College of American Pathologists
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2008 — October Case of the Month

Updated December 16, 2008


CAP Foundation October 2008 Online Case of the Month

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A previously healthy 69-year-old woman presented with an acute abdomen ten days after taking an antibiotic for a dental abscess. The specimen consisted of a total colectomy specimen with a portion of terminal ileum. The bowel wall was mildly thickened and the colonic mucosa was diffusely covered by tenacious gray-green exudate.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2005, Case 17 and is a pseudomembranous colitis.

Criteria for Diagnosis and Comments:
The slides demonstrate changes of pseudomembranous colitis. There is superficial necrosis of the mucosal glands with an overlying exudate consisting of mucin, fibrin and neutrophils forming typical pseudomembranes that in areas appear to erupt from the mucosa. Focal cryptitis is seen in some slides. The bowel wall shows edema and mild inflammatory changes.

Pseudomembranous colitis (PMC) is an inflammatory disease most often associated with antibiotic use leading to alteration of the normal gut flora with colonization and overgrowth of toxin producing bacteria. Clostridium difficile, which is ubiquitous in nature and part of the normal flora in up to 5% of healthy adults, is a spore forming gram positive bacillus and is the most common cause of antibiotic-associated diarrhea. Any antibiotic may potentially cause PMC, although it has been more frequently reported with clindamycin, lincomycin, ampicillin and the cephalosporins. Symptoms may occur within days to several weeks after exposure. Other conditions that alter the bowel flora can also predispose the patient to C. difficile-associated disease in the absence of antibiotics, including gastrointestinal surgery, immunocompromised states, and chemotherapy.

Clostridium infection may present clinically as colitis without pseudomembranes, pseudomembranous colitis or a fulminant colitis. Toxic megacolon can be a complicating factor in colitis with a potentially fatal outcome and has a reported incidence of up to 3 % in patients with PMC. Mucosal injury is due to elaboration of bacterial toxins (enterotoxin-A and a cytotoxin-B, so named from their elution patterns by anion exchange resins) that bind to gut epithelial cells and cause cellular damage including necrosis and increased capillary permeability. The rectum and sigmoid are most commonly involved, and the process may also involve the distal small bowel. In some cases (5-19%), the colitis is apparently confined to the proximal colon/cecum and could be potentially missed by flexible sigmoidoscopy. The gross appearance is that of yellowish-white elevated plaques that may be focal or may coalesce into larger lesions with either normal appearing or edematous and erythematous intervening mucosa. The histologic findings showing epithelial necrosis, with volcano-like masses of neutrophils, mucin and fibrin is typical.

The diagnosis of C. difficile associated colitis is based on the typical endoscopic features, history of recent antibiotic use and detection of toxins. Rapid enzyme immunoassays can detect both A and B toxins from stool and are specific (95-100%). Although not as sensitive (65-85%), enzyme immunoassays are more rapid and less laborious to perform than tissue cytotoxic assays. Stool cultures are sensitive but have low predictive value and identify non-toxigenic forms. Latex agglutination assays are rapid but lack adequate sensitivity and specificity. PCR methods for detection of C. difficile toxins have been developed that are both sensitive and specific but are not currently widely available.

Clostridium difficile is shed in feces, and transmission is by fecal-oral route. Therefore, prevention of C. difficile-associated disease is achieved by contact precautions in patients with known/suspected infection and diarrhea as well as judicious use of antibiotics. Treatment is aimed at discontinuation of the offending antibiotic and institution of oral metronidazole or oral vancomycin. In severe cases, surgical intervention may be required. Clostridium difficile can also rarely cause extra-intestinal disease including abscesses, osteomyelitis, and wound infections among others.

Pseudomembrane formation may be seen in other conditions and raises the possibility of a differential diagnosis that includes, but is not limited to, ischemia, neutropenic colitis, amebiasis, hemolytic uremic syndrome (HUS) and other infections, e.g. E. coli O157:H7. Ischemic colitis is probably the most common differential consideration and may show overlapping features with pseudomembranous colitis, as both may produce pseudomembranes. Ischemic lesions tend to show a segmental distribution, especially in areas of poor collateral distribution (splenic flexure, rectosigmoid), and often have a sharp line of demarcation from uninvolved mucosa. Endoscopic identification of diffuse pseudomembranes favors the diagnosis ofC. difficile. In ischemic colitis, typically the inflammatory response is generally less intense. Changes of chronic ischemia may be helpful histologic clues (e.g. crypt distortion, hemosiderin deposition, and lamina propria fibrosis), and the presence of thrombi or vasculitis would tend to favor ischemia. Other conditions with a component of ischemia, e.g. HUS, may also show pseudomembrane formation. HUS usually affects children and shows the triad of microangiopathic hemolytic anemia, thrombocytopenia, and oliguric renal failure.C. difficile toxin assays are negative.

Neutropenic enterocolitis most commonly occurs in the setting of marked granulocytopenia related to intensive chemotherapy. Mucosal injury allows invasion of bacteria and development of septicemia. Ischemic changes result from vascular invasion of bacteria with development of DIC. Pseudomembranes may be seen, but neutropenic enterocolitis lacks the intense neutrophilic infiltrate seen with C. difficile associated PMC.

In idiopathic inflammatory bowel disease, pseudomembranes are not a typical finding but can be seen with superimposed C. difficile infection or with coexisting ischemia. Mucosal changes of chronicity, basal plasmacytosis, and granulomas are not features of C. difficile associated PMC.

Collagenous colitis and lymphocytic colitis present as chronic watery diarrhea, abdominal pain and frequently weight loss. Collagenous colitis (CC) has a female predisposition while lymphocytic colitis appears to affect both sexes equally. Endoscopic exam is typically normal. Microscopically, there is inflammation of the lamina propria associated with either a prominent intraepithelial lymphocytosis (lymphocytic colitis) or subepithelial basement membrane collagen deposition (collagenous colitis). Pseudomembrane formation is not a usual feature of either entity, although it has been described as an uncommon histologic finding in patients with CC. Coexisting infectious or ischemic etiologies should be excluded.

Amebic colitis is due to infection with pathogenic amoebae. Entamoeba histolytica and Balantidium coli may produce similar histologic changes in the colon. B. coli trophozoites are larger, typically ciliated and characteristically show a large bean shaped macronucleus and a smaller round micronucleus. E. histolytica has a single nucleus and often shows erythrophagocytosis. Endoscopically, ulcers and sometimes pseudomembranes are seen. The lesions are characterized by discrete flask shaped ulcers with either adjacent normal mucosa or presence of hemorrhage and edema. Histologic pseudomembranes may overly the ulcers. The diagnosis is usually confirmed by identification of the trophozoites/ova in tissue or in stool specimens. Immunoperoxidase stains can identify E. histolytica organisms, and serologic tests are also available.

Supplementary Questions For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
1. Which entity has the most striking female predisposition? A.  Collagenous colitis
B.  Lymphocytic colitis
C.  Ischemic colitis
D.  Ulcerative colitis
E.  Neutropenic enterocolitis
2. Pseudomembrane formation may be evident in which of the following diseases? A.  Ischemic colitis
B.  Clostridium difficile associated colitis
C.  Amebic colitis
D.  All of the above
3. Stool culture is the most expedient preferred method for confirmation of Clostridium difficile associated colitis. A.  True
B.  False


  1. Lyerly DM, Krivan HC, Wilkins TD. Clostridium difficile: Its diseases and toxins. Clin Micro Reviews 1988;1:1-18.
  2. Yuan S, Reyes V, Bronner MP. Pseudomembranous collagenous colitis.Am J Surg Pathol. 2003;27:1375-1379.
  3. Fenoglio-Preiser CM, et al, Non-neoplastic lesions of the colon. In Gastrointestinal Pathology: an atlas and text. Second edition. Philadelphia, PA: Lippincott Williams & Wilkins; 1999.
  4. Poutanen SM, Simor AE. Clostridium difficile associated diarrhea in adults. CMAJ. 2004;171:51-58.
Kevin Wu, MD
Surgical Pathology Committee
Mayo Clinic, Jacksonville
Jacksonville, FL