Digestive Diseases and Sciences, Vol. 37, No. 8 (August 1992), pp. 1292-1296
CASE REPORT
Acute Typhlitis in an Immunocompromised Host Report of an Unusual Case and Review of the Literature T. H I R U K I , MD, B. F E R N A N D E S , MD, FRCPC, J. RAMSAY, MD, FRCPC and I. R O T H E R MD, FRCPC KEY WORDS: typhlitis; neutropenia; immunocompromised;malakoplakia.
Increasingly aggressive c h e m o t h e r a p y regimens, advances in transplantation technology, and the acquired immunodeficiency s y n d r o m e have resulted in a growing number o f immunocompromised patients. Infections are a major cause o f morbidity and mortality in this population. The gastrointestinal tract serves as an important site of host environment interaction and is a reservoir of vast numbers of potentially pathogenic microbial species (1). In normal individuals, mucosal integrity, gastric acidity, intestinal motility, gut associated lymphoid tissue, humoral immunity, and ecologic competition among members of the intraluminal flora serve as defenses to microbial infection and invasion (2). Compromise of these defenses renders the host susceptible to a wide range of infectious complications, and the gastrointestinal tract may be an important portal o f entry for pathogens in immunocompromised hosts (3). We report a case in which a neutropenic patient developed bacterial typhlitis with septicemia. Analysis o f the resected tissue revealed findings consistent with an early stage of malakoplakia. The simultaneous o c c u r r e n c e of these two lesions offers insight into the pathogenesis of septic complications in i m m u n o c o m p r o m i s e d individuals. CASE REPORT
A 41-year-old man was undergoing treatment for acute myelogenous leukemia. He was admitted to hospital for Manuscript received February 13, 1991; accepted April 29, 1991. From the Departments of Pathology and Medicine, Mount Sinai Hospital, and University of Toronto, Toronto, Canada. Address for reprint requests: D. B. Fernandes, Department of Pathology, Mount Sinai Hospital, 600 University Avenue, Toronto, Canada M5G IX5.
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his fourth course of chemotherapy, consisting of cytosine arabinoside and mitoxantrone hydrochloride. Ten days after starting chemotherapy, the patient developed parotitis and became febrile. He was treated with antibiotics (cefazolin sodium and tobramycin). Four days later the site of his in-dwelling intravenous catheter became tender and inflamed, and a blood culture was positive for gramnegative bacilli and gram-positive cocci. The intravenous catheter was removed, and culture of the catheter tip revealed a heavy growth of Staphylococcus aureus, coagulase-negative Staphylococci and Pseudomonas maltophilia. The patient's parotitis resolved after three days, but he remained febrile. Two days later he developed diarrhea and crampy, right lower quadrant abdominal pain with rebound tenderness and guarding. His hemoglobin was 76 g/liter, white blood cell count 0.2 • 109/liter and platelets 18 • 109/liter. Blood cultures were positive for E. coli. Radiological examination of the abdomen failed to show free peritoneal air or ileus. Ultrasound examination of the abdomen showed mild hepatosplenomegaly but no evidence of abscess formation. The abdominal pain worsened, and a laparotomy was performed. At surgery, there was a considerable amount of strawcoloured peritoneal fluid. The ileocecal region was thickened, but there was no obvious mass or perforation. A segmental resection of the terminal ileum and cecum was performed, with creation of an end ileostomy and mucus fistula. Culture of a swab of the peritoneal cavity was positive for E. coli. Postoperatively he remained febrile while on multiple antibiotics (ciprofloxacin, vancomycin, tobramycin, ceftazidime, and metronidazole), and developed an oral herpes virus infection. He also had numerous petechiae and remained pancytopenic. Four weeks after his operation, he began to have generalized seizures, and an intracranial bleed was suspected. He followed a progressively downward course and died one week later. Permission for postmortem examination was not obtained. Gross Pathology. The resected specimen consisted of a segment of terminal ileum with attached cecum and vermiform appendix. Some fibrinous exudate was present on the serosal surface. The ileocecal valve was edemaDigestive Diseases and Sciences, Vol. 37, No. 8 (August 1992)
0163-2116/92/0800-1292506.50/0 9 1992PlenumPublishingCorporation
ACUTE TYPHLITIS
Fig 1. Photomicrograph of ileocecal region. Note flattening of mucosa and marked edema of submucosa associated with congestion and vascular dilation (hematoxylin and eosin; •
tous and greatly thickened, measuring up to 2 cm in thickness. The apex of the ileocecal valve had an area of yellow discoloration of the mucosa surrounded by a hemorrhagic zone. The appendix was grossly unremarkable. Numerous enlarged mesenteric lymph nodes were identified. Microscopic Pathology. Microscopic examination revdaled flattening of the mucosa of the ileocecal valve with a localized area of necrosis involving the mucosa and adjacent submucosa. The surrounding cecum and terminal ileum demonstrated marked transmural edema with virtually no inflammatory cells or leukemic infiltrate (Figure 1). There were clusters of macrophages with abundant granular basophilic cytoplasm throughout the submucosa (Figure 2). These cells were also seen in small groups and as single cells in the muscularis propria and serosa. Gram stains revealed that these macrophages were stuffed with gram-negative rods. There were also gram-negative rods lying free within the tissue and concentrated around blood vessels in some areas. The appendix showed fibrous obliteration of the lumen. The proximal and distal resection margins of the specimen contained viable tissue. The regional lymph nodes demonstrated extensive edema and congestion with localized
Fig 3. Electron micrograph showing dumps of intact bacilli
within the cytoplasm of macrophages (hematoxylin and eosin; • 5625). areas of necrosis. There were scattered granular macrophages containing gram-negative rods within the lymph nodes and surrounding tissue. Gram-negative rods were also found lying free in the interstitial tissue. No Michaelis-Guttman bodies were identified by hematoxylin-eosin, Von Kossa or Perl's Prussian blue stains. Stains for fungus and acid-fast bacilli were also negative. Ultrastructural Pathology. Electron microscopy was performed on formalin-fixed tissue from the ileocecal valve. Ultrastructural examination of the macrophages showed cells of variable size and shape which contained abundant cytoplasm and small round to oval nuclei with one to two nucleoli. The chromatin was distributed in clumps along the nuclear membrane. The cytoplasm contained abundant, slightly dilated rough endoplasmic reticulum, mitochondria, polyribosomes, and small fat droplets. Numerous bacilliform bacteria morphologically consistent with E. coli were seen primarily in the cytoplasm of the macrophages and only occasionally within phagolysosomes (Figure 3). Although some degenerating forms were present, the bacteria were largely intact, their electron-dense chromatin enclosed by well-preserved membrane. No calcifications or Michaelis-Guttman bodies were identified. DISCUSSION
Fig 2. Photomicrograph of submucosa showing clumps of macrophages with distended granular cytoplasm (hematoxylin and eosin; x390). Digestive Diseases and Sciences, Vol. 37, No. 8 (August 1992)
Typhlitis, or inflammation o f the c e c u m (Greek: typhlon), also has b e e n t e r m e d leukopenic enteropathy (4) or ileocecal s y n d r o m e (5). It usually arises in patients i m m u n o c o m p r o m i s e d s e c o n d a r y to steroid or c h e m o t h e r a p y for malignancy. In the majority of cases the patients h a v e acute leukemia, although cases h a v e b e e n r e p o r t e d with aplastic anemia (6). Initially described in pediatric populations (4, 5, 7) there has b e e n a growing n u m b e r of
1293
HIRUKI ET AL descriptions of typhlitis in adults (8-11). Reported incidence of this infectious complication ranges from 10% to 12% of leukemic patients at postmortem examination (3, 7). Antemortem diagnosis is less frequent, possibly because of the often subtle presentation, the severity of the underlying disease (6), or the mimicry of chemotherapeutic side effects (11) or other causes of acute abdominal pain. The signs and symptoms of typhlitis are not unlike acute appendicitis and include fever, nausea and vomiting, and abdominal pain and tenderness localized to the right lower quadrant (5, 8). The cecum is sometimes palpable as a boggy mass (8). A case of typhlitis in which multiple enteric organisms were cultured from the blood on several occasions has been described (12), and it was suggested that recurrent bacteremia may be a sign of typhlitis. Radiological studies are sometimes helpful in the diagnosis of typhlitis. A right-sided soft tissue density or a pattern of ileus with complete or partial bowel obstruction may be seen on a plain abdominal roentgenogram (6-8) while a barium enema may show a spastic cecum with nodular mucosa (12). The latter examination may risk perforation when cecal necrosis is present. A wide range of pathological findings has been encountered in typhlitis, from simple cecal edema and thickening to punctate then confluent mucosal ulcerations to a frankly necrotic and perforated cecum (6, 8, 11, 13). Mucosal ulcerations commence abruptly at the ileocecal valve and may be covered by greyish green or mustard-colored exudate (4). The intact mucosa may have a shiny appearance and be covered by sanguineous exudate. The appendix is normal in most cases (7). Histologically, transmural edema and necrosis may be present (6). Inflammatory cells are sparse, in keeping with the patients' granulocytopenia (8). Intramural hemorrhage and evidence of intramural infection with gram-negative bacteria or fungi may be seen (6). Usually leukemic infiltration is absent. Blood vessels may be dilated and engorged but are patent (6, 7, 12). The etiology of typhlitis is uncertain, but likely multifactorial. Speculative primary events include leukemic infiltration, intramural hemorrhage, and massive bacterial invasion, with granulocytopenia and cytotoxic treatment playing permissive roles (9). No specific organisms are known to cause typhlitis. Microbes isolated or identified in surgical specimens or cultures have included gram-positive rods (8), gram-positive cocci (8, 9), gram-negative
1294
bacilli and enterococci (13), E. Coli (4), Klebsiella (4, 6), Pseudomonas (4, 7, 8), mixed organisms (9), and Candida (6, 13). Most of these are members of the normal enteric flora and likely invade the cecum in an opportunistic fashion. It has been suggested that antineoplastic drugs cause rapid disappearance of gastrointestinal leukemic infiltrates, with resulting weakening or damage of the architectural matrix or vascular supply of the intestinal wall, leading to inflammation, hemorrhage, and perforation (5). Some authors have suggested that steroids and chemotherapeutic agents may play a primary role in typhlitis, causing breakdown of mucosal resistance by inhibiting granulocyte function and normal repair processes (10, 14). It has been shown that cytosine arabinoside treatment results in a loss of mucus production and surface denudation of the colonic mucosa, possibly secondary to cellular necrosis, maturation arrest, and delayed cellular regeneration (13). Why the necrotizing process in typhlitis should preferentially involve the cecum is unknown. Unique properties of the cecum, such as decreased vascular perfusion and lymphatic drainage and greater distensibility and wall tension relative to the remainder of the colon, have been mentioned as possible but ultimately unsatisfactory explanations for this predilection (6, 8). The clinical implications of typhlitis are grave. It is frequently a late complication of leukemia, when patients are critically ill, near moribund, and severely debilitated (7). While medical therapy has been effective in rare cases (6, 15), the usual course is rapid progression to cecal perforation, with peritonitis and sepsis as terminal events (9). Predictive features have yet to be identified that will allow identification of patients at risk for cecal necrosis (16). Opinion is divided over the merits of surgery in typhlitis. In a report of 11 cases with a review of the surgical literature, it was found that average survival after surgery was 2.3 months (17). It was recommended that surgery be avoided ff possible, individualizing therapy by taking prognosis, treatment goals, and the patient's quality of life into consideration. It also has been suggested that surgery be delayed until the patient develops signs of diffuse peritonitis, indicating an inability to localize the infection (15). However, other studies have indicated that a favorable outcome in typhlitis relies on early recognition and surgical intervention. Several long-term survivors with surgery have been reported (3, 9, 12, 18). It has been suggested that leukopenia Digestive Diseases and Sciences, Vol. 37, No. 8 (August 1992)
ACUTE TYPHLITIS should not be a contraindication to surgery (6) and that indications for surgery should be the same for leukemic as nonleukemic patients (19). The patient that we have described would seem to be fairly typical of this disease entity: one of a growing number of immunocompromised adults developing typhlitis and sepsis, surviving less than two months after surgery. However, the case is unusual in the demonstration of bacteria within macrophage phagolysosomes. While mucosal invasion by bacteria has been described in published cases of typhlitis, no mention is made of the presence of macrophages containing bacteria (8, 9, 12, 15), and none of these reports includes an ultrastructural study of the affected tissue. Engorged with still-intact bacteria, the macrophages resembled those seen in the early stages of malakoplakia. Malakoplakia is a morphologically distinctive entity characterized by mucosal plaques composed of histiocytes with granular eosinophilic cytoplasm (von Hansemann cells). It is usually found in the urinary bladder; however, numerous other sites have been described (20-26). Malakoplakia of the cecum is usually associated with generalized colonic or small intestinal lesions (20), or as an extension of, or in association with, lesions in other sites such as the retroperitoneum or urinary bladder (21). Malakoplakia usually occurs in debilitated patients and is considered to be an abnormal response to a bacterial infection, usually E. coli, secondary to defective monocyte bacteriocidal activity. In the early stages, bacteria in various stages of morphological integrity are seen in macrophage phagolysosomes (27). The phagolysosomes progressively enlarge and become coalescent, then degenerate and accumulate calcium crystals, leading to the development of characteristic concentrically laminated end-stage Michaelis-Guttman bodies. Clinically malakoplakia is usually a low-grade inflammatory disease, responding to antibiotics. However, it may pursue an aggressive course and even cause death in debilitated and immunologically compromised individuals (23). In the patient we have described, septicemia was associated with acute typhlitis and malakoplakia in the cecum. The morphological demonstration of gram-negative bacteria in the ileocecal tissue is strong evidence that this was the site of entry of bacteria, leading to the E. coli septicemia. The presence of early malakoplakic changes suggests that defective macrophage function may have been present in addition to the neutropenia, contributing Digestive Diseases and Sciences, Vol. 37, No. 8 (August 1992)
to the immunocompromised state. It would be of interest to study macrophage bacteriocidal activity in leukemic patients who are neutropenic as a result of chemotherapy. It is possible that the presence of neutropenia and defective monocyte function renders these patients at increased risk of developing septicemia from gastrointestinal lesions. SUMMARY
A case of acute typhlitis arising in a neutropenic male is described. Light and electron microscopy reveal findings resembling those of an early stage of malakoplakia. The coexistence of these two uncommon lesions suggests a pathogenetic role in the development of septicemia in immunocompromised hosts. REFERENCES 1. Abrams GD: Pathogenesis of gastrointestinal infections. Am J Surg Pathol 12(suppl 1):76-81, 1988 2. Keren DF: Intestinal mucosal defence mechanism. Am J Surg Pathol 12(suppl 1):100-105, 1988 3. Bodey GP, Guerrant R: Infections of the gastrointestinal tract in the immunocompromised patient. Annu Rev Med 37:271-281, 1986 4. Moir DH, Ball PM: Necropsy findings in childhood leukemia emphasizing neutropenic enterocolitis and cerebral calcification. Pathology 18:247-258, 1976 5. Sherman NJ, Wooley MM: The ileocecal syndrome in childhood leukemia. Arch Surg 107:39-42, 1973 6. Dworkin B, Winawer SJ, Lightdale CJ: Typhlitis: Report of a case with long-term survival and a review of the recent literature. Dig Dis Sci 26:1032-1037, 1981 7. Wagner ML, Rosenberg HS, Fernbach DJ, Singleton EB: Typhlitis: A complication of leukemia in childhood. Am J Roentgenol 109:341-350, 1970 8. Ikard RW: Neutropenic typhlitis in adults. Arch Surg 116:943-945, 1981 9. Varki AP, Armitage JO, Feagler JR: Typhlitis in acute leukemia: Successful treatment by early surgical intervention. Cancer 43:695-697, 1979 10. Kingry RL, Hobson RW, Muir RW: Cecal necrosis and perforation with systemic chemotherapy. Am Surg 39:129133, 1973 11. Kies MS, Luedke DW, Boyd JF, McCue, MJ: Neutropenic entercolitis. Cancer 43:730-734, 1979 12. Porkorney B, Jones J, Shaikh B, Aber R: Typhlitis: A treatable cause of recurrent septicemia. JAMA 243:682-683, 1980 13. Slavin RE, Dias MA, Saral R: Cytosine arabinoside induced gastrointestinal toxic alterations in sequential chemotherapeutic protocols. Cancer 42:1747, 1978 14. Matolo N, Garfinkle S, Wolman E: Intestinal necrosis with perforation in patients receiving immunosuppressive drugs. Am J Surg 132:753-754, 1976 15. Shaked A, Shiner E, Freund H: Neutropenic colitis: A plea for conservatism. Dis Colon Rectum 26:351-352, 1983
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H I R U K I ET AL 16. Skibber JM, Matter GJ, Pizzo PA, Lotze MT: Right lower quandrant pain in young patients with leukemia: A surgical perspective. Ann Surg 206(6):711-716, 1987 17. Sherman N, Williams K, Wooley M: Surgical complications in patients with leukemia. J Pediatr Surg 8:235-244, 1973 18. Exelby PR, Ghandchi A, Lansigon N, Schwartz I: Management of the acute abdomen in children with leukemia. Cancer 35:826-829, 1975 19. Seligman BR, Risner F, Rety ND: Major surgery in patients with acute leukemia. Am J Surg 129:629-633, 1972 20. Wilkey IS, Rubel LR: Intestinal malakoplakia: Report of a case. Pathology 4:311-314, 1972 21. Teruer JY, Lattes R: Malakoplakia of the colon and retroperitoneium. Am J Clin Patho! 44:20-31, 1965 22. McClure J: Maiakoplakia. J Pathol 140:275-330, 1983
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23. Chaudhry AP, Satchidanand SK, Anthone R, Baumler, RA, Gaeta, JF: An unusual case of supraclavicular and colonic malakoplakia: A light and ultrastructural study. J Pathol 131:193-208, 1980 24. Shaba JK, Black, WA: Malacoplakic granuloma of the testis. J Urol 105:687-691, 1971 25. Colby TV: Malakoplakia: Two unusual cases which present diagnostic problems. Am J Surg Pathol 2(4):377-382, 1978 26. Esparza AR, McKay DB, Cronan JJ, Chazan JA: Renal parenchymal malakoplakia. Am J Surg Pathol 13(3):225-236, 1989 27. Lou TY, Teplitz C: Malakoplakia: Pathogenesis and ultrastructural morphogenesis. A problem of altered macrophage (phagolysosomal) response. Hum Pathol 5(2):191-207, 1974
Digestive Diseases and Sciences, Vol. 37, No. 8 (August 1992)
CASE REPORT
Acute Typhlitis in an Immunocompromised Host Report of an Unusual Case and Review of the Literature T. H I R U K I , MD, B. F E R N A N D E S , MD, FRCPC, J. RAMSAY, MD, FRCPC and I. R O T H E R MD, FRCPC KEY WORDS: typhlitis; neutropenia; immunocompromised;malakoplakia.
Increasingly aggressive c h e m o t h e r a p y regimens, advances in transplantation technology, and the acquired immunodeficiency s y n d r o m e have resulted in a growing number o f immunocompromised patients. Infections are a major cause o f morbidity and mortality in this population. The gastrointestinal tract serves as an important site of host environment interaction and is a reservoir of vast numbers of potentially pathogenic microbial species (1). In normal individuals, mucosal integrity, gastric acidity, intestinal motility, gut associated lymphoid tissue, humoral immunity, and ecologic competition among members of the intraluminal flora serve as defenses to microbial infection and invasion (2). Compromise of these defenses renders the host susceptible to a wide range of infectious complications, and the gastrointestinal tract may be an important portal o f entry for pathogens in immunocompromised hosts (3). We report a case in which a neutropenic patient developed bacterial typhlitis with septicemia. Analysis o f the resected tissue revealed findings consistent with an early stage of malakoplakia. The simultaneous o c c u r r e n c e of these two lesions offers insight into the pathogenesis of septic complications in i m m u n o c o m p r o m i s e d individuals. CASE REPORT
A 41-year-old man was undergoing treatment for acute myelogenous leukemia. He was admitted to hospital for Manuscript received February 13, 1991; accepted April 29, 1991. From the Departments of Pathology and Medicine, Mount Sinai Hospital, and University of Toronto, Toronto, Canada. Address for reprint requests: D. B. Fernandes, Department of Pathology, Mount Sinai Hospital, 600 University Avenue, Toronto, Canada M5G IX5.
1292
his fourth course of chemotherapy, consisting of cytosine arabinoside and mitoxantrone hydrochloride. Ten days after starting chemotherapy, the patient developed parotitis and became febrile. He was treated with antibiotics (cefazolin sodium and tobramycin). Four days later the site of his in-dwelling intravenous catheter became tender and inflamed, and a blood culture was positive for gramnegative bacilli and gram-positive cocci. The intravenous catheter was removed, and culture of the catheter tip revealed a heavy growth of Staphylococcus aureus, coagulase-negative Staphylococci and Pseudomonas maltophilia. The patient's parotitis resolved after three days, but he remained febrile. Two days later he developed diarrhea and crampy, right lower quadrant abdominal pain with rebound tenderness and guarding. His hemoglobin was 76 g/liter, white blood cell count 0.2 • 109/liter and platelets 18 • 109/liter. Blood cultures were positive for E. coli. Radiological examination of the abdomen failed to show free peritoneal air or ileus. Ultrasound examination of the abdomen showed mild hepatosplenomegaly but no evidence of abscess formation. The abdominal pain worsened, and a laparotomy was performed. At surgery, there was a considerable amount of strawcoloured peritoneal fluid. The ileocecal region was thickened, but there was no obvious mass or perforation. A segmental resection of the terminal ileum and cecum was performed, with creation of an end ileostomy and mucus fistula. Culture of a swab of the peritoneal cavity was positive for E. coli. Postoperatively he remained febrile while on multiple antibiotics (ciprofloxacin, vancomycin, tobramycin, ceftazidime, and metronidazole), and developed an oral herpes virus infection. He also had numerous petechiae and remained pancytopenic. Four weeks after his operation, he began to have generalized seizures, and an intracranial bleed was suspected. He followed a progressively downward course and died one week later. Permission for postmortem examination was not obtained. Gross Pathology. The resected specimen consisted of a segment of terminal ileum with attached cecum and vermiform appendix. Some fibrinous exudate was present on the serosal surface. The ileocecal valve was edemaDigestive Diseases and Sciences, Vol. 37, No. 8 (August 1992)
0163-2116/92/0800-1292506.50/0 9 1992PlenumPublishingCorporation
ACUTE TYPHLITIS
Fig 1. Photomicrograph of ileocecal region. Note flattening of mucosa and marked edema of submucosa associated with congestion and vascular dilation (hematoxylin and eosin; •
tous and greatly thickened, measuring up to 2 cm in thickness. The apex of the ileocecal valve had an area of yellow discoloration of the mucosa surrounded by a hemorrhagic zone. The appendix was grossly unremarkable. Numerous enlarged mesenteric lymph nodes were identified. Microscopic Pathology. Microscopic examination revdaled flattening of the mucosa of the ileocecal valve with a localized area of necrosis involving the mucosa and adjacent submucosa. The surrounding cecum and terminal ileum demonstrated marked transmural edema with virtually no inflammatory cells or leukemic infiltrate (Figure 1). There were clusters of macrophages with abundant granular basophilic cytoplasm throughout the submucosa (Figure 2). These cells were also seen in small groups and as single cells in the muscularis propria and serosa. Gram stains revealed that these macrophages were stuffed with gram-negative rods. There were also gram-negative rods lying free within the tissue and concentrated around blood vessels in some areas. The appendix showed fibrous obliteration of the lumen. The proximal and distal resection margins of the specimen contained viable tissue. The regional lymph nodes demonstrated extensive edema and congestion with localized
Fig 3. Electron micrograph showing dumps of intact bacilli
within the cytoplasm of macrophages (hematoxylin and eosin; • 5625). areas of necrosis. There were scattered granular macrophages containing gram-negative rods within the lymph nodes and surrounding tissue. Gram-negative rods were also found lying free in the interstitial tissue. No Michaelis-Guttman bodies were identified by hematoxylin-eosin, Von Kossa or Perl's Prussian blue stains. Stains for fungus and acid-fast bacilli were also negative. Ultrastructural Pathology. Electron microscopy was performed on formalin-fixed tissue from the ileocecal valve. Ultrastructural examination of the macrophages showed cells of variable size and shape which contained abundant cytoplasm and small round to oval nuclei with one to two nucleoli. The chromatin was distributed in clumps along the nuclear membrane. The cytoplasm contained abundant, slightly dilated rough endoplasmic reticulum, mitochondria, polyribosomes, and small fat droplets. Numerous bacilliform bacteria morphologically consistent with E. coli were seen primarily in the cytoplasm of the macrophages and only occasionally within phagolysosomes (Figure 3). Although some degenerating forms were present, the bacteria were largely intact, their electron-dense chromatin enclosed by well-preserved membrane. No calcifications or Michaelis-Guttman bodies were identified. DISCUSSION
Fig 2. Photomicrograph of submucosa showing clumps of macrophages with distended granular cytoplasm (hematoxylin and eosin; x390). Digestive Diseases and Sciences, Vol. 37, No. 8 (August 1992)
Typhlitis, or inflammation o f the c e c u m (Greek: typhlon), also has b e e n t e r m e d leukopenic enteropathy (4) or ileocecal s y n d r o m e (5). It usually arises in patients i m m u n o c o m p r o m i s e d s e c o n d a r y to steroid or c h e m o t h e r a p y for malignancy. In the majority of cases the patients h a v e acute leukemia, although cases h a v e b e e n r e p o r t e d with aplastic anemia (6). Initially described in pediatric populations (4, 5, 7) there has b e e n a growing n u m b e r of
1293
HIRUKI ET AL descriptions of typhlitis in adults (8-11). Reported incidence of this infectious complication ranges from 10% to 12% of leukemic patients at postmortem examination (3, 7). Antemortem diagnosis is less frequent, possibly because of the often subtle presentation, the severity of the underlying disease (6), or the mimicry of chemotherapeutic side effects (11) or other causes of acute abdominal pain. The signs and symptoms of typhlitis are not unlike acute appendicitis and include fever, nausea and vomiting, and abdominal pain and tenderness localized to the right lower quadrant (5, 8). The cecum is sometimes palpable as a boggy mass (8). A case of typhlitis in which multiple enteric organisms were cultured from the blood on several occasions has been described (12), and it was suggested that recurrent bacteremia may be a sign of typhlitis. Radiological studies are sometimes helpful in the diagnosis of typhlitis. A right-sided soft tissue density or a pattern of ileus with complete or partial bowel obstruction may be seen on a plain abdominal roentgenogram (6-8) while a barium enema may show a spastic cecum with nodular mucosa (12). The latter examination may risk perforation when cecal necrosis is present. A wide range of pathological findings has been encountered in typhlitis, from simple cecal edema and thickening to punctate then confluent mucosal ulcerations to a frankly necrotic and perforated cecum (6, 8, 11, 13). Mucosal ulcerations commence abruptly at the ileocecal valve and may be covered by greyish green or mustard-colored exudate (4). The intact mucosa may have a shiny appearance and be covered by sanguineous exudate. The appendix is normal in most cases (7). Histologically, transmural edema and necrosis may be present (6). Inflammatory cells are sparse, in keeping with the patients' granulocytopenia (8). Intramural hemorrhage and evidence of intramural infection with gram-negative bacteria or fungi may be seen (6). Usually leukemic infiltration is absent. Blood vessels may be dilated and engorged but are patent (6, 7, 12). The etiology of typhlitis is uncertain, but likely multifactorial. Speculative primary events include leukemic infiltration, intramural hemorrhage, and massive bacterial invasion, with granulocytopenia and cytotoxic treatment playing permissive roles (9). No specific organisms are known to cause typhlitis. Microbes isolated or identified in surgical specimens or cultures have included gram-positive rods (8), gram-positive cocci (8, 9), gram-negative
1294
bacilli and enterococci (13), E. Coli (4), Klebsiella (4, 6), Pseudomonas (4, 7, 8), mixed organisms (9), and Candida (6, 13). Most of these are members of the normal enteric flora and likely invade the cecum in an opportunistic fashion. It has been suggested that antineoplastic drugs cause rapid disappearance of gastrointestinal leukemic infiltrates, with resulting weakening or damage of the architectural matrix or vascular supply of the intestinal wall, leading to inflammation, hemorrhage, and perforation (5). Some authors have suggested that steroids and chemotherapeutic agents may play a primary role in typhlitis, causing breakdown of mucosal resistance by inhibiting granulocyte function and normal repair processes (10, 14). It has been shown that cytosine arabinoside treatment results in a loss of mucus production and surface denudation of the colonic mucosa, possibly secondary to cellular necrosis, maturation arrest, and delayed cellular regeneration (13). Why the necrotizing process in typhlitis should preferentially involve the cecum is unknown. Unique properties of the cecum, such as decreased vascular perfusion and lymphatic drainage and greater distensibility and wall tension relative to the remainder of the colon, have been mentioned as possible but ultimately unsatisfactory explanations for this predilection (6, 8). The clinical implications of typhlitis are grave. It is frequently a late complication of leukemia, when patients are critically ill, near moribund, and severely debilitated (7). While medical therapy has been effective in rare cases (6, 15), the usual course is rapid progression to cecal perforation, with peritonitis and sepsis as terminal events (9). Predictive features have yet to be identified that will allow identification of patients at risk for cecal necrosis (16). Opinion is divided over the merits of surgery in typhlitis. In a report of 11 cases with a review of the surgical literature, it was found that average survival after surgery was 2.3 months (17). It was recommended that surgery be avoided ff possible, individualizing therapy by taking prognosis, treatment goals, and the patient's quality of life into consideration. It also has been suggested that surgery be delayed until the patient develops signs of diffuse peritonitis, indicating an inability to localize the infection (15). However, other studies have indicated that a favorable outcome in typhlitis relies on early recognition and surgical intervention. Several long-term survivors with surgery have been reported (3, 9, 12, 18). It has been suggested that leukopenia Digestive Diseases and Sciences, Vol. 37, No. 8 (August 1992)
ACUTE TYPHLITIS should not be a contraindication to surgery (6) and that indications for surgery should be the same for leukemic as nonleukemic patients (19). The patient that we have described would seem to be fairly typical of this disease entity: one of a growing number of immunocompromised adults developing typhlitis and sepsis, surviving less than two months after surgery. However, the case is unusual in the demonstration of bacteria within macrophage phagolysosomes. While mucosal invasion by bacteria has been described in published cases of typhlitis, no mention is made of the presence of macrophages containing bacteria (8, 9, 12, 15), and none of these reports includes an ultrastructural study of the affected tissue. Engorged with still-intact bacteria, the macrophages resembled those seen in the early stages of malakoplakia. Malakoplakia is a morphologically distinctive entity characterized by mucosal plaques composed of histiocytes with granular eosinophilic cytoplasm (von Hansemann cells). It is usually found in the urinary bladder; however, numerous other sites have been described (20-26). Malakoplakia of the cecum is usually associated with generalized colonic or small intestinal lesions (20), or as an extension of, or in association with, lesions in other sites such as the retroperitoneum or urinary bladder (21). Malakoplakia usually occurs in debilitated patients and is considered to be an abnormal response to a bacterial infection, usually E. coli, secondary to defective monocyte bacteriocidal activity. In the early stages, bacteria in various stages of morphological integrity are seen in macrophage phagolysosomes (27). The phagolysosomes progressively enlarge and become coalescent, then degenerate and accumulate calcium crystals, leading to the development of characteristic concentrically laminated end-stage Michaelis-Guttman bodies. Clinically malakoplakia is usually a low-grade inflammatory disease, responding to antibiotics. However, it may pursue an aggressive course and even cause death in debilitated and immunologically compromised individuals (23). In the patient we have described, septicemia was associated with acute typhlitis and malakoplakia in the cecum. The morphological demonstration of gram-negative bacteria in the ileocecal tissue is strong evidence that this was the site of entry of bacteria, leading to the E. coli septicemia. The presence of early malakoplakic changes suggests that defective macrophage function may have been present in addition to the neutropenia, contributing Digestive Diseases and Sciences, Vol. 37, No. 8 (August 1992)
to the immunocompromised state. It would be of interest to study macrophage bacteriocidal activity in leukemic patients who are neutropenic as a result of chemotherapy. It is possible that the presence of neutropenia and defective monocyte function renders these patients at increased risk of developing septicemia from gastrointestinal lesions. SUMMARY
A case of acute typhlitis arising in a neutropenic male is described. Light and electron microscopy reveal findings resembling those of an early stage of malakoplakia. The coexistence of these two uncommon lesions suggests a pathogenetic role in the development of septicemia in immunocompromised hosts. REFERENCES 1. Abrams GD: Pathogenesis of gastrointestinal infections. Am J Surg Pathol 12(suppl 1):76-81, 1988 2. Keren DF: Intestinal mucosal defence mechanism. Am J Surg Pathol 12(suppl 1):100-105, 1988 3. Bodey GP, Guerrant R: Infections of the gastrointestinal tract in the immunocompromised patient. Annu Rev Med 37:271-281, 1986 4. Moir DH, Ball PM: Necropsy findings in childhood leukemia emphasizing neutropenic enterocolitis and cerebral calcification. Pathology 18:247-258, 1976 5. Sherman NJ, Wooley MM: The ileocecal syndrome in childhood leukemia. Arch Surg 107:39-42, 1973 6. Dworkin B, Winawer SJ, Lightdale CJ: Typhlitis: Report of a case with long-term survival and a review of the recent literature. Dig Dis Sci 26:1032-1037, 1981 7. Wagner ML, Rosenberg HS, Fernbach DJ, Singleton EB: Typhlitis: A complication of leukemia in childhood. Am J Roentgenol 109:341-350, 1970 8. Ikard RW: Neutropenic typhlitis in adults. Arch Surg 116:943-945, 1981 9. Varki AP, Armitage JO, Feagler JR: Typhlitis in acute leukemia: Successful treatment by early surgical intervention. Cancer 43:695-697, 1979 10. Kingry RL, Hobson RW, Muir RW: Cecal necrosis and perforation with systemic chemotherapy. Am Surg 39:129133, 1973 11. Kies MS, Luedke DW, Boyd JF, McCue, MJ: Neutropenic entercolitis. Cancer 43:730-734, 1979 12. Porkorney B, Jones J, Shaikh B, Aber R: Typhlitis: A treatable cause of recurrent septicemia. JAMA 243:682-683, 1980 13. Slavin RE, Dias MA, Saral R: Cytosine arabinoside induced gastrointestinal toxic alterations in sequential chemotherapeutic protocols. Cancer 42:1747, 1978 14. Matolo N, Garfinkle S, Wolman E: Intestinal necrosis with perforation in patients receiving immunosuppressive drugs. Am J Surg 132:753-754, 1976 15. Shaked A, Shiner E, Freund H: Neutropenic colitis: A plea for conservatism. Dis Colon Rectum 26:351-352, 1983
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H I R U K I ET AL 16. Skibber JM, Matter GJ, Pizzo PA, Lotze MT: Right lower quandrant pain in young patients with leukemia: A surgical perspective. Ann Surg 206(6):711-716, 1987 17. Sherman N, Williams K, Wooley M: Surgical complications in patients with leukemia. J Pediatr Surg 8:235-244, 1973 18. Exelby PR, Ghandchi A, Lansigon N, Schwartz I: Management of the acute abdomen in children with leukemia. Cancer 35:826-829, 1975 19. Seligman BR, Risner F, Rety ND: Major surgery in patients with acute leukemia. Am J Surg 129:629-633, 1972 20. Wilkey IS, Rubel LR: Intestinal malakoplakia: Report of a case. Pathology 4:311-314, 1972 21. Teruer JY, Lattes R: Malakoplakia of the colon and retroperitoneium. Am J Clin Patho! 44:20-31, 1965 22. McClure J: Maiakoplakia. J Pathol 140:275-330, 1983
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23. Chaudhry AP, Satchidanand SK, Anthone R, Baumler, RA, Gaeta, JF: An unusual case of supraclavicular and colonic malakoplakia: A light and ultrastructural study. J Pathol 131:193-208, 1980 24. Shaba JK, Black, WA: Malacoplakic granuloma of the testis. J Urol 105:687-691, 1971 25. Colby TV: Malakoplakia: Two unusual cases which present diagnostic problems. Am J Surg Pathol 2(4):377-382, 1978 26. Esparza AR, McKay DB, Cronan JJ, Chazan JA: Renal parenchymal malakoplakia. Am J Surg Pathol 13(3):225-236, 1989 27. Lou TY, Teplitz C: Malakoplakia: Pathogenesis and ultrastructural morphogenesis. A problem of altered macrophage (phagolysosomal) response. Hum Pathol 5(2):191-207, 1974
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