Gastric Carcinoma in Patients with Crohn Disease: Report of Four Cases

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1 X/91/ C American Roentgen Ray Society Seth N. GIick1 Received January 1 7, 1991 ; accepted after re vision March 1 2, Department of Diagnostic Radiology, Hahnemann University Hospital, Broad and Vine Sts., Philadelphia, PA Address reprint requests to S. N. Glick. Gastric Carcinoma in Patients with Crohn Disease: Report of Four Cases An association between Crohn disease and gastric carcinoma has not been described before. However, we report four patients with documented Crohn disease in whom gastric carcinoma developed later. In three of the four patients, onset of Crohn disease occurred after the age of 40. All of the patients had nonspecific constitutional symptoms and/or complaints referable to the upper gastrointestinal tract. No clinical evidence of active Crohn disease was present. In each patient, barium examination and CT showed either a mass (two cases) or other radiologic features of malignancy (two cases). Endoscopy with biopsy was performed in three patients and findings were misleading in two patients. The possibility of an increased risk of malignancy in sites remote from inflamed bowel segments has been reported. The findings in this study suggest that patients with Crohn disease, particularly disease of late onset, may be predisposed to the development of gastric carcinoma. AJR 157: , August 1991 The association between Crohn disease in the large and small intestine and the development of malignant tumors in these sites has been the subject of many reports [1-6]. Approximately 1 00 cases of cobonic cancer and a similar number of small-bowel cancers associated with Crohn disease have been documented in the literature. Most of the information concerning the relationship between these entities is derived from case reports and small series. In addition, the possibility that patients with Crohn disease may be more susceptible to malignancy at sites remote (both gastrointestinal and extraintestinal) from the part of the intestine involved by the inflammatory process also has been considered. In the past year, gastric carcinoma was diagnosed at this institution in four patients with previously documented Crohn disease. Several unique clinical and radiobogic features in these cases demonstrate the importance of radiology in clarifying the diagnostic problems in this setting and possibly in contributing to earlier diagnosis. The possible association between gastric carcinoma and Crohn disease also is discussed. Subjects and Methods Four patients with a known history of Crohn disease were referred between October 1989 and October i990, for upper gastrointestinal barium examination for the investigation of a variety of upper abdominal and constitutional complaints. One patient had been treated with H2-antagonists for 3 months. An upper gastrointestinal examination performed at another institution 1 year before had shown a duodenal ulcer. In three patients, the diagnosis of Crohn disease had been established on the basis of characteristic radiologic findings. The remaining patient had undergone ileal resection and total colectomy for intractable disease. A CT scan of the abdomen was obtained in all four patients. Three of the four patients underwent endoscopy and biopsy. In two of these three, the endoscopy was repeated. The gastric malignant neoplasm was resectable in all but one patient.

2 312 GLICK AJA:157, August 1991 Results There were two men and two women ranging in age from 29 to 68 (average, 54) years. The age at diagnosis of Crohn disease ranged from 15 to 60 (average, 45) years. Three of the four patients were more than 40 years old when Crohn disease was diagnosed and two of them were more than 60 years old. The interval between the diagnosis of Crohn disease and the diagnosis of gastric carcinoma ranged from 8 to 14 (average, 9.5) years; in three cases, it was exactly 8 years. The distribution of Crohn disease was terminal ileum (two cases), colon (one case), and ileocolitis (one case). All four patients were asymptomatic with respect to the Crohn disease. One patient was being treated with sulfasalazine and another with steroids. Two were not taking medication but had received sulfasalazine in the past. One of these two also had been treated with steroids and the other with azathioprine. Double-contrast upper gastrointestinal examinations showed abnormality in the gastric antrum in three patients and the gastric cardia in one patient. The antral abnormalities consisted of a large ulcer(fig. 1 A), concentric antral narrowing with thick nodular folds and multiple ulcers (Fig. 2A), and asymmetric antral narrowing with ulceration on the greater curvature (Fig. 3A). The fourth patient had mild narrowing of the distal esophagus and a mass in the gastric cardia (Fig. 4A). In all patients, the diagnosis of malignancy was suggested by the barium study. CT scans in these patients showed focal wall thickening (Fig. 1 B), a gastric mass (Fig. 3B, 3C, 4B) and symmetric thickening of the antral wall (Fig. 2B). In the first three cases, the CT findings supported the diagnosis of a neoplasm, and in the last case they were inconclusive. Endoscopy was performed in three patients. In one patient, the initial endoscopic diagnosis was gastric Crohn disease, whereas in another a firm region was found in the cardia but no definite mass was present. Biopsies in both patients did not Show malignancy. A second endoscopic examination in both cases confirmed the diagnosis. During surgery, the tumor was found to have invaded the full thickness of the gastric wall and to have spread to perigastric lymph nodes in all four patients. One of the lesions was unresectable, and one patient also had liver metastases. Histologic evaluation revealed two of the neoplasms to be poorly differentiated carcinomas, another neoplasm was poorly differentiated signet cell, and the last neoplasm was moderately differentiated. None of the patients had evidence of Crohn disease in the resected specimen. Discussion The association between Crohn disease and malignancy is incompletely defined. Considerable evidence supports a direct pathogenetic relationship [1-7]. However, investigations attempting to document an increased risk of gastrointestinal cancer in patients with Crohn disease compared with the general population are less conclusive. These studies are limited by the small numbers of patients and the methods of selecting patients. Retrospective evaluations from tertiary referral centers have reported an increased risk that varies widely in magnitude for both colonic [1, 6, 8] and small-bowel cancer [4, 6]. Conversely, population studies have not shown an increased risk of gastrointestinal carcinoma or carcinoma at specific gastrointestinal sites in patients with Crohn disease [8,9]. In view of the difficulties in documenting an increased risk of intestinal cancer in patients with Crohn disease in spite of pathologic and epidemiologic data supporting this association, it is understandable that a postulated association between gastric carcinoma and Crohn disease would be even more tenuous. The mechanism most widely accepted in Crohn-related intestinal cancer is long-standing inflammation. However, in our patients, this mechanism was absent. These patients may have a more generalized malignant diathesis. Immunologic compromise due to the underlying disease, the drugs used in its treatment, or both may play a role. Genetic predisposition to malignancy also could be a factor. Greenstein et al. [1 0] were unable to identify an overall increased risk of extraintestinal malignancy in patients with Crohn disease. However, there was a statistically significant increase Fig year-old woman with 2- month history of epigastric pain radiating to back. A, Spot film from upper gastrointestinal study shows large irregular ulcer crater in proximal part of antrum. A faint defect in barium pool (arrow) surrounding ulcer suggests presence of malignant tumor. B, CT scan from same patient shows gastric ulcer (small arrow) extending into focally and asymmetrically thickened gastric wall (large arrow).

3 AJR:157, August 1991 GASTRIC CARCINOMA AND CROHN DISEASE 313 Fig year-old man with increasing abdominal pain and weight loss for 10 months. A, Spot film from upper gastrointestinal study shows concentric narrowing of antrum extending into duodenal bulb. Mucosa is ulcerated and contours are nodular. Proximal transition with normal wall is abrupt. These features suggest neoplasm rather than inflammation. Initial endoscopic impression was gastric Crohn disease. B, CT scan shows uniform thickening of gastric antrum (arrows). Outer margins are indistinct, but no definite tumor mass is identified. A B C Fig year-old woman with an 8-pound (3.6 kg) weight loss in 6 months and a palpable abdominal mass. A, Spot film from upper gastrointestinal study shows large irregular mass (arrow) along greater curvature of antrum. Lumen is slightly compressed by extrinsic mass. B, CT scan shows nonuniform mural thickening (arrow) at junction of body and antrum. C, Lower section shows large heterogeneous soft-tissue mass (m), indicating presence of a neoplasm. Fig year-old man with a 3- month history of anorexia and dysphagia. A, Lateral view of fundus shows a well-defined, smooth-surfaced mass (arrows) that surrounds and distorts cardiac orifice. Mucosa is preserved and intraluminal protrusion is minimal. Distal esophagus was slightiy narrowed. Initialendoscopyand biopsy did not show tumor. B, CT scan shows soft-tissue mass (arrow) arising from cardia and growing predominantiy away from lumen. A B

4 314 GLICK AJA:157, August 1991 in neoplasms of the reticuboendothelial system. Crohn disease in association with lymphoma has been described [1 1, 12]. In a population study [9] from Denmark, the prevalence of extraintestinal cancers was increased in women with Crohn disease. However, in a population study [1 3] from England, no increased risk for extraintestinal malignant tumors was seen in these patients. Some evidence suggests that carcinoma of the gastrointestinal tract in Crohn disease may occur at sites remote from the inflammatory process [1 3]. Approximately one third of cobonic carcinomas have arisen in segments uninvolved by Crohn disease [2]. Gyde et ai. [1 3] found a statistically significant excess oftumors in the upper gastrointestinal tract. Eight of the nine lesions were at sites uninvolved by Crohn disease. Half of the gastrointestinal malignant neoplasms in this series were remote from the areas of inflammation. In another study [1 4], two (1 3%) of 15 gastrointestinal cancers of known origin were in the upper gastrointestinal tract and five (33%) of 1 5 were in uninvolved segments. A survey [15] of several institutions found 88 cases of gastrointestinal cancer with known site of origin. The malignant neoplasm was distant from the Crohn disease in seven patients (8%). Specific information on gastric carcinoma and Crohn disease is limited. Anecdotal references without mention of clinical features have been noted [1 4, 15]. The only detailed analysis is the description by Gyde et al. [1 3] of four patients. Three were women. Three of the patients were more than 50 years old when Crohn disease was diagnosed. The duration of the Crohn disease ranged from 5 to 23 (average, 1 4) years. The age at diagnosis of carcinoma ranged from 56 to 75 (average, 66) years. In three patients, the Crohn disease was confined to the small bowel, and in one patient the distribution was ileocecal. The number of patients with Crohn disease and gastric carcinoma may have been underestimated. In some cases, this association can go unrecognized, as the two entities are assumed to be unrelated. In other situations, the presence of Crohn disease in a patient with gastric carcinoma may be unsuspected. It is known that patients subsequently proved to have Crohn disease may have had vague symptoms for years. Alternatively, some patients initially have obstruction from a fibrotic stricture. In approximately 30% of patients with cobonic carcinoma and Crohn disease, Crohn disease was not diagnosed until the patients were examined for symptoms related to the carcinoma [2}. Approximately 12% of the smallbowel neoplasms were identified either coincidently or within 1 year of diagnosis of regional enteritis [13]. It is interesting that three of the four patients described here and all of the patients reported by Gyde et al. [1 3] were more than 40 years old when Crohn disease was diagnosed. Patients with onset of Crohn disease after age 40 constitute less than 20% of the total population of patients with Crohn disease. No other consistent patterns relating to medications, disease distribution, or duration of disease were found. Although a relationship between Crohn disease and gastric carcinoma is not established, these four cases demonstrate several important points. Patients with documented Crohn disease in whom symptoms referable to the upper gastrointestinal tract develop should undergo diagnostic examination. It should not be assumed that such symptoms are related to peptic disease, associated with drug therapy, or related to gastric Crohn disease. Radiobogic evaluation with barium and CT scanning can be important in the diagnosis of gastric carcinoma because results of endoscopy and biopsy can be vague or misleading. Any gastric narrowing, ulceration, or fold thickening seen on upper gastrointestinal examination should be carefully assessed for features that suggest malignancy. Furthermore, as patients with Crohn disease often have an upper gastrointestinal examination done in conjunction with small-bowel evaluation during the course of the disease, increased scrutiny for subtle gastric mucosal abnormalities may be warranted. Although our four patients and those reported by Gyde et al. [1 3] had advanced disease, more aggressive treatment could result in earlier diagnosis. Increased awareness of this potential association should produce additional reports that may clarify this issue. REFERENCES 1. Glotzer DJ. The risk of cancer in Crohn s disease. Gastroenterology 1985:89: Hamilton SR. Colorectal carcinoma in patients with Crohn s disease. Gastroenterology 1985:89: Collier PE, Turowski P, Diamond DL. Small intestinal adenocarcinoma complicating regional enteritis. Cancer 1985:55: Senay E, Sachar DB, Keohane M, Greenstein AJ. Small bowel carcinoma in Crohn s disease: distinguishing features and risk factors. Cancer 1989:63: Petras RE, Mir-Madjlessi SH, Farmer AG. Crohn s disease and intestinal carcinoma: a report of 1 1 cases with emphasis on associated epithelial dysplasia. Gastroenterology 1987:93: Richards ME, Rickert AR, Nance FC. Crohn s disease-associated carcinoma: a poorly recognized complication of inflammatory bowel disease. Ann Surg 1989;209: Savoca PE, Ballantyne GH, Cahow CE. Gastrointestinal malignancies in Crohn s disease. Dis Colon Rectum 1990:33: Fireman Z, Grossman A, Lilos P, et al. Intestinal cancer in patients with Crohn s disease: a population study in central Israel. Scand J. Gastroenterol 1989;24: Kvist N, Jacobsen 0, Norgaard P, et al. Malignancy in Crohn s disease. Scand J Gastroenterol 1986;21 : Greenstein AJ, Gennuso A, Sachar DB, et al. Extraintestinal cancers in inflammatory bowel disease. 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5 This article has been cited by: 1. Takahiro Zenda, Keizo Taniguchi, Tetsuo Hashimoto, Yasuo Takeshita, Syuichi Choto, Takaharu Masunaga, Hiroshi Minato Metastatic colon cancer mimicking Crohn's disease. Annals of Diagnostic Pathology 11:6, [CrossRef]