LLOYD E. PERINO, MICHAEL D. SCHUFFLER, SUNDER J. MEHTA, and GREGORY T. EVERSON Divisions of Gastroenterology, University of Colorado School of Medicine, Denver, Colorado; and University of Washington and Pacific Medical Center, Seattle, Washington
A case of intestinal pseudoobstruction occurring 30 yr after radiation therapy is described. Mechanical causes of obstruction were excluded by laparotomy. Histology of full-thickness sections of the small bowel revealed vascular ectasia and sclerosis, serosal fibrosis, neuronal proliferation within the submucosa, and degeneration of the muscle fibers of the circular layer of the muscularis propria. On the basis of the clinical and histologic findings we conclude that, in this patient, intestinal pseudoobstruction was due to muscular and neuronal injury from abdominal irradiation. The syndrome of intestinal pseudoobstruction is characterized by signs and symptoms of bowel obstruction. Radiologic studies of the bowel reveal dilation without an obstructing lesion. In spite of this, many patients undergo laparotomy to exclude anatomic obstruction. Both primary and secondary forms of pseudoobstruction have been described (1,Z). The secondary forms are associated with anticholinergic medications, narcotics, tricyclic antidepressants, clonidine, hypothyroidism, Addison’s disease, pheochromocytoma, neuromuscular disorders, scleroderma and other connective tissue diseases, amyloidosis, and malignancy. Only one previous case of pseudoobstruction secondary to radiation therapy has been described (3). However, in this report the bowel was not evaluated histologically and clinical details were lacking. For these reasons, we report a case of intestinal pseudoobstruction associated with prior abdominal Received September 9, 1985. Accepted April 11, 1986. Address requests for reprints to: Gregory T. Everson, M.D., Division of Gastroenterology, University of Colorado School of Medicine, 4200 East Ninth Avenue B-158, Denver, Colorado 80262. This work was supported in part by grant AM28180 from National Institutes of Health. The authors thank Zoe Jonak for technical assistance. 0 1986 by the American Gastroenterological Association 0016-5085/86/$3.50
irradiation. In addition, we review the literature describing the effects of radiation on the motility and structure of the small bowel. Case Report A 72-yr-old man was transferred to our hospital for evaluation and treatment of bowel distention. Thirty-six years before admission, carcinoma of the testis was diagnosed and he underwent bilateral orchiectomy with dissection of the lymph nodes of the retroperitoneum. In addition, he received 3850 rads of abdominal irradiation. Six years later he received 2500 rads to the anterior pelvis, 1600 rads to the periaortic area, and 2250 rads to the mediastinum. He experienced diarrhea during the courses of radiotherapy, but diarrhea was transient and cleared completely within 6 mo. For 30 yr he remained asymptomatic except for rare episodes of periumbilical bloating. Ten days before admission he experienced the sudden onset of nausea, vomiting, and diarrhea. The patient noted abdominal distention without pain, chills, or fever. He sought medical attention and was admitted to another hospital. Laboratory tests disclosed normal values for serum electrolytes, leukocyte counts, hematocrit, and liver enzymes. Abdominal films revealed loops of dilated small bowel. Sigmoidoscopy and barium enema were normal. An upper gastrointestinal and small bowel series showed that the jejunum and proximal ileum were dilated (Figure l), and no obstructing lesion was identified. The patient was subsequently transferred to Rose Medical Center, Denver, Colorado for further evaluation and treatment. On physical examination, changes of chronic radiation injury were noted on the skin of the lower abdomen and back. The abdomen was not tender, but was moderately distended with diminished bowel sounds. The liver and spleen were not palpable and the liver span was 10 cm by percussion. Rectal examination was normal and stool was negative for occult blood. Flexible sigmoidoscopy and barium enema were repeated and again did not demonstrate an obstructing lesion. However, the patient underwent exploratory laparotomy on the third hospital day for presumed intestinal obstruction. The serosa of the small bowel was thickened
showing dilated gas-filled loops of small bowel. Delayed films showed markedly delayed
transit of barium through the bowel. A. Fifteen minutes. B. Three hours.
and fibrotic, consistent with prior abdominal irradiation. Adhesions were lysed from the distal ileum, but no biopsy specimens were taken. The patient’s diarrhea, abdominal distention, nausea, and vomiting persisted after surgery. In addition, thyroid function studies, antinuclear antibody, and serum levels of magnesium, calcium, cortisol, and electrolytes were normal. Examinations and cultures of stool were negative for bacterial and parasitic infections. Repeated abdominal films revealed distended loops of small bowel. Despite trials of metoclopramide and urecholine, ileus persisted, and the patient had a second laparotomy (2 wk after the first). The small intestine was dilated and no obstruction was identified. A full-thickness biopsy specimen of the proximal ileum was obtained for conventional light microscopy (H & E and Masson trichrome stains), and an ileotransverse colostomy was performed. However, his ileus persisted postoperatively. On histologic examination, the mucosa of the small bowel was normal and the villus to crypt ratio was 4: 1. The submucosa was fibrotic and many of its vessels were ectatic and sclerotic [Figure z). The serosa was thickened and fibrotic and also had ectatic vessels (Figure 2). Enlarged, atypical fibroblasts were present in both the submucosa and serosa. Although the longitudinal layer of muscle fibers within the muscularis propria was normal, the fibers of the inner circular layer were markedly abnormal (Figure 3). Some of the cells were pale and swollen, some were waxy or highly eosinophilic with pyknotic nuclei, and some were markedly atrophic. There was scattered muscle cell dropout and fibrosis. In addition, the inner circular layer was broken up by fibrous septa extend-
ing into the muscle from the submucosa (Figure 4). Many of the septa contained neurons, a reflection of neuronal hyperplasia present in the submucosa. In just one section measuring 15 mm in length, 138 neurons were counted in the submucosa. This was significantly greater than the number of submucosal neurons counted in 76 sections of ileum from 10 control cases (mean ? SD = 38 * 17; p < 0.01). In contrast, the patient had 34 neurons within the myenteric plexus of that same section, which was not different from the contrast cases (mean ? SD = 41 + 18; p = NS). Although sufficient tissue was not available to do Smith’s silver stain on the myenteric plexus, it had a normal appearance on the sections stained with H & E. Two weeks after the second laparotomy a study of esophageal motility was performed. The lower esophageal sphincter pressure was diminished but present (Cl0 mmHg). In addition, the amplitude of contractions ranged from 30 to 50 mmHg [normal values in our laboratory, 60-120 mmHg (a)] and contractions in the distal twothirds of the esophagus were frequently nonperistaltic. Because of persistent ileus and lack of improvement, the patient elected to transfer to another hospital. While at the other hospital, he developed a persistent wound infection and an enterocutaneous fistula. The latter problem necessitated a third laparotomy and a resection of the fistula. After this operation the patient slowly, but gradually, improved. Three weeks after the operation he was able to tolerate oral feedings, although he continued to experience postprandial nausea, abdominal distention, and occasional vomiting. A repeat study of esophageal motility was normal. A small bowel motility study re-
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Full-thickness biopsy specimen of proximal ileum. A. The mucosa is normal and the thickness of the circular and longitudinal muscle layers are normal. The serosa is thickened. Masson’s trichrome, x20. B. The submucosa demonstrates fibrosis and ectatic vessels with hyalinized walls. H & E, x80.
vealed normal interdigestive migratory motor complexes in the proximal duodenum; the distal duodenum showed decreased amplitude and frequency of contractions, and no peristaltic contractions were recorded in the proximal jejunum and midjejunum. The patient has been followed for approximately 1 yr since his last operation. He remains symptomatic, with intermittent nausea, vomiting, and bloating, especially after meals.
Discussion The patient
in this report
tinal pseudoobstruction, and no cause other than radiation injury could be established by clinical, radiologic, surgical, or pathologic means.
3. Higher magnifications of Figure 2. A. The architecture of the circular muscle is distorted by bands of collagen extending from the submucosa (arrows]. Masson’s trichrome, X80. B. The smooth muscle cells of the circular muscle demonstrate variability of morphology and degenerative changes. Masson’s trichrome, ~504.
Radiation injury to the bowel may present acutely with nausea, vomiting, diarrhea, and abdominal distention secondary to mucosal injury. Histology of this injury reveals death of mucosal cells, loss of villi, ulceration, edema, and vascular congestion. Symptoms and histologic abnormalities usually resolve within weeks to a few months of therapy. Radiation injury may also present with delayed symptoms of obstruction, bleeding, or fistula formation secondary to fibrous strictures, or ischemia (5-i’). In addition, some studies suggest that radiation may cause gastrointestinal motor dysfunction. Conklin and Anuras (3) reported a case of recurrent pseudoobstruction following radiotherapy of the pelvis (13,000 rads). However, the patient was taking Immodium (Janssen Pharmaceutics Inc., Piscataway, N.J.), no surgical exploration was done
fibrosis invaginating the circular muscle Submucosal with associated neurons (arrow). H & E, X200.
to confirm the diagnosis, and no pathologic examination was available. In DeCosse’s retrospective review of radiation-induced bowel injury, 1 patient is presented who had persistent ileus after surgery for an anatomic small bowel obstruction (7). The persistent ileus may have been due to radiation-induced pseudoobstruction. Mason et al. (8) reviewed the radiologic studies in 30 cases of radiation enteritis, and observed that “affected loops showed diminished or absent peristalsis.” Esophageal dysmotility has been demonstrated in animal models of chronic radiation injury as well as in humans (9,10). In addition, abnormalities of motility caused by acute effects of irradiation have been noted in the rat jejunum (11). The pathologic basis of our patient’s pseudoobstruction was a markedly abnormal circular muscle characterized by muscle cell degeneration and fibrosis. Although these changes are infrequently reported as a consequence of radiation, they have been previously noted in both humans and animal models of radiation injury (12-19). Acute radiation injury in mice produces muscle cell injury by 5 days. By 15 days there is extensive muscle cell degeneration and early interstitial fibrosis (19). Muscle cell changes in humans seen months to years following radiation consist of swelling, atrophy, vacuolation
and hyaline degeneration of muscle cells, abnormal muscle cell nuclei, and fibrosis. Gastrointestinal smooth muscle is relatively insensitive to radiation, at least when compared to mucosa (15,19). Indeed, pseudoobstruction as a complication of abdominal irradiation is rare. However, it may also be true that motor dysfunction from muscle injury would be masked by the more serious complications of stenosis, obstruction, fistualization, mucosal ulceration, and localized abscesses. It is likely that our patient’s muscle disorder is secondary to irradiation rather than to another cause. He had features characteristic of radiation injury in the submucosa, serosa, and blood vessels, while lacking the vacuolar degeneration of familial or sporadic forms of visceral myopathy (2OJl). The patient had no clinical manifestations of the muscular dystrophies, progressive systemic sclerosis, or polymyositis. The smooth muscle cells in progressive systemic sclerosis appear normal or atrophic in size (21). They are not pale, swollen, or highly eosinophilic with pyknotic nuclei, as present in our patient. In contrast to the patient’s smooth muscle, his myenteric plexus appeared normal, at least by our conventional staining techniques. The only neuronal abnormality was a proliferation of neurons within the submucosa, many of them located within fibrous septa extending from the submucosa into the circular muscle. A proliferation of Meissner’s plexus neurons was noted in one previous report of radiation injury to the small intestine (22), with the neurons being extremely prominent near mucosal ulcers. The pathogenesis of the submucosal neuron proliferation and its relationship, if any, to his pseudoobstruction remain undefined. It is thought that intestinal neurons are incapable of undergoing mitosis, although one report suggested that this might be possible in Crohn’s disease as neurons containing paired centrioles, a marker for cell mitosis, were identified (23). In summary, we present a case of intestinal pseudoobstruction that occurred 30 yr after extensive abdominal irradiation. Based on clinical, surgical, and histologic evaluation, we believe the intestinal pseudoobstruction was caused by smooth muscle injury related to the previous irradiation. References Faulk DL, Anuras S, Christensen J. Clinical trends and topics; chronic intestinal pseudoobstruction. Gastroenterology 1978;74:922-31. Schuffler MD, Rohrmann CA, Chaffee RG, Brand DL, Delaney JW, Young JW. Chronic intestinal pseudo-obstruction. Medicine 1981;60:173-96. Conklin JL, Anuras S. Radiation-induced recurrent intestinal pseudoobstruction. Am J Gastroenterol 1981;75:440&4.
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4. Horton ML, Goff JS. Surgical treatment of nutcracker esophagus. Dig Dis Sci (in press). 5. Roswit B, Malsky SJ, Reid CB. Severe radiation injury to the stomach, small intestine, colon, and rectum. Am J Roentgen01 Radium Ther Nucl Med 1972;114:466-75. 6. Kinsella TJ, Bloomer WD. Tolerance of the intestine to radiation therapy. Surg Gynecol Obstet 1986;151:273-84. 7. DeCosse JJ, Rhodes RS, Wentz WB, Reagan JW, Dworken HJ, Holden WD. The natural history and management of radiation induced injury of the gastrointestinal tract. Ann Surg 1969;170:369-74. 8. Mason GR, Dietrich P, Friedland GW, Hanks GE. The radiological findings in radiation-induced enteritis and colitis, a review of 30 cases. Clin Radio1 1970;21:23247. 9. Northway MG, Libshitz HZ, West JJ, et al. The opossum as an animal model for studying radiation esophagitis. Radiology 1979;131:731-5. 10. Goldstein HM, Rodgers LF, Fletcher GH, Dodd GD. Radiological manifestations of radiation-induced injury to the normal upper gastrointestinal tract. Radiology 1975;117:135-40. 11. Conrad RA. Effect of x-irradiation on intestinal motility of the rat. Am J Physiol 1951;165:375-85. 12. Berthrong M, Fajardo LF. Radiation injury in surgical pathology. Part II. Alimentary tract. Am J Surg Path01 1981; 5:153-77. 13. Warren S. Effects of radiation on normal tissue. Arch Path01 1942;34:749-67.
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14. Warren S, Friedman NB. Pathology and pathologic diagnosis of radiation lesions in the gastrointestinal tract. Am J Path01 1942;18:499-507. 15. Novak JM, Collins JT, Donowitz M, Farman J, Sheahan DG, Spiro HM. Effects of radiation on the human gastrointestinal tract. J Clin Gastroenterol 1979;1:9-39. 16. Ferguson LK. Secondary effects of radiation upon the rectum following the treatment of extrarectal pelvic lesions. Am J Dig Dis Nutr 1938;4:712-19. 17. Jacobs LG. Unusual case of late post-irradiation damage to the ileum. Radiology 1963;80:57-60. 18. Seaman WB, Ackerman LV. The effects of radiation on the esophagus. Radiology 1957;68:534-40. 19. Huvos AG, Rogoff EE, Hilaris BS, Hahn EW. Pathological changes in mice following the intraperitoneal administration of radionuclides. Radiology 1974;113:263-7. 26. Mitros F, Schuffler MD, Teja K, Anwar S. Pathology of familial visceral myopathy. Hum Path01 1982;13:825-33. 21. Schuffler MD, Beegle RG. Progressive systemic sclerosis of the gastrointestinal tract and hereditary hollow visceral myopathy: two distinguishable disorders of intestinal smooth muscle. Gastroenterology 1979;77:664-71. 22. Schier J, Symmonds RE, Dahlin DC. Clinicopathologic aspects of actinic enteritis. Surg Gynecol Obstet 1964;119: 1019-25. 23. Siemers PT, Dobbins WO III. The Meissner plexus in Crohn’s disease of the colon. Surg Gynecol Obstet 1974;138:3942.