Multicentric Colonic Lymphoma Complicating Ulcerative Colitis J A M E S B. W A G O N F E L D , MD, C H A R L E S E. P L A T Z , MD, F R E D L. F I S H M A N , MD, R I C H A R D K. S I B L E Y , MD, and J O S E P H B. K I R S N E R , MD, PhD
A 72-year-old female with ulcerative colitis of 30 years duration underwent totalproctocolectomy for a cecal mass thought to be an adenocarcinoma. Pathologic examination of the colon revealed 22 tumors, all of which proved to be malignant lymphoma, histiocytic type. Thirteen cases of non-Hodgkins malignant lymphoma and 2 cases of Hodgkins disease of the colon arising in ulcerative colitis are reviewed and discussed.
Carcinomas of the colon, including those of multicentric origin, occur in patients with long-standing ulcerative colitis (1-4). Primary l y m p h o m a of the colon m a y be confused with ulcerative colitis (5-7), but malignant l y m p h o m a occurring in cases of longstanding ulcerative colitis is rare. We describe a case of multicentric, malignant l y m p h o m a of the colon occurring in a patient with ulcerative colitis of 30 years duration. Thirteen cases of n o n - H o d g k i n s malignant l y m p h o m a and 2 cases of Hodgkins disease complicating ulcerative colitis are reviewed and c o m p a r e d to c a r c i n o m a occurring in ulcerative colitis (8-17).
CASE REPORT A 50-year-old white female presented to the University of Chicago Hospitals in 1951 with a 9 year history of abFrom the Departments of Medicine and Pathology, The University of Chicago The Pritzker School of Medicine, Chicago, Illinois Supported in part by USPHS Training Grant AM-05147-15, USPHS Grant GM-000-44-15, and NIH Fellowship AM-05150 (Dr. Wagonfeld). Dr. Wagonfeld's present address is University of Oregon Health Sciences Center, Portland, Oregon. Dr. Platz's present address is University of Iowa College of Medicine, Iowa City, Iowa. Dr. Fishman's present address is Michael Reese Hospital and Medical Center, Chicago, Illinois. Dr. Sibley's present address is Stanford University College of Medicine, Stanford, California. Address for reprint requests: Dr. Joseph B. Kirsner, University of Chicago, Department of Medicine, Box 319,950 East 59th Street, Chicago, Illinois 60637.
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dominal pain, diarrhea, and intermittent hematochezia. Ulcerative colitis had been diagnosed one year previously. Physical examination was normal except for tenderness in the right flank. Proctoscopy to 12 cm revealed purulent exudate with granular, friable, and endematous mucosa. Laboratory studies revealed a normal blood count and urinalysis. The patient was treated with a low-residue diet, phenobarbital, and belladonna with little improvement. In February 1952 she was hospitalized for the first time. Stools for ova and parasites were negative. A barium enema revealed shortening and loss of haustration throughout the colon. Penicillin G, a nonabsorbable sulfa, and ACTH were added to her therapy with gradual clinical and proctoscopic improvement. The patient remained free of symptoms of ulcerative colitis between 1952 and 1970, although proctoscopy demonstrated continuous mild activity. An exacerbation of her colitis occurred in November 1970 but responded to medical therapy. A colon x-ray 3 months later revealed ulcerations in the proximal colon, but otherwise no change from previous examinations. In July 1971, she was placed on salicylazosulfapyridine because of recurrence of diarrhea. In July 1972, iron deficiency anemia and occult gastrointestinal bleeding were noted. Proctoscopy revealed only mild erythema. Three months later, deep vein thromboplebitis was diagnosed and the patient was hospitalized. A tender right flank mass and signs of deep vein thrombosis of the right lower extremity were present on physical examination. Colon x-ray (Figure 1) revealed a large mass in the cecum thought to represent carcinoma. Chest x-rays showed no mediastinal lymphadenopathy. Liver and spleen scan were normal. The patient underwent exploratory laparotomy at which time a fluctuant 10-cm mass was found in the cecum. There were enlarged lymph nodes in the mesentery, but no other palpable lymphadenopathy. The entire colon was felt to be involved with ulcerative colitis. The liver Digestive Diseases, Vol. 22, No. 6 (June 1977)
LYMPHOMA IN U L C E R A T I V E COLITIS
Fig 1. Barium enema reveals typical changes of chronic ulcerative colitis to the ascending colon with shortening, loss of haustrations, and destruction of mucosal detail. There is a mass lesion in the cecum which distends the bowel and has a marked nodular appearance. There is also compression of the terminal ileum by the mass.
and spleen were normal to palpation. A total colectomy and abdominal-perineal resection with lymph node dissection was performed and the inferior vena cava was ligated. Frozen section done at operation after the colon had been removed was interpreted as "undifferentiated carcinoma or histiocytic lymphoma." Liver biopsy and splenectomy were not performed. The patient survived surgery with no major complication. She reentered the hospital 4 months later with fever, abdominal pain, and an epigastric :mass. A liver scan showed 2 large filling defects. She died suddenly while undergoing evaluation. Permission for autopsy was refused. Digestive Diseases, Vol. 22, No. 6 (June 1977)
Pathology The proctocolectomy specimen (Figure 2) was received in two segments totaling 112 cm in length and included 15.5 cm of edematous terminal ileum. The cecum was obliterated by a tumor mass 7.5 cm in diameter with a deep, central excavation 5.5 cm in diameter. The tumor extended through the muscularis propria into the surrounding pericolic adipose tissue. Twenty-one additional round to oval, firm, tan, elevated tumor plaques ranging from 7.5 to 0.6 cm in diameter were present in the mucosa of the ascending, transverse, and descending colon. One of these additional tumors extended into the pericolic fat,
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Fig 2. Portion of the surgical specimen including terminal ileum, cecum, ascending, transverse, and part of descending colon. The large ulcerated cecal tumor is apparent, as are some of the smaller lesions. Punctate ulcerations and hemorrhages also are evidence in the flattened intervening mucosa.
2 to the muscularis propria, 16 to the submucosa, and 2 were confined to the lamina propria and muscularis mucosae. All were ulcerated. The proximal tumors were generally larger and the smallest tumors were the distal ones. The distal 20 cm of colon and rectum was free of tumor, although changes o f ulcerative colitis were evident throughout the entire colon. Histologically, all of the tumors were similar and were classified as malignant lymphomas of the diffuse histocytic type. Each tumor consisted of sheets of large cells having pale acidophilic, finely granular to foamy cytoplasm in variable amounts (Figure 3A). Occasional tumor cells contained phagocytosed erythrocytes. The cytoplasm was negative for glycogen and mucin (PAS and mucicarmine stains), although small droplets of lipid (oilred-O-positive) were occasionally noted. The nuclei were round to oval with coarsely clumped chromatin and one or two prominent acidophilic nucleoli (Figure 3B). Occasional cells contained several nuclei or nuclear segments.
504
Numerous mitoses were present and were often bizarre. Cell borders were quite distinct and in some areas many cells were individually surrounded by reticulin fibers (Wilder reticulum stain). In other areas, aggregates of cells were supported by a delicate fibrovascular stroma. The deeper penetrating tumors infiltrated the muscularis propria in a manner typical of a lymphoproliferative process, by penetrating and separating the muscle fibers without significant amounts of stromal connective tissue. No tumor nodules were found in lymphoid tissue aggregates; the smallest tumors were those limited to the mucosa and these had no surrounding mature lymphoid cells. Small numbers of inflammatory cells, including eosinophils, plasma cells, neutrophils, and lymphocytes, were scattered among the tumor cells. Electron-microscopic examination was consistent with histiocytic lymphoma. One hundred fourteen regional lymph nodes measuring 0.62.5 cm in diameter were examined. Of these lymph nodes, 46 were found to be involved by tumor histologically simiDigestive Diseases, Vol. 22, No. 6 (June 1977)
L Y M P H O M A IN U L C E R A T I V E COLITIS
Fig 3A. Margin of a typical tumor showing a uniform cell population obliterating the mucosa, wltia an ulcerated surface. No atypical epithelial changes are evident in the immediately adjacent mucosa (• 10).
Iar to that found in the colon. Forty-two of the involved lymph nodes, including the highest node, were in the distribution of the middle cotic vessels. Four were in the distribution of the right colic vessels. No nodes in the distribution of the left colic vessels contained tumor. Digestive Diseases, Vol. 22, No. 6 (June 1977)
The mucosa uninvolved by tumor was finery nodular, tan to red, and friable throughout the colon with absent mucosal folds. No ulcerations were grossly identifiable, but microscopically all areas showed changes consistent with chronic ulcerative colitis, including focal mucosal ul-
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O
Fig 3B. Tumor ceils are generally large with abundant acidophilic cytoplasm and vesicular nuclei with prominent nucleoli (• 160).
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LYMPHOMA IN ULCERATIVE COLITIS cerations with infiltrates of plasma cells, lymphocytes, occasional eosinophills, and regenerative epithelium. Focal atypical epithelial changes, similar to those described by Morson and Pang (18), were noted, but not in continuity with any of the lymphoid tumors. No epithelial malignancy was identified. DISCUSSION
This report documents the rare occurrence of a multicenltric, nonepithelial malignancy of the colon occurring in chronic ulcerative colitis. Multicentric synchronous and nonsynchronous carcinomas are not unusual in ulcerative colitis (1-4, 19), and multicentric origins have been reported in up to 25% of p r i m a r y l y m p h o m a s of the g a s t r o i n t e s t i n a l tract (20). Only 14 cases of malignant lymphoma complicating ulcerative colitis are reported in the English literature and only 1 additional case was discovered ~in French. An additional 2 cases of "sarcoma" arising in ulcerative colitis were reported by Edling and Ekl6f (13), but the lack of further histologic classification precludes their inclusion as malignant lymphomas. Of these 15 cases, at least 6 appear to have had two or more separate lesions (9, 11, 17) or to have shown "diffuse" involvement (15, 16) of at least a portion of the bowel. In 3 other cases both a lymphoma and adenocarcinoma were found (]2, 14, I5). In only 5 of 15 cases was a single lesion identified (8, 10, 12). Bargen (8) does not describe his second case, although it is implied in a later review (17) that all 3 cases reported from the Mayo Clinic were multiple lesions. It appears therefore that the frequency of multiplicity is greater in lymphoma arising in ulcerative colitis than in those colonic lymphomas arising de novo, although comparison must be derived from different sized populations in which the accuracy of diagnosis remains unverified. It cannot be stated with certainty that the numerous tumors in our case represent multifocal primary lymphomas. The decreasing size of the tumors from proximal to distal, and the absence of any foci of tumor arising in lymphoid aggregates with intact overlying epithelium, might be interpreted as indicating intraluminal spread from the large cecal tumor with implantation in distal ulcerated sites. The colon may be either primarily or secondarily involved by malignant lymphoma. The absence of palpable superficial lymphadenopathy, and mediastinal lymphadenopathy by chest x-ray; the confinement of lymph node involvement to those node Digestive Diseases, VoL 22, No. 6 (June 1977)
groups draining the affected area of colon, and lack of hepatic and splenic involvement at operation, all suggest a primary colonic lymphoma in our patient rather than secondary involvement of the colon by a disseminated lymphopro!iferative disease (21). The histologic typing of reported cases of malignant lymphoma complicating ulcerative colitis is difficult because of the lack of uniform nomenclature. Seven of the 15 reported cases are identified as reticulum cell sarcoma (10, 11, 12, 14, 17), 3 as lymphosarcoma (8, 16), 2 as Hodgkin's disease (9, 12), and one each as lymphoma (15), lymphoblastic sarcoma (11), and malignant lymphoma (15). Our case is identified as malignant lymphoma, histocytic type, diffuse, utilizing the classification delineated by Rappaport (22), and is presumably most similar to earlier cases called reticulum cell sarcoma. The spectrum of cell types is similar to that in series of primary colonic lymphomas unassociated with ulcerative colitis (17, 20, 13, 24) except for the absence of giant follicular lymphoma. The prognosis of lymphoma complicating ulcerative colitis is difficult to determine. Of the 16 reported cases (including the current case), followup is available in 14. Six of 14 died within 12 months, and a seventh tumor was diagnosed at autopsy, an overall l-year mortality of 50%. of the 7 other cases with followup information, 6 were alive at intervals of 6-18 months after operation and one at 6 years. Naqvi et al (23) reported an overall 5-year mortality of 38% in a series of colonic lymphomas where most were able to have definitive surgery. In the series of Dawson et al (21), 7 of 22 (36%) died within 1 year and 14 of 22 (64%) died within 2 years. In several series of carcinoma in ulcerative colitis (1, 3) the overall 1-year mortality ranged from 15 to 47%. In cases of gastrointestinal lymphoma there is a greater survival with lesions described histologically as giant follicular lymphoma and iymphosarcoma than with those described as reticulum cell sarcoma. It has been implied (21) that multiple sites of origin or lymph node involvement causes no apparent change in mortality from colonic lymphoma. However, in cases arising in ulcerative colitis, this does not appear to be true. Of 5 cases with nodes stated to be negative, all were alive at 6 months to 6 years (8, 10-12). Conversely, of 6 patients with positive nodes, 4 were dead within 1 year (9, 11, 12, 16). Of 5 patients with single lesions, 4 were alive from 6 months to 6 years after operation and one was dead at 5 months (8, 10, 12). All 3 patients with lymphoma and adenocarcinoma were
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d e a d w i t h i n 1 y e a r (12, 14, 15). O f the 6 p a t i e n t s with m u l t i p l e or diffuse l y m p h o m a , 3 w e r e alive at 12-15 m o n t h s a n d 3 w e r e dead w i t h i n 1 y e a r (9, 11, 15, 16, 17). U l c e r a t i v e colitis is a c c e p t e d as a p r e m a l i g n a n t g a s t r o i n t e s t i n a l lesion. It is a t t r a c t i v e to h y p o t h e size, as h a v e S h e r l o c k et al (24), that t h e r e is a relat i o n s h i p b e t w e e n u l c e r a t i v e colitis a n d l y m p h o m a a n d that there m a y be a p r e m a l i g n a n t state r e l a t e d to a b n o r m a l l y m p h o i d tissue in the l a m i n a p r o p r i a . T h e clinical e v i d e n c e , h o w e v e r , i n d i c a t e s the age of o n s e t , d i s t r i b u t i o n , cell t y p e s , a n d 1-year s u r v i v a l are similar to p r i m a r y c o l o n i c l y m p h o m a , p e r h a p s suggesting a coincidental occurrence of l y m p h o m a in u l c e r a t i v e colitis, w h i c h m a y be modified in the d i r e c t i o n of m u l t i p l i c i t y b y the p r e e x i s t i n g inflamm a t o r y disease.
ACKNOWLEDGMENTS The authors acknowledge the assistance of Dr. Henry Rappaport in the histological interpretation, Dr. Gerald Levine in the electron microscopic evaluation, Dr. David Rochester in reviewing the x-rays, and Ms Kathy Linneman in the preparation of the manuscript. Dr. George E. Block performed the proctocolectomy.
REFERENCES 1. Goldgraber MB, Kirsner JB: Carcinoma of the colon in ulcerative colitis. Cancer 17:657-665, 1964 2. Fennessy J J, Sparberg MB, Kirsner JB: Radiological findings in carcinoma of the colon complicating chronic ulcerative colitis. Gut 9:388--397, 1968 3. Edwards FC, Truelove SC: The course and prognosis of ulcerative colitis. Part IV. Carcinoma of the colon. Gut 5:1522, 1964 4. Hinton JM: Risk of malignant change in ulcerative colitis. Gut 7:427-432, 1966 5. Meadows R: Hodgkins disease of the colon presenting as disseminated sclerosis with associated ulcerative colitis. Aus. N.Z. J Surg 35:80-82, 1965 6. Friedman HB, Silver GM, Brown CH: Lymphoma of the colon simulating ulcerative colitis. Am J Dig Dis 13:910-917, 1968
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7. Federman J, Goldstein ME, Weingarten B: Malignant lymphoma of over 15 years' duration masquerading as ulcerative colitis. Am J Roentgenal 89:771-778, 1963 8. Bargen JA: Chronic ulcerative colitis associated with malignant disease. Arch Surg 17:561-576, 1928 9. Sataline LR, Mobley EM, Kirkham W: Ulcerative colitis complicated by colonic lymphoma. Gastroenterology 44:342-347, 1963 10. Delannoy E, Buffin RP: Rrticulosarcome sur rectocolite hrmorragique (colite ulcrrative). Presse Med 70:1006-1007, 1962 11. Comes JS, Smith JC, Southwood WFW: Lymphosarcoma in chronic ulcerative colitis. Br J Surg 49:50-53, 1961 12. Nugent FW, Zuben S, Bulan MB: Colonic lymphoma in ulcerative colitis. Lahey Clin Found Bull 21:104-111, 1972 13. Edling NPG, Eklrf O: Distribution of malignancy in ulcerative colitis. Gastroenterology 41:465-466, 1961 14. Cattell RB, Boehme E J: The importance of malignant degeneration as a complication of chronic ulcerative colitis. Gastroenterology 8:695-710, 1947 15. Warren KW: Malignant lymphoma of the duodenum, small intestine and colon. Surg Clin N Am 39:725-735, 1959 16. Walker FC, Weaver JPA: Lymphosarcoma in ulcerative colitis. Br J Surg 51:475-477, 1964 17. Wychulis AR, Beahrs OH, Woolner LB: Malignant lymphoma of the colon. A study of 69 cases. Arch Surg 93:215225, 1966 18. Morson BC, Pang LSC: Rectal biopsy as an aid to cancer control in ulcerative colitis. Gut 8:423-434, 1967 19. Hojman D, Garriz RA, Markman I: Multiple malignant tumors of the colon and rectum. Dis Colon Rectum 9:121-126, 1966 20. Allen AW, Donaldson G, Sniffen RC: Primary malignant lymphoma of the gastro-intestinal tract. Ann Surg 140:428438, 1954 21. Dawson IMP, Comes JS, Morson BC: Primary malignant lymphoid tumours of the intestinal tract. Report of 37 cases with a study of factors influencing prognosis. Br J Surg 49:80-89, 1961 22. Rappaport H: Tumors of the hernatopoietic system. Section III, Fasicle 8 of the Armed Forces Institute of Pathology Atlas of Tumor Pathology, 1968 23. Naqvi MS, Burrows L, and Kark AE: Lymphoma of the gastrointestinal tract: Prognostic guides based on 162 cases. Ann Surg 170:221-231, 1961 24. Sherlock P, Winawer SJ, Goldstein MJ: Malignant lymphoma of the gastrointestinal tract. Prog Gastroenterol 2:367-391, 1970
Digestive Diseases. Vol. 22. No. 6 (June 1977)
A 72-year-old female with ulcerative colitis of 30 years duration underwent totalproctocolectomy for a cecal mass thought to be an adenocarcinoma. Pathologic examination of the colon revealed 22 tumors, all of which proved to be malignant lymphoma, histiocytic type. Thirteen cases of non-Hodgkins malignant lymphoma and 2 cases of Hodgkins disease of the colon arising in ulcerative colitis are reviewed and discussed.
Carcinomas of the colon, including those of multicentric origin, occur in patients with long-standing ulcerative colitis (1-4). Primary l y m p h o m a of the colon m a y be confused with ulcerative colitis (5-7), but malignant l y m p h o m a occurring in cases of longstanding ulcerative colitis is rare. We describe a case of multicentric, malignant l y m p h o m a of the colon occurring in a patient with ulcerative colitis of 30 years duration. Thirteen cases of n o n - H o d g k i n s malignant l y m p h o m a and 2 cases of Hodgkins disease complicating ulcerative colitis are reviewed and c o m p a r e d to c a r c i n o m a occurring in ulcerative colitis (8-17).
CASE REPORT A 50-year-old white female presented to the University of Chicago Hospitals in 1951 with a 9 year history of abFrom the Departments of Medicine and Pathology, The University of Chicago The Pritzker School of Medicine, Chicago, Illinois Supported in part by USPHS Training Grant AM-05147-15, USPHS Grant GM-000-44-15, and NIH Fellowship AM-05150 (Dr. Wagonfeld). Dr. Wagonfeld's present address is University of Oregon Health Sciences Center, Portland, Oregon. Dr. Platz's present address is University of Iowa College of Medicine, Iowa City, Iowa. Dr. Fishman's present address is Michael Reese Hospital and Medical Center, Chicago, Illinois. Dr. Sibley's present address is Stanford University College of Medicine, Stanford, California. Address for reprint requests: Dr. Joseph B. Kirsner, University of Chicago, Department of Medicine, Box 319,950 East 59th Street, Chicago, Illinois 60637.
502
dominal pain, diarrhea, and intermittent hematochezia. Ulcerative colitis had been diagnosed one year previously. Physical examination was normal except for tenderness in the right flank. Proctoscopy to 12 cm revealed purulent exudate with granular, friable, and endematous mucosa. Laboratory studies revealed a normal blood count and urinalysis. The patient was treated with a low-residue diet, phenobarbital, and belladonna with little improvement. In February 1952 she was hospitalized for the first time. Stools for ova and parasites were negative. A barium enema revealed shortening and loss of haustration throughout the colon. Penicillin G, a nonabsorbable sulfa, and ACTH were added to her therapy with gradual clinical and proctoscopic improvement. The patient remained free of symptoms of ulcerative colitis between 1952 and 1970, although proctoscopy demonstrated continuous mild activity. An exacerbation of her colitis occurred in November 1970 but responded to medical therapy. A colon x-ray 3 months later revealed ulcerations in the proximal colon, but otherwise no change from previous examinations. In July 1971, she was placed on salicylazosulfapyridine because of recurrence of diarrhea. In July 1972, iron deficiency anemia and occult gastrointestinal bleeding were noted. Proctoscopy revealed only mild erythema. Three months later, deep vein thromboplebitis was diagnosed and the patient was hospitalized. A tender right flank mass and signs of deep vein thrombosis of the right lower extremity were present on physical examination. Colon x-ray (Figure 1) revealed a large mass in the cecum thought to represent carcinoma. Chest x-rays showed no mediastinal lymphadenopathy. Liver and spleen scan were normal. The patient underwent exploratory laparotomy at which time a fluctuant 10-cm mass was found in the cecum. There were enlarged lymph nodes in the mesentery, but no other palpable lymphadenopathy. The entire colon was felt to be involved with ulcerative colitis. The liver Digestive Diseases, Vol. 22, No. 6 (June 1977)
LYMPHOMA IN U L C E R A T I V E COLITIS
Fig 1. Barium enema reveals typical changes of chronic ulcerative colitis to the ascending colon with shortening, loss of haustrations, and destruction of mucosal detail. There is a mass lesion in the cecum which distends the bowel and has a marked nodular appearance. There is also compression of the terminal ileum by the mass.
and spleen were normal to palpation. A total colectomy and abdominal-perineal resection with lymph node dissection was performed and the inferior vena cava was ligated. Frozen section done at operation after the colon had been removed was interpreted as "undifferentiated carcinoma or histiocytic lymphoma." Liver biopsy and splenectomy were not performed. The patient survived surgery with no major complication. She reentered the hospital 4 months later with fever, abdominal pain, and an epigastric :mass. A liver scan showed 2 large filling defects. She died suddenly while undergoing evaluation. Permission for autopsy was refused. Digestive Diseases, Vol. 22, No. 6 (June 1977)
Pathology The proctocolectomy specimen (Figure 2) was received in two segments totaling 112 cm in length and included 15.5 cm of edematous terminal ileum. The cecum was obliterated by a tumor mass 7.5 cm in diameter with a deep, central excavation 5.5 cm in diameter. The tumor extended through the muscularis propria into the surrounding pericolic adipose tissue. Twenty-one additional round to oval, firm, tan, elevated tumor plaques ranging from 7.5 to 0.6 cm in diameter were present in the mucosa of the ascending, transverse, and descending colon. One of these additional tumors extended into the pericolic fat,
503
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Fig 2. Portion of the surgical specimen including terminal ileum, cecum, ascending, transverse, and part of descending colon. The large ulcerated cecal tumor is apparent, as are some of the smaller lesions. Punctate ulcerations and hemorrhages also are evidence in the flattened intervening mucosa.
2 to the muscularis propria, 16 to the submucosa, and 2 were confined to the lamina propria and muscularis mucosae. All were ulcerated. The proximal tumors were generally larger and the smallest tumors were the distal ones. The distal 20 cm of colon and rectum was free of tumor, although changes o f ulcerative colitis were evident throughout the entire colon. Histologically, all of the tumors were similar and were classified as malignant lymphomas of the diffuse histocytic type. Each tumor consisted of sheets of large cells having pale acidophilic, finely granular to foamy cytoplasm in variable amounts (Figure 3A). Occasional tumor cells contained phagocytosed erythrocytes. The cytoplasm was negative for glycogen and mucin (PAS and mucicarmine stains), although small droplets of lipid (oilred-O-positive) were occasionally noted. The nuclei were round to oval with coarsely clumped chromatin and one or two prominent acidophilic nucleoli (Figure 3B). Occasional cells contained several nuclei or nuclear segments.
504
Numerous mitoses were present and were often bizarre. Cell borders were quite distinct and in some areas many cells were individually surrounded by reticulin fibers (Wilder reticulum stain). In other areas, aggregates of cells were supported by a delicate fibrovascular stroma. The deeper penetrating tumors infiltrated the muscularis propria in a manner typical of a lymphoproliferative process, by penetrating and separating the muscle fibers without significant amounts of stromal connective tissue. No tumor nodules were found in lymphoid tissue aggregates; the smallest tumors were those limited to the mucosa and these had no surrounding mature lymphoid cells. Small numbers of inflammatory cells, including eosinophils, plasma cells, neutrophils, and lymphocytes, were scattered among the tumor cells. Electron-microscopic examination was consistent with histiocytic lymphoma. One hundred fourteen regional lymph nodes measuring 0.62.5 cm in diameter were examined. Of these lymph nodes, 46 were found to be involved by tumor histologically simiDigestive Diseases, Vol. 22, No. 6 (June 1977)
L Y M P H O M A IN U L C E R A T I V E COLITIS
Fig 3A. Margin of a typical tumor showing a uniform cell population obliterating the mucosa, wltia an ulcerated surface. No atypical epithelial changes are evident in the immediately adjacent mucosa (• 10).
Iar to that found in the colon. Forty-two of the involved lymph nodes, including the highest node, were in the distribution of the middle cotic vessels. Four were in the distribution of the right colic vessels. No nodes in the distribution of the left colic vessels contained tumor. Digestive Diseases, Vol. 22, No. 6 (June 1977)
The mucosa uninvolved by tumor was finery nodular, tan to red, and friable throughout the colon with absent mucosal folds. No ulcerations were grossly identifiable, but microscopically all areas showed changes consistent with chronic ulcerative colitis, including focal mucosal ul-
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O
Fig 3B. Tumor ceils are generally large with abundant acidophilic cytoplasm and vesicular nuclei with prominent nucleoli (• 160).
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LYMPHOMA IN ULCERATIVE COLITIS cerations with infiltrates of plasma cells, lymphocytes, occasional eosinophills, and regenerative epithelium. Focal atypical epithelial changes, similar to those described by Morson and Pang (18), were noted, but not in continuity with any of the lymphoid tumors. No epithelial malignancy was identified. DISCUSSION
This report documents the rare occurrence of a multicenltric, nonepithelial malignancy of the colon occurring in chronic ulcerative colitis. Multicentric synchronous and nonsynchronous carcinomas are not unusual in ulcerative colitis (1-4, 19), and multicentric origins have been reported in up to 25% of p r i m a r y l y m p h o m a s of the g a s t r o i n t e s t i n a l tract (20). Only 14 cases of malignant lymphoma complicating ulcerative colitis are reported in the English literature and only 1 additional case was discovered ~in French. An additional 2 cases of "sarcoma" arising in ulcerative colitis were reported by Edling and Ekl6f (13), but the lack of further histologic classification precludes their inclusion as malignant lymphomas. Of these 15 cases, at least 6 appear to have had two or more separate lesions (9, 11, 17) or to have shown "diffuse" involvement (15, 16) of at least a portion of the bowel. In 3 other cases both a lymphoma and adenocarcinoma were found (]2, 14, I5). In only 5 of 15 cases was a single lesion identified (8, 10, 12). Bargen (8) does not describe his second case, although it is implied in a later review (17) that all 3 cases reported from the Mayo Clinic were multiple lesions. It appears therefore that the frequency of multiplicity is greater in lymphoma arising in ulcerative colitis than in those colonic lymphomas arising de novo, although comparison must be derived from different sized populations in which the accuracy of diagnosis remains unverified. It cannot be stated with certainty that the numerous tumors in our case represent multifocal primary lymphomas. The decreasing size of the tumors from proximal to distal, and the absence of any foci of tumor arising in lymphoid aggregates with intact overlying epithelium, might be interpreted as indicating intraluminal spread from the large cecal tumor with implantation in distal ulcerated sites. The colon may be either primarily or secondarily involved by malignant lymphoma. The absence of palpable superficial lymphadenopathy, and mediastinal lymphadenopathy by chest x-ray; the confinement of lymph node involvement to those node Digestive Diseases, VoL 22, No. 6 (June 1977)
groups draining the affected area of colon, and lack of hepatic and splenic involvement at operation, all suggest a primary colonic lymphoma in our patient rather than secondary involvement of the colon by a disseminated lymphopro!iferative disease (21). The histologic typing of reported cases of malignant lymphoma complicating ulcerative colitis is difficult because of the lack of uniform nomenclature. Seven of the 15 reported cases are identified as reticulum cell sarcoma (10, 11, 12, 14, 17), 3 as lymphosarcoma (8, 16), 2 as Hodgkin's disease (9, 12), and one each as lymphoma (15), lymphoblastic sarcoma (11), and malignant lymphoma (15). Our case is identified as malignant lymphoma, histocytic type, diffuse, utilizing the classification delineated by Rappaport (22), and is presumably most similar to earlier cases called reticulum cell sarcoma. The spectrum of cell types is similar to that in series of primary colonic lymphomas unassociated with ulcerative colitis (17, 20, 13, 24) except for the absence of giant follicular lymphoma. The prognosis of lymphoma complicating ulcerative colitis is difficult to determine. Of the 16 reported cases (including the current case), followup is available in 14. Six of 14 died within 12 months, and a seventh tumor was diagnosed at autopsy, an overall l-year mortality of 50%. of the 7 other cases with followup information, 6 were alive at intervals of 6-18 months after operation and one at 6 years. Naqvi et al (23) reported an overall 5-year mortality of 38% in a series of colonic lymphomas where most were able to have definitive surgery. In the series of Dawson et al (21), 7 of 22 (36%) died within 1 year and 14 of 22 (64%) died within 2 years. In several series of carcinoma in ulcerative colitis (1, 3) the overall 1-year mortality ranged from 15 to 47%. In cases of gastrointestinal lymphoma there is a greater survival with lesions described histologically as giant follicular lymphoma and iymphosarcoma than with those described as reticulum cell sarcoma. It has been implied (21) that multiple sites of origin or lymph node involvement causes no apparent change in mortality from colonic lymphoma. However, in cases arising in ulcerative colitis, this does not appear to be true. Of 5 cases with nodes stated to be negative, all were alive at 6 months to 6 years (8, 10-12). Conversely, of 6 patients with positive nodes, 4 were dead within 1 year (9, 11, 12, 16). Of 5 patients with single lesions, 4 were alive from 6 months to 6 years after operation and one was dead at 5 months (8, 10, 12). All 3 patients with lymphoma and adenocarcinoma were
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d e a d w i t h i n 1 y e a r (12, 14, 15). O f the 6 p a t i e n t s with m u l t i p l e or diffuse l y m p h o m a , 3 w e r e alive at 12-15 m o n t h s a n d 3 w e r e dead w i t h i n 1 y e a r (9, 11, 15, 16, 17). U l c e r a t i v e colitis is a c c e p t e d as a p r e m a l i g n a n t g a s t r o i n t e s t i n a l lesion. It is a t t r a c t i v e to h y p o t h e size, as h a v e S h e r l o c k et al (24), that t h e r e is a relat i o n s h i p b e t w e e n u l c e r a t i v e colitis a n d l y m p h o m a a n d that there m a y be a p r e m a l i g n a n t state r e l a t e d to a b n o r m a l l y m p h o i d tissue in the l a m i n a p r o p r i a . T h e clinical e v i d e n c e , h o w e v e r , i n d i c a t e s the age of o n s e t , d i s t r i b u t i o n , cell t y p e s , a n d 1-year s u r v i v a l are similar to p r i m a r y c o l o n i c l y m p h o m a , p e r h a p s suggesting a coincidental occurrence of l y m p h o m a in u l c e r a t i v e colitis, w h i c h m a y be modified in the d i r e c t i o n of m u l t i p l i c i t y b y the p r e e x i s t i n g inflamm a t o r y disease.
ACKNOWLEDGMENTS The authors acknowledge the assistance of Dr. Henry Rappaport in the histological interpretation, Dr. Gerald Levine in the electron microscopic evaluation, Dr. David Rochester in reviewing the x-rays, and Ms Kathy Linneman in the preparation of the manuscript. Dr. George E. Block performed the proctocolectomy.
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Digestive Diseases. Vol. 22. No. 6 (June 1977)
