November 29, 2007

Duodenal Lymphoma: A Rare and Morbid Tumor

By Chestovich, Paul J Schiller, Gary; Sasu, Sebastian; Hiatt, Jonathan R

We conducted a retrospective tumor registry review of a 36-year experience in a university center and identified 10 patients with duodenal lymphoma (five localized, five disseminated). Histologic types included diffuse large B-cell in four patients, mucosa- associated lymphoid tumor in three, and Hodgkin, follicular, and unclassified (one each). Treatments included chemotherapy in four patients, radiation therapy (RT) in two patients, Helicobacter pylori treatment in two, and observation in one. Five patients underwent operations (emergent in two, elective in three) for indications including massive bleeding in two patients, obstruction in two, or both in one. Survival for surgical group was 25 per cent at 1 year. One-year survival for nonsurgical group was 100 per cent, and all nonoperated patients lived at least 5 years, except for one who is alive 2 years after diagnosis. Surgical patients were younger and had more advanced lesions and less favorable cell types. When operation is required for bleeding or obstruction from secondary tumors in younger patients with disseminated disease, surgical challenges are formidable and survival is very limited. Tumors of less aggressive histology have far better prognosis. LYMPHOMAS ARE MALIGNANT transformations of normal lymphoid cells and are categorized histologically as Hodgkin and non-Hodgkin types. Epidemiological^, there are approximately 8000 cases of Hodgkin lymphoma and 60,000 cases of non-Hodgkin lymphoma diagnosed each year. Although the more common presentation is of a solid tumor of lymphoid tissues, lymphomas may arise in solid organs in as many as 25 per cent to 50 per cent of cases with incidence varying widely by geographic region.1 Extranodal lymphomas have a wide variety of clinical presentations, morphologies, and molecular compositions, making them challenging to diagnose and treat.2

The most common extranodal site is the gastrointestinal tract.1- 3-4 Gastrointestinal lymphomas make up approximately one-third to one-half of extranodal lymphomas, approximately 12 per cent to 13 per cent of all lymphomas, and approximately 1 per cent of all gastrointestinal neoplasms. The stomach is the most common site for lymphomas of the gastrointestinal tract, accounting for 50 per cent to 60 per cent of cases, small intestine 20 per cent to 30 per cent, and colon 10 per cent to 20 per cent.1,5 The duodenum is the least common site, making up only approximately 5 per cent of gastrointestinal lymphomas, and is rarely reported as a site of incidence separate from the small intestine.6 Two recent cases of duodenal lymphoma requiring operative therapy prompted us to review our institutional experience with this rare malignancy.

Methods

The University of California-Los Angeles Medical Center tumor registry was searched for all patients with a diagnosis of gastrointestinal lymphoma and then for the subset with lymphoma present in the duodenum. Charts of the latter group were reviewed to identify patient demographics, histopathology, method of diagnosis, treatment, complications, and outcomes. Pathologic slides of all specimens were reviewed to assign histologic diagnoses using current nomenclature.7 Details of operative therapy and outcome were analyzed in detail. The University of California-Los Angeles Institutional Review Board approved this research project.

Results

We identified 10 patients with gastrointestinal lymphoma in the duodenum (Table 1). Patients were seen between 1970 and 2006; average age was 51 years (range, 19-81 years), and five were male. Cell types included diffuse large B-cell lymphoma (DLBCL) in four patients, mucosa-associated lymphoid tumor (MALT) in three, and follicular, Hodgkin, and unclassified lymphoma in one each. Lymphomas were localized to the duodenum in five patients and disseminated in five.

TABLE 1. Duodenal Lymphoma in 10 Patients

Diagnosis of lymphoma was made by endoscopic biopsy in six patients, operative biopsy in three patients, and mediastinal biopsy in one patient. Treatments included surgery in five patients, chemotherapy in four, radiation therapy in two, antibiotics in two, and observation in one. Overall Kaplan-Meier survival was 67 per cent at 1 and 5 years and 22 per cent at 12 years.

Of the five patients who were treated nonoperatively, three were female, and average age was 70 years (range, 61-81 years). Histologic diagnoses were made by endoscopic biopsy in all patients and included MALT in three, follicular in one, and DLBCL in one. One patient had evidence of disseminated disease at diagnosis. Two patients received radiation therapy, two received chemotherapy, and two received triple therapy against Helicobacter pylori (proton pump inhibitor and combination antibiotic therapy). There were no known complications of the treatments received. The five patients have lived an average of 6 years after diagnosis (range, 2-12 years), and all are currently alive except for one who died of an unknown cause at 5 years.

Of the five patients who underwent operation, three were male, and average age was 33 years (range, 1962 years). Histologic diagnoses were made by operative biopsy in three patients, endoscopic biopsy in one, and mediastinal biopsy of disseminated disease in one. Diagnoses included DLBCL in three patients, classical Hodgkin (mixed cellularity type) in one patient, and unclassified lymphoma in one. Of the three patients with DLBCL, one had an anaplastic variant and another had a high proliferative index. Radiation therapy was used preoperatively in one patient and postoperatively in one; two patients received chemotherapy.

The operations were elective in three patients and emergent in two and included resections in three patients, oversewing of a bleeding vessel in one, and exploration only in one (Table 2). Four patients had evidence of disseminated disease outside of the duodenum at the time of operation. Postoperative complications occurred in four patients and included severe bleeding in three patients, sepsis in two, and biliary obstruction, deep venous thrombosis, and gastric outlet obstruction in one patient each. Three patients required reoperation, two for bleeding and one for gastric outlet obstruction. Three patients died in the early postoperative period, one is alive at 5 months, and one lived for 7 years before dying of recurrence. Causes of death included gastrointestinal bleeding in two patients and sepsis in one.

TABLE 2. Operative Therapy in Five Patients

Emergent operations for two recent patients with severe upper gastrointestinal bleeding were particularly challenging. The first patient had erosion of the gastroduodenal artery by a large ulcerated duodenal lymphoma. The bleeding was treated successfully with duodenotomy and oversewing of the bleeding vessel, but he required a gastrojejunostomy for gastric outlet obstruction 4 weeks later. The second patient was transferred to the University of California-Los Angeles with an ulcerated duodenal lymphoma and a large tumor mass encasing the celiac axis as well as metastatic spread in the mediastinum. Nonoperative management with angiographic embolization and chemotherapy was unsuccessful, and she required multiple operative attempts to control hemorrhage that also were unsuccessful. Bleeding and operative management were complicated substantially by pancytopenia secondary to her chemotherapy.

Patients treated with operative or nonoperative therapy are compared in Table 3. Patients who required operative therapy were younger and had higher grade and disseminated tumors as well as markedly diminished survival.

Discussion

Duodenal lymphomas are the least common variety of gastrointestinal lymphomas, which also are rare. The English- language literature includes over 150 patients, limited mainly to case reports. In 1961, Dawson and colleagues established criteria for differentiating primary and disseminated tumors as well as factors influencing prognosis.8 In 1984, Najem reviewed 95 cases of duodenal lymphoma, 27 with sufficient treatment and survival data for analysis, and found 2-year survival of 47 per cent.5 We have reviewed literature from 1970 to the present and identified 55 cases with sufficient data for comparison with our series.5-6-9-41

Duodenal lymphomas in our series included four specific histologic diagnoses (DLBCL, classical Hodgkin, MALT, follicular) and one unclassified lymphoma. More aggressive tumors such as DLBCL afflicted younger patients, were more likely to present with disseminated disease, and were more likely to require operative therapies. MALT and follicular lymphomas were seen in older patients, usually were primary tumors at presentation, and were treated successfully with radiation, chemotherapy, antibiotics, and even observation. Our most common type was DLBCL, which is considered the most prevalent cell type in gastrointestinal lymphoma.4 We did not observe the preponderance of follicular types in the duodenum reported by one institution.6

TABLE 3. Comparison of Patients Receiving Operative or Nonoperative Treatments

In the 55 cases reported on in the literature since 1970, histologic types included MALT in 14 patients, follicular/low-grade B-cell in 11, T/NK-cell in six, DLBCL/high-grade B-cell in five, and Burkitt and Hodgkin types in one each. There were also seven unclassified non-Hodgkin lymphomas and seven unclassified lymphomas, primarily from older case reports before advancements in cellular staining and gene rearrangements led to the classification of these tumors.7 Presenting symptoms included abdominal pain in 52 per cent, gastrointestinal bleeding in 29 per cent, weight loss in 27 per cent, nausea or vomiting in 19 per cent, jaundice in 19 per cent, and 17 per cent of patients were asymptomatic. Manifestations of gastrointestinal bleeding included anemia, hematemesis, or melena, whereas severe, life-threatening hemorrhage was uncommon. Multiple case reports describe jaundice from tumors arising in the region of the ampulla of Vater.10-18 Overall survival for reported cases was 79 per cent at 1 year. Survival for the lower grade tumors (follicular, MALT) was 100 per cent at 1 year for all patients, which emphasizes the more indolent nature of these neoplasms.19-29 Higher grade tumors such as DLBCL had lower survival,12-14-18-30-31 whereas T/NK-cell tumors, not observed in our series, accounted for the worst overall survival of 40 per cent at 1 year 15.16.32-34 Operations in our patients were required for significant tumor complications of bleeding or intestinal obstruction. The operations were complicated by technical challenges, recurrent bleeding, and postoperative sepsis. Survival was 25 per cent at 1 year compared with 100 per cent for patients who did not require operation. Nonoperative methods of hemostasis, including angiographic embolization and endoscopic coagulation, provided only temporary control of bleeding followed by recurrent severe hemorrhage.

Reported cases describe operative therapy in 62 per cent of patients since 1970 and are compared with our patients in Table 4. Indications for operation included bleeding, obstruction, resectable tumor, and jaundice from biliary obstruction. Although it is estimated that 30 per cent to 50 per cent of gastrointestinal lymphomas present with abdominal emergencies,4 only two patients (6%) with duodenal lymphoma required emergency procedures, both for severe gastrointestinal hemorrhage, and both were alive at 1 year.5- 9 The remainder of patients underwent elective or semielective procedures for less severe bleeding and partial obstructions and had overall 1-year survival of 86 per cent. Our patients were younger than those reported in the literature and tended to have more aggressive, high-grade, and disseminated tumors in contrast to reported cases with more favorable cell types and the presumed finding of resectable disease treatable by pancreaticoduodenectomv 5,6, 9,13,15,18,19,22,23,27-30, 32-40

Table 4. Surgical cases of Duodenal Lymphoma 1970 to the Present

Patients with lower grade tumors such as MALT and follicular fared better. Previous reports have recommended conservative treatments for these tumors.20-41

Of three patients in our series with MALT, one was treated with observation alone and is alive after 12 years. Two patients received antibiotic and proton pump inhibitor treatment for H. pylori and did well. One was subsequently treated with chemotherapy and is currently alive 4 years later; the other received radiation and is alive after 5 years. Treatment of H. pylori is well described for gastric lesions but only recently has been used for duodenal MALT.20- 21 Because there is documentation of MALT persistence after the eradication of H. pylori,24' 28 as well as transformation into DLBCL,30 careful follow up is imperative. Treatment of the 14 patients with duodenal MALT in the literature included medical measures for H. pylori in five patients, chemotherapy in six, operations in six, and radiation in two. Reported survival for this group was 100 per cent at 1 year.19-29

Follicular lymphoma is a less aggressive B-cell tumor that may resolve spontaneously in up to onefourth of cases.42 Localized lesions are effectively treated using radiation therapy in combination with surgical resection.4 Disseminated disease requires chemotherapy, but resistance may develop and further treatment may be necessary for disease persistence. Rituximab, antiCD20 antibody, has shown effectiveness in treating recurrent or refractory follicular lymphoma.43 One patient in our series had Grade 1 follicular lymphoma treated with radiation and was alive 2 years after diagnosis. Of 11 reported follicular/lowgrade B-cell lymphomas, three underwent pancreaticoduodenectomy,6- 9-'3 and four had duodenal resection6- 40, with all patients alive after 1 year.

In summary, duodenal lymphoma is an uncommon malignancy that may present with elective or emergent operative indications. Cell type, grade, and presence of disseminated disease are the principal determinants of therapy and prognosis. Bleeding from high-grade lesions requires early and aggressive operative therapy. Lower grade malignancies such as follicular lymphoma are effectively treated with surgery and radiation when localized. MALT is treated principally with medical measures to eradicate H. pylori and radiation or chemotherapy for persistent lesions.

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PAUL J. CHESTOVICH, M.D.,* GARY SCHILLER, M.D.,[dagger] SEBASTIAN SASU, M.D-[double dagger] JONATHAN R. HIATT, M.D.*

From the *Division of General Surgery, Department of Surgery, the [dagger] Division of Hematology-Oncology,

Department of Medicine, and the & Dagger;Department of Pathology and Laboratory Medicine, David Geffen School

of Medicine at UCLA, Los Angeles, California

Presented at the 18th Annual Scientific Meeting of the Southern California Chapter of the American College of Surgeons, Santa Barbara, California, January 19-21, 2007.

Address correspondence and reprint requests to Jonathan R. Hiatt, M.D., Room 72-160 CHS, UCLA Medical Center, 650 C.E. Young Drive, South, Box 956904, 72-160 CHS, Los Angeles, CA 90095-6904. E-mail: [email protected]

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