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Surgical Pathology Criteria

Collagenous Colitis


  • Colorectal disease characterized by a thickened subepithelial collagen layer

Alternate/Historical Names

  • Microscopic colitis
    • Used by some to refer to both lymphocytic and collagenous colitis, while to others it refers to only lymphocytic colitis

Diagnostic Criteria

  • Thickened apical subepithelial collagen layer
    • Irregular collagen deposition
    • Ragged, spiculated deep edge
    • Surrounds and entraps capillaries, fibroblasts and inflammatory cells
    • Usually at least 15-20 microns thick
      • Frequently up to 50 microns
      • Normal thickness is 5-7 microns
    • Trichrome stain is useful for demonstration of layer
    • Below normal basement membrane
      • Demonstrable as type I and III collagen while normal basement membrane is type IV
      • Basement membrane remains intact and of normal thickness
  • Localized to apical (luminal) region
    • Does not surround crypts
  • Increased intramucosal chronic inflammatory cells
    • Increased lymphocytes and plasma cells in lamina propria
    • Increased eosinophils and mast cells may be seen in lamina propria
    • Surface mucosa may detach
      • Overt ulceration unusual but may occur
  • Increased intraepithelial lymphocytes
    • Frequently fewer (10-20 / 100 enterocytes) than seen in lymphocytic colitis
      • Normal is 5 / 100
    • T cell phenotype
    • Occasional neutrophils up to cryptitis may be seen in up to 30% of cases
      • Infrequently crypt abscesses are prominent
      • If present, infection and inflammatory bowel disease must be ruled out
    • Multinucleated giant cells may be seen
      • Located immediately below the thickened collagen layer
  • No significant crypt distortion
    • Mild crypt irregularity has been described in 8% of cases
  • May be variably distributed in colon
    • A single normal biopsy does not rule out the disease
    • Some biopsies may show only the chronic inflammatory infiltrate
    • Involvement usually more extensive in right colon
    • Terminal ileum may be involved by intramucosal lymphocytosis and occasionally collagen deposition
      • Normal levels reported from 2-8 T cells / 100 enterocyte
      • Collagenous ileitis can rarely occur in the absence of colorectal disease (O'Brien 2011)
  • Rare cases described with superficial ulceration or pseudomembranes
  • Lymphocytic colitis and collagenous colitis have been proposed to be related
    • They share an identical chronic inflammatory pattern and are distinguished only by the presence of a thickened collagen layer only in the latter
    • Cases are reported showing change from one to the other on sequential biopsies
    • Collagen deposition in collagenous colitis may be patchy, making interpretation of such observations difficult
    • Female:Male ratios originally reported as different
      • More recent studies find similar ratios of approximately 1-5:1 F:M (Kao 2009)

Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/updates: 11/11/09, 12/3/09, 10/25/10, 11/11/11, 1/28/12

Differential Diagnosis

Tangential Sectioning Collagenous Colitis
Present only where adjacent crypts cut as cross-sections Present even when adjacent crypts are cut longitudinally
Indistinct edges but no entrapped elements Jagged edges with entrapped capillaries and inflammatory cells
Lacks chronic inflammatory infiltrate Prominent chronic inflammatory infiltrate in lamina propria
  • Epithelial cell nuclei occasionally line up in the center of the cytoplasm leaving a uniform eosinophilic band of cytoplasm that may be confused with a thickened collagen layer
    • Usually resolvable by close inspection
    • Lacks irregular, spiculated base
    • Trichrome stain will show lack of collagen
  • Chronic colitis is a term best not used as a pathologic diagnosis
    • Moderate numbers of lymphocytes and plasma cells are normal in the lamina propria of the large intestine
    • The chronic changes associated with inflammatory bowel disease are better diagnosed as “crypt distortion” with a comment that it is consistent with chronic inflammatory bowel disease
    • An increased chronic inflammatory infiltrate in the absence of an increased collagen layer may be diagnosed as lymphocytic colitis
  • Lymphocytic colitis and collagenous colitis are distinguished by the presence of a thickened collagen layer only in the latter
    • They both exhibit a prominent intramucosal lymphocytic infiltrate
    • The thickened collagen layer may be variably distributed
      • Multiple biopsies may need to be examined
Systemic Sclerosis Collagenous Colitis
Fibrosis surrounds crypts Collagen restricted to apical zone
Fibrosis may extend into muscularis mucosae through to the serosa Collagen restricted to sub-basement membrane region

Amyloid Collagenous Colitis
Perivascular distribution usually present Restricted to sub-basement membrane zone
Congo red positive Congo red negative
Trichrome variable Trichrome stains blue

Ischemic Colitis and Radiation Damage Collagenous Colitis
Fibrosis surrounds crypts Collagen restricted to apical zone
Crypt distortion frequent Crypt distortion generally not presenet


  • Intractable watery diarrhea
  • No bleeding
  • May be acute, chronic or intermittent
  • Endoscopic appearance usually normal
    • Occasionally shows edema or hyperemia
    • Very rare superficial linear ulcers
  • No evidence of malabsorption
  • Variable course
    • May spontaneously resolve
  • Frequent associations
  • May be associated with autoimmune disease
    • Arthritis
    • Fibromyalgia
    • Thyroiditis
    • CREST syndrome (Calcinosis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia)
  • A wide variety of drugs have been implicated as causes, including NSADs (reviewed in Mahajan 2012)
  • Up to 5% of cases are found to be associated with (or a manifestation of ) celiac disease
    • Collagenous colitis may be the initial presentation
  • Age range 2-82 years
    • Mean age 50’s
    • Uncommon in children
  • Treatment may include drugs ranging from loperamide to budesonide or other steroids, depending upon the severity of disease (reviewed in Yen 2011, Mahajan 2012)
    • Relapses are frequent


  •  S, Reyes V, Bronner MP. Pseudomembranous collagenous colitis. Am J Surg Pathol. 2003 Oct;27(10):1375-9.
  • Ayata G, Ithamukkala S, Sapp H, Shaz BH, Brien TP, Wang HH, Antonioli DA, Farraye FA, Odze RD. Prevalence and significance of inflammatory bowel disease-like morphologic features in collagenous and lymphocytic colitis. Am J Surg Pathol. 2002 Nov;26(11):1414-23.
  • Rubio CA, Orrego A, Höög A, Porwitz A, Petersson F, Elmberger G, Glaessgen A, Eriksson E, Kanter L, Jaremko G, Egevad L, Laforga J, Liljefors M, Löfdahl B, Norman P, Larsson O, Wanat R, Wejde J, Zickert P, Björk J, Caini S, Palli D, Nesi G. Quantitative assessment of the subepithelial collagen band does not increase the accuracy of diagnosis of collagenous colitis. Am J Clin Pathol. 2008 Sep;130(3):375-81.
  • Lazenby AJ, Yardley JH, Giardiello FM, Bayless TM. Pitfalls in the diagnosis of collagenous colitis: experience with 75 cases from a registry of collagenous colitis at the Johns Hopkins Hospital. Hum Pathol. 1990 Sep;21(9):905-10.
  • Padmanabhan V, Callas PW, Li SC, Trainer TD. Histopathological features of the
    ileum in lymphocytic and collagenous colitis: a study of 32 cases and review of literature. Mod Pathol. 2003 Feb;16(2):115-9.
  • Sapp H, Ithamukkala S, Brien TP, Ayata G, Shaz B, Dorfman DM, Wang HH, Antonioli DA, Farraye FA, Odze RD. The terminal ileum is affected in patients with lymphocytic or collagenous colitis. Am J Surg Pathol. 2002 Nov;26(11):1484-92.
  • Gopal P, McKenna BJ. The collagenous gastroenteritides: similarities and differences. Arch Pathol Lab Med. 2010 Oct;134(10):1485-9.
  • O'Brien BH, McClymont K, Brown I. Collagenous ileitis: a study of 13 cases. Am J Surg Pathol. 2011 Aug;35(8):1151-7.
  • Yen EF, Pardi DS. Review of the microscopic colitides. Curr Gastroenterol Rep. 2011 Oct;13(5):458-64.
  • Kao KT, Pedraza BA, McClune AC, Rios DA, Mao YQ, Zuch RH, Kanter MH, Wirio S, Conteas CN. Microscopic colitis: a large retrospective analysis from a health maintenance organization experience. World J Gastroenterol. 2009 Jul 7;15(25):3122-7.
  • Mahajan D, Goldblum JR, Xiao SY, Shen B, Liu X. Lymphocytic colitis and collagenous colitis: a review of clinicopathologic features and immunologic abnormalities. Adv Anat Pathol. 2012 Jan;19(1):28-38.
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