Lymphoma in Inflammatory Bowel Disease

Transcription

1 1119 Lymphoma in Inflammatory Bowel Disease Adrian J. Greenstein, MD,* Gerard E. Mullin, MD,t James A. Strauchen, MD,$ Tomas Heimann, MD,* Henry D. Janowitz, MD, j Arthur H. Aufses Jr, MD,* and David B. Sachar, MDEj Nine patients with lymphoma occurring in association with inflammatory bowel disease were admitted to The Mount Sinai Hospital between 1960 and Five (two men and three women) occurred among 1156 patients (0.43%) with ulcerative colitis (UC) and four (men), among 1480 patients (0.27%) with Crohn's disease (CD), a strong male preponderance in the latter group. In all four of the patients with CD and in four of the five patients with UC, the lymphomas were extraintestinal. The mean age of onset of UC in these patients was late (46 years, 19 years older than in our overall series), with lymphomas occurring a mean of only 12 years later. By contrast, patients with CD had bowel disease much younger (mean age, 26 years), and their lymphomas appeared after a longer disease duration (mean, 24 years). The risk factors for the one patient with colonic lymphoma were similar to those with colitis-associated colorectal carcinoma: extensive and long-standing colitis and relatively young age when malignant disease developed. Four of the patients with lymphoma had associated colonic carcinoma; in three of them, the carcinoma appeared within the first decade of colitis, an unusual occurrence. A second malignant lesion also occurred in three patients with UC. Cancer 1992; The association of colorectal cancer with ulcerative colitis (UC) is well established.'+ Adenocarcinomas of both small and large bowel also occur more often than expected in Crohn's disease (CD).5-8 The issue of extraintestinal cancer is more controversial. Although earlier From the Departments of *Surgery, $Pathology, and Medicine, Division of Gastroenterology, Mount Sinai School of Medicine of the City University of New York, New York, New York. t Current address: Johns Hopkins University, 600 North Wolfe Street, Baltimore, MD The authors thank Jean DiCarlo and Sharon Richards for their assistance in the preparation of this report and Devaprasad Reuben for the work that made systematic collection of the data possible. Address for reprints: Adrian J. Greenstein, MD, Mount Sinai Medical Center, Department of Surgery, Box 1259, One Gustave L. Levy Place, New York, NY Accepted for publication May 31,1991. reports' including our own? found no excess of extraintestinal cancer, certain malignancies, including lymphoma, subsequently have been found to occur with increased frequency in these patients." The association of malignant lymphoma with UC was reported first in 1928 by Bargen." This association was considered to be a chance occurrence until recently. In 1977, a pathogenetic connection was suggested between CD and lymphoma; two patients were reported with this combination from the same geographic area within a 5-year period.12,13 We now report nine patients with lymphoma, five with UC and four with CD, occurring among 2636 patients with inflammatory bowel disease (IBD). We describe their demographic features, clinical patterns, therapy, and outcome. Materials and Methods We studied, retrospectively, the case records of 2636 patients with IBD admitted to The Mount Sinai Hospital between 1960 and Only those cases that fulfilled strict diagnostic criteria for UC and CD were in- ~1uded.l~ Cases were excluded if they did not have histologic evidence of both lymphoma and IBD. The patients with IBD were subdivided into 1156 with UC and 1480 with CD (573 with regional enteritis, 638 with ileocolitis, and 269 with Crohn's colitis). In our series, there were five patients with UC and four with CD and lymphomas, only one of which was of intestinal origin. The records of these nine patients were reviewed for anatomic distribution, clinical features, and therapy of both the IBD and the lymphoma. Original histologic material was reviewed in all cases, and lymphomas were reclassified according to current conventional criteria. The outcome in each case was determined from the patient records if the patient was dead or from either the patient or the referring physician when the chart data were incomplete. Current follow-up was obtained for all patients and is recorded with other clinical data in Tables 1 and 2.

2 Table 1, Clinical Features in Five Patients With Lymphoma Occurring During the Course of Ulcerative Colitis Age at onset Age at onset Medical Patient IBD lymphoma (yr)/ Interval IBD- therapy of Surgical Type of Area of Therapy for no. Sex (yr) year of onset lymphoma (yr) Site of IBD IBD procedures lymphoma Stage involvement lymphoma Outcome U1 M 51 54/ Sigmoid to Sulfonamides None Hodgkin s disease IVA Mediastinum to Radiation Died 59 yr rectum abdomen therapy, chemotherapy U2 F 47 60/ Universal Azulfidine, Cholecystectomy Large cell IVB Sigmoid colon Cecosigmoid Died 60 yr prednisone, (carcinoma of lymphoma mesenteric bypass, Diffuse Cortenemas gallbladder) (diffuse pelvic chemotherapy lymphoma histocytic) paraaortic + CA nodes gallbladder U3 M 19 UF F 62 49/ /1979 U5 F 51 60/1962 IBD: inflammatory bowel disease. * Review diagnosis (original histologic diagnosis) t Cured for 23 vears Universal None Total colectomy Large cell IA Right inguinal Chemotherapy In remission 14 ileostomy lymphoma nodes yr revised 3 times (reticulum cell sarcoma) Sigmoid Azulfidine None Lymphocytic lymphoma colon to rectum (poorly differentiated) prednisone lvmdhoblastoma follicular lymphoma None IVA Bilateral Chemotherapy lymph nodes, retroperitoneal cervical and Died at age 70 yr skin, hip, liver, spleen, bone LA Rightinguinal Radiation Alive at 83 yrt lymph nodes therapy with metastasis h ypemephroma in 1985

3 Lymphoma in Inflammatory Bowel Disease/Greenstein et al Results The patients with UC and lymphoma included two men and three women, but all four patients with CD and lymphoma were men. The ages at appearance of lymphoma were similar for both groups (mean age, 50 and 58 years; range, 46 to 59 years and 49 to 69 years, respectively). However, the mean age at onset of CD was much younger than that at onset of UC (24 versus 46 years). Therefore, the mean duration of IBD until development of lymphoma was much longer for CD than for UC (26 versus 12 years). Although the mean age at onset of CD (24 years) in the patients with CD and lymphoma was similar to the mean age at onset for all patients with CD, the mean age at onset of 46 years in the patients with UC and lymphoma was 17 years older than in our other patients with UC. Although all four patients with CD had lymphomas in the third decade of their IBD (range, 23 to 28 years), the patients with UC had their lymphoma from 3 to 30 years after onset of UC, with three of the five occurring during the first decade of disease. Three of the four patients with CD had internal fistulae, and three of the five patients with UC had a second malignant tumor. Amyloidosis occurred in one patient with CD and renal failure in two. Two patients, one in each group of IBD, had Hodgkin's disease. Four others had lymphocytic lymphoma (two, UC; two, CD), and the rest had large cell lymphoma (one, CD; two, UC). The clinical features of the lymphomas were interesting because four patients with UC and two patients with CD were asymptomatic, with lymphadenopathy alone at the time of presentation. Constitutional symptoms, such as fever, night sweats, and weakness, were found in only three patients (one, UC; two, CD); an abdominal mass, in two (UC); hepatomegaly, in four (three, UC; one, CD); and splenomegaly in four (two, CD; two, UC). Therapy is described in Tables 1 and 2. Radiation therapy was given to four patients and chemotherapy, to seven. Two patients who were diagnosed and treated in 1961 and 1962 received radiation therapy alone; one died within 1 year, and the other is alive 23 years later. Discussion Reticuloendothelial malignant lesions occur in association with IBD and include lymphomas of both the Hodgkin's and non-hodgkin's type and leukemia. Although leukemia with IBD affects primarily the extraintestinal reticuloendothelial system?15 lymphomas with both UC and CD previously were reported more commonly in the intestinal tract itself.16

4 1122 CANCER March 1,1992, Volume 69, No. 5 Since the report of non-hodgkin's lymphoma of the cecum in UC in 1928," there have been 27 complete and 5 incomplete case reports of UC with colonic lymphoma: 3 with Hodgkin's and 24 with non-hodgkin's lymph~ma.'~,'~ A review of their cases and a report of an additional case using new histochemical techniques suggested that a review of all previous cases should be done.17 In one patient previously reported to have Hodgkin's lymphoma, modem methods reclassified this tumor as a non-hodgkin's lymphoma. It has been ~uggested,'~ on the basis of five cases among 2500 patients with UC at the Lahey Clinic"*'9 and three at St. Mark's Hospital during a 16-year period,20*2' that this association is underappreciated. Our report of five patients among 1156 patients with UC supports this contention. The four patients with UC we studied with extraintestinal lymphoma seemed to differ in two respects from our one patient with UC and colonic lymphoma (and from such patients reported in the literature); they tended to be older and to have less extensive colic. The mean age at development of colonic lymphoma among the 21 previously reported patients with UC was 46 years, similar to the age of 47 years in our patient with UC and colonic lymphoma. However, the UC-associated extraintestinal lymphomas in this series appeared at an older mean age (58 years) and occurred among patients with unusually late onset. Moreover, the mean age at onset of UC (46 years) was 19 years older than the mean age at onset for our overall UC series (27 years). Our one patient UC and with colonic lymphoma was similar to all 26 previously reported such patients who had universal colitis. One reported patient had Ieft-sided By contrast, three of our four patients with UC and extraintestinal lymphomas had only proctosigmoiditis (two) or left-sided colitis (one), with normal proximal colons. Moreover, of the 26 reported patients with universal colitis, 10 had long quiescent periods, indicating that the development of lymphoma did not correlate with disease activity.16 In other words, the risk factors for colonic lymphoma in UC seemed, in three principal respects, to be similar to those of colitis-related colonic adenocarcinoma: younger age at cancer onset, universal colitis, and longstanding quiescent disease. Three patients among the 26 previously reported cases of colonic lymphoma with UC had concomitant colonic adenocarcinoma. l6 It is curious, however, that by contrast with the characteristically late development of UC-associated colorectal carcinoma, the four colonic carcinomas in patients with UC and lymphoma (three previously reported and one additional case) all appeared within the first decade of UC. An important finding among our patients was that the early diagnosis of lymphoma was difficult to make. Four of our five patients with UC and two of our four patients with CD were asymptomatic and had lymphadenopathy alone. Only one patient with UC and two with CD had the classic constitutional symptoms of lymphoma, with or without abdominal pain. The only important clinical clue among previously reported patients16 was an abrupt alteration in the clinical course or the presence of a palpable abdominal or rectal mass, which was found in approximately one half of cases. With respect to the possible association of lymphoma with CD, a review of the literature did not show a clear-cut association. The earliest reports of non- Hodgkin's lymph~ma~~-~~ gave few clinical details. Subsequent reports included patients, such as one whose long-standing CD was replaced completely by the tumor," as also occurred in several patients with adeno~arcinoma.~~*~~ An additional difficulty in assessing the association of lymphoma with CD is the radiologic similarity of the two condition^.'^ Because the radiologic features of intestinal CD also can be found in gastrointestinal lymphoma, independent histopathologic evidence of both CD and lymphoma are essential. To complicate matters further, it was shownz8 that two patients with UC and lymphoma had features of CD; three other cases of lymphoma simulated IBD and may have been superimposed on CD, obliterating evidence of the inflammatory disea~e.~~,~~ These diagnostic difficulties notwithstanding, there are at least five reports of the clear-cut association of Hodgkin's disease with CD,12*23*28*31-33 in addition to the onel7 reclassified as non-hodgkin's lymphoma. We believe the rest should be reexamined with modern histologic methods. Most of these cases involved small bowel and/or colon with or without spread to local lymph nodes, although one involved mediastinal and supraclavicular lymph nodes only?8 Non-Hodgkin's lymphoma was documented in ten patients with CD A s in UC, most of the lesions occurred in the intestinal tract, although one case" and all of ours were extraintestinal in origin. All four of our patients with CD were men, as were 12 of the 16 previously reported cases of lymphoma and CD.24,28 This strong male preponderance differs from the overall gender distribution for lymphomas in general, where the incidence figures show only a slight male prep~nderance.~~ The mean age for development of lymphoma in our four patients with CD was 50 years (mean duration from onset of disease, 26 years; range, 23 to 28 years). This is longer than the durations reported in the literature (mean, 6.6 years; range, l to 16 years). The cause of the lymphoma associated with IBD is obscure. Factors that may be suggested include primary immunologic defects associated with IBD,3"39 immunosuppressive therapy (corticosteroids or antimetabo-

5 Lymphoma in Inflammatory Bowel Disease/Greenstein et al lite~),~~ chronic inflammation as in celiac and/or frequent exposure to x-rays. Three patients had large cell lymphoma, known to occur exclusively with immunosuppression-induced lymphoma. Nevertheless, because five of the nine patients in our series had not received sulfasalazine or prednisone before diagnosis of lymphoma, these medications could not have played an essential role; furthermore, none of our patients had ever received antimetabolites. The prognosis in recent years with adequate chemotherapy and radiation therapy appears to be improving, but it still depends on the stage of the disease at the time of diagnosis. References 1. Prior P, Gyde SN, Macartney JC, Thompson H, Waterhouse JAH, Allan RN. Cancer morbidity in ulcerative colitis. Gut 1982; 23~ Greenstein AJ, Sachar DB, Smith H et al. Cancer in universal and left-sided ulcerative colitis: Factors determining risk. Gasfroenterology 1979; Edwards FC, Truelove SC. 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