Nour Hussein

Manar Hajeer

Mo Alfarra

5

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What we have left of the topics with Dr.Manar:

• Tumors

• Polyps

• Inflammatory bowel diseases Last time we have discussed the inflammatory bowel diseases which are 2 types:

1. Crohn’s Disease 2. Ulcerative Colitis

We have discussed the pathogenesis and age distribution.

Pathogenesis

o Involves complex of factors, multi-factorial disease

o Most important is the exaggerated immune response in the intestine where the

suggested that the ulcerative colitis usually follows lower GI infection, and it

would be the triggering factor of the disease, showing the symptoms afterwards.

o Crohn disease usually follows strong genetic basis and usually has family history

in first degree relatives.

o Intestinal epithelial dysfunction: Disease model that is suggested for both

Ulcerative colitis and Crohn’s disease is a result of epithelial cell defect where

tight junction between cells is not properly functional and loss of barrier in

intestine where bacteria will reach Lamina propria (Alterations in host

interactions with intestinal microbiota) and this causes activation to the immune

system (adaptive and innate).

o Innate is represented by macrophages and is not specific.

o Adaptive immune mechanism is where including activating T-lymphocytes

(TH-1 & TH-2), which leads to the release of inflammatory mediators TNF, IL,

cytokines which will augment the response and activate the inflammation more

and more, which will lead us to a cycle of activation and more bacterial influx and

progression of the disease.

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Morphology and clinical picture

UC & CD

Major difference

o Crohn’s is a disease of the whole GI tract from mouth to anus.

o Ulcerative Colitis is a disease of the colon.

we also have differences in the morphology and clinical picture, and pathologists

find it hard to differentiate between CD and UC.

- It is easier to have a small intestine biopsy since UC does not infect the small

intestine.

- But it is hard to differentiate between UC and CD using a colon biopsy; unless

there was a progression of the disease and other symptoms and morphologies

where seen.

Macroscopic and microscopic

Chron’s Disease

• Regional enteritis: disease may be in one region only

Any area of GIT.

• Most common sites: terminal ileum, ileocecal valve, and

cecum. (discontinuity)

1. Small intestine alone 40% of cases

2. Small intestine and colon (Large intestine) 30% → easy to

diagnose

3. Colon only 30% → hard to differentiate between UC.

• Skip lesions: involved area next to normal area

• Strictures common: inflammation is transmural (existing or occurring across the

entire wall of an organ or blood vessel) and inflammation is followed by fibrosis

and includes fibrous thickening of bowel wall which will result in stenosis and

strictures formation which may lead to intestinal obstruction

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- This bowel segment is opened showing large

diameter of lumen compared to the constricted

narrow lumen above. This is typical for CD.

- Submucosal fibrosis and bowel wall thickening due

to transmural inflammation and edema leading to

narrowing of the lumen.

- Purulent material (Pus) showing active disease.

• Earliest lesion: Aphthous ulcer (shallow ulcer)

• Elongated, Serpentine ulcers along the long access of bowel

and it is shown in the progression of the disease.

(snake like. while UC has shallow, wide ulcers).

• Edema, loss of bowel folds.

• Fissures, perforations.

- Ulcer means mucosa and part of the submucosa. If the

ulcer reached the muscularis, then it will be named as

fissure. If the fissure continued to the serosa, it will lead to

a perforation.

Mucosa + Submucosa → Ulcer

Muscularis → Fissure

Serosa → Perforation / Rupture

• When perforations, rupture or transmural inflammation occur, fibrosis and

adhesion between bowel segments are observed.

• Stricture as a term is usually used when narrowing is caused by contraction of

smooth muscle (e.g. achalasia); stenosis is usually used when narrowing is caused

by lesion that reduces the space of lumen (e.g. atherosclerosis).

• Fistulas: Transmural inflammation that reach serosa might lead to a fissure

entering deep into another bowel segment resulting in connection between 2

bowel segments.

- Small Bowel and another loop of small bowel

- Small Bowel and Large Bowel

Linear Ulcers in CD

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- Small Bowel and Urinary Bladder (patient passing stool with urine)

- Bowel Loop and Vagina (in females) leading to passing of stool from vaginal

orifice.

- And so, Fistulas is considered a complication of CD,

between bowel segments together or bowel

segment and other visceral organs principally the

urethra, urinary bladder and vagina

- If this fistula is found in the rectum, it might open

on perianal skin calling it a perianal fistula. This

might be the only symptom or earliest

manifestation of a patient having perianal

ulceration, perianal fistula results in passage of stool through the fistula and

not through the rectal/anal orifice, And these are typical in CD.

Recap (Features of Chron’s disease):

1. Serpentine ulcers

2. Loss of bowel folds due to edema

3. Fissures, fistulas, perforations. 4. Thick Bowel wall resulting in strictures and stenosis (transmural inflammation,

edema, fibrosis, hypertrophic MP)

5. Since it is a chronic disease, with time, muscularis propria becomes very thick and

this is visible under the microscope (thickened muscularis propria and thicker

muscularis mucosa)

6. Cobblestone appearance:

Depressed: Areas involved in the ulceration

Elevated: Normal Region -mucosa-

7. Creeping fat: The abdominal cavity is filled

with mesenteric fat. During transmural

inflammation, fat is accumulated upon the

areas with serositis (inflammation of the

serosa).

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Crohn’s Disease Microscopically

What we see depends on whether the disease is active or in the chronic phase (inactive).

Crohn’s disease is a chronic inflammatory bowel disease, it consists of active and inactive phases.

• Neutrophils helps in differentiating active disease since it is active inflammatory

cell. Biopsy will be filled with neutrophils in lamina propria attacking glands of

colon, and even in the lamina of crypts (crypt abscesses) along with ulcerations,

erosions and fissures.

• When we deal with a patient with Chron’s disease the architecture of normal

colon is distorted, and we call it, distortion of mucosal architecture.

• Haphazardly arranged crypts: Crypts are no longer arranged, lamina propria is

filled with chronic inflammatory cells.

• Paneth cell metaplasia in left colon: Cells normally found int the intestine, up

until the transverse colon. If Paneth Cells are found in the rectum or sigmoid, this

is considered abnormal. • Mucosal atrophy happens over time due to loss of crypts. • Fibrosis and muscle hypertrophy lead to thickened bowel wall • Noncaseating granulomas (hallmark), no center of necrosis like TB.

Used to confirm CD. The problem is that non-caseating granuloma is found only

in 35% of cases.

They are found in

1. Areas with active inflammation

2. Areas that are not inflamed (skip areas)

3. Mesenteric Lymph nodes around bowel

• Cells that are observed in granulomas are lymphocytes,

epithelioid macrophages and multinucleated giant cells.

Normal Colon Haphazardly arranged crypts

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Clinical Features

• It is a chronic disease meaning it is persistent or otherwise long-lasting in its

effects. Meaning that whenever the patient is diagnosed, they will not be cured.

• Fluctuating condition: -ups and downs-

Flair of the disease with active symptoms, and then disease subsides, and patient

will undergo asymptomatic intervals which might persist for one year, and then

they will have a flair of disease again if there were some triggering factors.

• Intermittent attacks of mild diarrhea, low grade fever, and abdominal pain.

Symptoms like gastroenteritis (lower abdominal pain and cramps)

• Sometimes if the disease is located in the terminal ileum and ileocecal valve; Pain

is localized in the right lower quadrant, like appendicitis.

The patient shows up in the ER, with suspicion of appendicitis. If they are a known

case of Crohn’s disease, it might be an active inflammation of Chron’s.

If the doctor confirmed appendicitis, and during surgery appendix is found

normal, however terminal ileum, ileocecal valve and cecum is inflamed and this

might be the first presentation of Crohn’s disease. This is typical for patients who

show up with acute right lower quadrant abdominal pain mimicking appendicitis

and is observed in 20% of cases.

• Bloody diarrhea and abdominal pain (colonic disease) → UC &CD

• Asymptomatic intervals (weeks, months and up to a year)

• Triggers (attack of active Crohn’s disease): physical or emotional stress, specific

dietary items, NSAID use, and cigarette smoking.

-May provoke the attack of Chron’s disease.

Complications

• Iron-deficiency anemia due to ulceration and blood loss.

• Malabsorption: since it is a disease that effects the small bowel which is the site

of absorption for most nutrients (Vitamin B12)

• Vitamin B12: holds into the intrinsic factor in the stomach and moves along to

the terminal ileum where absorption takes place. Diseases effecting the ileum

might cause Vitamin B12 deficiency anemia. • Constipation may take place in the case of intestinal obstruction. But the feature

of inflammatory disease is related to diarrhea more than constipation. • Hypoproteinemia and hypoalbuminemia, and bile salts deficiency.

• Fistulas, peritoneal abscesses, strictures and perianal fistulas.

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Crohn’s disease is an immune mediated disease and the main site is the GI tract

These diseases have Extraintestinal Manifestations

• Uveitis: uveal inflammation, red eye

• Migratory polyarthritis: inflammation in different joints (swelling, redness,

edema)

• Sacroiliitis: inflammation of the sacroiliac joint.

• Ankylosing spondylitis: effecting the spine

• Erythema nodosum: patient will have painful/tender red

macule below the knee level.

Erythema: Red

Nodosum: Firm Nodule.

• Nail Clubbing of the fingertips: Prominent curvature of

the nail.

clubbing is not only associated with Crohn’s disease it

may be associated with the respiratory system, and

cystic fibrosis and many other diseases cause clubbing.

• Primary sclerosing cholangitis (more with UC): Disease in the liver causing

obstructive jaundice. Obstruction and fibrosis of the bile ducts.

• Risk of colonic adenocarcinoma!! → most feared complication after 8-10 years from active disease as a result of irritation, inflammation,

damage and regeneration results in mutations in the colonic mucosa and increase

risk of colonic adenocarcinoma, which is why after a certain period of time,

patients must undergo screening, colonoscopy to see if there is area of dysplasia

which might change to carcinoma.

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Ulcerative Colitis

• Disease of the colon

• Almost always start at the rectum progresses proximally

• In severe cases it might cause pan colitis and reach the

cecum

• Small intestine and other parts of the GI are not involved

• Occasionally focal appendiceal involvement; since the

appendix is extension of the cecum, or even cecal

involvement. In this case, the patient has no continuity of

involvement between rectum and cecum, which is very

rare, usually inflammation is continuous from the rectum to the cecum. So, in

some patients, rarely, might have rectal disease and focal cecal disease at the

same time. This is not the typical scenario, but it can occur.

• Ulcerative Proctitis: Disease in the rectum only.

• Ulcerative proctosigmoiditis: Disease in the sigmoid colon only.

• Small intestine is normal -except in backwash ileitis- Backwash: in severe cases, patients might have pan colitis which reaches the

cecum this causes retrograde (Moving Backward) extension to the terminal ileum

through ileocecal valve –not truly in the terminal ileum-, backwash of the

inflammatory material from the cecum to terminal ileum

Ileitis: inflammation of the terminal ileum

Macroscopic

• Wide Broad-based ulcers:

• Pseudopolyps: mucosa will appear like a polypoid due to inflammation and

regeneration

• Mucosal atrophy in long standing cases: like CD

Differentiate between CD and UC

• Mural thickening absent → UC has no stenosis or stricture formation

• Serosal surface normal → UC has no transmural inflammation

• Toxic megacolon: inflammation might cause damage to nerve plexuses in the wall

which may cause loss of peristalsis leading to proximal dilatation of bowel and

rupture due to obstruction of stool in the bowel. This is typically seen in UC

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Microscopic - Similar to CD

• Inflammatory infiltrates

• Crypt abscesses (full of neutrophils within the lumen of the glands in between the lamina propria indicates active disease; in colonoscopy they will find this creamy colored membrane indicating exudate, mucopurulent material and ulceration)

• Architectural distortion

What can help us differentiate, is a biopsy that shows normal and effected regions which may confirm skip lesions.

• Crypt distortion

• Epithelial metaplasia

• Submucosal fibrosis without thickening

• Inflammation limited to mucosa and submucosa → no transmural inflammation

• No skip lesions

• No granulomas Pan Colitis

This is an inflammation of the whole colon, severe case of Ulcerative Colitis

area that is inflamed is proximally extended in a continuous manner, with complete normal area after it. No skip lesions.

Abrupt transition

- Between diseased area and non-diseased area - Inflammation is only in mucosa and submucosa - Muscularis and serosa are not affected.

limited to mucosa

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Clinical Features of Ulcerative Colitis

• Relapsing remitting disorder: like Chron’s

• Attacks of bloody mucoid diarrhea + lower abdominal cramps

• Temporarily relieved by defecation

• Attacks may last for days, weeks, or months.

• Asymptomatic intervals, it may not recur unless there was a triggered by emotional stress or bacterial or viral gastroenteritis.

• If the patient is lucky, they will only have 1 or 2 attacks.

• Infectious enteritis may trigger disease onset.

• Cessation of smoking, this is only associated with UC. Weirdly, if the patient smokes, attacks are less likely to occur. If the patient stops smoking, they are more likely to experience an attack. -this is still under study-

• Colectomy cures intestinal disease only

Rule of surgery UC & CD

• Immune modulators and immune-suppressants.

• Surgery is reserved for complicated cases like strictures, stenosis, fistulas and fissures.

• Ulcerative Colitis: Colectomy is curative, since the disease is in the colon, the disease has no possibility in recurring if we remove the colon. - However, this solution is not suitable for Crohn’s Disease since the disease

may recur in any part of the GI tract. And so, you will not cure the disease.

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We have mentioned before that the most feared complication is neoplasia associated with inflammatory bowel disease.

Colitis-Associated Neoplasia

• Long standing UC and CD -associated more with UC-

• Begins as dysplasia and then progresses to carcinoma.

• Screening is very important, along with colonoscopy every 6 months to detect dysplasia and if dysplasia was found, management will be different.

Risk depends on

• Duration of disease: increase after 8-10 years

• Extent of involvement: pancolitis will set the patient to a higher risk than a disease that is just confined to the rectum

• Degree of active Inflammation: triggers mutations, increase of attacks and active inflammation increases chance of mutations leading to cancer. Frequency & severity of active disease can be measured by observing neutrophils.

• Early detection is protective. Detection in dysplastic stage before progression into invasive carcinoma. Surveillance programs approximately start 8-10 years after diagnosis

• Exception is with PSC (Primary Sclerosing Cholangitis) patients which is associated more with Ulcerative Colitis, screening starts early (at diagnosis) since they are more susceptible to colonic adenocarcinoma.

- Please understand the association of CD and UC with carcinoma very well.

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Polyps and neoplastic diseases

• Projection above the level of the mucosa

• Polyp can be benign or malignant, neoplastic or non-neoplastic

• Colon is the most common site of polyp.

• Polyp according to the configuration can be sorted depending on its architecture: 1. Sessile polyp: no stalk → elevation (dome shaped) 2. Pedunculated polyp: stalk → helps anchoring with underlying mucosa

Architectural configuration does not relate to the polyp being benign or malignant.

• Neoplastic polyps: adenoma. • Non-neoplastic polyps: inflammatory, hamartomatous, or hyperplastic

– benign course-

• The most important neoplastic polyp is the colonic adenoma because it is pre-cancerous, which is why we are undergoing screening and colonoscopy to detect colon cancer at this stage.

• Risk of adenoma increases with age, after the 5th decade, we start screening and we should immediately remove any observed adenoma.

Inflammatory Polyps

• Most likely to occur in the rectum

• Solitary rectal ulcer syndrome. • Caused by Recurrent abrasion and ulceration of the overlying rectal mucosa

leading to regenerative changes at that site which results in inflammatory polyp made of granulation tissue, fibrous tissue and inflammatory cells and so it projects above the surface of mucosa.

• We take a biopsy, and view it under the microscope, we will observe granulation tissue and ulceration → and so we call it inflammatory polyp

• It is benign

• Chronic cycles of injury and healing give a polypoid mass of inflamed and reactive mucosal tissue.

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Hamartomatous Polyps

• Hamartoma is disorganized, tumor-like growth composed of mature cell types normally present at that site.

• Hamartomatous polyps in the contains smooth muscles that are normally found in small intestine/colon.

• Sporadic or syndromatic (familial).

1. Juvenile Polyps (sporadic and familial) 2. Peutz-Jeghers Syndrome (Sporadic and familial)

• Familial: multiple which increases risk of colonic adenocarcinoma.

• Sporadic: just one polyp, in hamartomatous appearance, and is totally benign.

Juvenile Polyps

• Most common hamartomatous polyp • Sporadic are solitary, just one polyp. • Children younger than 5 years of age that

appears with rectal mass. • Most commonly in rectum. • Syndromic are multiple. • 3 to as many as 100. Mean age 5 years • Autosomal dominant syndrome of juvenile

polyposis syndrome • Transforming growth factor-β (TGF-β) mutation. • Increased risk for colonic adenocarcinoma. • Large polyp covered on the surface with granulation tissue, inflammation, blood

vessels, crypts and glands are dilated.

• During macroscopic examination crypts and gland are similar to cystic spaces.

• Pedunculated • Reddish lesions • Cystic spaces on cut sections • Dilated glands filled with mucin and inflammatory debris. • Granulation tissue on surface.

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Peutz-Jeghers Syndrome

• Autosomal dominant pattern of inheritance, rare • Mean age: 10-15 years -young age group- • Multiple gastrointestinal hamartomatous polyps • Most common in the small intestine. • Increased risk for several malignancies: colon, pancreas, breast, lung, ovaries,

uterus, and testes. • Mutation: LKB1/STK11 gene. – I don’t think you have to memorize it-

• Mucocutaneous hyperpigmentation

(brownish pigmentation on skin, mouth and mucus membranes)

Peutz-Jeghers polyp

• Large. • Christmas tree pattern. • Smooth muscles are very prominent arcades.

• Arborizing network of connective tissue, smooth muscle, lamina propria in between the crypts given the Christmas tree like appearance.

• Glands lined by normal-appearing intestinal epithelium. • They are benign, however if it was multiple non- sporadic

polyps, it increases the risk of colonic adenocarcinoma.

Good Luck.