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Celiac sprue complicated by lymphoma presenting with multiple gastric ulcers
GASTROENTEROLOGY
1986;91:740-5
Celiac Sprue Complicated by Lymphoma Presenting With Multiple Gastric Ulcers RICHARD L. ROEHRKASSE, INGRAM M. ROBERTS, ARNOLD WALD, THOMAS S. TALAMO, and HARVEY Departments of Medicine and Pathology, Medicine, Pittsburgh, Pennsylvania
Montefiore
A 4%yr-old woman with celiac sprue, which had responded clinically and histologically to gluten elimination, subsequently developed gastrointestinal lymphoma. Although this has been described in the small intestine of patients with celiac sprue, the unique feature in this patient was her initial presentation with multiple gastric ulcers refractory to conventional medical therapy. This case demonstrates that Iymphoma complicating celiac sprue may present with multiple refractory gastric ulcers in addition to those occurring in the small intestine. An uncommon and often fatal complication of celiac sprue is the development of multiple intestinal ulcers (1,2). The most common site of involvement is the jejunum, but involvement of the duodenum, ileum, and colon have been described. There are no reports of their occurrence in the stomach, however (193). Malignant intestinal lymphoma, particularly the variant identified as malignant histiocytosis of the intestine (4), also occurs as a fatal complication of celiac sprue. This neoplasm has also developed in those patients with ulcerative, nongranulomatous jejunoileitis (5). In this report, we describe a patient with treated celiac sprue who developed multiple gastric ulcers refractory to conventional ulcer therapy. Subsequent studies revealed that these ulcers were the initial manifestation of gastrointestinal lymphoma.
Case Report cember
A 40-yr-old Amish woman was healthy until De1981, when she was hospitalized with a 4-wk
Received July 18, 1985. Accepted March 19, 1986. Address requests for reprints to: Arnold Wald, M.D., Montefiore Hospital, 3459 Fifth Avenue, Pittsburgh, Pennsylvania 15213. The authors thank Dr. John H. Yardley for reviewing the pathological material. 0 1986 by the American Gastroenterological Association 0016-5085/86/$3.50
Hospital,
University
MENDELOW
of Pittsburgh
School
of
history of nausea, vomiting, abdominal pain, and watery diarrhea. Initial evaluation revealed bilateral pleural effusions, ascites, and anasarca. Laboratory tests disclosed the following values: a hemoglobin level of 10.9 g/dl, a hematocrit of 33%, and a white blood cell count of 9300/mm3 (44% neutrophils, 34% bands, 9% lymphocytes, 2% eosinophils, 2% atypical lymphocytes, and 9% monocytes). The serum cholesterol level was 54 mg/dl, albumin was 1.9 g/dl, and total protein was 4.5 g/dl. Proteinuria was absent and serum bilirubin, aspartate transaminase, alanine transaminase, and prothrombin time were normal. Both the pleural effusion and the ascites were transudates, and examination of both of these fluids disclosed no malignant cells. Multiple stool specimens were negative for enteric pathogens. Serum o-xylose was 14 mg/dl (normal, 21-57 mg/dl) 1 h after a 25-g oral dose, and the 5-h urine o-xylose was 1.7 g/5 h (normal, > 5 g/5 h). An upper gastrointestinal series disclosed edematous, dilated loops of small intestine containing increased fluid; no strictures or ulcerations were identified. An abdominal computed tomography scan showed ascites but no liver abnormalities, no nodal enlargement, and no gastrointestinal wall thickening. A small intestinal biopsy specimen was consistent with celiac sprue (Figure la). Institution of a gluten-free diet and a short course of intravenous hyperalimentation resulted in clinical and biochemical resolution, including complete disappearance of the ascites, pleural effusion, and anasarca. The patient’s weight increased from 86 to 107 lb and a repeat small intestinal biopsy specimen obtained in July 1983 showed substantial improvement (Figure lb). The patient remained well until June 1984 when she was admitted to another hospital with abdominal pain and hematemesis. An upper gastrointestinal series suggested a small duodenal ulcer. After transfusion of 4 U of packed red blood cells, she was discharged on cimetidine and antacids. One month later, she was hospitalized with melena. Upper endoscopy and biopsy reportedly revealed a 2-cm gastric ulcer and small duodenal ulcers. Treatment with cimetidine and antacids was continued. In September 1984 she was admitted to Montefiore
September
Figure
1986
CELIAC SPRUE AND LYMPHOMA
741
1 Early jejunal biopsy specimens. a. Initial jejunal biopsy specimen showing histologic evidence of celiac sprue, with villous atrophy, crypt hyperplasia, chronic inflammatory infiltrate, and degeneration of the surface epithelium. (H&E, cxiginal magnification X200.) b. Jejunal biopsy specimen taken after gluten withdrawal, showing partial reversal of mucosal c:hanges toward normal with formation of new villi and regeneration of normal surface epithelium. (H&E, original magnification x 250.)
742
ROEHRKASSE ET AL.
Figure
2.
GASTROENTEROLOGY Vol. 91, No. 3
Resected gastric segment. a. Gross photograph of resected stomach (antrum and pyloric area) containing multiple ulcers (arrows). The markedly thickened pylorus is seen at the right (arrowhead). b. Photomicrograph illustrating gastric ulcer (center), with adjacent intact mucosa and extensive mucosal and submucosal cellular infiltrate. (H&E, original magnifilcation X20.) c. Photomicrograph of ulcer base showing acute vasculitis with fibrinoid necrosis of the vessel wall (arrow). Rare abnormal mononuclear cells were present within an acute and chronic inflammatory cell infiltrate. (H&E, original m;Ignification x200.) d. Photomicrograph of infiltrate at ulcer base Eontaming large atypical cells (arrows) with lobulated nmclei, increased nuclear-to-cytoplasmic ratio, and prominent nucleoli. (H&E, original magnification x1000.)
Hospii :a1I with worsening epigastric pain, vomiting, and progre SS#iveweight loss. Physical examination revealed an afebril e cachectic woman weighing 82 lb. There was no scleral ic:terus, lymphadenopathy, or hepatosplenomegaly, but thl e was mild epigastric abdominal tenderness. The
stool was guaiac-negative; there was no clubbing, c:yanosis, or edema of the extremities. Laboratory studies disclosed the following valu es: a white blood cell count of 12,300/mm3, a hemoglobin level of 11.7 g/d], a hematocrit of 35.2%, and a mean corpus cular
September
Figure
2.
1986
CELIAC SPRUE AND LYMPHOMA
743
Continued.
volume of 80 pm3. Serum cholesterol was 107 mg/dl, albumin was 3.3 g/dl, and total protein was 6.6 g/dl. Alkaline phosphatase was 141 III/L (normal, 30-115 III/L), with an elevated liver isoenzyme fraction. Bilirubin, aspartate transaminase, alanine transaminase, prothrombin time, amylase, blood urea nitrogen, creatinine, electrolytes, magnesium, calcium, phosphorus, fasting serum
gastrin, and quantitative immunoglobulin levels were normal. Her chest and abdominal radiographs were normal except for a moderately distended stomach. An upper endoscopy revealed multiple gastric ulcers. Biopsy specimens showed acute and chronic inflammation, foci of coagulative musosal necrosis producing ulceration, and minimal
744
ROEHRKASSE
ET AL.
gastritis involving the antral mucosa adjacent to the ulcers. Duodenal biopsy specimens showed partial villous atrophy consistent with treated celiac sprue. No viral inclusions, fungi, or malignant cells were seen. The patient was treated with total parenteral nutrition, nasogastric suction, and intravenous cimetidine for z wk without improvement After a repeat upper endoscopy disclosed an increase in size and number of the gastric ulcers, the patient underwent a subtotal gastrectomy, gastrojejunostomy, and vagotomy. At surgery, the small intestine and liver appeared normal. The surgical specimen (Figure 2a) contained numerous irregular, necrotic ulcers in the stomach, which penetrated into the submucosa and were accompanied by an intense, pleomorphic, predominantly mononuclear, inflammatory cell infiltrate involving the ulcers and adjacent mucosa (Figure 2b). Foci of necrotizing vasculitis involving small arteries and veins were found in the ulcer bases (Figure 2c), with intravascular thrombi and involvement of vessel walls by a pleomorphic infiltrate containing occasional abnormal mononuclear cells. These mononuclear cells [Figure 2d) had moderate amounts of cytoplasm with positive immunoperoxidase staining for lysozyme, (Yeantitrypsin, and al-antichymotrypsin. Although surface marker studies were not performed on fresh tissue, immunoperoxidase studies demonstrated both K- and A-chain staining in some of the lymphoid cells within the infiltrates, indicating their polyclonal nature. Similar cellular infiltrates were present in the lamina propria of the intact adjacent mucosa. Based on these findings, a diagnosis of lymphoma (malignant histiocytosis of the intestine) was made. A bone marrow biopsy specimen revealed focal paratrabecular infiltrates composed of large atypical cells with the morphologic appearance of malignant histiocytes. As recurrent abdominal pain, bloating, nausea, and vomiting precluded adequate oral caloric intake, parenteral nutrition was reinstituted. Repeat upper endoscopy of the gastric remnant and the efferent limb of the Billroth II anastomosis revealed multiple ulcerations in the jejunum and in the gastric remnant. Jejunal biopsy specimens of mucosa adjacent to the ulcers showed changes consistent with ulcerative jejunitis in the absence of malignantappearing mononuclear cells. Chemotherapy was recommended but refused by the patient. She died 2 mo later and permission for autopsy was not granted.
Discussion Small intestinal lymphoma was first recognized as a complication of celiac sprue in 1962 (6). Such lymphomas may occur in the setting of longstanding celiac sprue (5,7,8) but may also develop without an antecedent clinical history of malabsorption; in the latter cases, villous atrophy and crypt hyperplasia may be found in mucosa uninvolved with gross tumor (4,5,9). Although patients with celiac sprue who fail to respond to gluten withdrawal are thought to be at particularly high risk for the development of lymphoma (4), most patients with celiac sprue who develop lymphoma initially
GASTROENTEROLOGY
Vol. 91. No. 3
have histologic
improvement on gluten withdrawal (8,lO). Isaacson (5) has described an early histologic lesion that he has suggested may identify those patients with sprue who will go on to develop lymphoma. The origin of the cells comprising lymphomas complicating celiac sprue is controversial. These lymphomas have been variously classified as Hodgkin’s disease, reticulum cell sarcoma, lymphosarcoma, or a pseudolymphomatous reaction (7,11-14). Subsequent studies indicated that the majority of these lymphomas could be classified histologically and immunohistochemically as malignant histiocytosis of the intestine (3,5,9,14,15). In
one study, 90% of lymphomas associated with celiac sprue were identified as malignant histiocytosis and >80% of these cases initially presented with small intestinal involvement (8). However, recent studies using monoclonal antibody immunocytochemical staining and tumor DNA analysis have shown that
lymphomas previously classified as malignant histiocytosis of the intestine by morphologic and immunohistologic criteria are, in fact, T-cell lymphomas
(16-18). These lymphomas typically present without hepatosplenomegaly or lymphadenopathy, in contrast to classical systemic malignant histiocytosis. Most patients present with recurrent symptoms of celiac sprue despite adherence to a gluten-free diet, or with an acute complication such as gastrointestinal bleeding, perforation, or small bowel obstruction (1,7,9). Another major complication of celiac sprue is the occurrence of multiple small intestinal ulcers. Bayless et al. (2) described 16 patients with definite or probable celiac sprue who developed multiple ulcerations of the small intestine. A similar entity, termed “chronic ulcerative nongranulomatous jejunoileitis” (1%23), has also been described in association with subtotal villous atrophy unresponsive to gluten withdrawal (1,2). In their review of a large group of
patients with small intestinal ulcers and malabsorption, Baer et al. (1)found that in some, the ulcerations accompanied or preceded the development of intestinal lymphoma, although the ulcers appeared histiologically benign. They also found that apparently benign small intestinal ulcers resected years before the diagnosis of lymphoma contained large, atypical, “histiocytic” cells at the ulcer base. Similar findings have been described by others and have led some investigators to conclude that early malignant histiocytosis is the cause of most, if not all, cases of ulcerative jejunitis complicating celiac sprue (4,5,9). In our patient, the initial diagnosis of celiac sprue was based on the characteristic clinical, laboratory, and histologic findings, which reverted toward normal after gluten withdrawal. Subsequently, she de-
September
1986
veloped a gastrointestinal lymphoma with multiple gastric and small intestinal ulcerations. Tumor cells were not demonstrated in biopsy specimens from the small intestine. This may simply represent sampling error, as mucosal biopsies can easily miss involved areas (5). The lymphoma was morphologically and immunohistologically consistent with a diagnosis of malignant histiocytosis of the intestine. Although the true phenotype of the malignant cells cannot be determined with certainty in the absence of more extensive immunocytochemical and gene rearrangement studies, recent evidence favors a T-cell origin (16-18). Similar findings have been frequently described in the small intestine of patients with lymphoma complicating celiac sprue. This case illustrates that gastric ulcers refractory to medical therapy, occurring in a patient with celiac sprue, may be the initial manifestation of such lymphomas.
References
CELIAC SPRUE AND LYMPHOMA
8. Swinson 9. 10. 11.
12.
13.
14.
15. 16.
17.
1. Baer AN, Bayless TM, Yardley JH. Intestinal
2.
3.
4.
5. 6. 7.
ulceration and malabsorption syndromes. Gastroenterology 1980;79:754-65. Bayless, TM, Kapelowitz RF, Shelley WM, Ballinger WF, Hendrix TR. Intestinal ulceration: a complication of celiac disease. N Engl J Med 1967;276:996-1002. Robertson DAF, Dixon MF, Scott BB, Simpson FG, Losowsky MS. Small intestinal ulceration: diagnostic difficulties in relation to coeliac disease. Gut 1983;24:565-74. Isaacson, P, Wright DH. Malignant histiocytosis of the intestine: its relationship to malabsorption and ulcerative jejunitis. Hum Path01 1978;9:661-7. Isaacson P. Malignant histiocytosis of the intestine: the early histological lesion. Gut 1980;21:381-6. Gough KR, Read AE, Naish JM. Intestinal reticulosis as a complication of idiopathic steatorrhea. Gut 1962;3:232-9. Cooper BT, Holmes GKT, Ferguson R, Cooke WT. Celiac disease and malignancy. Medicine 1980;59:249-61.
745
18. 19. 20.
CM, Coles EC, Slavin G, Booth CC. Coeliac disease and malignancy. Lancet 1983;i:lll-5. Hodges JR, Isaacson P, Smith CL, Sworn MJ. Malignant histiocytosis of the intestine. Dig Dis Sci 1979;24:631-8. Cooke WT, Thompson H, Williams JA. Malignancy and adult coeliac disease. Gut 1969;10:108-11. Austad WI, Cornes JS, Gough KR, McCarthy CF, Read AE. Steatorrhea and malignant lymphoma: the relationship of malignant tumors of lymphoid tissue and celiac disease. Am J Dig Dis 1967;12:475-90. Artinian B, Lough JO, Palmer JD. Idiopathic ulcer of small bowel with pseudolymphomatous reaction: a clinicopathological study of six cases. Arch Path01 1971;91:327-33. Harris OD, Cooke WT, Thompson H, Waterhouse JAH. Malignancy in adult celiac disease and idiopathic steatorrhea. Am J Med 1967;42:899-912. Isaacson P, Wright DH, Judd MA. Mepham BL. Primary gastrointestinal lymphomas: a classification of 66 cases. Cancer 1979;43:1805-19. Isaacson P, Wright DH. Intestinal lymphoma associated with malabsorption. Lancet 1978;i:67-70. Isaacson PG, Spencer J, Connolly CE, et al. Malignant histiocytosis of the intestine: a T-cell lymphoma. Lancet 1985; ii:688-91. Loughran TP, Kadin ME, Deeg HJ. T-cell intestinal lymphoma associated with celiac sprue. Ann Intern Med 1986;104:44-7. Isaacson PG. Malignant histiocytosis of the intestine (lett). J Path01 1985;147:227-8. Brunton FJ, Guyer PB. Malignant histiocytosis and ulcerative jejunitis of the small intestine. Clin Radio1 1983;34:291-5. Modigliani R, Poitras P, Galian A, et al. Chronic non-specific ulcerative duodenojejunoileitis: report of four cases. Gut
1979;20:318-28. 21. Jeffries GH, Steinberg
H, Sleisenger MH. Chronic ulcerative (nongranulomatous) jejunitis. Am J Med 1968;44:47-59. 22. Corlin RF, Pops MA. Nongranulomatous ulcerative jejunoileitis with hypogammaglobulinemia: clinical remission after treatment with gamma-globulin. Gastroenterology 1972; 62:473-8. 23. Moritz
M, Moran JM, Patterson JF. Chronic ulcerative jejunitis: report of a case and discussion of classifications. Gastroenterology 1971;60:96-102.
1986;91:740-5
Celiac Sprue Complicated by Lymphoma Presenting With Multiple Gastric Ulcers RICHARD L. ROEHRKASSE, INGRAM M. ROBERTS, ARNOLD WALD, THOMAS S. TALAMO, and HARVEY Departments of Medicine and Pathology, Medicine, Pittsburgh, Pennsylvania
Montefiore
A 4%yr-old woman with celiac sprue, which had responded clinically and histologically to gluten elimination, subsequently developed gastrointestinal lymphoma. Although this has been described in the small intestine of patients with celiac sprue, the unique feature in this patient was her initial presentation with multiple gastric ulcers refractory to conventional medical therapy. This case demonstrates that Iymphoma complicating celiac sprue may present with multiple refractory gastric ulcers in addition to those occurring in the small intestine. An uncommon and often fatal complication of celiac sprue is the development of multiple intestinal ulcers (1,2). The most common site of involvement is the jejunum, but involvement of the duodenum, ileum, and colon have been described. There are no reports of their occurrence in the stomach, however (193). Malignant intestinal lymphoma, particularly the variant identified as malignant histiocytosis of the intestine (4), also occurs as a fatal complication of celiac sprue. This neoplasm has also developed in those patients with ulcerative, nongranulomatous jejunoileitis (5). In this report, we describe a patient with treated celiac sprue who developed multiple gastric ulcers refractory to conventional ulcer therapy. Subsequent studies revealed that these ulcers were the initial manifestation of gastrointestinal lymphoma.
Case Report cember
A 40-yr-old Amish woman was healthy until De1981, when she was hospitalized with a 4-wk
Received July 18, 1985. Accepted March 19, 1986. Address requests for reprints to: Arnold Wald, M.D., Montefiore Hospital, 3459 Fifth Avenue, Pittsburgh, Pennsylvania 15213. The authors thank Dr. John H. Yardley for reviewing the pathological material. 0 1986 by the American Gastroenterological Association 0016-5085/86/$3.50
Hospital,
University
MENDELOW
of Pittsburgh
School
of
history of nausea, vomiting, abdominal pain, and watery diarrhea. Initial evaluation revealed bilateral pleural effusions, ascites, and anasarca. Laboratory tests disclosed the following values: a hemoglobin level of 10.9 g/dl, a hematocrit of 33%, and a white blood cell count of 9300/mm3 (44% neutrophils, 34% bands, 9% lymphocytes, 2% eosinophils, 2% atypical lymphocytes, and 9% monocytes). The serum cholesterol level was 54 mg/dl, albumin was 1.9 g/dl, and total protein was 4.5 g/dl. Proteinuria was absent and serum bilirubin, aspartate transaminase, alanine transaminase, and prothrombin time were normal. Both the pleural effusion and the ascites were transudates, and examination of both of these fluids disclosed no malignant cells. Multiple stool specimens were negative for enteric pathogens. Serum o-xylose was 14 mg/dl (normal, 21-57 mg/dl) 1 h after a 25-g oral dose, and the 5-h urine o-xylose was 1.7 g/5 h (normal, > 5 g/5 h). An upper gastrointestinal series disclosed edematous, dilated loops of small intestine containing increased fluid; no strictures or ulcerations were identified. An abdominal computed tomography scan showed ascites but no liver abnormalities, no nodal enlargement, and no gastrointestinal wall thickening. A small intestinal biopsy specimen was consistent with celiac sprue (Figure la). Institution of a gluten-free diet and a short course of intravenous hyperalimentation resulted in clinical and biochemical resolution, including complete disappearance of the ascites, pleural effusion, and anasarca. The patient’s weight increased from 86 to 107 lb and a repeat small intestinal biopsy specimen obtained in July 1983 showed substantial improvement (Figure lb). The patient remained well until June 1984 when she was admitted to another hospital with abdominal pain and hematemesis. An upper gastrointestinal series suggested a small duodenal ulcer. After transfusion of 4 U of packed red blood cells, she was discharged on cimetidine and antacids. One month later, she was hospitalized with melena. Upper endoscopy and biopsy reportedly revealed a 2-cm gastric ulcer and small duodenal ulcers. Treatment with cimetidine and antacids was continued. In September 1984 she was admitted to Montefiore
September
Figure
1986
CELIAC SPRUE AND LYMPHOMA
741
1 Early jejunal biopsy specimens. a. Initial jejunal biopsy specimen showing histologic evidence of celiac sprue, with villous atrophy, crypt hyperplasia, chronic inflammatory infiltrate, and degeneration of the surface epithelium. (H&E, cxiginal magnification X200.) b. Jejunal biopsy specimen taken after gluten withdrawal, showing partial reversal of mucosal c:hanges toward normal with formation of new villi and regeneration of normal surface epithelium. (H&E, original magnification x 250.)
742
ROEHRKASSE ET AL.
Figure
2.
GASTROENTEROLOGY Vol. 91, No. 3
Resected gastric segment. a. Gross photograph of resected stomach (antrum and pyloric area) containing multiple ulcers (arrows). The markedly thickened pylorus is seen at the right (arrowhead). b. Photomicrograph illustrating gastric ulcer (center), with adjacent intact mucosa and extensive mucosal and submucosal cellular infiltrate. (H&E, original magnifilcation X20.) c. Photomicrograph of ulcer base showing acute vasculitis with fibrinoid necrosis of the vessel wall (arrow). Rare abnormal mononuclear cells were present within an acute and chronic inflammatory cell infiltrate. (H&E, original m;Ignification x200.) d. Photomicrograph of infiltrate at ulcer base Eontaming large atypical cells (arrows) with lobulated nmclei, increased nuclear-to-cytoplasmic ratio, and prominent nucleoli. (H&E, original magnification x1000.)
Hospii :a1I with worsening epigastric pain, vomiting, and progre SS#iveweight loss. Physical examination revealed an afebril e cachectic woman weighing 82 lb. There was no scleral ic:terus, lymphadenopathy, or hepatosplenomegaly, but thl e was mild epigastric abdominal tenderness. The
stool was guaiac-negative; there was no clubbing, c:yanosis, or edema of the extremities. Laboratory studies disclosed the following valu es: a white blood cell count of 12,300/mm3, a hemoglobin level of 11.7 g/d], a hematocrit of 35.2%, and a mean corpus cular
September
Figure
2.
1986
CELIAC SPRUE AND LYMPHOMA
743
Continued.
volume of 80 pm3. Serum cholesterol was 107 mg/dl, albumin was 3.3 g/dl, and total protein was 6.6 g/dl. Alkaline phosphatase was 141 III/L (normal, 30-115 III/L), with an elevated liver isoenzyme fraction. Bilirubin, aspartate transaminase, alanine transaminase, prothrombin time, amylase, blood urea nitrogen, creatinine, electrolytes, magnesium, calcium, phosphorus, fasting serum
gastrin, and quantitative immunoglobulin levels were normal. Her chest and abdominal radiographs were normal except for a moderately distended stomach. An upper endoscopy revealed multiple gastric ulcers. Biopsy specimens showed acute and chronic inflammation, foci of coagulative musosal necrosis producing ulceration, and minimal
744
ROEHRKASSE
ET AL.
gastritis involving the antral mucosa adjacent to the ulcers. Duodenal biopsy specimens showed partial villous atrophy consistent with treated celiac sprue. No viral inclusions, fungi, or malignant cells were seen. The patient was treated with total parenteral nutrition, nasogastric suction, and intravenous cimetidine for z wk without improvement After a repeat upper endoscopy disclosed an increase in size and number of the gastric ulcers, the patient underwent a subtotal gastrectomy, gastrojejunostomy, and vagotomy. At surgery, the small intestine and liver appeared normal. The surgical specimen (Figure 2a) contained numerous irregular, necrotic ulcers in the stomach, which penetrated into the submucosa and were accompanied by an intense, pleomorphic, predominantly mononuclear, inflammatory cell infiltrate involving the ulcers and adjacent mucosa (Figure 2b). Foci of necrotizing vasculitis involving small arteries and veins were found in the ulcer bases (Figure 2c), with intravascular thrombi and involvement of vessel walls by a pleomorphic infiltrate containing occasional abnormal mononuclear cells. These mononuclear cells [Figure 2d) had moderate amounts of cytoplasm with positive immunoperoxidase staining for lysozyme, (Yeantitrypsin, and al-antichymotrypsin. Although surface marker studies were not performed on fresh tissue, immunoperoxidase studies demonstrated both K- and A-chain staining in some of the lymphoid cells within the infiltrates, indicating their polyclonal nature. Similar cellular infiltrates were present in the lamina propria of the intact adjacent mucosa. Based on these findings, a diagnosis of lymphoma (malignant histiocytosis of the intestine) was made. A bone marrow biopsy specimen revealed focal paratrabecular infiltrates composed of large atypical cells with the morphologic appearance of malignant histiocytes. As recurrent abdominal pain, bloating, nausea, and vomiting precluded adequate oral caloric intake, parenteral nutrition was reinstituted. Repeat upper endoscopy of the gastric remnant and the efferent limb of the Billroth II anastomosis revealed multiple ulcerations in the jejunum and in the gastric remnant. Jejunal biopsy specimens of mucosa adjacent to the ulcers showed changes consistent with ulcerative jejunitis in the absence of malignantappearing mononuclear cells. Chemotherapy was recommended but refused by the patient. She died 2 mo later and permission for autopsy was not granted.
Discussion Small intestinal lymphoma was first recognized as a complication of celiac sprue in 1962 (6). Such lymphomas may occur in the setting of longstanding celiac sprue (5,7,8) but may also develop without an antecedent clinical history of malabsorption; in the latter cases, villous atrophy and crypt hyperplasia may be found in mucosa uninvolved with gross tumor (4,5,9). Although patients with celiac sprue who fail to respond to gluten withdrawal are thought to be at particularly high risk for the development of lymphoma (4), most patients with celiac sprue who develop lymphoma initially
GASTROENTEROLOGY
Vol. 91. No. 3
have histologic
improvement on gluten withdrawal (8,lO). Isaacson (5) has described an early histologic lesion that he has suggested may identify those patients with sprue who will go on to develop lymphoma. The origin of the cells comprising lymphomas complicating celiac sprue is controversial. These lymphomas have been variously classified as Hodgkin’s disease, reticulum cell sarcoma, lymphosarcoma, or a pseudolymphomatous reaction (7,11-14). Subsequent studies indicated that the majority of these lymphomas could be classified histologically and immunohistochemically as malignant histiocytosis of the intestine (3,5,9,14,15). In
one study, 90% of lymphomas associated with celiac sprue were identified as malignant histiocytosis and >80% of these cases initially presented with small intestinal involvement (8). However, recent studies using monoclonal antibody immunocytochemical staining and tumor DNA analysis have shown that
lymphomas previously classified as malignant histiocytosis of the intestine by morphologic and immunohistologic criteria are, in fact, T-cell lymphomas
(16-18). These lymphomas typically present without hepatosplenomegaly or lymphadenopathy, in contrast to classical systemic malignant histiocytosis. Most patients present with recurrent symptoms of celiac sprue despite adherence to a gluten-free diet, or with an acute complication such as gastrointestinal bleeding, perforation, or small bowel obstruction (1,7,9). Another major complication of celiac sprue is the occurrence of multiple small intestinal ulcers. Bayless et al. (2) described 16 patients with definite or probable celiac sprue who developed multiple ulcerations of the small intestine. A similar entity, termed “chronic ulcerative nongranulomatous jejunoileitis” (1%23), has also been described in association with subtotal villous atrophy unresponsive to gluten withdrawal (1,2). In their review of a large group of
patients with small intestinal ulcers and malabsorption, Baer et al. (1)found that in some, the ulcerations accompanied or preceded the development of intestinal lymphoma, although the ulcers appeared histiologically benign. They also found that apparently benign small intestinal ulcers resected years before the diagnosis of lymphoma contained large, atypical, “histiocytic” cells at the ulcer base. Similar findings have been described by others and have led some investigators to conclude that early malignant histiocytosis is the cause of most, if not all, cases of ulcerative jejunitis complicating celiac sprue (4,5,9). In our patient, the initial diagnosis of celiac sprue was based on the characteristic clinical, laboratory, and histologic findings, which reverted toward normal after gluten withdrawal. Subsequently, she de-
September
1986
veloped a gastrointestinal lymphoma with multiple gastric and small intestinal ulcerations. Tumor cells were not demonstrated in biopsy specimens from the small intestine. This may simply represent sampling error, as mucosal biopsies can easily miss involved areas (5). The lymphoma was morphologically and immunohistologically consistent with a diagnosis of malignant histiocytosis of the intestine. Although the true phenotype of the malignant cells cannot be determined with certainty in the absence of more extensive immunocytochemical and gene rearrangement studies, recent evidence favors a T-cell origin (16-18). Similar findings have been frequently described in the small intestine of patients with lymphoma complicating celiac sprue. This case illustrates that gastric ulcers refractory to medical therapy, occurring in a patient with celiac sprue, may be the initial manifestation of such lymphomas.
References
CELIAC SPRUE AND LYMPHOMA
8. Swinson 9. 10. 11.
12.
13.
14.
15. 16.
17.
1. Baer AN, Bayless TM, Yardley JH. Intestinal
2.
3.
4.
5. 6. 7.
ulceration and malabsorption syndromes. Gastroenterology 1980;79:754-65. Bayless, TM, Kapelowitz RF, Shelley WM, Ballinger WF, Hendrix TR. Intestinal ulceration: a complication of celiac disease. N Engl J Med 1967;276:996-1002. Robertson DAF, Dixon MF, Scott BB, Simpson FG, Losowsky MS. Small intestinal ulceration: diagnostic difficulties in relation to coeliac disease. Gut 1983;24:565-74. Isaacson, P, Wright DH. Malignant histiocytosis of the intestine: its relationship to malabsorption and ulcerative jejunitis. Hum Path01 1978;9:661-7. Isaacson P. Malignant histiocytosis of the intestine: the early histological lesion. Gut 1980;21:381-6. Gough KR, Read AE, Naish JM. Intestinal reticulosis as a complication of idiopathic steatorrhea. Gut 1962;3:232-9. Cooper BT, Holmes GKT, Ferguson R, Cooke WT. Celiac disease and malignancy. Medicine 1980;59:249-61.
745
18. 19. 20.
CM, Coles EC, Slavin G, Booth CC. Coeliac disease and malignancy. Lancet 1983;i:lll-5. Hodges JR, Isaacson P, Smith CL, Sworn MJ. Malignant histiocytosis of the intestine. Dig Dis Sci 1979;24:631-8. Cooke WT, Thompson H, Williams JA. Malignancy and adult coeliac disease. Gut 1969;10:108-11. Austad WI, Cornes JS, Gough KR, McCarthy CF, Read AE. Steatorrhea and malignant lymphoma: the relationship of malignant tumors of lymphoid tissue and celiac disease. Am J Dig Dis 1967;12:475-90. Artinian B, Lough JO, Palmer JD. Idiopathic ulcer of small bowel with pseudolymphomatous reaction: a clinicopathological study of six cases. Arch Path01 1971;91:327-33. Harris OD, Cooke WT, Thompson H, Waterhouse JAH. Malignancy in adult celiac disease and idiopathic steatorrhea. Am J Med 1967;42:899-912. Isaacson P, Wright DH, Judd MA. Mepham BL. Primary gastrointestinal lymphomas: a classification of 66 cases. Cancer 1979;43:1805-19. Isaacson P, Wright DH. Intestinal lymphoma associated with malabsorption. Lancet 1978;i:67-70. Isaacson PG, Spencer J, Connolly CE, et al. Malignant histiocytosis of the intestine: a T-cell lymphoma. Lancet 1985; ii:688-91. Loughran TP, Kadin ME, Deeg HJ. T-cell intestinal lymphoma associated with celiac sprue. Ann Intern Med 1986;104:44-7. Isaacson PG. Malignant histiocytosis of the intestine (lett). J Path01 1985;147:227-8. Brunton FJ, Guyer PB. Malignant histiocytosis and ulcerative jejunitis of the small intestine. Clin Radio1 1983;34:291-5. Modigliani R, Poitras P, Galian A, et al. Chronic non-specific ulcerative duodenojejunoileitis: report of four cases. Gut
1979;20:318-28. 21. Jeffries GH, Steinberg
H, Sleisenger MH. Chronic ulcerative (nongranulomatous) jejunitis. Am J Med 1968;44:47-59. 22. Corlin RF, Pops MA. Nongranulomatous ulcerative jejunoileitis with hypogammaglobulinemia: clinical remission after treatment with gamma-globulin. Gastroenterology 1972; 62:473-8. 23. Moritz
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