A 72-year-old woman presents to the emergency department with copious watery diarrhea for three days. Her abdomen shows diffuse tenderness on palpation. She is febrile (101.5˚F), mildly hypotensive, and clinically appears dehydrated. She notes an episode of sinusitis three weeks ago that was treated with antibiotics. Her previous medical and surgical history is uneventful. She is admitted to the hospital. She fails medical management and requires surgical intervention.

Master List of Diagnoses

  • Ischemic colitis
  • Necrotizing enteritis
  • Pseudomembranous colitis
  • Signet-ring cell carcinoma
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This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2017, Case 31, and is pseudomembranous colitis of the colon.

Criteria for Diagnosis and Comments

Histologic sections show colonic mucosa with a prominent cap of fibrinopurulent exudate. The underlying glands demonstrate acute colitis, with relatively well-preserved architecture. The crypts are dilated with luminal neutrophils and mucin. The lamina propria is markedly edematous with scattered neutrophils. The inflammation extends throughout the bowel wall reaching the serosa. These features are consistent with Clostridium difficile (C. difficile)-associated pseudomembranous colitis (PMC).

PMC was first described in 1893 as diphtheritic colitis in an autopsy case report. This initial label was assigned because of the severe ulceration seen. Forty years later, C. difficile (first termed Bacillus difficile) was described. Antibiotic-associated diarrhea was first studied in the 1950s. However, investigation which would link the 2 entities together did not begin until the 1970s. Work was accomplished in a hamster model that showed an isolatable Clostridium species which had been injected with stool from PMC patients. Currently, C. difficile is the second most commonly implicated anaerobic pathogen in patients with diarrhea (second to Clostridium perfringens [C. perfringens]). C. difficile is in the most common cause of nosocomial diarrhea and continues to receive significant clinical attention because of its resistance to multiple antibiotic agents.

Clostridium spp. are anaerobic, spore-forming, gram negative rods. There are over 100 species in the genus. Clostridia are markedly toxigenic, producing some of the most potent bacterial toxins known. C. difficile has been implicated in multiple disease states of the colon including acute infectious colitis, antibiotic-associated colitis, pseudomembranous colitis, and neutropenic enterocolitis. The disease typically presents with watery diarrhea. Rarely, blood may be seen in the stool. Abdominal pain, fever, and leukocytosis can be seen. These symptoms are most commonly associated with antibiotic administration. Clostridial infection may occur during the course of an antibiotic or it may occur weeks later. Thus, some patients may experience a delay in clinical diagnosis if there is a significant lag period.

Multiple antibiotics have been implicated in causing PMC, including clindamycin, penicillins, cephalosporins, and fluoroquinolones. These antibiotics share the common characteristic of oral administration. As the antibiotic passes through the gut, the usual intestinal flora is eradicated. This lack of microbial barriers allows for C. difficile to opportunistically colonize the gut. Many of the cases of PMC present in patients over the age of 65. It is alleged that a decline in normal flora increases susceptibility to antibiotic eradication and subsequent Clostridium colonization. Also, some suggest that this age group is most likely to use antibiotics or stay in the hospital for protracted periods of time.

C. difficile gleans its pathogenicity from 2 virulence factors. Toxins A and B are enzymes, which have been shown to disrupt the actin cytoskeleton leading to cell death. The toxins also disrupt tight junctions between enterocytes, leading to copious diarrhea. In addition to the direct effects on the intercellular proteins, toxins A and B recruit neutrophils and upregulate cytokines to further exacerbate colonic edema.

Endoscopically, the lesions of PMC are creamy-tan well-demarcated areas. There is typically an abrupt transition between individual lesions and the intervening normal colonic mucosa. The affected areas range from the size of a pinpoint to total involvement of the colon. In cases with patchy involvement, a biopsy from both the affected and unaffected areas may be helpful in making the diagnosis. The affected colonic mucosa often makes a sharp transition at the ileocecal valve, displaying a completely unremarkable ileum. As the lesions resolve, they tend to form small, discrete ulcerated areas.

Histology shows areas of eruptive exudate likened to volcanoes or mushrooms. The superficial mucosa is denuded into the exudate and, along with red blood cells and fibrin, forms the prototypical pseudomembrane. As the cells progressively shed, the pseudomembrane assumes a laminated configuration with lateral streaming. The crypt bases commonly remain intact. However, the crypts become dilated with neutrophils and mucin. Goblet cells may slough and resemble signet-cell carcinoma. The spaces between the crypts show necrosis and edema. Small biopsy specimens may lack the pseudomembrane, but often retain neutrophilic inflammation in the upper glands (sparing the crypts) and show lamina propria edema. The architecture typically remains intact. Long-standing or severe cases may result in the complete loss of mucosal architecture. Biopsies of patchy PMC may show nonspecific acute colitis with or without crypt abscesses and may require further studies to confirm the diagnosis.

Treatment often involves oral administration of vancomycin or metronidazole. If the patient is currently receiving a medication that could be implicated in causing PMC, that agent should also be discontinued. In recalcitrant cases or where standard therapy is not tolerated, donor fecal transplant has proven to be effective in reestablishing normal gut flora to outcompete the opportunistic clostridial bacteria.

Ischemic colitis (IC) is typically the most common entity considered in the differential diagnosis of PMC. Both IC and PMC can result in the formation of pseudomembranes. The pseudomembranes seen in IC are more commonly small and focal. Thus, an endoscopy reporting large pseudomembranes favors the diagnosis of PMC. Atrophic (withering) crypts are also generally seen in IC. Hyalinization and hemorrhage of the lamina propria is commonly reported in IC but is not usually a feature of PMC.

Necrotizing enteritis (NE), secondary to C. perfringens, can show similar findings to PMC and IC. Segmental dusky mucosa with ulceration and necrosis is seen on endoscopy. The mucosa shows necrosis with edema in the retained portions. Marked neutrophilic infiltrate with underlying crypt atrophy is present. The significant inflammation can result in pneumatosis or perforation. The diagnosis of NE may not be clear from histology alone and may require assay investigation.

Signet cell carcinoma (SCC) may also be considered in the differential diagnosis of PMC. A significant portion of PMC cases show signet cell changes. As the cytological features of signet cell carcinoma are often bland, distinguishing these entities on routine histology may be difficult. A panel of immunostains can be used to differentiate the 2 diagnoses. The cells of SCC tend to lose expression of E-cadherin while cells with signet cell change retain expression. SCC often shows positivity for p53 and shows an increased mitotic index with Ki-67 immunostaining. Clear cell changes within PMC are generally negative for p53 and show a low Ki-67 index.

  1. Which of these histologic findings would favor the diagnosis of ischemic colitis in a biopsy specimen?

    1. Dilated basal crypts
    2. Hyalinization of the lamina propria
    3. Lamina propria edema
    4. Prominent clear cell change
    5. Pseudomembrane formation
  2. Which of the following immunostain profiles is most commonly associated with signet cell carcinoma?

    1. E-cadherin (-), p53 (-), Ki-67 (normal)
    2. E-cadherin (-), p53 (+), Ki-67 (increased)
    3. E-cadherin (-), p53 (+), Ki-67 (normal)
    4. E-cadherin (+), p53 (-), Ki-67 (increased)
    5. E-cadherin (+), p53 (+), Ki-67 (increased)
  3. Which of these statements regarding the natural history of pseudomembranous colitis is correct?

    1. Can occur weeks following oral antibiotics
    2. Commonly treated by intravenous vancomycin
    3. Most commonly associated with parenteral antibiotics
    4. Most commonly caused by Clostridium perfringens
    5. Typically observed in patients younger than 50 years

References

  1. Borriello SP. Clostridial disease of the gut. Clin Infect Dis. 1995;20 Suppl 2:S242-50.
  2. Dignan CR, Greenson JK. Can ischemic colitis be differentiated from C difficile colitis in biopsy specimens? Am J Surg Pathol. 1997;21(6):706-710.
  3. Jain D. Enteric infections and associated diseases. In: Riddell R, Jain D, eds. Lewin, Weinstein and Riddell's Gastrointestinal Pathology and Its Clinical Implications. Lippincott Williams & Wilkins; 2014: Chapter 19.
  4. Lamps L. Bacterial Gastrointestinal Infections. In: Procop GW, Pritt B, eds. Pathology of Infectious Diseases. Saunders; 2014: Chapter 16.
  5. Wang K, Weinrach D, Lal A, et al. Signet-ring cell change versus signet-ring cell carcinoma: a comparative analysis. Am J Surg Pathol. 2003;27(11):1429-1433.

Author

J. Clint Stanfill, MD
Surgical Pathology Committee
East Tennessee State University
Johnson City, TN


Answer Key

  1. Hyalinization of the lamina propria (b)
  2. E-cadherin (-), p53 (+), Ki-67 (increased) (b)
  3. Can occur weeks following oral antibiotics (a)