Microscopic Colitis

Slide 1 · Microscopic Colitis

Clinicopathologic diagnosis, histologic subtypes, and diagnostic pitfalls

Collagenous colitis • Lymphocytic colitis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Recognize the clinical–endoscopic–histologic diagnostic triad.

Differentiate collagenous from lymphocytic colitis on colonic biopsy.

Apply biopsy sampling and ancillary stain principles.

Avoid common differential-diagnostic and interpretation errors.

Slide 3 · Clinical entry point: Normal-looking colon

A 62-year-old woman reports persistent nonbloody, watery diarrhea. Colonoscopy shows no conspicuous mucosal lesion; Random colonic biopsies have been obtained.

Apply the morphology

What mucosal abnormalities may be occult endoscopically?

Which two tissue features should be examined first?

Slide 4 · A histologic diagnosis behind a bland endoscopy

Microscopic colitis is defined by abnormal colonic biopsies, often despite a normal endoscopic appearance.

Chronic watery, typically nonbloody diarrhea is the clinical setting.

Histology separates major subtypes that symptoms alone cannot distinguish.

Slide 5 · Three-part diagnostic framework

Chronic watery diarrhea

Normal / near-normal colonoscopy

Diagnostic biopsy pattern

All three contribute; Histologic subtype must be assigned using tissue findings.

Slide 6 · Major morphologic entities

Collagenous colitis

Thickened subepithelial collagen band.

Surface epithelial injury and mucosal inflammation.

Lymphocytic colitis

Prominent surface intraepithelial lymphocytes.

No diagnostic collagen band thickening.

Slide 7 · Why two subtypes matter

Both commonly produce the same watery-diarrhea phenotype.

Collagen band thickness is the discriminator for collagenous colitis.

Surface epithelial lymphocyte density is the discriminator for lymphocytic colitis.

Clinical data and adequate biopsy samples are required for interpretation.

Slide 8 · How morphology refines the diagnosis

Clinical suspicion

Colonic mucosal biopsy

Collagen band + IEL assessment

Specify histologic subtype

IEL = intraepithelial lymphocyte; Measurements are interpreted on well-oriented H&E sections.

Slide 9 · Clinical presentation: The core syndrome

Chronic or recurrent watery diarrhea.

Typically nonbloody stools; Colonoscopy often looks unremarkable.

Clinical manifestations of collagenous and lymphocytic colitis substantially overlap.

Do not assign a histologic subtype from symptoms alone.

Slide 10 · Why the examination can appear normal

Endoscopic perspective

No obvious erosions or ulcers may be evident.

Microscopic epithelial and lamina propria abnormalities can remain invisible.

Pathology perspective

Surface epithelium and subepithelial compartment are the diagnostic targets.

Adequate biopsies bridge the endoscopic–histologic gap.

Slide 11 · Additional symptoms: Beyond stool consistency

Urgency, nocturnal stools, and fecal incontinence can occur.

Abdominal pain and impairment of quality of life can accompany diarrhea.

A presentation without weight loss; Broader clinical reviews note that some patients lose weight.

Neither weight loss nor its absence is a histologic discriminator.

Slide 12 · Clinical sex and age association

Collagenous colitis occurs particularly in middle-aged and older women.

The demographic pattern raises suspicion but is not diagnostic.

Lymphocytic colitis also occurs in adults beyond this group.

Slide 13 · Associations and triggers

Immune-associated conditions

Celiac disease.

Graves disease and rheumatoid arthritis.

Autoimmune or lymphocytic gastritis.

Medications

NSAID-associated histologic changes are recognized.

A possible association with proton pump inhibitors is noted by Robbins.

Medication review is essential; Association does not establish causality.

Slide 14 · Celiac disease deserves active consideration

An association with celiac disease is particularly prominent in lymphocytic colitis.

Assess clinical context and perform appropriate celiac screening when indicated.

Coexistence is possible; These diagnoses are not mutually exclusive.

Slide 15 · The medication-association caveat

Exposure is a clue; It is not proof that a drug caused the colitis.

Review the timeline of use, symptom onset, and alternatives.

Avoid interpreting an epidemiologic association as a pathognomonic biopsy pattern.

Slide 16 · Conceptual pathophysiology, not a single proven pathway

Susceptibility / exposure

Mucosal immune activation

Epithelial functional disturbance

Watery diarrhea

Schematic synthesis: The exact initiating mechanism is incompletely established; This is not a definitive molecular pathway.

Slide 17 · Why watery diarrhea develops

Observed tissue pattern

Surface epithelial alterations.

Lamina propria inflammatory infiltrate.

Intraepithelial immune cells.

Functional interpretation

These abnormalities plausibly disrupt mucosal fluid handling.

Do not derive a quantitative secretory mechanism from morphology alone.

Slide 18 · Normal reference: Surface, lamina propria, and crypts

Schematic — not a histologic specimen

Reference architecture

Surface columnar epithelium covers the mucosa.

Crypts descend into the lamina propria.

Only limited normal IELs are expected.

Slide 19 · Start with the colonic biopsy at low power

Determine whether the mucosa is well oriented.

Review surface epithelial integrity and crypt architecture.

Identify lamina propria inflammatory expansion.

Evaluate collagen deposition beneath surface epithelium.

Slide 20 · Surface epithelium is the diagnostic compartment

Schematic — not a histologic specimen

Lymphocytic pattern

IELs sit within the surface epithelial layer.

Do not count lamina propria lymphocytes as epithelial lymphocytes.

A surface-oriented assessment is essential.

Slide 21 · Intraepithelial lymphocytes are T cells

Small, dark lymphocyte nuclei within surface epithelium are diagnostically informative.

The cells as intraepithelial T lymphocytes.

CD3 staining may assist in equivocal cases; H&E remains the primary diagnostic platform.

Slide 22 · Count surface IELs consistently

Choose intact surface epithelium

Count IEL nuclei within epithelium

Count surface colonocytes

Express IELs per 100 epithelial cells

Apply validated histologic criteria to H&E-stained tissue; Avoid tangential or denuded epithelium.

Slide 23 · Lymphocytic colitis: Key threshold

≥20 intraepithelial lymphocytes per 100 surface epithelial cells

The lamina propria also shows increased inflammation.

The subepithelial collagen band is not significantly thickened.

Slide 24 · Lymphocytic colitis: Simplified tissue map

Schematic — not a histologic specimen

Lymphocytic pattern

Numerous dark IEL profiles lie in surface epithelium.

A mixed inflammatory infiltrate expands lamina propria.

The collagen band remains thin.

Slide 25 · Lamina propria inflammation in lymphocytic colitis

Lymphocytes and plasma cells commonly predominate.

Other inflammatory cells may be present.

This increase supports the diagnosis but is not specific in isolation.

Surface IEL density remains the defining feature.

Slide 26 · Surface injury accompanying lymphocytic colitis

Surface epithelial flattening or mucin depletion may occur.

Inflammatory change can coexist with relatively preserved crypt architecture.

Epithelial injury supports the pattern but does not replace IEL assessment.

Slide 27 · Collagenous colitis: Defining thickness

Subepithelial collagen band ≥10 µm on appropriately oriented tissue

A dense band greater than 10 µm.

European consensus uses ≥10 µm with accompanying lamina propria inflammation.

Slide 28 · Collagenous colitis: Simplified tissue map

Schematic — not a histologic specimen

Collagenous pattern

A conspicuous band lies immediately beneath surface epithelium.

IELs may also be increased.

Lamina propria shows mixed inflammatory cells.

Slide 29 · Read the band beneath the surface epithelium

The diagnostically relevant deposit is subepithelial.

Band thickness can be irregular and variable between fragments.

Entrapped small vessels or inflammatory cells may be visible.

A correctly oriented surface segment supports measurement.

Slide 30 · Collagenous colitis: Linked tissue abnormalities

Subepithelial band

Dense collagen accumulation immediately below surface.

An irregular deep interface may be evident.

Surface and lamina propria

Epithelium may be flattened, damaged, or focally detached.

Mixed inflammatory cells occupy lamina propria.

Slide 31 · The collagen band is not an isolated finding

A thick band should be interpreted alongside mucosal inflammation and epithelial change.

A focal apparent band can be misleading in poorly oriented tissue.

Context reduces the risk of reporting a nonspecific artifact as disease.

Slide 32 · Direct comparison: Dominant histologic findings

Feature

Collagenous colitis

Lymphocytic colitis

Subepithelial band

≥10 µm

Not significantly thickened

Surface IELs

Often increased

≥20 per 100 cells

Lamina propria

Mixed inflammatory infiltrate

Mixed inflammatory infiltrate

Crypt architecture

Usually largely preserved

Usually largely preserved

Slide 33 · The histologic spectrum includes incomplete forms

Borderline biopsy abnormalities may fall short of full collagenous or lymphocytic criteria.

The European 2021 guideline defines incomplete forms.

Robbins’ short section describes the two major entities, not the incomplete subcategories.

Slide 34 · Incomplete forms: Consensus definitions

Incomplete collagenous colitis

Subepithelial collagen band >5 µm but <10 µm.

Inflammatory infiltrate must be considered.

Incomplete lymphocytic colitis

>10 but <20 IELs per 100 surface cells.

Normal collagen band with mild lamina propria inflammation.

Slide 35 · Interpreting a borderline pattern

Check orientation and distribution

Review H&E morphology

Consider ancillary stain if needed

Correlate with symptoms and sampling

Do not automatically classify borderline abnormalities as a fully developed major subtype.

Slide 36 · Ancillary stains: Distinct purposes

Trichrome / collagen stains

May delineate a thickened subepithelial collagen band.

Aids borderline or subtle collagen deposition.

CD3 immunohistochemistry

Highlights intraepithelial T cells.

May aid recognition/counting of IELs in difficult specimens.

Slide 37 · CD3 immunostaining requires interpretive restraint

Counts obtained by CD3 may exceed counts appreciated on H&E.

European guidance identifies potential overdiagnosis if H&E cutoffs are transferred uncritically to immunostains.

A confirmed phenotype and routine morphology remain central.

Slide 38 · Collagen band artifact: How it arises

Tangential sectioning

Oblique passage through surface tissue can exaggerate apparent thickness.

A poorly oriented fragment cannot support a reliable thickness measurement.

Mitigation

Seek vertically oriented, intact mucosal surfaces.

Review deeper levels or supplementary stain when genuinely needed.

Slide 39 · Pitfall: Damaged surface epithelium

Denudation can remove the very compartment needed for IEL assessment.

Crush, tangential sectioning, and fragmentation limit confidence.

Do not infer a normal IEL count from a biopsy lacking evaluable surface.

State specimen limitations in the report when consequential.

Slide 40 · Pitfall: Site-related physiologic variation

Right- and left-colon samples may differ in baseline cellularity.

Knowledge of biopsy site helps interpret subtle/borderline changes.

Separately labeled containers may reduce ambiguity.

Morphology is evaluated in clinical and anatomic context.

Slide 41 · Biopsy sampling must be anatomically adequate

Guidance recommends biopsies from at least the right and left colon.

A normal-appearing colon still requires tissue sampling when MC is suspected.

Rectal-only sampling is not sufficient for dependable exclusion.

Slide 42 · Practical biopsy workflow

Clinical suspicion

Ileocolonoscopy

Right + left colon biopsies

Histologic assessment

If location-specific questions matter, submit right and left samples in separate labeled containers.

Slide 43 · Why sampling strategy matters

Patchiness / distribution

Diagnostic features can vary by colonic segment.

Limited distal sampling risks missed disease.

Report-level context

Anatomic site informs normal variation.

A well-sampled negative study is more informative than rectal-only sampling.

Slide 44 · An organized pathology report

State whether the findings support collagenous, lymphocytic, or incomplete microscopic colitis.

Document the relevant collagen-band and/or surface IEL findings.

Comment on orientation or sampling limitations when material.

Correlate with the clinical history and medication exposure.

Slide 45 · Normal colonoscopy does not exclude microscopic colitis

The biopsy, not the gross examination, establishes the microscopic diagnosis.

Macroscopic disease may be absent or nonspecific.

Visible subtle changes do not reliably separate the two subtypes.

Slide 46 · Fecal calprotectin is not an exclusion test

A low or normal fecal calprotectin value does not reliably rule out microscopic colitis.

European recommendations do not support calprotectin for exclusion or routine monitoring.

Persistent clinical suspicion should guide biopsy rather than this marker alone.

Slide 47 · Microscopic colitis versus IBS-D

Possible clinical overlap

Chronic loose or watery stools can resemble a functional bowel disorder.

A visually normal colonoscopy does not resolve the distinction.

Decisive discriminator

Microscopic colitis shows a characteristic mucosal biopsy pattern.

IBS-D does not require the defining collagen/IEL abnormalities.

Slide 48 · Microscopic colitis versus active classic IBD

Pattern

Microscopic colitis

Classic active IBD

Endoscopic appearance

Often near normal

May show visible active mucosal injury

Histologic focus

IELs and/or collagen band

Activity and chronic crypt abnormalities

Crypt architecture

Often largely preserved

Chronic distortion may occur

Clinical correlation

Watery, nonbloody diarrhea

Phenotype and activity variable

Slide 49 · Alternative causes of watery diarrhea

Competing processes

Celiac disease or bile acid diarrhea can coexist or mimic symptoms.

Medication exposure may contribute.

Pathologic discipline

Do not force a diagnosis when changes are nondiagnostic.

Consider additional workup when biopsy findings fail to explain symptoms.

Slide 50 · Drug-related microscopic-colitis-like changes

NSAIDs, and possibly PPIs, can be associated with a similar histologic pattern.

A compatible tissue pattern does not independently prove drug causation.

Clinical medication review remains essential.

Slide 51 · Differentiating other colitides in context

Diversion colitis

Occurs in a defunctionalized bowel segment.

Prominent mucosal lymphoid follicles favor the diversion context.

Graft-versus-host injury

Follows allogeneic transplantation.

Epithelial/crypt apoptosis is a key morphologic clue.

Slide 52 · A second adjacent mimic: Apoptotic colitis

Checkpoint inhibitor-related enterocolitis

May show prominent epithelial apoptosis.

Oncology exposure and severity inform interpretation.

Mycophenolate-associated injury

Apoptotic enterocolitis can follow immunosuppression.

Drug history and injury pattern matter.

Slide 53 · Clinical care focuses on symptoms, not histologic surveillance

Routine follow-up biopsies are not recommended solely to document microscopic response.

Symptom burden guides clinical assessment.

Therapeutic response does not substitute for establishing the initial diagnosis.

Slide 54 · Evidence-based induction: Oral budesonide

European and AGA guidance recommend budesonide for symptomatic disease.

Recommendation applies to both collagenous and lymphocytic colitis.

Treatment is a clinical decision after diagnostic evaluation.

The histologic subtype is informative but treatment responses overlap.

Slide 55 · Relapse can occur after initial improvement

Recurrence after induction may require maintenance-directed clinical management.

AGA guidance supports budesonide maintenance after recurrent symptoms.

European guidance recognizes maintenance benefit, strongest evidence in collagenous colitis.

Slide 56 · Nonresponse: Reconsider causes of ongoing diarrhea

Diagnostic review

Reassess tissue adequacy and original histologic findings when indicated.

Review medication contributors and alternative diagnoses.

Clinical reassessment

Celiac disease merits screening in MC.

Bile acid diarrhea may be considered when budesonide fails.

Slide 57 · Case 1: A subepithelial band

A 59-year-old woman has watery, nonbloody diarrhea. Her colonic biopsy shows a broad subepithelial collagen layer, flattened surface cells, and increased lamina propria mononuclear cells.

Apply the morphology

Which finding establishes the likely subtype?

What sectioning artifact must be excluded?

Slide 58 · Case 1: Interpretation

Collagenous colitis—provided the band is genuinely thickened in well-oriented surface mucosa.

The relevant threshold in European guidance is ≥10 µm.

Confirm the inflammatory context and avoid a tangential-section false positive.

Slide 59 · Case 2: Prominent surface lymphocytes

A 48-year-old patient with celiac disease develops persistent watery diarrhea. The colon looks normal, but biopsy shows conspicuous surface epithelial lymphocytes and no thickened collagen band.

Apply the morphology

Which cell population should be counted?

What threshold supports lymphocytic colitis?

Slide 60 · Case 2: Interpretation

Lymphocytic colitis if surface IELs meet the accepted criterion (≥20 per 100 surface epithelial cells).

Inflammatory cells in lamina propria are supportive, not the IEL denominator.

Celiac disease may coexist with lymphocytic colitis.

Slide 61 · Case 3: Borderline numbers

A patient has watery diarrhea. Biopsy shows a collagen band of 7 µm on well-oriented H&E and a mild inflammatory infiltrate, without the full lymphocytic-colitis pattern.

Apply the morphology

Does the specimen meet major collagenous-colitis criteria?

Which consensus category may be appropriate?

Slide 62 · Case 3: Interpretation

The findings may fit incomplete collagenous colitis—not definitive classic collagenous colitis.

European incomplete collagenous criteria: >5 µm and <10 µm with inflammation.

Sampling, orientation, and clinical correlation still matter.

Slide 63 · Case 4: A tempting false negative

An older adult has persistent watery diarrhea. Only a small rectal biopsy was taken and shows no diagnostic collagen band or surface intraepithelial lymphocytosis.

Apply the morphology

Can microscopic colitis be excluded confidently?

What sampling strategy should follow if suspicion persists?

Slide 64 · Case 4: Interpretation

Rectal-only negative tissue is insufficient to confidently exclude microscopic colitis.

Obtain sampling from right and left colon when clinically appropriate.

Do not overstate the negative predictive value of a limited specimen.

Slide 65 · Integrated diagnostic pathway

Chronic watery diarrhea

Review risks and mimics

Right + left colon biopsies

Subtype by IELs / collagen

The pathologist and endoscopist contribute complementary evidence; Neither a normal scope nor symptoms alone can subtype the disease.

Slide 66 · High-yield morphologic discriminators

Question

Answer

What is dominant in CC?

Subepithelial collagen band ≥10 µm

What is dominant in LC?

Surface IELs ≥20 per 100 cells

Are crypts usually destroyed?

No; architecture often largely preserved

Can endoscopy be normal?

Yes; obtain appropriate biopsies

What undermines measurement?

Tangential surface section or denudation

Slide 67 · Five diagnostic errors to avoid

Reassuring a patient solely because colonoscopy appears normal.

Measuring a tangentially cut collagen layer as true thickening.

Counting lamina propria lymphocytes as surface IELs.

Excluding disease from rectal-only or poorly preserved tissue.

Attributing microscopic colitis to a drug without clinical corroboration.

Slide 68 · Core references

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026), Chapter 17, pp. 733–734.

Miehlke S, et al. European guidelines on microscopic colitis. UEG J. 2021;9:13–37.

Nielsen OH, et al. Microscopic colitis: etiopathology, diagnosis, and rational management. eLife. 2022;11:e79397.

AGA Institute. Medical management of microscopic colitis. Gastroenterology. 2016.