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Progressive Villous Atrophy of the Ileum Used as a Urinary Conduit
Vol. 52, No.5 Printed in U.S.A.
GASTROENTEROLOGY
Copyright © 1967 by The Williams & Wilkins Co.
PROGRESSIVE VILLOUS ATROPHY OF THE ILEUM USED AS A URINARY CONDUIT MICHAEL
J.
GOLDSTEIN, M.D., MYRON
R.
MELAMED, M.D., HARRY GRABSTALD,
M.D., AND PAUL SHERLOCK, M.D.
Gastroenterology Section, General Medical Service of the Department of Medicine, the Department of Pathology, and the Urology Service of the Department of Surgery of the Memorial Hospital for Cancer and Allied Diseases, and the James Ewing Hospital,. and the Sloan-Kettering Institute for Cancer Research, New York, New York
It was originally believed that the following morphological changes in the small intestinal mucosa were specific for celiac disease: replacement of normal mucosa by short, thick, flat villi; replacement of columnar epithelial cells by cuboidal cells; infiltration of lamina propria by inflammatory cells. It is now recognized that the intestinal mucosa may respond in a similar way to other forms of severe chronic injury, either experimentally produced or occurring naturally. Rubin and Dobbins,1 in a recent review of the subject, mentioned many types of injury which produce these morphological changes. In 1950, Bricker2 described the use of an isolated segment of small bowel as a urinary conduit after pelvic exenteration. Since that time, the ileal conduit has been used fairly extensively as a bladder substitute. Considerable controversy exists in the literature concerning the changes, if any, that occur in the mucosa of the segment of ileum used as a conduit. Kucera and Malinsky 3 noted marked mucosal villous atrophy in human ileal conduits biopsied up to 7 years after construction. Joseph and Thomas,4 after reviewing the medical literature to 1956, found that alReceived November 22, 1966. Accepted December 19, 1966. The observations in this paper were presented, in part, at the Third World Congress of Gastroenterology, Tokyo, Japan, September 1966. Address requests for reprints to: Dr. Paul Sherlock, 444 East 68th Street, New York, New York 10021. This work was supported by Gastroenterology Training Grant 2A-5091 from the United States Public Health Service. 859
though many investigators had constructed ileal bladders in dogs, none had noted changes in ileal mucous membranes up to 2 years after the operation. The work of Shoemaker et al.,5 also in animals, supported this. The accessibility of mucosa in an ileal conduit provides an unusual opportunity to follow the morphological changes that occur in a segment of small bowel when its environment is modified and its function changed. 'Ve were interested in studying the progression of these changes and were able to obtain for study a population of patients who have had functioning ileal conduits for varying lengths of time. Material and Methods Between January and June 1965, patients were selected at random from the Urology Clinic and from the Urology Service at Memorial and James Ewing Hospitals. The patients studied consisted of 15 men and 7 women. Their ages ranged from 36 to 82 years. The pathological diagnosis prior to cystectomy and ileal conduit construction was epidermoid or transitional cell carcinoma of the bladder in 20 patients; bladder tumor, not further identified and not available for review by us, in 1 patient; and papillomatosis involving the entire bladder in 1 patient. Twenty patients received irradiation to the abdomen, with tumor doses varying between approximately 3000 rand 6000 r, prior to conduit construction. The length of time between construction of the conduit and biopsy ranged from 7 days to 5 years and 8 months. Twenty-four suction biopsies of ileal bladder mucosa were obtained from the 22 patients. In addition, specimens of normal ileum were obtained from 2 patients during construction of the conduit.
860
GOLDSTEIN ET AL.
Biopsies were obtained by using the Woods tube. The biopsy capsule was inserted approximately 5 cm beyond the mucocutaneous margin of the stoma under aseptic technique. The specimens were immediately removed from the capsule, oriented on heavy blotting paper or plastic mesh screen, fixed in 10% neutral formalin, and serially sectioned. The biopsy specimens were stained with hematoxylin, eosin, mucicarmine, and periodic acid-Schiff stains. All biopsies were examined by one of the authors (M . R. M.) without prior knowledge of the time that had elapsed between construction of the conduit and subsequent biopsy.
Results
Progressive villous atrophy was noted. The earliest minimal changes were already present at 1 week, the time of the first biopsy. These changes continued from mild to moderate villous, mucosal, and submucosal edema with consequent broadening, blunting, and apparent shortening of villi within the first few months (fig. 1). The change was patchy or irregular and interspersed with areas of relatively normal or mildly edematous villi. For the next few months there was progressive shortening of the villi with partial replacement by deeper crypt formation (fig. 2). Blunting and broadening of the villi progressed to loss of villous structure and flattening of the mucosa (figs. 3 and 4). There was individual variation in the rate at which the loss of villous structure developed, but in most patients it was fairly complete by 2 years. No consistent change in the relative number of goblet cells or Paneth cells was noted. Although some of the biopsies demonstrated mild inflammatory infiltrate in the lamina propria, this was found in a minority of cases and was not correlated with the interval between operation and biopsy. Discussion Precautions were taken to orient, fix, and section the biopsy specimens properly, and serial sections were made from each specimen. In general, we found that progressive villous atrophy occurred in the segment of ileum used as a urinary conduit. This confirms the findings of Kucera and Malin-
Vol. 52, No.5
sky,3 who biopsied ileal conduits through a cystoscope and, after 1 year, observed short, wide villi, increased number of goblet cells, and infiltration of lamina propria with plasma cells and lymphocytes. After 4 to 7 years the villi appeared shorter, the mucosa appeared "practically flat," and the goblet cells appeared more numerous, in some areas forming the entire epithelial surface. Under the electron microscope, soon after conduit construction, the microvilli of the columnar cells were noted to be shorter and fewer in number; after 5 years they had completely disappeared. Also noted was simultaneous alteration of the ultrastructure of epithelial cells and their transformation into cells of mucussecreting type; enlargement of the sacs of the endoplasmic reticulum; increase in the sacs of the Golgi apparatus; and increase in the number of mucoid vacuoles and globules. Rattner et al. 6 biopsied 8 patients who had had small bowel conduits constructed up to 3 years previously. Mucosal inflammatory infiltration and edema with normal mucosal pattern were noted up to 28 months after conduit construction. General mucosal flattening was noted in 1 patient biopsied 2 years after diversion, and fiat mucosa was observed in a postmortem specimen 3 years after diversion. Joseph and Thomas 4 constructed ileocystoplasties in rabbits with loops of ileum, each with an intact vascular supply. The ileal mucosal structure remained normal even after 400 days, except for flattening and broadening of the villi, which was felt to be secondary to stretching of the wall. Normal alkaline phosphatase activity was noted in the free edge of the columnar cells up to 30 days , after which time variable results were noted, but generally a decrease or even absence of activity was observed. Although the authors did not think atrophy was present, their results suggest that villous changes did, in fact, occur. Shoemaker et al. 5 constructed urinary conduits in dogs with ileal grafts and biopsied the ileal mucosa at postoperative intervals of up to 9 months. They noted varying degrees of inflammatory cell in-
May 1967
VILLOUS ATROPHY OF ILEUM
861
2.... FIG. 1. struction, (x 140). FIG. 2. struction, tration in
Photomicrograph of an ileal bladder mucosal biopsy 5 weeks after surgical conshowing mucosal edema and some mild broadening and blunting of the villi Photomicrograph of an ileal bladder mucosal biopsy 6 months after surgical conshowing some blunting and loss of villous structure with increased cellular infilthe lamina propria (X 140).
filtration in otherwise normal mucosa. Normal ileal mucosa comparable to that observed in the preceding experiment was noted to have regenerated from raw submucosal surface in ileal grafts in which the mucosa had previously been stripped. How-
ever, in one of the photomicrographs the "normal" mucosa appeared to be flat and without villi. We also noted considerable individual variation in the rate and degree of villous atrophy. For example, the ileal conduit
862
GOLDSTEIN ET AL .
Vol. 52, No.5
.FIG. 3. Photomicrograph of an ileal bladder mucosal biopsy 5 months after surgical construction, showing loss of villous structure and flattened mucosa ( X 140). FIG. 4. Photomicrograph of an ileal bladder mucosal biopsy 2 years 2 months after surgical construction, showing mucosal flattening with loss of villous structure (X 140).
mucosa appeared considerably more abnormal in 1 patient biopsied 10 weeks after conduit construction than in others biopsied 1 year later. The possible causes for this are differences in surgical technique, variable degrees of villous atrophy occurring within the same conduit, or radiation effect. As cited by Rubin and Dobbins,! previous investigators havc noted that small
intestinal villous mucosal atrophy may occur as a response to a variety of injurious or toxic agents and disease processes. Collins and Isselbacher 7 reported severe mucosal damage of the small intestine, similar to that seen in celiac disease, in a patient with diffuse and ulcerating ileojejunitis and in a patient with agammaglobulinemia with malabsorption. Townley et al. 8 in-
May 1967
863
VILLOUS ATROPHY OF ILEUM
stilled hydrochloric acid in exposed ileum in dogs, resulting in temporary loss of villous structure, giving a flat appearance to the mucosa. In the same paper, biopsies of an ileal conduit in a boy with ectopic vesicae, performed 5 years earlier, revealed an over-all flat appearance similar to our observations. No prior radiotherapy was given. We are uncertain as to the cause of ileal conduit mucosal change. Factors that must be considered include radiotherapy prior to surgery; disturbance in the lymphatic, nerve or blood supply, or both, as a result of the operative procedure; change in function of ileum with exposure to urine which may differ markedly in pH and chemical composition from normal chyme and which may contain metabolic products toxic to the ileal mucosa. The first possibility seems unlikely in view of the presence of normal lymphoid follicles in some atrophic mucosa. Also, the ileum obtained at surgery was normal in 2 patients who had had a previous course of radiotherapy, and identical villous changes were noted in the 2 nonirradiated patients and in the ones who were radiated prior to surgery. Although this does not rule out the possible mucosal effects of radiation, it would make it less likely as a maj or contributing factor. In addition, as mentioned previously, 1 patient reported by Townley et al. 8 and 2 patients reported by Rattner et al. 6 without cancer and without prior irradiation had similar villous changes. Spiro and Pearse9 noted that, although sublethal doses of irradiation produced marked morphological and histochemical abnormalities in the small bowel of mice, these were repaired within 4 to 5 days. This, however, does not rule out the development of later chronic changes secondary to radiation. Other investigators have noted mucosal changes when segments of ileum were transplanted elsewhere in the body and exposed to abnormal environments. Joseph 1o noted that when whole thickness segments of ileum were grafted into the ears of rabbits, the columnar epithelium either disappeared completely or formed cystic structures. Zetterbund l l transplanted small intestine segments together with blood sup-
ply to the anterior abdominal wall in rats. Cystic epithelial structures were subsequently noted to form. The mucosa shown in their photomicrographs appears flat. Watson et alP autografted segments of ileum with blood supply to colon in rats. They noted shortening and broadening of villi beginning at the 3rd week, with subsequent development of "partial villous atrophy." Despite these changes, the enzymes normally present in surface epithelium of mucosal villi in the rat, alkaline phosphatase, acid phosphatase, and leucine aminopeptidase all persisted, although a reduction in activity was noted in some cases. They also noted no change in the surface epithelial cells with their brush borders or in the goblet cells or in the relative number of mitoses among the crypt cells. Paneth cells appeared distended with typical granules, the lamina propria was infiltrated by chronic inflammatory cells, and crypts appeared elongated and branched. No change in the normal mucosal pattern was noted when autografts of ileum were transplanted to ileum. They suggest that this supports their conclusion that it is the exposure of the ileal grafts to colonic contents and not the grafting procedure per se which produces the ileal mucosal atrophy. Kucera and Malinsky 3 concluded that the mucosal changes they noted in ileal conduits are adaptive changes which protect the patients with ileoplasties from absorption of urine. However, Rattner et al. 6 believe that significant absorption does occur, as shown by the hyperchloremic acidosis in these patients if they have significant impairment of renal function. This electrolyte abnormality, however, occurs less frequently than in patients who have ureterocolic anastomoses. The observations reported herein would suggest that the ileal conduit may provide a model for physiological and functional studies of small intestinal atrophy in man. Summary
An ileal conduit used as a urinary bladder in man provides an unusual opportunity to follow the morphological and functional changes that occur in a segment of small
864
GOLDSTEIN ET AL.
intestine when its environment is modified and its function changed. The histological alterations in ileal bladder occurring at various intervals following surgical construction were studied. Twenty-four biopsies of ileal bladder mucosa were obtained from 22 patients from 1 week to nearly 6 years after surgery. Progressive villous atrophy was noted. The earliest changes were already present at 1 week. Blunting and broadening of the villi progressed to loss of villous structure and flattening of the mucosa. There was individual variation in the rate at which villous atrophy developed, but in most patients it was fairly complete by 2 years. REFERENCES 1. Rubin, C. E., and W. O. Dobbins, III. 1965.
Peroral biopsy of the small intestine. Gastroenterology 49: 676-697. 2. Bricker, E. H. 1950. Bladder substitution after pelvic evisceration. Surg. Clin. N. Amer. 30: 1511-1521. 3. Kucera, J., and J. Malinsky. 1964. The mucous membrane of the intestinal loop introduced into the urinary passages-as observed by light and electron microscopy. In XIII' Congres de la Societe Internationale d'Urologie, Londres. 2: 218-225. 4. Joseph, J., and G. A. Thomas. 1958. The behavior of auto grafts of ileum transplanted
Vol. 52, No.5
into urinary bladder in rabbits. J. Anat. 92: 551-558.
5. Shoemaker, W. C., C. G. Tedeschi, and P. J. Grotzinger. 1956. Morphologic changes of intestinal grafts used in bladder reconstruction. Arch. Surg. 72: 525--529. 6. Rattner, W. H., J. J. Moran, and J. J. Murphy. 1959. The histologic appearance of small bowel segments used as a urinary conduit. J. Urol. 82: 236-239. 7. Collins, J. R, and K. J. Isselbacher. 1965. The occurrence of severe small intestinal mucosal damage in conditions other than celiac disease (nontropical sprue). Gastroenterology 49: 425-432. 8. Townley, R R W., M. H. Cass, and C. M. Anderson. 1964. Small intestinal mucosal patterns of coeliac disease and idiopathic steatorrhea seen III other situations. Gut 5: 51-55. 9. Spiro, H. M., and A. G. E. Pearse. 1964. A histochemical analysis of the effect of irradiation on murine duodenal mucosa. J. Path. Bact. 88: 55-60. 10. Joseph, J. 1960. Autografts of ileum and lining of urinary bladder to the ears of rabbits. Plast. Reconstr. Surg. 25: 27-38. 11. Zetterbund, C. G. 1962. Buried strip of intestinal wall. Process of healing studied in the rat. Acta Chir. Scand. 125: 467-473. 12. Watson, A. J., J. W. Watson, and F. C. Walker. 1965. The behavior of pedicle autographs of ileum transplanted into the colon in the rat. Amer. J. Path. 46: 553-565.
GASTROENTEROLOGY
Copyright © 1967 by The Williams & Wilkins Co.
PROGRESSIVE VILLOUS ATROPHY OF THE ILEUM USED AS A URINARY CONDUIT MICHAEL
J.
GOLDSTEIN, M.D., MYRON
R.
MELAMED, M.D., HARRY GRABSTALD,
M.D., AND PAUL SHERLOCK, M.D.
Gastroenterology Section, General Medical Service of the Department of Medicine, the Department of Pathology, and the Urology Service of the Department of Surgery of the Memorial Hospital for Cancer and Allied Diseases, and the James Ewing Hospital,. and the Sloan-Kettering Institute for Cancer Research, New York, New York
It was originally believed that the following morphological changes in the small intestinal mucosa were specific for celiac disease: replacement of normal mucosa by short, thick, flat villi; replacement of columnar epithelial cells by cuboidal cells; infiltration of lamina propria by inflammatory cells. It is now recognized that the intestinal mucosa may respond in a similar way to other forms of severe chronic injury, either experimentally produced or occurring naturally. Rubin and Dobbins,1 in a recent review of the subject, mentioned many types of injury which produce these morphological changes. In 1950, Bricker2 described the use of an isolated segment of small bowel as a urinary conduit after pelvic exenteration. Since that time, the ileal conduit has been used fairly extensively as a bladder substitute. Considerable controversy exists in the literature concerning the changes, if any, that occur in the mucosa of the segment of ileum used as a conduit. Kucera and Malinsky 3 noted marked mucosal villous atrophy in human ileal conduits biopsied up to 7 years after construction. Joseph and Thomas,4 after reviewing the medical literature to 1956, found that alReceived November 22, 1966. Accepted December 19, 1966. The observations in this paper were presented, in part, at the Third World Congress of Gastroenterology, Tokyo, Japan, September 1966. Address requests for reprints to: Dr. Paul Sherlock, 444 East 68th Street, New York, New York 10021. This work was supported by Gastroenterology Training Grant 2A-5091 from the United States Public Health Service. 859
though many investigators had constructed ileal bladders in dogs, none had noted changes in ileal mucous membranes up to 2 years after the operation. The work of Shoemaker et al.,5 also in animals, supported this. The accessibility of mucosa in an ileal conduit provides an unusual opportunity to follow the morphological changes that occur in a segment of small bowel when its environment is modified and its function changed. 'Ve were interested in studying the progression of these changes and were able to obtain for study a population of patients who have had functioning ileal conduits for varying lengths of time. Material and Methods Between January and June 1965, patients were selected at random from the Urology Clinic and from the Urology Service at Memorial and James Ewing Hospitals. The patients studied consisted of 15 men and 7 women. Their ages ranged from 36 to 82 years. The pathological diagnosis prior to cystectomy and ileal conduit construction was epidermoid or transitional cell carcinoma of the bladder in 20 patients; bladder tumor, not further identified and not available for review by us, in 1 patient; and papillomatosis involving the entire bladder in 1 patient. Twenty patients received irradiation to the abdomen, with tumor doses varying between approximately 3000 rand 6000 r, prior to conduit construction. The length of time between construction of the conduit and biopsy ranged from 7 days to 5 years and 8 months. Twenty-four suction biopsies of ileal bladder mucosa were obtained from the 22 patients. In addition, specimens of normal ileum were obtained from 2 patients during construction of the conduit.
860
GOLDSTEIN ET AL.
Biopsies were obtained by using the Woods tube. The biopsy capsule was inserted approximately 5 cm beyond the mucocutaneous margin of the stoma under aseptic technique. The specimens were immediately removed from the capsule, oriented on heavy blotting paper or plastic mesh screen, fixed in 10% neutral formalin, and serially sectioned. The biopsy specimens were stained with hematoxylin, eosin, mucicarmine, and periodic acid-Schiff stains. All biopsies were examined by one of the authors (M . R. M.) without prior knowledge of the time that had elapsed between construction of the conduit and subsequent biopsy.
Results
Progressive villous atrophy was noted. The earliest minimal changes were already present at 1 week, the time of the first biopsy. These changes continued from mild to moderate villous, mucosal, and submucosal edema with consequent broadening, blunting, and apparent shortening of villi within the first few months (fig. 1). The change was patchy or irregular and interspersed with areas of relatively normal or mildly edematous villi. For the next few months there was progressive shortening of the villi with partial replacement by deeper crypt formation (fig. 2). Blunting and broadening of the villi progressed to loss of villous structure and flattening of the mucosa (figs. 3 and 4). There was individual variation in the rate at which the loss of villous structure developed, but in most patients it was fairly complete by 2 years. No consistent change in the relative number of goblet cells or Paneth cells was noted. Although some of the biopsies demonstrated mild inflammatory infiltrate in the lamina propria, this was found in a minority of cases and was not correlated with the interval between operation and biopsy. Discussion Precautions were taken to orient, fix, and section the biopsy specimens properly, and serial sections were made from each specimen. In general, we found that progressive villous atrophy occurred in the segment of ileum used as a urinary conduit. This confirms the findings of Kucera and Malin-
Vol. 52, No.5
sky,3 who biopsied ileal conduits through a cystoscope and, after 1 year, observed short, wide villi, increased number of goblet cells, and infiltration of lamina propria with plasma cells and lymphocytes. After 4 to 7 years the villi appeared shorter, the mucosa appeared "practically flat," and the goblet cells appeared more numerous, in some areas forming the entire epithelial surface. Under the electron microscope, soon after conduit construction, the microvilli of the columnar cells were noted to be shorter and fewer in number; after 5 years they had completely disappeared. Also noted was simultaneous alteration of the ultrastructure of epithelial cells and their transformation into cells of mucussecreting type; enlargement of the sacs of the endoplasmic reticulum; increase in the sacs of the Golgi apparatus; and increase in the number of mucoid vacuoles and globules. Rattner et al. 6 biopsied 8 patients who had had small bowel conduits constructed up to 3 years previously. Mucosal inflammatory infiltration and edema with normal mucosal pattern were noted up to 28 months after conduit construction. General mucosal flattening was noted in 1 patient biopsied 2 years after diversion, and fiat mucosa was observed in a postmortem specimen 3 years after diversion. Joseph and Thomas 4 constructed ileocystoplasties in rabbits with loops of ileum, each with an intact vascular supply. The ileal mucosal structure remained normal even after 400 days, except for flattening and broadening of the villi, which was felt to be secondary to stretching of the wall. Normal alkaline phosphatase activity was noted in the free edge of the columnar cells up to 30 days , after which time variable results were noted, but generally a decrease or even absence of activity was observed. Although the authors did not think atrophy was present, their results suggest that villous changes did, in fact, occur. Shoemaker et al. 5 constructed urinary conduits in dogs with ileal grafts and biopsied the ileal mucosa at postoperative intervals of up to 9 months. They noted varying degrees of inflammatory cell in-
May 1967
VILLOUS ATROPHY OF ILEUM
861
2.... FIG. 1. struction, (x 140). FIG. 2. struction, tration in
Photomicrograph of an ileal bladder mucosal biopsy 5 weeks after surgical conshowing mucosal edema and some mild broadening and blunting of the villi Photomicrograph of an ileal bladder mucosal biopsy 6 months after surgical conshowing some blunting and loss of villous structure with increased cellular infilthe lamina propria (X 140).
filtration in otherwise normal mucosa. Normal ileal mucosa comparable to that observed in the preceding experiment was noted to have regenerated from raw submucosal surface in ileal grafts in which the mucosa had previously been stripped. How-
ever, in one of the photomicrographs the "normal" mucosa appeared to be flat and without villi. We also noted considerable individual variation in the rate and degree of villous atrophy. For example, the ileal conduit
862
GOLDSTEIN ET AL .
Vol. 52, No.5
.FIG. 3. Photomicrograph of an ileal bladder mucosal biopsy 5 months after surgical construction, showing loss of villous structure and flattened mucosa ( X 140). FIG. 4. Photomicrograph of an ileal bladder mucosal biopsy 2 years 2 months after surgical construction, showing mucosal flattening with loss of villous structure (X 140).
mucosa appeared considerably more abnormal in 1 patient biopsied 10 weeks after conduit construction than in others biopsied 1 year later. The possible causes for this are differences in surgical technique, variable degrees of villous atrophy occurring within the same conduit, or radiation effect. As cited by Rubin and Dobbins,! previous investigators havc noted that small
intestinal villous mucosal atrophy may occur as a response to a variety of injurious or toxic agents and disease processes. Collins and Isselbacher 7 reported severe mucosal damage of the small intestine, similar to that seen in celiac disease, in a patient with diffuse and ulcerating ileojejunitis and in a patient with agammaglobulinemia with malabsorption. Townley et al. 8 in-
May 1967
863
VILLOUS ATROPHY OF ILEUM
stilled hydrochloric acid in exposed ileum in dogs, resulting in temporary loss of villous structure, giving a flat appearance to the mucosa. In the same paper, biopsies of an ileal conduit in a boy with ectopic vesicae, performed 5 years earlier, revealed an over-all flat appearance similar to our observations. No prior radiotherapy was given. We are uncertain as to the cause of ileal conduit mucosal change. Factors that must be considered include radiotherapy prior to surgery; disturbance in the lymphatic, nerve or blood supply, or both, as a result of the operative procedure; change in function of ileum with exposure to urine which may differ markedly in pH and chemical composition from normal chyme and which may contain metabolic products toxic to the ileal mucosa. The first possibility seems unlikely in view of the presence of normal lymphoid follicles in some atrophic mucosa. Also, the ileum obtained at surgery was normal in 2 patients who had had a previous course of radiotherapy, and identical villous changes were noted in the 2 nonirradiated patients and in the ones who were radiated prior to surgery. Although this does not rule out the possible mucosal effects of radiation, it would make it less likely as a maj or contributing factor. In addition, as mentioned previously, 1 patient reported by Townley et al. 8 and 2 patients reported by Rattner et al. 6 without cancer and without prior irradiation had similar villous changes. Spiro and Pearse9 noted that, although sublethal doses of irradiation produced marked morphological and histochemical abnormalities in the small bowel of mice, these were repaired within 4 to 5 days. This, however, does not rule out the development of later chronic changes secondary to radiation. Other investigators have noted mucosal changes when segments of ileum were transplanted elsewhere in the body and exposed to abnormal environments. Joseph 1o noted that when whole thickness segments of ileum were grafted into the ears of rabbits, the columnar epithelium either disappeared completely or formed cystic structures. Zetterbund l l transplanted small intestine segments together with blood sup-
ply to the anterior abdominal wall in rats. Cystic epithelial structures were subsequently noted to form. The mucosa shown in their photomicrographs appears flat. Watson et alP autografted segments of ileum with blood supply to colon in rats. They noted shortening and broadening of villi beginning at the 3rd week, with subsequent development of "partial villous atrophy." Despite these changes, the enzymes normally present in surface epithelium of mucosal villi in the rat, alkaline phosphatase, acid phosphatase, and leucine aminopeptidase all persisted, although a reduction in activity was noted in some cases. They also noted no change in the surface epithelial cells with their brush borders or in the goblet cells or in the relative number of mitoses among the crypt cells. Paneth cells appeared distended with typical granules, the lamina propria was infiltrated by chronic inflammatory cells, and crypts appeared elongated and branched. No change in the normal mucosal pattern was noted when autografts of ileum were transplanted to ileum. They suggest that this supports their conclusion that it is the exposure of the ileal grafts to colonic contents and not the grafting procedure per se which produces the ileal mucosal atrophy. Kucera and Malinsky 3 concluded that the mucosal changes they noted in ileal conduits are adaptive changes which protect the patients with ileoplasties from absorption of urine. However, Rattner et al. 6 believe that significant absorption does occur, as shown by the hyperchloremic acidosis in these patients if they have significant impairment of renal function. This electrolyte abnormality, however, occurs less frequently than in patients who have ureterocolic anastomoses. The observations reported herein would suggest that the ileal conduit may provide a model for physiological and functional studies of small intestinal atrophy in man. Summary
An ileal conduit used as a urinary bladder in man provides an unusual opportunity to follow the morphological and functional changes that occur in a segment of small
864
GOLDSTEIN ET AL.
intestine when its environment is modified and its function changed. The histological alterations in ileal bladder occurring at various intervals following surgical construction were studied. Twenty-four biopsies of ileal bladder mucosa were obtained from 22 patients from 1 week to nearly 6 years after surgery. Progressive villous atrophy was noted. The earliest changes were already present at 1 week. Blunting and broadening of the villi progressed to loss of villous structure and flattening of the mucosa. There was individual variation in the rate at which villous atrophy developed, but in most patients it was fairly complete by 2 years. REFERENCES 1. Rubin, C. E., and W. O. Dobbins, III. 1965.
Peroral biopsy of the small intestine. Gastroenterology 49: 676-697. 2. Bricker, E. H. 1950. Bladder substitution after pelvic evisceration. Surg. Clin. N. Amer. 30: 1511-1521. 3. Kucera, J., and J. Malinsky. 1964. The mucous membrane of the intestinal loop introduced into the urinary passages-as observed by light and electron microscopy. In XIII' Congres de la Societe Internationale d'Urologie, Londres. 2: 218-225. 4. Joseph, J., and G. A. Thomas. 1958. The behavior of auto grafts of ileum transplanted
Vol. 52, No.5
into urinary bladder in rabbits. J. Anat. 92: 551-558.
5. Shoemaker, W. C., C. G. Tedeschi, and P. J. Grotzinger. 1956. Morphologic changes of intestinal grafts used in bladder reconstruction. Arch. Surg. 72: 525--529. 6. Rattner, W. H., J. J. Moran, and J. J. Murphy. 1959. The histologic appearance of small bowel segments used as a urinary conduit. J. Urol. 82: 236-239. 7. Collins, J. R, and K. J. Isselbacher. 1965. The occurrence of severe small intestinal mucosal damage in conditions other than celiac disease (nontropical sprue). Gastroenterology 49: 425-432. 8. Townley, R R W., M. H. Cass, and C. M. Anderson. 1964. Small intestinal mucosal patterns of coeliac disease and idiopathic steatorrhea seen III other situations. Gut 5: 51-55. 9. Spiro, H. M., and A. G. E. Pearse. 1964. A histochemical analysis of the effect of irradiation on murine duodenal mucosa. J. Path. Bact. 88: 55-60. 10. Joseph, J. 1960. Autografts of ileum and lining of urinary bladder to the ears of rabbits. Plast. Reconstr. Surg. 25: 27-38. 11. Zetterbund, C. G. 1962. Buried strip of intestinal wall. Process of healing studied in the rat. Acta Chir. Scand. 125: 467-473. 12. Watson, A. J., J. W. Watson, and F. C. Walker. 1965. The behavior of pedicle autographs of ileum transplanted into the colon in the rat. Amer. J. Path. 46: 553-565.