Small intestine & ampulla

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• Standardized histologic criteria were developed at the pathology workshop of the VIII International Small Bowel Transplant Symposium (Transplant Proc 2004;36:335)
• Acute cellular rejection
  • Grading based on apoptotic bodies per 10 consecutive crypts, amount of lamina propria mixed inflammation (lymphocytes, eosinophils and neutrophils) and amount of epithelial injury (crypt dropout, erosions or ulceration) (see table below)
  • Other features include edema, villous blunting, reactive epithelial changes and vascular congestion
• Antibody mediated rejection
  • Capillaritis, lamina propria inflammation, mucosal erosion / ulceration, fibrin thrombi within lamina propria vasculature and edema (Am J Transplant 2018;18:2250)
• Chronic rejection
  • Nonspecific findings: mild ischemic changes, apoptotic bodies (< 6/10 consecutive crypts) and mild fibrosis of the lamina propria

Grading of acute cellular rejection (adapted from Arch Pathol Lab Med 2012;136:761, Transplant Proc 2004;36:335)

Grade	Apoptotic bodies / 10 consecutive crypts	Crypt dropout	Amount of lamina propria inflammation	Surface epithelial damage	Additional findings
0 (no ACR)	< 2	None	Not increased	None	Unremarkable mucosa
Indeterminate (grade ind)	< 6	None	Focal minimal	None	Focal mild villous blunting
Mild (grade 1)	≥ 6	None	Mild	Focal damage / erosion	Mucin depletion, nuclear enlargement and hyperchromasia
Moderate (grade 2)	≥ 6; possibly confluent	Focal	Moderate to severe	Erosion	Moderate to marked architectural distortion and villous blunting, edema and congestion
Severe (grade 3)	Variable	Extensive	Moderate to severe	Extensive erosion / ulceration	Moderate to marked architectural distortion, granulation tissue formation

Contributed by Jen Rytych, M.D.

A 35 year old patient with a history of small bowel transplantation presents with diarrhea, abdominal pain and weight loss. Out of concern for acute cellular rejection (ACR), endoscopic biopsies of both the transplanted small bowel and segment of native small bowel are obtained. Histologic examination of the transplanted bowel shows the findings displayed in the representative photomicrograph. What additional findings, if present, would be most supportive of the diagnosis of acute cellular rejection of the transplant bowel in this patient?

1. Identification of eosinophilic nuclear inclusions
2. Increased mitotic rate
3. Occasional crypt dropout and apoptotic figures in the native small bowel
4. Occasional crypt dropout and erosion of the surface epithelium in the transplanted small bowel

D. Occasional crypt dropout and erosion of the surface epithelium in the transplanted small bowel. The histological findings described, including ≥ 6 apoptotic bodies per 10 consecutive crypts, when combined with the additional findings of occasional crypt dropout and focal erosion, are indicative of moderate acute cellular rejection (grade 2) in transplanted small bowel. Grade 2 rejection is characterized by ≥ 6 apoptotic bodies per 10 consecutive crypts, moderate to extensive inflammation in the lamina propria, focal crypt dropout and focal erosion of the epithelium. Answer B is incorrect because an increased mitotic rate is not specifically associated with acute cellular rejection. Answer A is incorrect because identification of viral mediated cellular changes, such as Cowdry-like nuclear inclusions, would be more suggestive of infectious etiologies affecting the transplanted bowel. Answer C is incorrect because identification of crypt apoptosis, crypt injury and epithelial injury in the native small bowel may suggest medication induced injury (such as mycophenolate), infection or graft versus host disease.

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Reference: Rejection

Which of the following factors is a known risk factor for the development of chronic rejection in small bowel transplant recipients?

1. Frequent surveillance biopsies
2. History of multiple acute cellular rejection episodes
3. Long term immunosuppressive therapy
4. Short duration of cold ischemia time during transplant surgery
5. Younger age at transplant

B. History of multiple acute cellular rejection episodes. The development of chronic rejection is typically preceded by episodes of acute cellular rejection (ACR). Increased number of episodes of ACR, higher grade of ACR and earlier onset of ACR are all associated with an increased risk of chronic rejection. Answers A and C are incorrect because frequent surveillance biopsies and long term immunosuppressive therapy are necessary for the maintenance and surveillance of the health of the graft and are not associated with the development of chronic rejection. Answer E is incorrect because patients < 18 years old at transplant have an improved 5 year graft survival compared to adults and age at transplant is not associated with chronic rejection. Answer D is incorrect because shorter ischemic times have been associated with improved graft outcomes and ischemic time is not directly related to the development of chronic rejection.

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Reference: Rejection