on 162 cases. Ann Surg 170:221-231, 1969 27. Novak S, Caraveo I, Trowbridge AA: Primary lymphomas of the gastrointestinal tract. South Med J 72:1154-1158, 1979 28. Orlando R III, Pastuszak W, Preissler PL, et al: Gastric lymphoma: A clinicopathological reappraisal. Am J Surg 143:450-455, 1982 29. Posner G, Lightdale q, Cooper M, et al: Reappraisal of endoscopic tissue diagnosis in secondary gastric lymphoma. Gastrointest Endosc 21:123-125, 1975 30. Rao AR, Kagan AR, Potyk 0, et al: Management of gastrointestinal lymphoma. Am J Clin Oncol 7:213-219, 1984 31. Rappaport H: Tumors of the Hematopoietic System. In Atlas of Tumor Pathology Series. Washington, De, Armed Forces Institute of Pathology, 1966 32. Rosen CB, van Heerden JA, Martin JK, et al: Is an aggressive surgical approach to the patient with gastric lymphoma warranted? Ann Surg 205:634-640, 1987 33. Sheridan WP, Medley G, Brodie GN: Non-Hodgkin's lymphoma of the stomach: A

1M

GASTRIC LYMPHOMA TREATMENT

34. 35. 36. 37. 38. 39. 40. 41.

431

prospective pilot study of surgery plus chemotherapy in early and advanced disease. J Clin Oncol 3:495-500, 1985 Shimm DS, Dosoretz DE, Anderson T, et al: Primary gastric lymphoma: An analysis with emphasis on prognostic factors and radiation therapy. Cancer 52:2044-2048, 1983 Shiu MH, Karas M, Nisce L, et al: Management of primary gastric lymphoma. Ann Surg 195:196-202, 1982 Solidoro A, Payet C, Sanchez-Lithon J, et al: Gastric lymphomas: Chemotherapy as a primary treatment. Semin Surg Oncol 6:218-225, 1990 Spinelli P, Gullo CL, Pizzetti P: Endoscopic diagnosis of gastric lymphomas. Endoscopy 12:211-214, 1980 Taal BG, der Hartig J, Tytgat G: The endoscopic spectrum of non-Hodgkin's lymphoma of the stomach. Endoscopy 19:190-192, 1987 Talamonti MS, Dawes LG, Joehl RJ, et al: Gastrointestinal lymphoma-A case of primary surgical resection. Arch Surg 125:972-977, 1990 Villar HV, Wong R, Paz B, et al: Immunophenotyping in the management of gastric lymphoma. Am J Surg 161:171-176, 1991 Walker K, Frazee RC, Roberts JW: Trefltment of gastric lymphoma. Am Surg, in press

Address reprint requests to Richard C. Frazee, MD Scott & White Clinic 2401 South 31st Street Temple, TX 76508