Last updated: 10/1/2024 Prepared by Dr.

Kurt Schaberg

Inflammatory Bowel Disease

Normal Colon
Crypts should be oriented parallel to one another,
perpendicular to the surface (like test tubes in a rack),
resting on the muscularis mucosae.
Regional Variation
Right Colon Left Colon
More lymphocytes Less lymphocytes
Paneth cells normal Paneth Cells abnormal
Fewer goblet cells More goblet cells

Some architectural distortion and muciphages in the rectum is considered normal.

Intraepithelial lymphocytes (and even rare neutrophils) over lymphoid follicles is also normal.

Patterns of Damage in IBD

The inflammation in IBD is characterized by the presence/absence of “Activity,” defined as neutrophilic
inflammation of the epithelium and lamina propria, and “Chronicity,” including architectural distortion,
a basal lymphoplasmacytosis, and Paneth cell metaplasia.
These words are combined such that you can have an “Active colitis,” a “Chronic active colitis,” or a
“Chronic inactive colitis,” which is also sometimes called “Quiescent colitis.”
Crypt architectural distortion
Activity = Neutrophils Chronicity Crypt shortening
Think of those test tubes being
Crypt branching
melted (like a by a torch)
Cryptitis Crypt dropout
Crypt Abscess Loss of crypt parallelism
PMNs in crypt epithelium PMNs in crypt lumen
Villiform surface
Basal lymphoplasmacytosis
Paneth cell metaplasia and
hyperplasia
Pyloric gland metaplasia
Lamina propria and submucosal
fibrosis

New onset, untreated IBD ~ 1 month Typical appearance IBD in recent remission
(hasn’t had time for of active disease Treatment (eventually it can normalize)
untreated
chronicity to develop)
Chronic Active Chronic inactive
Active Colitis Colitis (Quiescent) Colitis
IBD General Info:
Chronic, idiopathic, relapsing and remitting inflammatory disease of the gastrointestinal tract resulting from
inappropriate mucosal immune activation. Thought to involve aberrant immune response with altered
intestinal microbiome in genetically susceptible individuals.
More common in industrialized nations, where there are fewer parasites/infections to train/distract the
immune system (“Hygiene hypothesis”).

Ulcerative Colitis
Chronic active inflammation in the rectum
proceeding proximally in continuous, diffuse
pattern
Typical findings:
Chronic Active Colitis limited to mucosa and
superficial submucosa with ulceration
Can see deeper inflammation with severe
“fulminant” colitis
Can have increased inflammation in cecum near
appendiceal orifice (“cecal patch”)
Can have inflammation in terminal ileum
(“backwash ileitis”).

**In Kids, can have upper tract findings, relative

rectal sparing, and less initial chronicity.**

Crohn’s Disease
Patchy Transmural chronic active
inflammation in any part of the GI tract
Typical findings:
Transmural inflammation
Skip areas and patchy inflammation, both
microscopically and grossly
Granulomas
Ulcers: superficial apthous to fissuring
Muscle and nerve hypertrophy
Pyloric gland metaplasia (esp. in TI)
Fibrosis and strictures
Fistulas

Indeterminate Colitis aka: IBD, type unclassified

Approximately 10% of patients unclassifiable, due to the pathologic and clinical overlap between UC and
CD. Placeholder term--this is NOT a specific entity. Often due to insufficient data or fulminant colitis.
Differential Diagnosis: IBD is a diagnosis of exclusion!

Active Colitis Neutrophilic Cryptitis

But, Chronicity ABSENT
(aka Acute Self-limited Colitis)
Relatively more neutrophils in superficial lamina propria
Causes: E. Coli, Salmonella, Shigella, (away from crypts)
Campylobacter, Viruses Crypt abscesses
E. coli O157:H7→ ischemic changes Hemorrhage, edema
Possible erosions
Looks similar: Some medications (e.g., NSAIDS, Checkpoint inhibitors), New onset IBD

Focal Active Colitis FOCAL Neutrophilic Cryptitis

Chronicity ABSENT
Causes:
NSAIDS → + Increased apoptoses, ischemic-like changes
Bowel preparation artifact → + Increased apoptoses, edema, mucin depletion
Early infection → Days 0-4 after onset
Ischemic changes → often with lamina propria hyalinization, crypt withering

Microscopic Colitis Increased Intraepithelial Lymphocytes (IELs)

Neutrophils rare to absent
Lymphocytic Colitis Collagenous Colitis
IEL ≥20/100 surface epithelial cells IEL >10-20/100 surface epithelial cells
Normal architecture Increased Subepithelial Collagen
Chronic inflammation in lamina propria Entraps capillaries and lymphocytes
(usu. superficial) Highlighted by Trichrome stain

Additional Diagnoses to Consider:

Top infectious causes of colitis in patients with IBD: CMV and C. difficile→ always get CMV IHC in a
patient with refractory IBD now with severe disease on treatment (esp. steroids)
If Older→ Especially rule out Medication-effect and Diverticular disease
Common Drug pattern: Intraepithelial lymphocytes, relatively preserved crypt architecture, apoptoses,
with some neutrophils

Ischemic colitis → Hyalinized lamina propria, withered crypts, minimal inflammation

Radiation colitis → Ischemic changes, Atypical stromal cells, Telangiectatic blood vessels
Diverticular disease–associated colitis → In colonic segment with diverticulosis
Diversion colitis → Colon isolated from fecal stream, Follicular lymphoid hyperplasia
Prolapse → Fibromuscular hyperplasia, Angulated diamond-shaped crypts
Vasculitis → Inflammatory destruction of vessels, Fibrinoid necrosis
Eosinophilic/Allergic Colitis → >60 Eos/10 HPF, Few PMNs, Absent chronicity
STD Proctitis → Often chlamydia or syphilis due to anal receptive intercourse. Lots of ulceration, plasma
cells, and histiocytes. Confined to rectum.
 Medical Management
Usually 2 phases: 1) Induction (to induce remission) and 2) Maintenance (to maintain remission)
These may use same or different medications/dosages.
Old management model: “Step-up therapy,” start with a mild drug (e.g., mesalamine) and only move
up to a more powerful drug if they “fail” that drug.
Modern Management model: “Top down,” start with a more powerful medication (e.g., monoclonal
antibody). This shows better complication-free long-term survival.

Three pillars of modern IBD care: 1)Early intervention, 2)Treat to target, 3)Tight control
Treat to specific measurable endpoints, like normal Fecal Calprotectin (a good surrogate marker for
inflammation), mucosal healing (an endoscopic impression), or histologic normalization. Engage in
frequent monitoring to ensure ideally “deep remission.”

Medications:
Generally, reduce autoimmune inflammation by immunosuppression via a variety of mechanisms.
Often increased risk of infection (somewhat drug dependent).

“Classic” medications
Mesalamine (5-ASA) – mechanisms of action unknown. Low activity. Usually used orally or rectally for
mild UC.
Sulfasalazine – like 5-ASA (mechanism of action unknown). Usually used for mild ileocolic CD.
Budesonide – steroid taken orally with little system effect (mainly works on GI tract).
Prednisone – oral steroid often used to induce remission in active IBD. Long-term use limited due to
side effects. Use in both CD and UC.
Azathioprine/6-Mercaptopurine – Thiopurines, inhibit DNA synthesis, thereby reducing WBC
production and inflammation. Risk of lymphoma. Used in both CD and UC.

Anti-TNFα antibodies: Suppresses TNF-mediated inflammatory response.

Used in UC and CD. Good for penetrating disease. May develop drug antibodies, limiting use.
Examples: Adalimumab (Humira), Infliximab (Remicade), and others, including generic biosimilars.

Janus kinase (JAK) inhibitor: interfering with the JAK-STAT signaling pathway in lymphocytes.
Oral pill. Powerful & fast. Used for UC more than CD.
Examples: Tofacitinib (Xeljanz), Upadacitinib (Rinvoq)

Anti-α4β7 antibody: anti gut-specific integrin→ inhibiting WBC diapedesis to gut

Used in both CD and UC, but likely better for UC. Very few side-effects as gut-specific.
Examples: Vedolizumab (Entyvio)

Anti-IL23/12 and anti-IL23 antibody: blocks cytokines that activate certain T-cells.
Used more in CD, but can use in UC. Good for penetrating disease. Good safety profile.
Examples: Ustekinumab (Stelara), Risankizumab (Skyrizi)

Sphingosine-1-Phosphate Receptor (S1PR) agonist: Sequester lymphocytes to peripheral lymphoid

organs, away from their sites of chronic inflammation. Oral therapy for UC.
Examples: Ozanimod (Zeposia)
Pre-malignant and Malignant lesions in IBD:
Generally, follows stepwise progression of: Non-neoplastic → Low-grade dysplasia → High-grade
dysplasia → Adenocarcinoma. However, there are cases where it appears to go from low-grade (or even
normal appearing) to adenocarcinoma very quickly or directly.
Conventional Dysplasia (look like usual colon adenomas):
Indefinite for Dysplasia
Unable to classify as definitely reactive or dysplastic.
Often atypia in setting of severe inflammation or ulceration.
Sometimes surface not present for evaluation.
Management: Treat active disease and repeat biopsy in 3-12
months.

Low-Grade Dysplasia
Looks like a sporadic Adenoma.
Enlarged, hyperchromatic, smooth, “pencillate” nuclei.
Pseudostratified nuclei with maintained basal orientation.
Higher N:C ratios; Little to no surface maturation.
Often abrupt transition (corresponding with clone)
Prominent apoptoses.
Molecular: IBD-associated dysplasia show more copy number
aberrations and aneuploidy than sporadic adenomas. TP53
mutations are very frequently present early. Possibly reflecting a
faster progression toward cancer.

Hint: Try using a lymphocyte as what is

“normochromatic”

High-Grade Dysplasia
Enlarged, hyperchromatic, pleomorphic nuclei.
Often plumper than LGD.
Irregular nuclear contours. Prominent nucleoli.
Loss of nuclear polarity.
Complex architecture: Cribriforming, crypt
branching/budding.

Immunohistochemistry in IBD dysplasia: P53 staining often highlights both grades

Dysplasia→ Strong P53 staining (or null). Some authors require abnormal p53 at the surface, while others
just want it to be significantly increased compared to the background colon.
Negative/Indefinite for dysplasia if weak/wild-type staining
SATB2 is frequently lost in IBD dysplasia also, but this is used less often as a marker.
H&E is still the gold standard though, so only do it on cases that are equivocal!
 Nonconventional lesions: (doesn’t look like usual colon adenomas)
Serrated Epithelial Change
Controversial diagnosis, with differing criteria
Original Hopkins Criteria: Serrations at top and bottom of crypts.
Distorted crypt architecture where some crypts do not reach the
muscularis mucosae (unlike SSL). Normal nuclei. Goblet cell-rich
epithelium.
UCSF Criteria: Hyperplastic polyp (HP)-like mucosal change without Note: The colon in IBD patients can show
morphologic evidence of dysplasia detected on random biopsy surface serrations/hyperplasia, particularly
Controversial risk of CRC. Many studies show increased risk of in the distal colon, making this diagnosis
dysplasia/carcinoma. Essentially, treat as “indefinite.” especially hard and controversial.

Non-Conventional Dysplasia Often present with conventional dysplasia.

More common on left side as polypoid mass.
Hypermucinous—Villous architecture with prominent
cytoplasmic mucin.
Traditional Serrated Adenoma (TSA)-like
Sessile serrated lesion (SSL)-like
Paneth cell differentiation
Goblet cell deficient—absence of goblet cells
“Terminal epithelial differentiation,” TED, or “Crypt
cell dysplasia,” CCD –flat lesions, round to oval
hyperchromatic nuclei. Can be just in crypts.

Helpful tip: Must see cytologic atypia (hyperchromatic, crowded nuclei).

In uncertain cases, get p53 IHC. If not altered→ better to hedge as “indeterminate for dysplasia” and
state change type (e.g., “Hypermucinous epithelium, Indefinite for dysplasia)

Adenocarcinoma
Invasive through basement membrane:
- Infiltrating glands/cells
- Broad, expansive confluent growth of glands
Compared to Sporadic, IBD-associated CRC is:
- More often multifocal (field defect)
- More often higher grade
- More often advances stage
- More often signet-ring or mucinous
Unique variant:
Low-grade tubuloglandular adenocarcinoma—very bland small to medium-sized round glands that
invade with little desmoplastic stroma. Often CK7 (+). Loss of SATB2. Frequent IDH1 mutations.
 Cancer Risk and Screening Cancer Risk:
Ulcerative colitis = ~2.4 fold risk
Crohn’s Disease = ~1.9 fold risk
(~ 2x risk)
Inflammation → DNA oxidation/damage → Cancer
Risk proportional to severity/duration of inflammation.
Screening recommendations:
First 8-10 yrs after diagnosis→ No increased screening (not enough time for carcinogenesis).
Exception: Individuals with PSC, who are at dramatically increased risk of sever inflammation and cancer
→ start annual screening colonoscopies at diagnosis.
After first screening, space out as below.

From: Murthy SK, et al. Gastroenterology. 2021 Sep;161(3):1043-1051 PMID: 34416977.

Chromoendoscopy: High-Definition Dye-spraying

Allows for better visualization of White Light Chromoendoscopy
the bowel surface and crypt pattern endoscopy
(which is often altered in dysplasia).
This can be done via spraying of dye Lesion
that settles in crypts (e.g., Lesion
methylene blue) or “virtually” via
technologies like narrow band
imaging. Hard to see, isn’t it! Much easier to see, isn’t it!

Screening principles:
Targeted biopsies should be performed where mucosal findings are suspicious for dysplasia or are
inexplicably different from the surrounding mucosa.
Endoscopic resection is preferred to biopsies when lesions are clearly demarcated without stigmata of
invasive cancer or submucosal fibrosis. Mucosal biopsies surrounding a resected lesion are not required
unless there are concerns about resection completeness.
Dye-spraying chromoendoscopy should be considered, but virtual chromoendoscopy (VCE) is a suitable
alternative when using high-definition endoscopy.
If chromoendoscopy is being used, then non-targeted biopsies are not routinely required, but should be
considered if there is a history of dysplasia or primary sclerosing cholangitis.
If NOT using chromoendoscopy: Extensive nontargeted biopsies (roughly 4 adequately spaced biopsies
every 10 cm) should be taken from flat colorectal mucosa in areas previously affected by colitis.
Endoscopic Lesion Terminology
Lesions are now described using the Paris system (see below) based on size, morphology, clarity of
borders, presence of ulceration, location, presence within an area of past or current colitis, perceived
completeness of resection, and whether any special techniques were used for visualization.

This is the old terminology you may see

From: Murthy SK, et al. Gastroenterology. 2021 Sep;161(3):1043-1051 PMID: 34416977.

This is the current terminology you should see

 Treatment of Dysplasia
Once a dysplastic lesion has been resected, in the absence of surrounding dysplasia, ongoing meticulous
colonoscopic surveillance is appropriate.
Proctocolectomy is usually only recommended for dysplasia if endoscopic resection is not possible, or if
nonvisible high-grade dysplasia or adenocarcinoma or invisible multifocal dysplasia are found.

From: Murthy SK, et al. Gastroenterology. 2021 Sep;161(3):1043-1051 PMID: 34416977.