GASTROINTESTINAL MANIFESTATIONS OF MALIGNANT

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1 GASTROENTEROLOGY CopYright 1968 by The Williams & Wilkins Co. Vol. 54, No.6 Printed in U.S.A. GASTROINTESTINAL MANIFESTATIONS OF MALIGNANT L Y M P H O ~ I A ALVIN N. EHRLICH, M.D., GEORGE STALDER, M.D., WILLIAM GELLER, M.D., AND PAUL SHERLOCK, M.D. Gastroenterology Section of the General Medical Service and the Medical Oncology Service of the Department of Medicine, Memorial Hospital for Cancer and Ailied Diseases and the James Ewing Hospital, and the Department of Medicine, Cornell University Medical College, New York, New York There have been many reports in the literature of lymphoma involving portions of the gastrointestinal tract.1-9 However, the majority of these reports have dealt with tumors classified as the primary type l - 6 and little consideration has been given to secondary involvement of the gastrointestinal tract in patients with disseminated disease. It is the purpose of this paper to evaluate the incidence and various manifestations which occur either as a result of tumor in the gastrointestinal tract or as a result of therapy given for the disease. Materials and Methods A review was made of the charts of all patients with lymphoma who came to autopsy at Memorial and James Ewing Hospitals during the 5-year period from 1960 through These cases were divided into three groupsreticulum cell sarcoma, lymphosarcoma, and Hodgkin's disease-depending on the final histological diagnosis. The clinical course and the findings at autopsy were evaluated in detail and analyzed in all cases with pathological evidence of gastrointestinal disorders due to tumor, therapy, or other related conditions. The entire gastrointestinal tract from the esophagus to the rectum, including the pancreas, the bili- Received January 4, Accepted February 6,1968. Address requests for reprints to: Paul Sherlock, M.D., Memorial Sloan-Kettering Cancer Center, 444 East 68th Street, New York, New York 1002l. Dr. Ehrlich was supported by Public Health Service Traineeship 455 A66, Cancer Control Program. Dr. Stalder was supported by a Visiting Research Fellowship, Sloan-Kettering Institute for Cancer Research ary tree, and the serosal surface, was considered, with the exception of the liver and the spleen. Results A total of 323 patients with lymphoma came to autopsy during this 5-year period. Of the 323 cases, 125 were classified as reticulum cell sarcoma, 75 as lymphosarcoma, and 123 as Hodgkin's disease; 203 (63%) had pathological findings in at least one part of the gastrointestinal tract; 107 (33%) had direct involvement at one site or more by tumor; and 46 (15%) had gastrointestinal manifestations related to the disease but not due to tumor metastases; 50 (15%) had both tumor and nontumor pathological changes present. The most common nontumor pathological changes were erosions, ulcerations, secondary fungal and bacterial infestations, and radiation and drug effects. As noted in figure 1, pathological changes in the gastrointestinal tract were present in 82% of 125 cases with reticulum cell sarcoma, and these were most often of tumor origin. Fifty per cent of the patients had tumor alone, and an additional 22% had tumor associated with other pathological findings in the gastrointestinal tract. Of the 75 cases with lymphosarcoma, 57% had gastrointestinal disease, with tumor the most common finding (27% tumor alone, 15% both tumor and nontumor) but one-half as common as in reticulum cell sarcoma. In the 123 cases of Hodgkin's disease, 48% had gastrointestinal changes and these were almost equally divided between the tumor (20%) and nontumor (18%) conditions, with

2 1116 EHRLICH ET AL. Vol. 54, No ,.. '".,.. :3 '0 C 40 Q) u... a.. '" 20 ~ Non-tumor Q Tumor and non-tumor In 71 instances pathological changes were preeent in the esophagus. It is of maj or interest that in two-thirds of these l e s i o n ~ the changes were nontumorous (24 were due to tumor involvement, 47 to nol1- tumor disorders). Reticulum cell sarcoma was the most common tumor in the esophagus (15 cases) ; 7 patients had o Res LSA HD FIG. 1. Frequency of gastrointestinal involvement (percentage of total number of cases) in patients with reticulum cell sarcoma, lymphosarcoma, and Hodgkin's disease. Jejunum Tumor Ileum ~ Non-tumor Colon Jejunum Ileum Tumor mll Non-tumor Biliary tract Serosa FIG. 3. Frequency (percentage) of organ involvement by tumor and nontumerous lesions in 75 patients with hymphosarcoma. Colon Biliary tract Serosa Tumor Jejunum I1f:iil Non-tumor FIG. 2. Frequency (percentage) of organ in- Ileum volvement by tumor and nontumerous lesions in 125 patients with reticulum cell sarcoma. Colon 10% having both. In both reticulum cell sarcoma and lymphosarcoma 50% had more than one organ involved with tumor, whereas in Hodgkin's disease single organ involvement was most common. In the following sections the pathological findings are considered as they affected each organ separately (figs. 2 to 4). Biliary tract Serosa FIG. 4. Frequency (percentage) of organ involvement by tumor and nontumorous lesions ill 123 patients with Hodgkin's disease.

3 June 1968 MALIGNANT LYMPHOMA 1117 Hodgkin's disease; 2 patients had lymphosarcoma involving the esophagus. The lesions were predominantly of the nodular type (17 cases) and ulcerated in 7 cases. They were secondary to mediastinal node involvement in the great majority of patients. Nontumor pathological changes were twice as common and consisted invariably of ulcerating lesions. Fungi were found in 24 of the nontumor ulcers and bacterial invasion was felt to be of major significance in nine others. The most frequent complication was bleeding. In only 1 case was bleeding found to have originated from a tumor, whereas in 14 cases the bleeding resulted from non tumorous ulcerations. Other complications were rare. In 2 cases with Hodgkin's disease there was a perforation resulting in a fistula from the esophagus into the mediastinum; 1 patient with reticulum cell sarcoma became obstructed by tumor. This organ showed abnormalities in 128 patients. In 77 cases there was tumor involvement which ranked the stomach second only to the pancreas in incidence of tumor in the gastrointestinal tract. The infiltrates were mostly nodular (35 cases) and less frequently ulcerated (27 cases) or masslike (15 cases). Benign ulcerations and erosions were found in the other 51 cases. Again, the tumors observed were most often reticulum cell sarcoma (39 cases). However, in contrast to the tumors in the esophagus, Hodgkin's disease (16 cases) was less common than lymphosarcoma (22 cases). Again, bleeding was the most common complication. It occurred in 46 cases and was again more often secondary to nontumor pathological changes (28 cases) than of tumor origin (18 cases). The tumors that did bleed were most often reticulum cell sarcoma (12 or 18 cases). In 4 cases the tumors resulted in perforation of the stomach; however, in 3 other cases no tumor was found at the site of perforation and this appeared to be the result of recent tumor therapy. With one exception, all of the perforations occurred in patients with reticulum cell sarcoma. Other complications were gastric obstruction in 2 patients with reticulum cell sarcoma and fistulization due to tumor in 2 patients with reticulum cell sarcoma and 2 patients with Hodgkin's disease. Secondary fungal invasion was present in 20 patients and significant bacterial growths in 4 others. Tumor involvement in the duodenum was found in 14 cases, 10 of which were reticulum cell sarcoma. Other lesions were equally infrequent (14 ulcers) and in five instances were the origin of gastrointestinal bleeding. Although none of the tumors bled, in 1 case the tumor resulted in perforation. Another perforation appeared to be related to antecedent therapy. Two cases of reticulum cell sarcoma resulted in obstruction. Secondary invasion resulted from fungi in 5 cases and from bacteria in 1. Jejunum Tumor invasion of the Jejunum was present in 34 instances. It was predominantly due to reticulum cell sarcoma (22 cases) and lymphosarcoma (10 cases) with only 2 cases of Hodgkin's disease. It was most often a nodular infiltrate (27 cases), although in 7 cases ulcerating lesions were found. Nontumorous ulceration was less common (10 cases) and on only one occasion was it the cause of bleeding. In 2 cases tumors were the origin of the bleeding. In 4 cases perforation occurred, 3 due to the tumor (2 reticulum cell, 1 lymphosarcoma) and in 1 case apparently as a consequence of the therapy. Two patients with reticulum cell sarcoma had tumors which obstructed the jejunum. An additional patient became obstructed because of postoperative adhesions. There were three fungal and two secondary bacterial infections. Ileum There were 28 patients in whom tumor was present in the ileum, 23 of which were reticulum cell sarcoma. In only 6

4 1118 EHRLICH ET AL. Vol. 54, 1\' i2l Res III LSA HD pain J/lSlrULI.lUfll Perforation FIG. 5. Mean survival time from the onset of various signs and symptoms in patients with lymphoma and gastrointestinal involvement. cases were the lesions ulcerated. There was, however, a high incidence of perforations (4 cases) and obstructive complications (9 cases) in the group with reticulum cell sarcoma. In 3 of these patients the tumor alone obstructed the bowel and in 5 others ileocecal intussusception with tumor occurred. These were in small children and young adults. An additional patient became obstructed from postoperative adhesions. There was no known bleeding from the tumors, from the 3 nontumorour ulcerations, or in the 1 patient with a secondary fungal lesion. In 2 patients with reticulum cell sarcoma there was an associated history of regional enteritis; in patient had resection of the terminal ileum and cecum. However at postmortem in 1961 there was no evidence of granulomatous disease. The other patient was found to have both reticulum cell sarcoma and regional enteritis in the small bowel at atuopsy. Colon The colon was the site of pathological findings in 36 instances. In 23 cases the lesion was due to tumor with 14 reticulum cell sarcoma, 5 lymphosarcoma, and 4 Hodgkin's disease. In 13 of the cases nontumorous ulcerations were present and bleeding occurred in 4 of these. None of the tumors were found to have bled but in 1 case of reticulum cell sarcoma the tumor caused rectal obstruction. There were also 3 cases of fungal and 2 cases of secondary bacterial invasion. Serosa and Omentum These structures were invaded by tumor in 61 cases. This occurred much more frequently in reticulum cell sarcoma than in the other lymphomas and was most often associated with bowel wall invasion and frequently with ascites. On occasion, the tumor was so extensive as to result in a diffusely "frozen" abdomen with extension from the diaphragm to the pelvis. In 2 cases, this extensive serosal involvement resulted in multiple intestinal obstructions. Extrahepatic Biliary Obstruction The wall of the gall bladder was invaded by tumor in 27 cases, the majority being reticulum cell sarcoma (22 cases). In none was this the cause of jaundice. The common duct was the site of tumor in 13 cases (11 were retriculum cell sarcoma) and this resulted in obstructive jaundice in 6 patients. In an additional 4 patients, obstructive jaundice resulted from lymph node involvement in the region of the distal common duct. The pancreas was the most common gastrointestinal organ to be secondarily invaded by tumor. This occurred in 86 patients (53 with reticulum cell sarcoma,

5 June' 1968 MALIGNANT LYMPHOMA with lymphosarcoma, 15 with Hodgkin's disease). In 4 patients obstructive jaundice resulted from tumor in the head of the pancreas. The clinical incidence of pan 'creatitis or diabetes was not evaluated. :\1any patients with pancreatic involvement had pain due to extensive retroperitoneal involvement. Survival The mean survival time for the three groups from the onset of clinical symptoms was 24 months for reticulum cell sarcoma, 33 months for lymphosarcoma, and 59 months for Hodgkin's disease. This was compared with the mean survival time after the onset of various gastrointestinal symptoms and complications (fig. 5). In reticulum cell sarcoma, the onset of abdominal pain or a palpable mass anteceded death by 6 months. The onset of dysphagia was followed by death in 4 months, and bleeding preceded death by 3 months. When vomiting constituted a problem, the patients survived the initial attack by an average time of 3 months. The most ominous complications were obstruction or perforation, and patients with these complications died in less than 2 months. The trend in lymphosarcoma was simi- ",lar to that in the previous group. However, the over-all survival time was better. From an over-all mean survival time of 33 months, there' was a reduction to 18, 17, and 14 months from the onset of abdominal pain, abdominal mass, or vomiting. The onset of gastrointestinal bleeding and perforation in this group was associated with survival no greater than 1 month. There were no instances of obstruction or dyspahgia in the lymphosarcoma group. Patients with Hodgkin's disease had a considerably longer over-all survival period of 59 months. After the onset of abdominal pain the survival period was 24 months and after the appearance of an abdominal mass 28 months. Death followed dysphagia in 7 months and vomiting in 6 months. Bleeding was associated again with a poor prognosis and death resulted in 2 months. The 2 cases that perforated died within a few weeks. There were no cases of obstruction. Discussion It has been stressed that secondary lymphoma of the gastrointestinal tract is much more common than the primary variety.l The majority of reports in the past, however, have dealt exclusively with the latter. The lack of interest in the secondary type may reflect the failure to achieve permanent cures which have been observed when the disease is solely limited to the stomach or small bowel. Gastrointestinal complications and manifestations of disseminated lymphoma, however, are a common problem and there is a lack of information as to the diagnosis, management, and prognosis of these situations. Involvement of the gastrointestinal tract by tumor was most commonly noted in reticulum cell sarcoma followed by lymphosarcoma and lastly Hodgkin's disease. It was inversely related to the length of survival of the three diseases and to the incidence of nontumorous changes which were most commonly found in Hodgkin's disease. Thus, whereas the primary lymphomas of the gastrointestinal tract are associated with a fairly good prognosis, when this is a secondary manifestation of the disease, the prognosis is altered for the worse. This becomes even more striking when complications such as obstruction, perforation, and bleeding occur. An important findings is that "all" is not tumor in patients with lymphoma. This can be emphasized by noting the incidence of pathological involvement from the esophagus to the rectum (excluding the pancreas, biliary tract, and omentum) with respect to tumor versus non tumor disease. A total of 200 tumor lesions was noted (123 reticulum cell sarcoma; 46 lymphosarcoma; 31 Hodgkin's disease) as compared with 139 nontumor lesions (in 39 patients with reticulum cell sarcoma; 45 with lymphosarcoma and 55 with Hodgkin's disease). Thus, in reticulum cell sarcoma, the lesions were tumorous

6 1120 EHRLICH ET AL. Vol. 54, No. 6 in 75%, while in Hodgkin's disease tumor comprised only 36% of the total pathological lesions. In lymphosarcoma, the lesions were equally divided between tumor and nontumor. These figures take on further significance when one considers the etiology of gastrointestinal bleeding in patients with disseminated lymphoma. Over-all, 21 patients had documented bleeding from tumor sources, while non tumor pathological changes were documented as the site of bleeding in 52 patients. This becomes even more impressive on evaluation of the site of bleeding in the upper gastrointestinal tract. In 14 instances, the cause was nontumorous in the esophagus, while in only 1 case was it due to esophageal tumor. In the stomach there were 28 cases of nontumor bleeding, compared to 18 caused by tumor. The duodenum was the site of bleeding in 5 cases, all of nontumor origin. This shows that gastrointestinal bleeding originated more often from the upper gastrointestinal tract (66 of 73 "bleeders") and in most of these cases it was secondary to a nontumor source. Thus, if a tumor in the stomach can be excluded, upper gastrointestinal bleeding will almost always be found to be from a non tumor source. Although many of these patients have had extensive therapy, including platelet-depressing agents, perhaps a "vigorous diagnostic approach" is indicated, including esophagoscopy (since esophagitis, especially of fungal etiology, was not uncommon) and gastroscopy. When the cause is established, then the appropriate therapy may increase what is now a short survival time following gastrointestinal bleeding. Perforation of the bowel has been previously reported in patients with lymphoma. 1o 11 In some, the disease was responsible, whereas in others this complication appeared during or shortly after therapy. Of the 21 perforations and fistulizations in the present series, 16 were directly related to the tumor and five were a direct consequence of the therapy, since there was no tumor present at the site of the lesion. Twelve perforations and two fistulizations occurred in patients with reticulum cell sarcoma. In ' 10 cases with perforation and in the 2 with fistula, the tumor appeared responsi': ble for the perforation. Lymphosarcoma, accounted for five perforations with two due to tumor; 2 patients with Hodgkin's disease presented with fistula in the esophagus, secondary to tumor in ad- ' jacent organs. Thus, although caution, must be exercised in treating the bowel with antineoplastic agents, the danger o f ~ perforation from the tumor itself appears much greater. There were 20 cases of obstruction in. the gastrointestinal tract: 1 esophagus; 2 stomach; 2 duodenum; 12 small bowel,! 1 colon; 2 multiple obstructions due to extensive serosal involvement. All 20 had' reticulum cell sarcoma. Everywhere but in the small intestine, the tumor was the obstructing element. In the small bowel, 5 cases presented with ileocolic intussusception of the tumor (ages 3 to 31), 5 had tumor alone causing the obstruction directly, and 2 became obstructed by postoperative adhesions. Obstructive jaundice was a complication in 14 cases, 6 of which were due to common duct invasion ; all were reticulum cell sarcoma. In 4 cases, nodal compression of the extrahepatic biliary tree was t h~ e cause (2 Hodgkin's disease, 2 lympho-. sarcoma) and tumor of the head of the pancreas resulted in 4 additional cases (3 reticulum cell sarcoma, 1 Hodgkin's disease). This contrasts with the over-all incidence of 86 cases of tumor in the> pancreas. Rosenberg et al.,12 in a study of 1269 cases of lymphosarcoma and re-' ticulum cell sarcoma, noted an over-all incidence of jaundice of 12.5% with 1.4% due to obstruction. In the present series of 200 cases of reticulum cell sarcoma and lymphosarcoma, there were 11 documented cases of obstructive jaundice, an incidence, of 5.5%. In the 123 patients with Hodgkin's disease, there were 3 with obstructive jaundice, an incidence of 2.4%. This is slightly higher than the 0.7% incidence of

7 June 1968 MALIGNANT LYMPHOMA 1121 obstructive jaundice in the autopsied patients reviewed by Levitan and Diamond. 13 Diarrhea was an uncommon symptom. In only 12 of 323 cases was it of a significant nature. Although lymphoma may, on occasion, present as malabsorption,14,15 this is quite uncommon. In none of the above 12 cases was the evaluation thorough enough to document malabsorption. The diarrhea was not the presenting,.complaint in any of the cases. Summary A review was made of 323 patients with lymphoma who came to autopsy at Memorial and James Ewing Hospitals during the 5-year period from 1960 through Of these 323 cases, 203 had pathological changes in the gastrointestinal tract. The clinical course and the findings at autopsy in this group were evaluated in detail. The cases were divided into reticulum cell sarcoma, lymphosarcoma,.and Hodgkin's disease on the basis of the final histological diagnosis. Each subgroup was then evaluated with respect to gastrointestinal manifestations, both tumor nontumor, and average survival times, with particular reference to the effect of various complications on survival. Upper gastrointestinal bleeding was most often of non tumor ongm particularly )when there was no evidence of tumor in the stomach. Perforation was found to be more commonly due to the tumor itself rather than to therapy. Obstructions were found only in patients with reticulum cell sarcoma,,and 60% of these were in the jejunum or ileum. Ileocecal intussusception was found in 5 children or young adults. Obstructive jaundice was a complication in 14 cases, a slightly higher incidence than in previous series. REFERENCES 1. McNeer, G., and J. W. Berg The clinical behavior and management of primary malignant lymphoma of the stomach. Surgery 46: Friedman, A. I Primary lymphosarcoma of the stomach. A clinical study of 75 cases. Amer. J. Med 26: Thorbjarnarson, B., J. M. Beal, and J. M. Pearce Primary malignant lymphoid tumors of the stomach. Cancer 9: Allen, A. W., G. Donaldson, R. C. Sniffen, and F. Goodale Primary malignant lymphoma of the gastrointestinal tract. Ann. Surg. 140: Ellis, H. A., and R. Lannigan Primary lymphoid neoplasms of the stomach. Gut 4: Dawson,!. M. P., J. S. Comes, and B. C. Morson Primary lymphoid tumors of the intestinal tract. Brit. J. Surg. 49: Portmann, U. V., E. F. Dunne, and J. B. Hazard Manifestations of Hodgkin's disease of the gastrointestinal tract. Amer. J. Roentgen. 72: Wychulis, A. R., O. H. Beahrs, and L. B. Woolner Malignant lymphoma of the colon. Arch. Surg. (Chicago) 93: Gall, E. A., and T. B. Mallory Malignant lymphoma: a clinico-pathologic s u r v e ~ ' of 618 cases. Amer. J. Path. 18: Irvine, W. T., and J. M. Johnstone Lymphosarcoma of the small intestine, with special reference to perforating tumours. Brit. J. Surg. 42: Sherlock, P., and R. Oropeza Jejunal perforation in lymphoma after chemotherapy. Arch. Intern. Med. (Chicago) 110: Rosenberg, S. A., H. D. Diamond, B. Jaslowitz, and L. F. Craver Lymphosarcoma: a review of 1269 cases. Medicine (BaIt.) 40: Levitan, R., H. D. Diamond, and L. F. Craver Jaundice in Hodgkin's disease. Amer. J. Med. 30: Sleisenger, M. H., T. P. Almy, and D. P. BatT Sprue syndrome secondary to lymphoma of small bowel. Amer. J. Med. 15: Eidelman, S., R. A. Parkins, and C. E. Rubin Abdominal lymphoma presenting as malabsorption: a clinicopathologic study of nine cases in Israel and a review of tlw literature. Medicine (Bait.) 45: