559641
research-article2014
IJSXXX10.1177/1066896914559641International Journal of Surgical PathologyByrns and Canterbury
Case Report
Concomitant Pseudomembranous Colitis in Colonic Resection for Acute Diverticulitis
International Journal of Surgical Pathology 2015, Vol. 23(4) 325–328 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896914559641 ijs.sagepub.com
Simon Byrns, MD1 and Laura A. Canterbury, MD1
Abstract Diverticulitis and Clostridium difficile infection (CDI) are common conditions in the surgical population. However, they are usually 2 distinct clinical entities. Here, we report the case of acute diverticulitis with concomitant pseudomembranous colitis, presumably due to CDI. The clinical course as well as gross and microscopic pathology findings are discussed. A literature search revealed a single previous report of these findings concomitant in a surgical specimen. A brief discussion of the pathophysiology of CDI and acute diverticulitis is included. Keywords acute diverticulitis, pseudomembranous colitis, Clostridium difficile, colon resection, infectious colitis
Introduction The incidence of diverticular disease is increasing and is now the third most common cause of hospitalization due to gastrointestinal disease in the United States.1 While milder, uncomplicated cases can be treated conservatively with bowel rest and antibiotics, complicated diverticulitis requires hospital admission and more invasive procedures such as percutaneous draining or surgical resection. Unfortunately, the antimicrobial therapy prescribed for diverticulitis can result in a disturbance in normal enteric flora, and occasionally, Clostridium difficile infection (CDI). CDI occurs in up to 20% of patients receiving antibiotic therapy.2 Most CDI infections are mild but can progress to more severe infections resulting in systemic toxicity and shock. While both acute diverticulitis and CDI are common, there is a paucity of literature describing their simultaneous occurrence.
Case Report A 62-year-old gentleman was admitted to the acute surgical service for nausea, anorexia, worsening abdominal pain, and diarrhea following discharge 9 days prior for an episode of diverticulitis. He reported a 1-day history of fever and sharp left lower quadrant pain with frequent loose bowel movements and a new symptom of pneumaturia. His previous medical history was significant for hypertension, a 60-pack-year history of smoking and diverticulosis with 2 previous episodes of diverticulitis, one of which required percutaneous abscess drainage. At presentation he was afebrile and his vital signs were stable and in the normal range.
He had been unsuccessfully treated as an outpatient with oral antibiotics, including courses of metronidazole and trimethoprim-sulfamethoxizole. At admission, broad-spectrum antibiotics were initiated (Tazocin) and a computed tomography scan was requested which showed acute sigmoid diverticulitis as well as a complex colovesicular-ileal fistula, diffuse mucosal thickening of the right colon and cecum and a 3-cm abscess cavity above the dome of the bladder. Empiric antibiotic therapy was broadened on postadmission day 1 to include vancomycin; this was based on culture results obtained from aspirating the abscess cavity 2 weeks prior, which showed multiple Enterococcus species. No other pathogenic isolates were recovered. Despite maximum medical therapy, the patient failed to improve substantially and surgical intervention was offered. On postadmission day 4, the patient was taken to the operating room where he underwent an exploratory laparotomy, rectosigmoid resection, resection of colovesicular fistula, evacuation of pericolic abscess, and appendectomy prior to a colorectal anastomosis and creation of a diverting loop ileostomy. The patient tolerated the procedure well. His ostomy began functioning on postoperative day 2, and he was advanced to a regular diet on postoperative day 5. His 1
University of Alberta, Edmonton, Alberta, Canada
Corresponding Author: Laura A. Canterbury, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, 5B4.21 Walter Mackenzie Health Sciences Centre, 8440-112 Street, Edmonton, Alberta T6G 2B7, Canada. Email: [email protected]
326
Figure 1. Gross photograph of multiple areas of tan to yellow superficially adherent material to the mucosa, representing multiple pseudomembranes involving the rectosigmoid mucosa. As shown here, this typical gross appearance is virtually pathognomonic for pseudomembranous colitis.
discharge was delayed secondary to high output ostomy, which was controlled with intermittent loperamide. Discharge home occurred on postoperative day 6. While pseudomembranous colitis was definitively observed in the pathological specimen both grossly and histologically, testing for C difficile toxin was not performed, so this remained a presumptive diagnosis. As the patient was diverted proximally and was systemically well, no additional treatment for CDI was initiated. Relevant pertinent negatives included normal renal function throughout the clinical course, no neutropenia and no known exposure to heavy metals or chemotherapeutic agents. The surgical specimen included a 30-cm length of sigmoid and rectum. In the distal sigmoid gross examination revealed evidence of hemorrhagic perforation and fistula. Multiple diverticula were observed. There was no evidence of lumen obstruction. Numerous tan adherent pseudomembranes were noted throughout the mucosa (Figure 1). Pertinent negatives included no histologic features of ischemic colitis, no amebae organisms, no viral inclusions, and no increased intraepithelial lymphocytic inflammation or basement membrane thickening diagnostic of microscopic colitis seen. No cytologic atypia suggestive of chemotherapy effect or hyperplastic mucosal changes commonly seen in the context of mucosal prolapse were found. Microscopic examination revealed multiple diverticula with areas of acute diverticulitis and perforation with contained abscess formation in the rectosigmoid adipose tissue. (Figure 2) Pseudomembrane formation was also confirmed microscopically in multiple areas. (Figure 3)
International Journal of Surgical Pathology 23(4)
Figure 2. The area of abscess within the pericolorectal soft tissue is confirmed microscopically, showing multiple back-to-back neutrophils surrounded by chronic inflammatory cells (100×).
Figure 3. Areas of pseudomembrane formation are microscopically classical in appearance with necropurulent material composing the pseudomembrane adherent to the superficial aspect of the mucosa (50×). Pseudomembranes are often described as “exploding crypts” or “eruptive” acute inflammatory exudate resembling a volcano.3 Because the adherent exudate appears to erupt from the superficially eroded surface, the histologic appearance is said to resemble lava from a volcano in shape, as seen in this photomicrograph. Note that the underlying mucosa shows no evidence of mucosal necrosis, atrophic crypts, or hyalinized lamina propria, which are relatively specific findings for ischemic colitis that may also be associated with pseudomembrane formation. The lack of other mucosal abnormality strongly favors pseudomembranous colitis due to Clostridium difficile infection in this case.
Discussion Pseudomembranes may be caused by multiple etiologies. The most common cause is antibiotic associated colitis
327
Byrns and Canterbury due to CDI, and is discussed below. However, the second most common etiology is ischemia.3 In cases due to ischemia, the damage tends to be segmental reflecting the arterial blood flow. Microscopic examination can often confirm concurrent ischemic colitis type changes that generally have atrophic or “withered” crypts and areas of hyalinization of the lamina propria. Other possible causes of pseudomembranous colitis that have been reported are comparatively rare. These causes include, but are not limited to, hemolytic uremic syndrome, heavy metal toxicity, chemotherapy-induced intestinal damage, neutropenic enterocolitis, Shigellosis, colitis complicating obstruction, amebiasis, mucosal prolapse, and rarely microscopic colitis.4 Clostridium difficile infection should be considered whenever antiobiotics are prescribed, even a single prophylactic dose preoperatively has been implicated.5 The most common antibiotics associated with CDI are fluroroquinolones but other antibiotics, including those that are used as therapy for CDI have been implicated as well. Unfortunately, the incidence of CDI has increased 2- to 4-fold over the past 2 decades, especially in the elderly population.6 Risk factors include age >65 years, recent hospitalization, increased length of hospital stay, residence in long-term care, antibiotic or proton-pump inhibitor exposure, and immunosuppression. C difficile is an anaerobic gram-positive, spore forming bacillus. In the colon, the spores convert to a vegetative toxin producing form that release exotoxins that result in colitis and diarrhea. The exotoxin-mediated mucosal cell death results in the typical findings of pseudomembranes on endoscopy and microscopy. When suspected, a stool sample can be submitted to the laboratory for diagnosis via polymerase chain reaction (PCR) assay, which detects genes encoding toxin specific to C difficile. The reported sensitivity of PCR testing is greater than 90% with specificities approaching 100%.7 Because of relatively high sensitivity and specificity, the PCR assay is now considered by many to be a superior alternative to enzyme immunoassay for toxins A and B or enzyme immunoassay for glutamate dehydrogenase detection in conjunction with cell culture cytotoxicity neutralization assays, which lack comparable sensitivity.8 However, if PCR testing is not available, these alternative test methodologies are also helpful in the clinical setting of suspected CDI. While the pathophysiology of diverticulitis is not completely understood, several risk factors have been identified, including low dietary fiber intake, obesity, and lack of physical activity.2 Diverticulitis results from the acute inflammation of a diverticulum, which can subsequently perforate and result in a spectrum of complicated disease. However, the factors that lead to microscopic or gross
perforation are not well understood. The presence of abscess, fistula, perforation, stricture or obstruction describes complicated disease for which surgical therapy can be considered.2 In the absence of these, patients are typically managed with bowel rest and antibiotic therapy. While a sigmoid colectomy with end colostomy (Hartmann procedure) was the procedure of choice previously, primary anastomosis with or without diverting ileostomy has been shown to have decreased long term morbidity and is now favored.9 We performed a MEDLINE search using a search strategy of Diverticulitis AND (Entercolitis, Pseudomem branous OR Clostridium difficile), which returned 22 abstracts, none of which described synchronous pseudomembranous colitis and diverticulitis. A search on Google Scholar returned a case report on CDI-associated pseudomembranous colitis in a patient with perforated diverticulitis following antibiotic and steroid treatment for an exacerbation of chronic obstructive pulmonary disease.10 In the context of recent antibiotic use and lack of microscopic diagnostic ischemic changes, the most likely cause of this patient’s pseudomembranous colitis is CDI. Correlation with clinical findings and relevant clinical laboratory testing essentially excluded other possibilities in this patient. This case reemphasizes the need for appropriate antibiotic stewardship and need to remain cognizant of the risk of CDI in patients prescribed broad-spectrum antibiotics. Acknowledgments The authors would like to acknowledge the efforts of Mr. Tom Turner for help with preparing the figures in this report.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Peery AF, Dellon ES, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology. 2012;143:1179-1187. 2. Fagenholz P, de Moya M. Acute inflammatory surgical disease. Surg Clin North Am. 2014;94:1-30. 3. Dignan C, Greenson J. Can ischemic colitis be differentiated from C difficile colitis in biopsy specimens? Am J Surg Pathol. 1997;21:706-710.
328 4. Yuan S, Reyes V, Bronner M. Pseudomembranous collagenous colitis. Am J Surg Pathol. 2003;27:1375-1379. 5. Carignan A, Allard C, Pepin J, Cossette B, Nault V, Valiquette L. Risk of Clostridium difficile infection after perioperative antibacterial prophylaxis before and during an outbreak of infection due to a hypervirulent strain. Clin Infect Dis. 2008;46:1838-1843. 6. Ricciardi R, Rothenberger D, Madoff R, Baxter N. Increasing prevalence and severity of Clostridium difficile colitis in hospitalized patients in the United States. Arch Surg. 2007;142:624-631. 7. Khanna S, Pardi D, Rosenblatt J, Patel R, Kammer P, Baddour L. An evaluation of repeat stool testing for
International Journal of Surgical Pathology 23(4) Clostridium difficile infection by polymerase chain reaction. J Clin Gastroenterol. 2012;46:846-849. 8. Carroll K. Tests for the diagnosis of Clostridium difficile infection: the next generation. Anaerobe. 2011;17:170-174. 9. Oberkofler C, Rickenbacher A, Raptis D. A multicenter randomized clinical trial of primary anastomosis or Hartmann’s procedure for perforated left colonic diverticulitis with purulent or fecal peritonitis. Ann Surg. 2012;256:819-826. 10. Froberg M, Palavecino E, Dykoski R, Gerding D, Peterson L, Johnson S. Staphylococcus aureus and Clostridium difficile cause distinct pseudomembranous intestinal diseases. Clin Infect Dis. 2004;39:747-750.
Copyright of International Journal of Surgical Pathology is the property of Sage Publications Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
research-article2014
IJSXXX10.1177/1066896914559641International Journal of Surgical PathologyByrns and Canterbury
Case Report
Concomitant Pseudomembranous Colitis in Colonic Resection for Acute Diverticulitis
International Journal of Surgical Pathology 2015, Vol. 23(4) 325–328 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896914559641 ijs.sagepub.com
Simon Byrns, MD1 and Laura A. Canterbury, MD1
Abstract Diverticulitis and Clostridium difficile infection (CDI) are common conditions in the surgical population. However, they are usually 2 distinct clinical entities. Here, we report the case of acute diverticulitis with concomitant pseudomembranous colitis, presumably due to CDI. The clinical course as well as gross and microscopic pathology findings are discussed. A literature search revealed a single previous report of these findings concomitant in a surgical specimen. A brief discussion of the pathophysiology of CDI and acute diverticulitis is included. Keywords acute diverticulitis, pseudomembranous colitis, Clostridium difficile, colon resection, infectious colitis
Introduction The incidence of diverticular disease is increasing and is now the third most common cause of hospitalization due to gastrointestinal disease in the United States.1 While milder, uncomplicated cases can be treated conservatively with bowel rest and antibiotics, complicated diverticulitis requires hospital admission and more invasive procedures such as percutaneous draining or surgical resection. Unfortunately, the antimicrobial therapy prescribed for diverticulitis can result in a disturbance in normal enteric flora, and occasionally, Clostridium difficile infection (CDI). CDI occurs in up to 20% of patients receiving antibiotic therapy.2 Most CDI infections are mild but can progress to more severe infections resulting in systemic toxicity and shock. While both acute diverticulitis and CDI are common, there is a paucity of literature describing their simultaneous occurrence.
Case Report A 62-year-old gentleman was admitted to the acute surgical service for nausea, anorexia, worsening abdominal pain, and diarrhea following discharge 9 days prior for an episode of diverticulitis. He reported a 1-day history of fever and sharp left lower quadrant pain with frequent loose bowel movements and a new symptom of pneumaturia. His previous medical history was significant for hypertension, a 60-pack-year history of smoking and diverticulosis with 2 previous episodes of diverticulitis, one of which required percutaneous abscess drainage. At presentation he was afebrile and his vital signs were stable and in the normal range.
He had been unsuccessfully treated as an outpatient with oral antibiotics, including courses of metronidazole and trimethoprim-sulfamethoxizole. At admission, broad-spectrum antibiotics were initiated (Tazocin) and a computed tomography scan was requested which showed acute sigmoid diverticulitis as well as a complex colovesicular-ileal fistula, diffuse mucosal thickening of the right colon and cecum and a 3-cm abscess cavity above the dome of the bladder. Empiric antibiotic therapy was broadened on postadmission day 1 to include vancomycin; this was based on culture results obtained from aspirating the abscess cavity 2 weeks prior, which showed multiple Enterococcus species. No other pathogenic isolates were recovered. Despite maximum medical therapy, the patient failed to improve substantially and surgical intervention was offered. On postadmission day 4, the patient was taken to the operating room where he underwent an exploratory laparotomy, rectosigmoid resection, resection of colovesicular fistula, evacuation of pericolic abscess, and appendectomy prior to a colorectal anastomosis and creation of a diverting loop ileostomy. The patient tolerated the procedure well. His ostomy began functioning on postoperative day 2, and he was advanced to a regular diet on postoperative day 5. His 1
University of Alberta, Edmonton, Alberta, Canada
Corresponding Author: Laura A. Canterbury, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, 5B4.21 Walter Mackenzie Health Sciences Centre, 8440-112 Street, Edmonton, Alberta T6G 2B7, Canada. Email: [email protected]
326
Figure 1. Gross photograph of multiple areas of tan to yellow superficially adherent material to the mucosa, representing multiple pseudomembranes involving the rectosigmoid mucosa. As shown here, this typical gross appearance is virtually pathognomonic for pseudomembranous colitis.
discharge was delayed secondary to high output ostomy, which was controlled with intermittent loperamide. Discharge home occurred on postoperative day 6. While pseudomembranous colitis was definitively observed in the pathological specimen both grossly and histologically, testing for C difficile toxin was not performed, so this remained a presumptive diagnosis. As the patient was diverted proximally and was systemically well, no additional treatment for CDI was initiated. Relevant pertinent negatives included normal renal function throughout the clinical course, no neutropenia and no known exposure to heavy metals or chemotherapeutic agents. The surgical specimen included a 30-cm length of sigmoid and rectum. In the distal sigmoid gross examination revealed evidence of hemorrhagic perforation and fistula. Multiple diverticula were observed. There was no evidence of lumen obstruction. Numerous tan adherent pseudomembranes were noted throughout the mucosa (Figure 1). Pertinent negatives included no histologic features of ischemic colitis, no amebae organisms, no viral inclusions, and no increased intraepithelial lymphocytic inflammation or basement membrane thickening diagnostic of microscopic colitis seen. No cytologic atypia suggestive of chemotherapy effect or hyperplastic mucosal changes commonly seen in the context of mucosal prolapse were found. Microscopic examination revealed multiple diverticula with areas of acute diverticulitis and perforation with contained abscess formation in the rectosigmoid adipose tissue. (Figure 2) Pseudomembrane formation was also confirmed microscopically in multiple areas. (Figure 3)
International Journal of Surgical Pathology 23(4)
Figure 2. The area of abscess within the pericolorectal soft tissue is confirmed microscopically, showing multiple back-to-back neutrophils surrounded by chronic inflammatory cells (100×).
Figure 3. Areas of pseudomembrane formation are microscopically classical in appearance with necropurulent material composing the pseudomembrane adherent to the superficial aspect of the mucosa (50×). Pseudomembranes are often described as “exploding crypts” or “eruptive” acute inflammatory exudate resembling a volcano.3 Because the adherent exudate appears to erupt from the superficially eroded surface, the histologic appearance is said to resemble lava from a volcano in shape, as seen in this photomicrograph. Note that the underlying mucosa shows no evidence of mucosal necrosis, atrophic crypts, or hyalinized lamina propria, which are relatively specific findings for ischemic colitis that may also be associated with pseudomembrane formation. The lack of other mucosal abnormality strongly favors pseudomembranous colitis due to Clostridium difficile infection in this case.
Discussion Pseudomembranes may be caused by multiple etiologies. The most common cause is antibiotic associated colitis
327
Byrns and Canterbury due to CDI, and is discussed below. However, the second most common etiology is ischemia.3 In cases due to ischemia, the damage tends to be segmental reflecting the arterial blood flow. Microscopic examination can often confirm concurrent ischemic colitis type changes that generally have atrophic or “withered” crypts and areas of hyalinization of the lamina propria. Other possible causes of pseudomembranous colitis that have been reported are comparatively rare. These causes include, but are not limited to, hemolytic uremic syndrome, heavy metal toxicity, chemotherapy-induced intestinal damage, neutropenic enterocolitis, Shigellosis, colitis complicating obstruction, amebiasis, mucosal prolapse, and rarely microscopic colitis.4 Clostridium difficile infection should be considered whenever antiobiotics are prescribed, even a single prophylactic dose preoperatively has been implicated.5 The most common antibiotics associated with CDI are fluroroquinolones but other antibiotics, including those that are used as therapy for CDI have been implicated as well. Unfortunately, the incidence of CDI has increased 2- to 4-fold over the past 2 decades, especially in the elderly population.6 Risk factors include age >65 years, recent hospitalization, increased length of hospital stay, residence in long-term care, antibiotic or proton-pump inhibitor exposure, and immunosuppression. C difficile is an anaerobic gram-positive, spore forming bacillus. In the colon, the spores convert to a vegetative toxin producing form that release exotoxins that result in colitis and diarrhea. The exotoxin-mediated mucosal cell death results in the typical findings of pseudomembranes on endoscopy and microscopy. When suspected, a stool sample can be submitted to the laboratory for diagnosis via polymerase chain reaction (PCR) assay, which detects genes encoding toxin specific to C difficile. The reported sensitivity of PCR testing is greater than 90% with specificities approaching 100%.7 Because of relatively high sensitivity and specificity, the PCR assay is now considered by many to be a superior alternative to enzyme immunoassay for toxins A and B or enzyme immunoassay for glutamate dehydrogenase detection in conjunction with cell culture cytotoxicity neutralization assays, which lack comparable sensitivity.8 However, if PCR testing is not available, these alternative test methodologies are also helpful in the clinical setting of suspected CDI. While the pathophysiology of diverticulitis is not completely understood, several risk factors have been identified, including low dietary fiber intake, obesity, and lack of physical activity.2 Diverticulitis results from the acute inflammation of a diverticulum, which can subsequently perforate and result in a spectrum of complicated disease. However, the factors that lead to microscopic or gross
perforation are not well understood. The presence of abscess, fistula, perforation, stricture or obstruction describes complicated disease for which surgical therapy can be considered.2 In the absence of these, patients are typically managed with bowel rest and antibiotic therapy. While a sigmoid colectomy with end colostomy (Hartmann procedure) was the procedure of choice previously, primary anastomosis with or without diverting ileostomy has been shown to have decreased long term morbidity and is now favored.9 We performed a MEDLINE search using a search strategy of Diverticulitis AND (Entercolitis, Pseudomem branous OR Clostridium difficile), which returned 22 abstracts, none of which described synchronous pseudomembranous colitis and diverticulitis. A search on Google Scholar returned a case report on CDI-associated pseudomembranous colitis in a patient with perforated diverticulitis following antibiotic and steroid treatment for an exacerbation of chronic obstructive pulmonary disease.10 In the context of recent antibiotic use and lack of microscopic diagnostic ischemic changes, the most likely cause of this patient’s pseudomembranous colitis is CDI. Correlation with clinical findings and relevant clinical laboratory testing essentially excluded other possibilities in this patient. This case reemphasizes the need for appropriate antibiotic stewardship and need to remain cognizant of the risk of CDI in patients prescribed broad-spectrum antibiotics. Acknowledgments The authors would like to acknowledge the efforts of Mr. Tom Turner for help with preparing the figures in this report.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Peery AF, Dellon ES, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology. 2012;143:1179-1187. 2. Fagenholz P, de Moya M. Acute inflammatory surgical disease. Surg Clin North Am. 2014;94:1-30. 3. Dignan C, Greenson J. Can ischemic colitis be differentiated from C difficile colitis in biopsy specimens? Am J Surg Pathol. 1997;21:706-710.
328 4. Yuan S, Reyes V, Bronner M. Pseudomembranous collagenous colitis. Am J Surg Pathol. 2003;27:1375-1379. 5. Carignan A, Allard C, Pepin J, Cossette B, Nault V, Valiquette L. Risk of Clostridium difficile infection after perioperative antibacterial prophylaxis before and during an outbreak of infection due to a hypervirulent strain. Clin Infect Dis. 2008;46:1838-1843. 6. Ricciardi R, Rothenberger D, Madoff R, Baxter N. Increasing prevalence and severity of Clostridium difficile colitis in hospitalized patients in the United States. Arch Surg. 2007;142:624-631. 7. Khanna S, Pardi D, Rosenblatt J, Patel R, Kammer P, Baddour L. An evaluation of repeat stool testing for
International Journal of Surgical Pathology 23(4) Clostridium difficile infection by polymerase chain reaction. J Clin Gastroenterol. 2012;46:846-849. 8. Carroll K. Tests for the diagnosis of Clostridium difficile infection: the next generation. Anaerobe. 2011;17:170-174. 9. Oberkofler C, Rickenbacher A, Raptis D. A multicenter randomized clinical trial of primary anastomosis or Hartmann’s procedure for perforated left colonic diverticulitis with purulent or fecal peritonitis. Ann Surg. 2012;256:819-826. 10. Froberg M, Palavecino E, Dykoski R, Gerding D, Peterson L, Johnson S. Staphylococcus aureus and Clostridium difficile cause distinct pseudomembranous intestinal diseases. Clin Infect Dis. 2004;39:747-750.
Copyright of International Journal of Surgical Pathology is the property of Sage Publications Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
