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Intestinal ulceration and malabsorption syndromes
GASTROENTEROLOGY
79:754-765,
1980
Intestinal Ulceration and Malabsorption Syndromes ALAN
N. BAER,
THEODORE
JOHN
H. YARDLEY
M. BAYLESS,
and
Departments of Medicine and Pathology, The Johns Hopkins University Medicine and The Johns Hopkins Hospital, Baltimore, Maryland
Data from 47 patients with malabsorption and small intestinal ulceration were reviewed to provide information on the relationship of the ulcerative process to celiac disease and to Jymphoma. Presentations included: (a) worsening of malabsorptive symptoms and abdominal pain in a patient with celiac disease in his or her fifth or sixth decade; (b) an unexplained, unresponsive malabsorption syndrome with a j7attened jejunal mucosa; or (c) complications including obstruction, perforation, or hemorrhage. UJcer diagnosis was usually first made at surgery and not radiologically. The ulcers were morphologically nonspecific, usually multiple, and predominantly jejunal. Twenty-two patients with benign ulceration could be classified as celiac disease. Eleven others with “unclassified sprue” had similar jejunal biopsies, often with a long history of malabsorption. They did not go into remission with gluten withdrawal or adrenocorticosteroids. In some, this may have been because of the ulcers. Intestinal resection “cured” 4 of 13 patients. Steroid therapy was associated with prolonged remissions in 2 of 13, but intestinal perforation occurred in 10 while on steroids. Currently 29 of the 40 patients with benign ulceration are known to have died as a result of the uJcers. Lymphoma was antedated for months or years by benign ulceration in 3 patients and by histiocytic cells in pleomorphic atypical ulcers probably representing early subtle Jymphoma in 2 others. When intestinal ulceration accompanied by malabsorption is Received August 6,1979. Accepted May 13, 1980. Address requests for reprints to: Theodore M. Bayless, M.D., Division of Gastroenterology, The Johns Hopkins Hospital, Baltimore, Maryland 21205. Dr. Baer was a Henry Strong Denison Scholar for 1977-1978, The Johns Hopkins University School of Medicine. Gratitude is expressed to all the physicians who supplied information and materials for this registry, to Dr. Berton Ashman for referring pne of the patients for care, and to Drs. Risa Mann and Thomas R. Hendrix who provided critical support. 0 1980 by the American Gastroenterological Association @X6-5085/80/100754-12$02.25
School of
suspected, exploratory Japarotomy for biopsy and bowel resection and to search for Jymphoma is reasonable. Use of the term “nongranulomatous ulcerative jejunoileitis” may be misleading and is not recommended. Multiple nonmalignant ulcers of the small intestine are an uncommon, but frequently fatal complication of celiac disease (gluten-induced enteropathy).’ Along with the development of lymphoma, this type of intestinal ulceration is one of the leading causes of premature death of patients with celiac disease. The ulcers are morphologically nonspecific and have no known etiology. Similar ulceration has been described in patients with malabsorption associated with diffuse or patchy jejunal villus blunting who do not respond to a gluten-free diet. The term “chronic nongranulomatous ulcerative jejunoileitis” has been applied to many of these patients.‘m4 Confusion has resulted from use of this term in a nonspecific fashion for patients with underlying primary disorders such as well-documented celiac disease, hypogammaglobulinemia, and patients who subsequently were found to have intestinal lymphoma.“-* Some patients with celiac disease who develop intestinal lymphomas will present with histologically benign intestinal ulceration or with atypical but not frankly lymphomatous lesions.*-*’ This report is based upon a registry of 47 patients with malabsorption and small intestinal ulceration. It was our opinion that these patients had a primary malabsorptive disorder complicated by intestinal ulceration. Although our initial focus was on patients with benign ulceration, we identified several patients in whom benign ulcers were related to intestinal lymphoma. Because of the frequent fatal complications of the intestinal ulcerations in this group of 47 patients as well as the eventual development of lymphoma in others, an aggressive diagnostic and therapeutic ap-
INTESTINAL ULCERATION AND MALABSORPTION
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Table
I.
Patients
755
with Malabsorption and Small Intestinal Ulceration Sources of patients included in registry Published case numbers with references
Celiac disease (n = 22)
1." 2,'23,'94,'45.159,'10," 11’ ,6 121I713II814II915I2o 16'l17 , ,*219232024 > , 215
Unclassified sprue (n = 11)
23.2524,*’253’ 263’ 27 9’ 28327 29,3 324
Lymphoma (n = 7) Miscellaneous malabsorbtion Villus blunting
34,3 35:’ 36,2938,’ 39,3040=
Unpublished case numbers with sources and dates 6 (JF Fordtran,
A Kassanoff 1966) 7,8 (J Phillips 1966) 18 (GD Cain 1973) 22 (BL Morson 1976) 30 (RB Ruskin 1973) 31 (M Shapiro 1973) 33 (TM Bayless 1977) 37 (R Wintroub 1974-77)
Pathological material reviewed Case numbers 6,8.9,14.15,21,22
30-33
35-39
disorders 41 93242 ,3243 96 44 !95.34
-
-
45 33 46 33547”O
-
-
(n = 4) Normal villus architecture (n = 3)
preach to patients with malabsorption by intestinal ulceration is proposed.
complicated
Material and Methods Forty-seven patients with intestinal ulceration (grossly visible in 45) and malabsorption were included in the registry (Table l).* There were no known causes of ulceration such as potassium tablet ingestion, tuberculosis, syphilis, vasculitis, ischemia, Crohn’s disease, ZollingerEllison syndrome, or tumors other than lymphoma.37,38 The pathology material from 15 patients was reviewed. Results of postmortem examinations were available of the 37 patients who are known to have died.
on 33
Results Classification
of Patients in Registry
Forty patients had intestinal ulcers not associated with intestinal lymphoma. Thirty-seven of these patients had malabsorption associated with marked villus blunting in the proximal small intestine at some time during their illness. These included 22 patients with celiac disease (gluten-induced enteropathy), 11 patients with “unclassified sprue”, and 4 patients with miscellaneous malab*Twenty-four previously reported patients with malabsorption and small intestinal ulceration were not included in the registry. There was inadequate detail in some39-44; ulcers were microscopic and confined to the intestinal mucosa in others*5-“; 2 patients with celiac disease had an associated vasculitis,z, 4s while 2 other celiac patients had only duodenal ulcers.50, 51 Two others had a nongranulomatous ulcerative process attributed to Crohn’s disease.52, 53Another had ileal ulcerations associated with splenic atrophy and liquefactive necrosis of the mesenteric lymph nodes.“4 One patient with malabsorption and active tuberculosis had ileal ulcers containing mycelia.
sorptive disorders. Three patients had malabsorption associated with normal villus architecture (Table 1). Five patients, including two with celiac disease, had malabsorption and histologically benign intestinal ulcers associated with intestinal lymphoma. Two additional patients with celiac disease and lymphoma presented with ulcers containing an atypical pleomorphic cellular infiltrate.
Patients with Celiac Disease (Gluten-Induced Enteropathy) and “Unclassified Sprue” Definitions. The 22 patients with celiac disease varied with respect to the documentation of their diagnosis. In all, the characteristic flat jejunal mucosa of celiac disease was documented either with jejunal biopsy or with adequately preserved postmortem specimens (Table 2). A characteristic clinical, biochemical, or histologic response to a gluten-free diet or gluten refeeding supported the diagnosis in 17 patients. In 5 patients in whom a trial of a gluten-free diet was either inadequate or not performed, other features of their illness, such as a long history of steatorrhea with or without childhood diarrhea and/or a response to corticosteroids strongly suggested the diagnosis of celiac disease (Figure 1). The term “unclassified sprue” was used for 11 patients with malabsorption and a flat jejunal mucosa similar to that seen in celiac disease who: (a) failed to respond satisfactorily to adequate trials of a gluten-free diet or adrenocorticosteroids, either alone or in combination; and (b) in whom no known etiology for the villus blunting could be identified. Although there were many similarities to patients with celiac disease, this diagnosis could not be clearly estab-
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lished (Table 2). Six of the 11 patients had been published as examples of “nongranulomatous ulcerative jejunoileitis.” Clinical features. On the average, the patients with “unclassified sprue” were 8 yr older than the patients with celiac disease. The majority of these patients with “unclassified sprue” also had evidence of malabsorption for over 1.5 yr before the onset of the ulcers (Figure 2). This feature of preceding malabsorption is a strong point in the consideration that some of these patients may have had underlying celiac disease. Jntestinal ulceration. At the onset of ulcer-related symptoms, 9 patients with celiac disease were in a clinical remission on a gluten-free diet, either alone or with adrenocorticosteroids. The onset of ulceration in these patients was usually marked by the appearance of abdominal symptoms, including pain, anorexia, weight loss, and diarrhea as well as low grade fever. Ulcers presented in the setting of renewed symptoms after the cessation of a gluten-free diet in 3 patients. Two patients were begun on a gluten-free diet within 5 mo of the onset of the ulcer 1 responded only after resection of a manifestations; jejunal stricture, while another with microscopic jejunal ulcers responded with the addition of adrenocorticosteroids. A progressively worsening malabsorption syndrome, unresponsive to therapy, had been present for over 1.5 yr at the onset of the ulcers in most patients with “unclassified sprue”. Four such patients were begun on unsuccessful trials of a gluten-free diet or adrenocorticosteroids, either alone or in combination, within 3 mo or less of the documentation of ulcers or the onset of ulcer-related symptoms. The onset of the ulcers may have prevented or obscured any therapeutic response to measures directed at malabsorption. Complications of the ulcers, including intestinal obstruction, gastrointestinal bleeding, and intestinal perforation, usually provided the first objective evidence of the presence of ulcers in both groups of patients (Table 3). The complications, particularly intesiinal perforation, were frequently fatal. Twenty-three of the 33 patients died of ulcer complications. Small bowel obstruction was the most common indication for surgery. Surgical resection of involved bowel offered the greatest chance for survival. Five of the thirteen patients with celiac disease and both patients with “unclassified sprue” who underwent surgical resection lived for 1 or more yr postoperatively. Four of these patients survived for more than 12 yr but 3 required further resections or bypass procedures. Medical therapy, including adrenocorticosteroids, was not associated with prolonged survival except in 2 patients with ce-
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Table 2. Clinical Features of the Patients with Celiac Disease and “Unclassified Sprue” “Unclassified sprue”
Clinical features
Celiac disease
Number of patients
2.2’(14/8)
x1(3/8)
48.2 f 10.8 yr (1 SE)
56.2 rt 11.8 yr (1 BE)
(M/F) Age Duration of preceding malabsorption >1.5 years <7 months Complications: Intestinal obstruction GI bleeding: occult gross Intestinal perforation Mortality 5-yr survival
16 (average 13 yr) 3 11 (lO)b 2 6 (3) 10 (6) 13 6
9 (average 4.6 yr) 2 2 (2)b 0 6 (4) 5 (4) 10 1
0 All numbers indicate number of patients unless otherwise specified. bThe number in parentheses represents the patients in whom the complication was the presenting problem.
liac disease, both without complications and with relatively superficial ulcerations, who lived for over 5 yr after the onset of the ulcers. Prednisone seemed to be injurious in some patients by promoting the perforation of existing ulcers. Adrenocorticosteroids were either in use or had been used within 1 mo of the time of perforation in 10 of the 15 patients who developed this complication. Only 14 of the 33 patients were receiving steroids within 6 mo of the onset of the ulcers. Pathologic features. The histopathologic features of the ulcers from 7 patients with celiac disease and 3 with “unclassified sprue” in whom slides were reviewed were similar and nonspecific (Table 3). The ulcers varied in depth, penetrating to the muscularis mucosa in 1 patient and to the muscularis propria in most others. Extensive submucosal edema and fibrosis were prominent features in some. The inflammatory infiltrate was largely confined to the base of the ulcers and was typically a mixture of lymphocytes, plasma cells, histiocytes and polymorphonuclear leukocytes (Figures 3-5). Descriptions and photographs in published cases are similar in most of these aspects.
Radiologic Studies X-ray examinations were usually not helpful in documenting the presence of intestinal ulceration. A small bowel series was performed in 15 of the 33 registry patients with celiac disease or “uncltissified sprue” within 3 mo or less of surgical or autopsy documentation of their nonspecific ulcers. Ulcers
INTESTINAL
October 1990
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Figure 1. Clinical courses of 22 patients
with celiac disease and intestinal ulceration. The duration of malabsorptive symptoms and of responses to gluten restriction or adrenal steroid therapy in months or years, are shown to the left of the central area (time of ulcer documentation). Malabsorption had been present for over 1.5 yr in 16 patients. The age at the time of ulcer documentation is shown. The duration of survival after ulcer diagnosis is shown to the right of the central area. Five are known to be alive.
were seen in only 2 of the 15 patients, and these ulcers were associated with strictures in the proximal small intestine. Strictures of the duodenum or jejunum but without evidence of ulceration were documented in 6 other individuals. Flocculation and seg-
mentation of the barium presumably made detection of mucosal lesions difficult. The ulcers that were not seen radiographically but subsequently documented pathologically were in the jejunum in 6 patients and in the ileum in three.
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rTlME rAGE
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~OCUUENTATION
AT DOCUMENTATION
PATIENT 23 24
Figure 2. Clinical courses of 11 patients with “unclassified sprue” and intestinal ulceration and 7 patients with lymphoma and ulceration. The symbols utilized and the format are the same as in Figure 1;DH = dermatitis herpetiformis. Malabsorption or abdominal symptoms had been present for over 1.5 yr before the time of ulcer documentation in 9 of the 11 patients with “unclassified sprue.” On the average, they were 8 yr older than the patients with celiac disease. Only 1 patient survived for over 2 yr. Four of the 7 patients with lymphoma had documented celiac disease for over 3.5 yr before ulceration was demonstrated. A fifth had a childhood history of celiac disease. The time of documentation of definite lymphoma is indicated by the symbol L.
Patients with intestinal
Lymphoma
Clinical features. This group included 7 patients: 3 males and 4 females with an average age of 55.4 + 11.2 yr (k 1 SE) at the onset of intestinal ulceration. Four patients had celiac disease; 3 had been on a gluten-free diet in the past while 1 was being treated at the onset of the ulcers. Two other pstients had features of celiac disease, including mZllabsorption and jejunal villus blunting, but failed to respond to trials of a gluten-free diet that were begun either just before or after the onset of ulceration. One patient had jejunal villus blunting associated with a dense lymphohistiocytic infiltrate and mild
malabsorption without steatorrhea, but was never placed on a gluten-free diet. It is important to note that 5 patients had histologically benign intestinal ulcers. These ulcers were present, on average, 15 mo before development and/ or recognition of intestinal lymphoma in 3, while in 2 others they were present at the same time as the lymphoma, but in another part of the small bowel. The nonspecific ulcers were in the jejunum in 4 patients and in both jejunum and ileum in another. The ulcers were attributed to “benign nongranulomatous ulcerative jejunitis” in 3 of these 5 patients. Two additional patients who were eventually found to have lymphoma presented with ulcers re-
INTESTINAL ULCERATION AND MALABSORPTION
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Table 3.
759
Pathologic Features of Patients with Celiac Disease and “Unclassified Sprue”
Pathologic features Ulcers multiple solitary Location of Ulcers jejunum ileum jejunum and ileum duodenum colon Perforations ileum jejunum Intervening mucosa Villus blunting jejunum ileum Normal sized villi Patchy villus blunting
Celiac disease
“Unclassified sprue”
21”
10
1
1
10
4
2 9 2 4
1
7 4
6 0 0 5 1 4
12 4 5 0
6 0 1 2
11
a All figures indicate number of patients.
lated to a polymorphous lymphomatous infiltrate. One was published as “pseudolymphoma” and the other had areas of nonspecific ulceration called “nongranulomatous ulcerative jejunitis” adjacent to the tumor. Pathologic features. All 7 patients in this group either presented with or eventually developed lymphoma involving the small bowel. All were classified as either mixed lymphocytic-“histiocytic” or “histiocytic” in type.
Figure 3. Case 22. Ulceration in celiac disease. The adjacent mucosa shows marked blunting of villi. Note widened space between crypt bases and muscularis mucosae (arrow), an occasional feature of unknown significance (x18).(Courtesy of Dr. Basil Morson, St. Mark’s Hospital, London, England.)
A possible evolutionary process in which lymphoma became increasingly evident was observed in the small bowel in association with the ulcerations in 1 patient (courtesy of Dr. Robert Wintroub). A solitary jejunal ulcer, resected 3 yr before the development of frank lymphoma, was believed to be nonspecific. However, in retrospect, it was noted that
Figure 4. Case 9. Ulceration in celiac disease after long-term gluten-free diet with good response. A. Villi are present in adjacent mucosa (X18).B. The ulcer base shows only inflamed granulation tissue (X250).
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even then there was a heavy inflammatory infiltrate with occasional large atypical “histiocytic” cells at the base of the ulcer (Figure 6). Two years later, two additional stenosing jejunal ulcers were resected. Interpretation at that time was benign ulceration due to “nongranulomatous ulcerative jejunitis.” However on later review, while benign-looking ulceration was evident at low power in one area (Figure 73, elsewhere a distinctly pleomorphic cell infiltrate consistent with “histiocytic” lymphoma was associated with ulceration (Figure 8). A further jejunal resection 1 yr later demonstrated an even more uniformly pleomorphic histiocytic lymphoma (Figure 9). This patient is reminiscent of 4 patients reported by Freeman et al. in whom ulcerating “histiocytic” lymphoma of the small bowel was initially misinterpreted as “benign nongranulomatous ulcerative jejunoileitis.“’ Similar cases are described also by Isaacson and Wright.“’ In our registry, 2 other patients with reportedly nonspecific ulcers subsequently developed “histiocytic” lymphoma, but the slides of the ulcers were not available for review. Small intestinal lymphoma and benign nonspecific ulcers were present simultaneously in 2 patients. The tumors in both had mixed lymphocytic“histiocytic” characters, consisting of pleomorphic large cells in a context of chronic inflammatory cells. In the patient from whom slides were available, benign ulcers were adjacent to the tumor and showed a dense infiltrate of chronic inflammatory cells in the lamina propria and upper submucosa. Similar findings were noted in the published report from the
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Figure 5. Case 33. Ulceration in “unclassified sprue.” The patient also had dermatitis herpetiformis. Adjacent mucosa shows blunted villi. Autopsy specimen (x18).
second patient. An additional patient with celiac disease and ulcerating lymphoma demonstrated nonulcerated areas of flattened mucosa containing chronic inflammation and occasional pleomorphic cells (Figure 10) (Courtesy of Dr. James J. Galdabini). Patients with Miscellaneous Malabsorptive Disorders Nonspecific intestinal ulceration occurred in 4 patients with malabsorption associated with various disorders and villus blunting in the proximal small intestine. One patient had hypogammaglobulinemia
Figure 6. Case 37. Initial “benign” ulceration in patient who later developed frank lymphoma. A. uverview showing prominent cellular infiltrate at base of ulcer (X18).B. Detail of cellular infiltrate. It consists of a polymorphous inflammatory reaction with occasional large, atypical histiocytic cells (arrows) (x550).(Courtesy of Dr. Robert Wintroub.)
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disease of the colon; in 1 four colonic strictures were resected 36 yr before the current illness. A poorly characterized colitis accompanied the small bowel disease in the second. All 3 patients died as a result of their intestinal disorder.
Discussion Ulceration of the small intestine and occasionally the colon can occur as a complication of several malabsorption syndromes, most of which are associated with a flat mucosa in the proximal small intestine. Many but not all of the patients have evidence of celiac disease. The ulcers, for which an etiology is not obvious, are usually multiple and may result in significant mortality. In a few patients, the nonspecific ulcers precede the development and/or recognition of intestinal lymphoma.
CeJiac Disease Figure 7. Case 37. Benign appearing ulceration with only supecfickil inflammatory infiltrate seen 2 yc after lesion in Figure 6. Note, however, absence of villi in adjacent mu-
cosa (X16).
and superficial mucosal ulcers. Two had resided in the tropics (Ceylon and Palestine), and one had alpha-1-antitrypsin deficiency. The latter 3 patients died after intestinal perforation. Three patients Normal villus architecture. were reported as examples of “nongranulomatous ulcerative jejunoileitis” with gross small intestinal ulceration and a malabsorption syndrome associated with normal villus architecture. Two had associated
The largest group of patients with malabsorption and gross small intestinal ulceration were those with celiac disease (gluten-induced enteropathy). The role of gluten in the pathogenesis of these ulcers is not clear. One concept is based on damage by gluten causing increased cell turnover wtih eventual crypt “exhaustion” and resultant mucosal breakdown and u1ceration.3.47.58Any hypothesis involving gluten, however, must account also for the occurrence of ulceration in patients with celiac disease in remission on a gluten-free diet and the occasional presence of ulcers in the ileum and colon, where the exposure to gluten is minimal. Klaeveman et al. sug-
Figure 8. Case 37. Another ulcer removed at same operation shown in Figure 7. A. A heavy infiltrate penetrates through and appears to destroy muscle wall (x9). B. In this location the infiltrate is a mixed lymphocytic-“histiocytic” lymphoma with numerous large, pleomocphic cells (x550).
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Figure 9. Case 37. Ulcer at third resection 1 yr after that shown in Figure 7. A. The lymphomatous tive (x9). B. The tumor shows even more pleomorphic cells than previously (x550).
gested that a supervening nongluten dependent immunologic process might be involved in the pathogenesis of these ulcers.’ “Unclassified
Sprue”
The term “unclassified sprue” is used in this report to designate individuals in whom the underlying malabsorptive disorder could not be adequately defined. We feel that some, if not most, had
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infiltrate is heavy and highly destruc-
celiac disease, but failed to respond to therapy because of ulceration or their advanced age. In our experience, elderly patients with celiac disease may either not respond promptly to a gluten-free diet or become refractory to the diet. In vitro organ culture techniques, HLA tissue-typing, and repeat jejunal biopsies following dietary gluten restriction could help to identify or refute a pathogenetic role for gluten in patients with ulcerations who fail to respond to a gluten-free diet.
Figure 10. Case 39. Frank histiocytic lymphoma with ulcers was present elsewhere in small intestine. A. Focus of cellular infiltrate away from ulcer causing flattened mucosa. Such sites might become ulcerated without evidence of lymphoma being found (x16). B. Detail of infiltrate that appears to be inflammatory but which might be an “early” lymphocytic-“histiocytic” tumor. Note occasional larger cells with pyknotic nuclei (x550). (Courtesy of Dr. James Galdabini.)
October 1980
The term “nongranulomatous ulcerative jejunoileitis” was previously applied by the original authors to many of the patients in this registry. The terminology was initially used to indicate that ulceration was a primary component of the illness and thought to be responsible for the associated malabsorption and villus blunting.‘x3 We feel that the term has, unfortunately, become too nonspecific and can be clinically misleading. Its continued use obscures the fact that an underlying primary malabsorptive disorder such as celiac disease and/or early intestinal lymphoma may be present. Delays in exploratory laparotomy or other diagnostic maneuvers have resulted from the “labeling” of patients with this nonspecific term. Lymphoma The clinical features of intestinal lymphoma and of benign intestinal ulceration occurring in association with malabsorption may be indistinguishable. The patients are in roughly the same age range, 49-55 yr in lymphoma complicating celiac disease,57.58and 48.2 yr in benign ulceration complicating celiac disease. Furthermore, the onset of both intestinal lymphoma and of benign ulceration are marked by a recurrence or increase in malabsorptive symptomatology along with abdominal pain, fever, and weight loss. In addition, intestinal lymphoma may ulcerate at sites of lymphomatous infiltration and resemble benign ulcers producing hemorrhage, obstruction, and perforation. Although important aspects of the pathogenesis and classification of lymphomas remain unresolved, much progress has been made recently. Application of techniques such as immunocytochemistry for categorizing tumor cells as B lymphocytes, T lymphocytes, and moncytes/histiocytes have been especially helpful. The widely used classification of Rappaport, which was developed on the basis of morphologic features, identifies the large cells seen in some lymphomas as “histiocytic.” There is now good evidence that such large cells are almost always transformed lymphocytes. Nevertheless, lymphomas containing large cells are still usually designated “histiocytic” or mixed lymphocytic-“histiocytic” depending on proportion of large and small (lymphocytic) cell types.” These terms were, according to accepted usage, applied to the present cases. At the same time, it is now less clear that intestinal lymphomas fall readily into standard classification schemes, schemes that are in fact chiefly based on findings in lymphomas which originate outside the intestinal tract. Indeed, Isaacson and Wright, who described cases of intestinal lymphoma comparable to those reported here, concluded from
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various staining and other characteristics that the malignancies were truly histiocytic rather than lymphocytic in origin.“‘sM The pathologic diagnosis of malignant ulcer?tion was not difficult if there was a classic monomorphic lymphomatous infiltrate at the base of the ulcer. In some cases, however, the lymphomatous infiltrate was polymorphous, containing various chronic inflammatory cells in addition to atypical forms. Such a picture has proved difficult to differentiate from reactive changes of inflammation. In addition, the absence of involvement of mesenteric nodes in early lymphoma can make this distinction even more difficult. Nonspecific intestinal ulcers with occasional atypical cells in their infiltrate were observed in 2 patients who were subsequently recognized to have intestinal lymphoma. A comparable evolution was described by Whitehead in patients with celiac disease who later developed frank intestinal lymphoma.” He observed a stage before recognition of lymphoma in which there was a dense inflammatory infiltrate, ulceration extending to the muscularis propria, and increasing atypical, pleomorphic reticulum cells (equals “histiocytic” cells) in the infiltrate. It is not known how often benign-looking ulcers may be the harbinger of intestinal lymphoma. Diagnosis of Intestinal
Ulceration
The diagnosis of intestinal ulceration in celiac disease and other malabsorption syndromes may be difficult. The clinical settings include: (a) a patient in the fifth or sixth decade with known celiac disease who has a recurrence of malabsorptive symptoms; (b) a patient with a flat jejunal biopsy and malabsorption which proves refractory to a gluten-free diet and/or adrenocorticosteroid therapy; (c) as well as the occurrence of abdominal pain, fever, intestinal perforation, obstruction, or hemorrhage in an individual with malabsorption. The diagnosis of small intestinal ulceration has usually been demonstrated only at exploratory laparotomy with fullthickness biopsy resection of abnormal appearing small bowel. Barium contrast techniques were usually not diagnostic and only demonstrated ulceration when it was accompanied by strictures. In the future, barium given through a small bowel tube,‘l upper intestinal endoscopy, or multiple biopsy specimens, may be helpful. Vigorous attempts to define the underlying malabsorptive process are needed, including trials of a gluten-free diet with repeat jejunal biopsies, particularly in the absence of a clinical response. In vitro organ culture techniques with gluten addition may also be helpful in the future. A peroral biopsy will
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often provide evidence either suggestive or diagnostic of lymphoma, but since the presence of apparently benign ulceration does not exclude lymphoma, a laparotomy with biopsy-resections of the small bowel and mesenteric nodes is usually indicated. Repeat laparotomy with biopsy may also be needed in an individual who fails to improve as lymphoma may only become apparent later. Therapy
of Ulcerations
Successful therapy of benign ulceration has usually included resection of the ulcers, particularly if localized to one part of the intestine. Corticosteroid therapy has been utilized with apparent benefit in a few patients with uncomplicated ulcers; however, the danger of intestinal perforation with steroid therapy must be recognized. Parenteral alimentation may improve nutritional status preoperatively and may lead to improvement in a gluten-induced enteropathy, if present. Reporting of all patients with intestinal ulceration and malabsorptionez as well as a follow-up on treatment response, lymphoma development and survival either in the literature or in a central registry is encouraged for better understanding of this problem.
References 1. Bayless TM, Kapelowitz
2. 3. 4.
5. 6.
7. 6.
9. 10.
11.
12.
RF, Shelley WM, et al: Intestinal ulceration--a complication of celiac disease. N Engl J Med 276996-1002, 1967 Goulston KJ, Skyring AP, McGovern VJ: Ulcerative jejunitis associated with malabsorption. Aust Ann Med 14:57-64,1965 Jeffries GH, Steinberg H, Sleisenger MH: Chronic ulcerative (nongranulomatous) jejunitis. Am J Med 44:47-59, 1968 Strauch M, Lohr JJ, Ottenjam R: Chronische ulzerative jejunitis mit malabsorptions syndrom. Med Klin 68~1113-1116, 1973 Klaeveman HL, Gebhard FL, Sessoms C, et al: In vitro studies of ulcerative ileojejunitis. Gastroenterology 68:572-582, 1975 Corlin RF, Pops MA: Nongranulomatous ulcerative jejunoileitis with hypogammaglobulinemia. Gastroenterology 62:473-478, 1972 Case records of the Massachusetts General Hospital. Case 391975. N Engl J Med 293:712-717,1975 Freeman HJ, Weinstein WM, Shnitka TK, et al: Primary abdominal lymphoma: presenting manifestation of celiac sprue or complicating dermatitis herpetiformis. Am J Med 63:585594, 1977 Whitehead R: Primary lymphadenopathy complicating idiopathic steatorrhea. Gut 9:569-575, 1988 Isaacson P, Wright DH: Malignant histiocytosis of the intestine. Its relationship to malabsorption and ulcerative jejunitis. Hum Path 9:861-677,‘1978 Himes HW, Gabriel JB, Adlersberg D: Previously undescribed clinical and post-mortem observations in non-tropical sprue: Possible role of prolonged corticdsteroid therapy. Gastroenterology 32:60-71, 1957 Golden R: Radiologic Examination of the Small Intestine. Sec-
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ond edition. Springfield, Illinois, Charles C. Thomas, 1959, p 285 13. London DR, Bamforth J, Creamer B: Steatorrhea presenting with gastrointestinal protein loss. Lancet 218-19, 1961 14. Hindle W, Creamer B: Significance of a flat small-intestinal mucosa. Br Med J 2455-458, 1965 15. Smitskamp H, Kuipers FC: Steatorrhea and ulcerative jejuno. ileitis. Acta Med Stand 177~37-42, 1985 16. Wagner A, Meiser J; Dunndarm ulcera.and fieber bie endogener sprue. Schweiz Med Wochenscr g&892-898, 1968 17. Davidson AR: Recurrent benign ileal ulcer occurring with the coeliac syndrome. Br Med J 3:341, 1989 16. Kavin H: A case of adult coeliac disease (clinico-path conference). S Afr J Surg 8:95-97, 1970 19. Moritz M, Moran JM, Patterson JF: Chronic ulcerative jejunitis. Report of a case and discussion of classification. Gastroenterology 6096-102, 1971 20. Stuber JL, Wiegman H, Crosby I, et al: Ulcers of the colon and jejunum in celiac disease. Radiology 99:339-346, 1971 21. Dowling RH, Henry K: Non-responsive coeliac disease. Br Med J 3:824-631, 1972 22. Armstrong BK, Ammon RK, Finlay-Jones LR, et al: A further case of chronic ulcerative enteritis. Gut 14649-852, 1973 23. Jones PE, Gleeson MH: Mucosal ulceration and mesenteric lymphadenopathy in coeliac disease. Br Med J 3:212-213,1973 24, Connon JJ, McFarland J, Kelly A, et al: Acute abdominal complications of coeliac disease. Stand J Gastroenterol X):843848, 1975 25. Shiner M: Effect of a gluten-free diet in 17 patients with idiopathic steatorrhea. A follow-up study. Am J Dig Dis 8:969-983, 1963 28. Collins JR, Isselbacher KJ: The occurrence of severe small intestinal mucosal damage in conditions other than celiac disease (nontropical sprue). Gastroenterology 49:425-432, 1965 27. Klion FM: Malabsorption in an elderly male. J Mt Sinai Hosp 34:519-528, 1967 28. Artinian B, Lough JO, Palmer JD: Idiopathic ulceration of small bowel with pseudolymphomatous reaction. A clinicopathological study of 6 cases. Arch Path 91:327-333, 1971 29. Blau‘JS, Stolzenberg J, Toffler RB: Small bowel ulcerationsan unusual complication of celiac disease. J Can Assoc Radiologists 25:77-78, 1974 30. Case records of the Massachusetts General Hospital. Case 481976., N Engl J Med 295:1242-1248,1978 31. Tqnder M, Sorlie D, Kearney MS: Adult Coeliac disease. A case with ulceration, dermatitis herpetiformis and reticulosarcoma. Stand J Gastroenterol 11:107-111, 1976 32. Manson-Bahr P: The morbid anatomy and pathology of sprue and their bearing upon aetiology. Lancet 1:1148-1151, 1924 33. Sweeney EC: Adult cu,-antitrypsin deficiency. J Clin Path 26:613-619, 1975 Neale G: A case of malabsorption, intestinal mucosal atrophy 34. and ulceration, cirrhosis and emphysema. Br Med J 3:207-212, 1970. 35. Case records of the Massachusetts General Hospital. Case 161969. N Engl J Med 280~885-894, 1969 36. Karz S, Guth PH. Polonsky L: Chronic ulcerative jejunoileitis. Am J Gastroenterol 5661-87, 1971 37. Guest JL: Non-specific ulceration of intestine. Published by Franklin H. Martin Memorial Foundation, Chicago, Ill. Internat Abst Surg 117:409-418, 1963 (Also published as pait of Surg Gyn & Obstet 117:409-416, 1963) or 38. Wayte DM, Helwig EB: Small bowel ulceration-iatrogenic multifactorial origin? Am J Clin Path01 4926-40, 1966 39. Stokes PL, Holme GKT: Malignancy. In: Clinics in Gastroenterology. Ce!iac Disease. Edited by WT Cooke, P Asquith.
October 1980
40.
41. 42.
43. 44. 45. 48. 47. 48. 49. 50.
51.
52.
London, England, W.B. Saunders Co., Ltd., Vol. 3, No. 1,1974, p 91-107 Burrows FGO, Toye DKM: Barium Studies. In: Clinics in Gastroenterology. Celiac Disease. Edited by WT Cooke, P Asquith. London, England, W.B. Saunders Co., Ltd., Vol. 3, No. 1, 1974, p 91-107 Thompson H: Necropsy studies on adult coeliac disease. J Clin Path01 27:716-721,1974 Benson GD, Kowlessar OD, Sleisenger MH: Adult celiac disease with emphasis upon response to the gluten-free diet. Medicine (Baltimore) 43:1-46, 1964 Nyman E: Ulcerous jejuno-ileitis with symptomatic sprue. Acta Med Stand 134:275-283, 1949 Rosendahl G: Et Tilfaelde av sprue opstaat i Norge. Med Rev (Bergen) 12:872-678, 1927 Kelley ML, Terry R: Clinical and histological observations in fatal non-tropical sprue. Am J Med 25:460-489, 1958 Neale G: A case of adult coeliac disease resistant to treatment. Br Med J 2:678-684, 1968 Paulley JW: Jejunal mucosa in idiopathic steatorrhea. Lancet 2646-648, 1959 Patterson M, Ong H, Drake A: Protein-losing enteropathy: report of two new cases. Am J Med Sci 251:563-569, 1966 Doe WF, Evans D, Hobbs JR, et al: Coeliac disease, vaculitis, and cryoglobulinemia. Gut 13:112-123, 1972 Seliger G, Goldman AB, Firooznia H, et al: Ulceration of the small intestine complicating celiac disease. Am J Dig Dis 18:820-824, 1973 Finlayson NDC, Shearman DJC, Girdwood RH: A case of coexisting duodenal ulceration and idiopathic steatorrhea. Gastroenterology 55:628-631, 1968 Shiner M, Drury RAB: Abnormalities of the small intestinal
INTESTINAL ULCERATION AND MALABSORPTION
53. 54.
55. 56. 57.
58.
59.
66.
61.
62.
765
mucosa in Crohn’s disease (regional enteritis). Am J Dig Dis 7:744-759, 1962 Booth C: A case of Crohn’s disease in a patient with treated adult coeliac disease. Br Med J 4222-228, 1967 Marche C. Bocquet L, Mignon M, et al: Snydrome de malabsorption avec cavitation ganglionnaire mesenterique et atrophie splenique. A propos dune nouvelle observation anatomo-clinique. Sem Hop Paris 50:879-886, 1974 Barry RE, Morris JS, Read AEA: A case of small-intestinal mucosal atrophy. Gut ll:743-747,197O Hayflick L: The cell biology of human aging. N Engl J Med 295:1302-1368, 1976 Harris OD, Cooke WT, Thompson H, et al: Malignancy in adult coeliac disease and idiopathic steatorrhea. Am J Med 42899-912, 1967 Austad WI, Cornes JS, Gough KR, et al: Steatorrhea and malignant lymphoma. The relationship of malignant tumors of lymphoid tissue and celiac disease. Am J Dig Dis 12:475-490, 1967 Mann RB, Jaffe ES, Berard CW: Malignant lymphomas: a conceptual understanding of morphologic diversity. Human Path01 94:105-176, 1979 Isaacson P, Wright DH, Tudd MA, et al: Primary gastrointestinal lymphomas. The classification of 66 cases. Cancer 43:1805-1819, 1979 Muller WFH, Pena AS: Enterocylsis in coeliac disease-a preliminary report. In: Coeliac Disease. Edited by WTJM Hekkens, AS Pena. Leiden, Netherlands, Stenfert Kroese, 1974, p 421-427 Modigliani R, Poitras P, Galian A, et al: Chronic non-specific ulcerative duodenojejunoileitis: report of four cases. Gut 20:318-328, 1979
79:754-765,
1980
Intestinal Ulceration and Malabsorption Syndromes ALAN
N. BAER,
THEODORE
JOHN
H. YARDLEY
M. BAYLESS,
and
Departments of Medicine and Pathology, The Johns Hopkins University Medicine and The Johns Hopkins Hospital, Baltimore, Maryland
Data from 47 patients with malabsorption and small intestinal ulceration were reviewed to provide information on the relationship of the ulcerative process to celiac disease and to Jymphoma. Presentations included: (a) worsening of malabsorptive symptoms and abdominal pain in a patient with celiac disease in his or her fifth or sixth decade; (b) an unexplained, unresponsive malabsorption syndrome with a j7attened jejunal mucosa; or (c) complications including obstruction, perforation, or hemorrhage. UJcer diagnosis was usually first made at surgery and not radiologically. The ulcers were morphologically nonspecific, usually multiple, and predominantly jejunal. Twenty-two patients with benign ulceration could be classified as celiac disease. Eleven others with “unclassified sprue” had similar jejunal biopsies, often with a long history of malabsorption. They did not go into remission with gluten withdrawal or adrenocorticosteroids. In some, this may have been because of the ulcers. Intestinal resection “cured” 4 of 13 patients. Steroid therapy was associated with prolonged remissions in 2 of 13, but intestinal perforation occurred in 10 while on steroids. Currently 29 of the 40 patients with benign ulceration are known to have died as a result of the uJcers. Lymphoma was antedated for months or years by benign ulceration in 3 patients and by histiocytic cells in pleomorphic atypical ulcers probably representing early subtle Jymphoma in 2 others. When intestinal ulceration accompanied by malabsorption is Received August 6,1979. Accepted May 13, 1980. Address requests for reprints to: Theodore M. Bayless, M.D., Division of Gastroenterology, The Johns Hopkins Hospital, Baltimore, Maryland 21205. Dr. Baer was a Henry Strong Denison Scholar for 1977-1978, The Johns Hopkins University School of Medicine. Gratitude is expressed to all the physicians who supplied information and materials for this registry, to Dr. Berton Ashman for referring pne of the patients for care, and to Drs. Risa Mann and Thomas R. Hendrix who provided critical support. 0 1980 by the American Gastroenterological Association @X6-5085/80/100754-12$02.25
School of
suspected, exploratory Japarotomy for biopsy and bowel resection and to search for Jymphoma is reasonable. Use of the term “nongranulomatous ulcerative jejunoileitis” may be misleading and is not recommended. Multiple nonmalignant ulcers of the small intestine are an uncommon, but frequently fatal complication of celiac disease (gluten-induced enteropathy).’ Along with the development of lymphoma, this type of intestinal ulceration is one of the leading causes of premature death of patients with celiac disease. The ulcers are morphologically nonspecific and have no known etiology. Similar ulceration has been described in patients with malabsorption associated with diffuse or patchy jejunal villus blunting who do not respond to a gluten-free diet. The term “chronic nongranulomatous ulcerative jejunoileitis” has been applied to many of these patients.‘m4 Confusion has resulted from use of this term in a nonspecific fashion for patients with underlying primary disorders such as well-documented celiac disease, hypogammaglobulinemia, and patients who subsequently were found to have intestinal lymphoma.“-* Some patients with celiac disease who develop intestinal lymphomas will present with histologically benign intestinal ulceration or with atypical but not frankly lymphomatous lesions.*-*’ This report is based upon a registry of 47 patients with malabsorption and small intestinal ulceration. It was our opinion that these patients had a primary malabsorptive disorder complicated by intestinal ulceration. Although our initial focus was on patients with benign ulceration, we identified several patients in whom benign ulcers were related to intestinal lymphoma. Because of the frequent fatal complications of the intestinal ulcerations in this group of 47 patients as well as the eventual development of lymphoma in others, an aggressive diagnostic and therapeutic ap-
INTESTINAL ULCERATION AND MALABSORPTION
October 1980
Table
I.
Patients
755
with Malabsorption and Small Intestinal Ulceration Sources of patients included in registry Published case numbers with references
Celiac disease (n = 22)
1." 2,'23,'94,'45.159,'10," 11’ ,6 121I713II814II915I2o 16'l17 , ,*219232024 > , 215
Unclassified sprue (n = 11)
23.2524,*’253’ 263’ 27 9’ 28327 29,3 324
Lymphoma (n = 7) Miscellaneous malabsorbtion Villus blunting
34,3 35:’ 36,2938,’ 39,3040=
Unpublished case numbers with sources and dates 6 (JF Fordtran,
A Kassanoff 1966) 7,8 (J Phillips 1966) 18 (GD Cain 1973) 22 (BL Morson 1976) 30 (RB Ruskin 1973) 31 (M Shapiro 1973) 33 (TM Bayless 1977) 37 (R Wintroub 1974-77)
Pathological material reviewed Case numbers 6,8.9,14.15,21,22
30-33
35-39
disorders 41 93242 ,3243 96 44 !95.34
-
-
45 33 46 33547”O
-
-
(n = 4) Normal villus architecture (n = 3)
preach to patients with malabsorption by intestinal ulceration is proposed.
complicated
Material and Methods Forty-seven patients with intestinal ulceration (grossly visible in 45) and malabsorption were included in the registry (Table l).* There were no known causes of ulceration such as potassium tablet ingestion, tuberculosis, syphilis, vasculitis, ischemia, Crohn’s disease, ZollingerEllison syndrome, or tumors other than lymphoma.37,38 The pathology material from 15 patients was reviewed. Results of postmortem examinations were available of the 37 patients who are known to have died.
on 33
Results Classification
of Patients in Registry
Forty patients had intestinal ulcers not associated with intestinal lymphoma. Thirty-seven of these patients had malabsorption associated with marked villus blunting in the proximal small intestine at some time during their illness. These included 22 patients with celiac disease (gluten-induced enteropathy), 11 patients with “unclassified sprue”, and 4 patients with miscellaneous malab*Twenty-four previously reported patients with malabsorption and small intestinal ulceration were not included in the registry. There was inadequate detail in some39-44; ulcers were microscopic and confined to the intestinal mucosa in others*5-“; 2 patients with celiac disease had an associated vasculitis,z, 4s while 2 other celiac patients had only duodenal ulcers.50, 51 Two others had a nongranulomatous ulcerative process attributed to Crohn’s disease.52, 53Another had ileal ulcerations associated with splenic atrophy and liquefactive necrosis of the mesenteric lymph nodes.“4 One patient with malabsorption and active tuberculosis had ileal ulcers containing mycelia.
sorptive disorders. Three patients had malabsorption associated with normal villus architecture (Table 1). Five patients, including two with celiac disease, had malabsorption and histologically benign intestinal ulcers associated with intestinal lymphoma. Two additional patients with celiac disease and lymphoma presented with ulcers containing an atypical pleomorphic cellular infiltrate.
Patients with Celiac Disease (Gluten-Induced Enteropathy) and “Unclassified Sprue” Definitions. The 22 patients with celiac disease varied with respect to the documentation of their diagnosis. In all, the characteristic flat jejunal mucosa of celiac disease was documented either with jejunal biopsy or with adequately preserved postmortem specimens (Table 2). A characteristic clinical, biochemical, or histologic response to a gluten-free diet or gluten refeeding supported the diagnosis in 17 patients. In 5 patients in whom a trial of a gluten-free diet was either inadequate or not performed, other features of their illness, such as a long history of steatorrhea with or without childhood diarrhea and/or a response to corticosteroids strongly suggested the diagnosis of celiac disease (Figure 1). The term “unclassified sprue” was used for 11 patients with malabsorption and a flat jejunal mucosa similar to that seen in celiac disease who: (a) failed to respond satisfactorily to adequate trials of a gluten-free diet or adrenocorticosteroids, either alone or in combination; and (b) in whom no known etiology for the villus blunting could be identified. Although there were many similarities to patients with celiac disease, this diagnosis could not be clearly estab-
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BAER ET AL.
lished (Table 2). Six of the 11 patients had been published as examples of “nongranulomatous ulcerative jejunoileitis.” Clinical features. On the average, the patients with “unclassified sprue” were 8 yr older than the patients with celiac disease. The majority of these patients with “unclassified sprue” also had evidence of malabsorption for over 1.5 yr before the onset of the ulcers (Figure 2). This feature of preceding malabsorption is a strong point in the consideration that some of these patients may have had underlying celiac disease. Jntestinal ulceration. At the onset of ulcer-related symptoms, 9 patients with celiac disease were in a clinical remission on a gluten-free diet, either alone or with adrenocorticosteroids. The onset of ulceration in these patients was usually marked by the appearance of abdominal symptoms, including pain, anorexia, weight loss, and diarrhea as well as low grade fever. Ulcers presented in the setting of renewed symptoms after the cessation of a gluten-free diet in 3 patients. Two patients were begun on a gluten-free diet within 5 mo of the onset of the ulcer 1 responded only after resection of a manifestations; jejunal stricture, while another with microscopic jejunal ulcers responded with the addition of adrenocorticosteroids. A progressively worsening malabsorption syndrome, unresponsive to therapy, had been present for over 1.5 yr at the onset of the ulcers in most patients with “unclassified sprue”. Four such patients were begun on unsuccessful trials of a gluten-free diet or adrenocorticosteroids, either alone or in combination, within 3 mo or less of the documentation of ulcers or the onset of ulcer-related symptoms. The onset of the ulcers may have prevented or obscured any therapeutic response to measures directed at malabsorption. Complications of the ulcers, including intestinal obstruction, gastrointestinal bleeding, and intestinal perforation, usually provided the first objective evidence of the presence of ulcers in both groups of patients (Table 3). The complications, particularly intesiinal perforation, were frequently fatal. Twenty-three of the 33 patients died of ulcer complications. Small bowel obstruction was the most common indication for surgery. Surgical resection of involved bowel offered the greatest chance for survival. Five of the thirteen patients with celiac disease and both patients with “unclassified sprue” who underwent surgical resection lived for 1 or more yr postoperatively. Four of these patients survived for more than 12 yr but 3 required further resections or bypass procedures. Medical therapy, including adrenocorticosteroids, was not associated with prolonged survival except in 2 patients with ce-
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Table 2. Clinical Features of the Patients with Celiac Disease and “Unclassified Sprue” “Unclassified sprue”
Clinical features
Celiac disease
Number of patients
2.2’(14/8)
x1(3/8)
48.2 f 10.8 yr (1 SE)
56.2 rt 11.8 yr (1 BE)
(M/F) Age Duration of preceding malabsorption >1.5 years <7 months Complications: Intestinal obstruction GI bleeding: occult gross Intestinal perforation Mortality 5-yr survival
16 (average 13 yr) 3 11 (lO)b 2 6 (3) 10 (6) 13 6
9 (average 4.6 yr) 2 2 (2)b 0 6 (4) 5 (4) 10 1
0 All numbers indicate number of patients unless otherwise specified. bThe number in parentheses represents the patients in whom the complication was the presenting problem.
liac disease, both without complications and with relatively superficial ulcerations, who lived for over 5 yr after the onset of the ulcers. Prednisone seemed to be injurious in some patients by promoting the perforation of existing ulcers. Adrenocorticosteroids were either in use or had been used within 1 mo of the time of perforation in 10 of the 15 patients who developed this complication. Only 14 of the 33 patients were receiving steroids within 6 mo of the onset of the ulcers. Pathologic features. The histopathologic features of the ulcers from 7 patients with celiac disease and 3 with “unclassified sprue” in whom slides were reviewed were similar and nonspecific (Table 3). The ulcers varied in depth, penetrating to the muscularis mucosa in 1 patient and to the muscularis propria in most others. Extensive submucosal edema and fibrosis were prominent features in some. The inflammatory infiltrate was largely confined to the base of the ulcers and was typically a mixture of lymphocytes, plasma cells, histiocytes and polymorphonuclear leukocytes (Figures 3-5). Descriptions and photographs in published cases are similar in most of these aspects.
Radiologic Studies X-ray examinations were usually not helpful in documenting the presence of intestinal ulceration. A small bowel series was performed in 15 of the 33 registry patients with celiac disease or “uncltissified sprue” within 3 mo or less of surgical or autopsy documentation of their nonspecific ulcers. Ulcers
INTESTINAL
October 1990
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ULCERATION
AND MALABSORPTION
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Figure 1. Clinical courses of 22 patients
with celiac disease and intestinal ulceration. The duration of malabsorptive symptoms and of responses to gluten restriction or adrenal steroid therapy in months or years, are shown to the left of the central area (time of ulcer documentation). Malabsorption had been present for over 1.5 yr in 16 patients. The age at the time of ulcer documentation is shown. The duration of survival after ulcer diagnosis is shown to the right of the central area. Five are known to be alive.
were seen in only 2 of the 15 patients, and these ulcers were associated with strictures in the proximal small intestine. Strictures of the duodenum or jejunum but without evidence of ulceration were documented in 6 other individuals. Flocculation and seg-
mentation of the barium presumably made detection of mucosal lesions difficult. The ulcers that were not seen radiographically but subsequently documented pathologically were in the jejunum in 6 patients and in the ileum in three.
758
BAER ET AL.
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LASS
1 Fj
E
D
SPRUE
rTlME rAGE
OF ULCER
Vol. 79, No. 4
~OCUUENTATION
AT DOCUMENTATION
PATIENT 23 24
Figure 2. Clinical courses of 11 patients with “unclassified sprue” and intestinal ulceration and 7 patients with lymphoma and ulceration. The symbols utilized and the format are the same as in Figure 1;DH = dermatitis herpetiformis. Malabsorption or abdominal symptoms had been present for over 1.5 yr before the time of ulcer documentation in 9 of the 11 patients with “unclassified sprue.” On the average, they were 8 yr older than the patients with celiac disease. Only 1 patient survived for over 2 yr. Four of the 7 patients with lymphoma had documented celiac disease for over 3.5 yr before ulceration was demonstrated. A fifth had a childhood history of celiac disease. The time of documentation of definite lymphoma is indicated by the symbol L.
Patients with intestinal
Lymphoma
Clinical features. This group included 7 patients: 3 males and 4 females with an average age of 55.4 + 11.2 yr (k 1 SE) at the onset of intestinal ulceration. Four patients had celiac disease; 3 had been on a gluten-free diet in the past while 1 was being treated at the onset of the ulcers. Two other pstients had features of celiac disease, including mZllabsorption and jejunal villus blunting, but failed to respond to trials of a gluten-free diet that were begun either just before or after the onset of ulceration. One patient had jejunal villus blunting associated with a dense lymphohistiocytic infiltrate and mild
malabsorption without steatorrhea, but was never placed on a gluten-free diet. It is important to note that 5 patients had histologically benign intestinal ulcers. These ulcers were present, on average, 15 mo before development and/ or recognition of intestinal lymphoma in 3, while in 2 others they were present at the same time as the lymphoma, but in another part of the small bowel. The nonspecific ulcers were in the jejunum in 4 patients and in both jejunum and ileum in another. The ulcers were attributed to “benign nongranulomatous ulcerative jejunitis” in 3 of these 5 patients. Two additional patients who were eventually found to have lymphoma presented with ulcers re-
INTESTINAL ULCERATION AND MALABSORPTION
October 1960
Table 3.
759
Pathologic Features of Patients with Celiac Disease and “Unclassified Sprue”
Pathologic features Ulcers multiple solitary Location of Ulcers jejunum ileum jejunum and ileum duodenum colon Perforations ileum jejunum Intervening mucosa Villus blunting jejunum ileum Normal sized villi Patchy villus blunting
Celiac disease
“Unclassified sprue”
21”
10
1
1
10
4
2 9 2 4
1
7 4
6 0 0 5 1 4
12 4 5 0
6 0 1 2
11
a All figures indicate number of patients.
lated to a polymorphous lymphomatous infiltrate. One was published as “pseudolymphoma” and the other had areas of nonspecific ulceration called “nongranulomatous ulcerative jejunitis” adjacent to the tumor. Pathologic features. All 7 patients in this group either presented with or eventually developed lymphoma involving the small bowel. All were classified as either mixed lymphocytic-“histiocytic” or “histiocytic” in type.
Figure 3. Case 22. Ulceration in celiac disease. The adjacent mucosa shows marked blunting of villi. Note widened space between crypt bases and muscularis mucosae (arrow), an occasional feature of unknown significance (x18).(Courtesy of Dr. Basil Morson, St. Mark’s Hospital, London, England.)
A possible evolutionary process in which lymphoma became increasingly evident was observed in the small bowel in association with the ulcerations in 1 patient (courtesy of Dr. Robert Wintroub). A solitary jejunal ulcer, resected 3 yr before the development of frank lymphoma, was believed to be nonspecific. However, in retrospect, it was noted that
Figure 4. Case 9. Ulceration in celiac disease after long-term gluten-free diet with good response. A. Villi are present in adjacent mucosa (X18).B. The ulcer base shows only inflamed granulation tissue (X250).
789
BAER ET AL.
even then there was a heavy inflammatory infiltrate with occasional large atypical “histiocytic” cells at the base of the ulcer (Figure 6). Two years later, two additional stenosing jejunal ulcers were resected. Interpretation at that time was benign ulceration due to “nongranulomatous ulcerative jejunitis.” However on later review, while benign-looking ulceration was evident at low power in one area (Figure 73, elsewhere a distinctly pleomorphic cell infiltrate consistent with “histiocytic” lymphoma was associated with ulceration (Figure 8). A further jejunal resection 1 yr later demonstrated an even more uniformly pleomorphic histiocytic lymphoma (Figure 9). This patient is reminiscent of 4 patients reported by Freeman et al. in whom ulcerating “histiocytic” lymphoma of the small bowel was initially misinterpreted as “benign nongranulomatous ulcerative jejunoileitis.“’ Similar cases are described also by Isaacson and Wright.“’ In our registry, 2 other patients with reportedly nonspecific ulcers subsequently developed “histiocytic” lymphoma, but the slides of the ulcers were not available for review. Small intestinal lymphoma and benign nonspecific ulcers were present simultaneously in 2 patients. The tumors in both had mixed lymphocytic“histiocytic” characters, consisting of pleomorphic large cells in a context of chronic inflammatory cells. In the patient from whom slides were available, benign ulcers were adjacent to the tumor and showed a dense infiltrate of chronic inflammatory cells in the lamina propria and upper submucosa. Similar findings were noted in the published report from the
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Figure 5. Case 33. Ulceration in “unclassified sprue.” The patient also had dermatitis herpetiformis. Adjacent mucosa shows blunted villi. Autopsy specimen (x18).
second patient. An additional patient with celiac disease and ulcerating lymphoma demonstrated nonulcerated areas of flattened mucosa containing chronic inflammation and occasional pleomorphic cells (Figure 10) (Courtesy of Dr. James J. Galdabini). Patients with Miscellaneous Malabsorptive Disorders Nonspecific intestinal ulceration occurred in 4 patients with malabsorption associated with various disorders and villus blunting in the proximal small intestine. One patient had hypogammaglobulinemia
Figure 6. Case 37. Initial “benign” ulceration in patient who later developed frank lymphoma. A. uverview showing prominent cellular infiltrate at base of ulcer (X18).B. Detail of cellular infiltrate. It consists of a polymorphous inflammatory reaction with occasional large, atypical histiocytic cells (arrows) (x550).(Courtesy of Dr. Robert Wintroub.)
October 1980
INTESTINAL ULCERATION AND MALABSORPTION
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disease of the colon; in 1 four colonic strictures were resected 36 yr before the current illness. A poorly characterized colitis accompanied the small bowel disease in the second. All 3 patients died as a result of their intestinal disorder.
Discussion Ulceration of the small intestine and occasionally the colon can occur as a complication of several malabsorption syndromes, most of which are associated with a flat mucosa in the proximal small intestine. Many but not all of the patients have evidence of celiac disease. The ulcers, for which an etiology is not obvious, are usually multiple and may result in significant mortality. In a few patients, the nonspecific ulcers precede the development and/or recognition of intestinal lymphoma.
CeJiac Disease Figure 7. Case 37. Benign appearing ulceration with only supecfickil inflammatory infiltrate seen 2 yc after lesion in Figure 6. Note, however, absence of villi in adjacent mu-
cosa (X16).
and superficial mucosal ulcers. Two had resided in the tropics (Ceylon and Palestine), and one had alpha-1-antitrypsin deficiency. The latter 3 patients died after intestinal perforation. Three patients Normal villus architecture. were reported as examples of “nongranulomatous ulcerative jejunoileitis” with gross small intestinal ulceration and a malabsorption syndrome associated with normal villus architecture. Two had associated
The largest group of patients with malabsorption and gross small intestinal ulceration were those with celiac disease (gluten-induced enteropathy). The role of gluten in the pathogenesis of these ulcers is not clear. One concept is based on damage by gluten causing increased cell turnover wtih eventual crypt “exhaustion” and resultant mucosal breakdown and u1ceration.3.47.58Any hypothesis involving gluten, however, must account also for the occurrence of ulceration in patients with celiac disease in remission on a gluten-free diet and the occasional presence of ulcers in the ileum and colon, where the exposure to gluten is minimal. Klaeveman et al. sug-
Figure 8. Case 37. Another ulcer removed at same operation shown in Figure 7. A. A heavy infiltrate penetrates through and appears to destroy muscle wall (x9). B. In this location the infiltrate is a mixed lymphocytic-“histiocytic” lymphoma with numerous large, pleomocphic cells (x550).
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Figure 9. Case 37. Ulcer at third resection 1 yr after that shown in Figure 7. A. The lymphomatous tive (x9). B. The tumor shows even more pleomorphic cells than previously (x550).
gested that a supervening nongluten dependent immunologic process might be involved in the pathogenesis of these ulcers.’ “Unclassified
Sprue”
The term “unclassified sprue” is used in this report to designate individuals in whom the underlying malabsorptive disorder could not be adequately defined. We feel that some, if not most, had
Vol. 79, No. 4
infiltrate is heavy and highly destruc-
celiac disease, but failed to respond to therapy because of ulceration or their advanced age. In our experience, elderly patients with celiac disease may either not respond promptly to a gluten-free diet or become refractory to the diet. In vitro organ culture techniques, HLA tissue-typing, and repeat jejunal biopsies following dietary gluten restriction could help to identify or refute a pathogenetic role for gluten in patients with ulcerations who fail to respond to a gluten-free diet.
Figure 10. Case 39. Frank histiocytic lymphoma with ulcers was present elsewhere in small intestine. A. Focus of cellular infiltrate away from ulcer causing flattened mucosa. Such sites might become ulcerated without evidence of lymphoma being found (x16). B. Detail of infiltrate that appears to be inflammatory but which might be an “early” lymphocytic-“histiocytic” tumor. Note occasional larger cells with pyknotic nuclei (x550). (Courtesy of Dr. James Galdabini.)
October 1980
The term “nongranulomatous ulcerative jejunoileitis” was previously applied by the original authors to many of the patients in this registry. The terminology was initially used to indicate that ulceration was a primary component of the illness and thought to be responsible for the associated malabsorption and villus blunting.‘x3 We feel that the term has, unfortunately, become too nonspecific and can be clinically misleading. Its continued use obscures the fact that an underlying primary malabsorptive disorder such as celiac disease and/or early intestinal lymphoma may be present. Delays in exploratory laparotomy or other diagnostic maneuvers have resulted from the “labeling” of patients with this nonspecific term. Lymphoma The clinical features of intestinal lymphoma and of benign intestinal ulceration occurring in association with malabsorption may be indistinguishable. The patients are in roughly the same age range, 49-55 yr in lymphoma complicating celiac disease,57.58and 48.2 yr in benign ulceration complicating celiac disease. Furthermore, the onset of both intestinal lymphoma and of benign ulceration are marked by a recurrence or increase in malabsorptive symptomatology along with abdominal pain, fever, and weight loss. In addition, intestinal lymphoma may ulcerate at sites of lymphomatous infiltration and resemble benign ulcers producing hemorrhage, obstruction, and perforation. Although important aspects of the pathogenesis and classification of lymphomas remain unresolved, much progress has been made recently. Application of techniques such as immunocytochemistry for categorizing tumor cells as B lymphocytes, T lymphocytes, and moncytes/histiocytes have been especially helpful. The widely used classification of Rappaport, which was developed on the basis of morphologic features, identifies the large cells seen in some lymphomas as “histiocytic.” There is now good evidence that such large cells are almost always transformed lymphocytes. Nevertheless, lymphomas containing large cells are still usually designated “histiocytic” or mixed lymphocytic-“histiocytic” depending on proportion of large and small (lymphocytic) cell types.” These terms were, according to accepted usage, applied to the present cases. At the same time, it is now less clear that intestinal lymphomas fall readily into standard classification schemes, schemes that are in fact chiefly based on findings in lymphomas which originate outside the intestinal tract. Indeed, Isaacson and Wright, who described cases of intestinal lymphoma comparable to those reported here, concluded from
INTESTINAL
ULCERATION
AND MALABSORPTION
763
various staining and other characteristics that the malignancies were truly histiocytic rather than lymphocytic in origin.“‘sM The pathologic diagnosis of malignant ulcer?tion was not difficult if there was a classic monomorphic lymphomatous infiltrate at the base of the ulcer. In some cases, however, the lymphomatous infiltrate was polymorphous, containing various chronic inflammatory cells in addition to atypical forms. Such a picture has proved difficult to differentiate from reactive changes of inflammation. In addition, the absence of involvement of mesenteric nodes in early lymphoma can make this distinction even more difficult. Nonspecific intestinal ulcers with occasional atypical cells in their infiltrate were observed in 2 patients who were subsequently recognized to have intestinal lymphoma. A comparable evolution was described by Whitehead in patients with celiac disease who later developed frank intestinal lymphoma.” He observed a stage before recognition of lymphoma in which there was a dense inflammatory infiltrate, ulceration extending to the muscularis propria, and increasing atypical, pleomorphic reticulum cells (equals “histiocytic” cells) in the infiltrate. It is not known how often benign-looking ulcers may be the harbinger of intestinal lymphoma. Diagnosis of Intestinal
Ulceration
The diagnosis of intestinal ulceration in celiac disease and other malabsorption syndromes may be difficult. The clinical settings include: (a) a patient in the fifth or sixth decade with known celiac disease who has a recurrence of malabsorptive symptoms; (b) a patient with a flat jejunal biopsy and malabsorption which proves refractory to a gluten-free diet and/or adrenocorticosteroid therapy; (c) as well as the occurrence of abdominal pain, fever, intestinal perforation, obstruction, or hemorrhage in an individual with malabsorption. The diagnosis of small intestinal ulceration has usually been demonstrated only at exploratory laparotomy with fullthickness biopsy resection of abnormal appearing small bowel. Barium contrast techniques were usually not diagnostic and only demonstrated ulceration when it was accompanied by strictures. In the future, barium given through a small bowel tube,‘l upper intestinal endoscopy, or multiple biopsy specimens, may be helpful. Vigorous attempts to define the underlying malabsorptive process are needed, including trials of a gluten-free diet with repeat jejunal biopsies, particularly in the absence of a clinical response. In vitro organ culture techniques with gluten addition may also be helpful in the future. A peroral biopsy will
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BAER ET AL.
often provide evidence either suggestive or diagnostic of lymphoma, but since the presence of apparently benign ulceration does not exclude lymphoma, a laparotomy with biopsy-resections of the small bowel and mesenteric nodes is usually indicated. Repeat laparotomy with biopsy may also be needed in an individual who fails to improve as lymphoma may only become apparent later. Therapy
of Ulcerations
Successful therapy of benign ulceration has usually included resection of the ulcers, particularly if localized to one part of the intestine. Corticosteroid therapy has been utilized with apparent benefit in a few patients with uncomplicated ulcers; however, the danger of intestinal perforation with steroid therapy must be recognized. Parenteral alimentation may improve nutritional status preoperatively and may lead to improvement in a gluten-induced enteropathy, if present. Reporting of all patients with intestinal ulceration and malabsorptionez as well as a follow-up on treatment response, lymphoma development and survival either in the literature or in a central registry is encouraged for better understanding of this problem.
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