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Pathology of the Large Intestine

last updated May 2015

J William, MD PhD



Anatomy of



Segmental Colonic Anatomy

Colon

Segment Serosa

Taenia

coli

Epiploic

appendages Mesentery Omentum

Ileum + - - + -

Appendix

+ + +/- + -Cecum + + - - -

Ascending + + + +/- -

Transverse + + + + +

Descending + + + +/- -

Sigmoid + + + + -

Rectum - - - - -

Anus - - - - -

In the sigmoid and transverse colons, the bowel is covered completely by visceral peritoneum (serosa), which is co

the mesentery. In contrast, the ascending and descending colon lie within the lateral peritoneal cavity with their p

lateral surfaces in the retroperitoneum. At these levels, the visceral peritoneum is only present anteriorly and med

true mesentery, since the developing mesentery has fused to the posterior parietal peritoneum. The upper portion

lies above the peritoneal reflection. The anterior surface is covered by peritoneum (which forms the rectovesical pthe rectouterine pouch in women); there is no serosa over its posterior surface.The lower rectum lies beneath the

and has no serosal layer.



LARGE INTESTINE ANATOMY

Rect

sp

Large intestine vascular supply



LARGE INTESTINE

Muscularis Propria

Submucosa

Muscularis Mucosa

Mucosa

(= Epithelium +Lamina propria)

Submucosa



NORMAL COLONIC MUCOSA

The crypts ar

linedpredominant

by goblet cel



Category Neoplasm Subtype

Benign • Hamartoma

• Hyperplastic polyp

• Sessile serrated polyp (adenoma)

• Conventional adenoma

• Hyperplastic/serrated polyp with dysplasia (mixed

hyperplastic/adenomatous polyp)

Malignant • Primary colorectal adenocarcinoma

• Other types of primary colorectal carcinoma

• Metastatic carcinoma



A GI polyp is defined as a mass that protrudes into the lumen of thPolyps can be subdivided according to:

1. Attachment to the bowel wall (e.g., sessile or pedunculated),

2. Histopathologic appearance (e.g., hyperplastic, adenomatous,

hamartomatous)

3. Neoplastic potential (i.e., benign or malignant).

By themselves, polyps are not often symptomatic. Their clinical

importance lies in their potential for malignant transformation and

association with certain genetic syndromes.



SESSILE VS. PEDUNCULATED POLYPS

SESSILE POLYP

PEDUNCULATED POLYP

Pedunculated po

slender fibromus

containing promi

vessels derived f

submucosa, whe

polyps tend to ha

appearance and d

a stalk.



An open metal snare is tightened

around the polyp stalk and anelectrical current is applied

through the metal loop of the

snare, which helps cut through the

stalk and cauterize blood vessels.

Endoscopic biopsy forceps.

An open metal snare.

S

The use of a biopsy forceps instead of a metal sn

cautery artifact. However, forceps can cause crus

For the removal of large polyps in on piece, the lo

cautery method is generally preferred.

Polyp removal by endoscopic snare polypectomy:



Cautery Artifact with Snare polypectomy

Areas of tissue that have been cauterized are

generally non-diagnostic, due to the oblitera

normal architecture by the cautery.

Note the “stretched out” appearance of all t

blue nuclei (yellow arrows) and loss of archit

details.

Cauterized Base from

polypectomy specimen

In some instances, cautery arti

useful in polypectomies remov

cautery because the cauterized

microscopically identify the ba

of the polypectomy specimen



Intestinal polyps can be classified as nonneoplastic or neoplastic. The nonne

polyps can be further defined as hyperplastic, inflammatory, or hamartomat• Hyperplastic polyps are benign epithelial proliferations most commonly found in t

colon and rectum. They have no malignant potential, and must be distinguished fr

serrated adenomas.

• Inflammatory polyps form as a result of chronic cycles of injury and healing.

•

Hamartomatous polyps occur sporadically or as a part of genetic diseases. The lat juvenile polyposis and Peutz-Jeghers Syndrome, which are associated with increa

malignancy.

• Benign epithelial neoplastic polyps of the intestines are termed adenomas. The ha

these lesions, which are the precursors of colonic adenocarcinomas, is cytologic dy

• In contrast to traditional adenomas, sessile serrated adenomas lack cytologic dysp

share morphologic features with hyperplastic polyps.

Taken from Robbins, Pathologic Basi

Benign proliferative lesions of the colon: Ke

concepts



Hyperplastic polyps are benign sessile polyps that have a regenerative appearance, show no features

They are the most common non-neoplastic polyp of the colon and >50% are found in the rectosigmo

They are usually small (< 5 mm), sessile, and have the same colour as the surrounding mucosa.

Unlike adenomas, there are numerous goblet cells within these polyps and the nuclei are small, basal

and show no pseudostratification. Unless associated with a syndrome, these lesions generally carry nomalignancy and do not warrant extra screening.

http://www.pathology.pitt.edu

HAMARTOMATOUS POLYPS IN PEUTZ JEGHERS SYNDROME

http://www.pathology.pitt.edu/




JUVENILE POLYPOSIS COLI: A syndrome chara

hamartomatous polyps, especially in the rectos

polyps are not pre-malignant and are fewer inJuvenile polyps are benign hamartomatous polyps . Grossly, they are

appear rounded and smooth with an erythematous cap of eroded tissue.

HAMARTOMATOUS POLYPS IN PEUTZ-JEGHERS SYNDROME

Peutz-Jegher’s syndrome is an autosomal dominant hereditary

disorder characterized by intestinal hamartomatous polyps and

mucocutaneous melanin pigmentation, which is most evident on the

buccal mucosa. The polyps occur mostly in the proximal small

intestine but are sometimes seen in the stomach and the colon.

Patients have symptoms of obstruction or intussusception in up to ¼ of

cases. However, the diagnosis is more often suspected when there isabnormal pigmentation in an otherwise asymptomatic person.

Peutz-Jeghers polyps are generally considered benign, but 3% of

patients develop adenocarcinoma, although not necessarily in the GI

tract. They are at increased risk of developing cancers in the breast,

pancreas, testis and ovary The intestinal polyps should only be resected

if they are causing symptoms.

Hamartomatous


JUVENILE POLYPS





Inflammatory polyps & in

pseudopolyps are most c

seen in conditions such acolitis.

Microscopically, they usu

regenerative crypts in an

inflammatory background

neutrophils).

In ulcerative colitis, the se

inflammation results to u

large areas of mucosa. Ad

islands of non-eroded mu

therefore appear as poly

projections adjacent to th

mucosa. Hence the term

Eroded mucosa

Inflammatory pseudopolypsEroded mucosa



Adenomas are intraepithelial neoplasms that may range from small, often pedunculated polyps to

lesions. Colorectal adenomas are characterized by the presence of epithelial dysplasia. They are

50% of > people over the age of 60. Most intestinal adenomas (90%) are found in the colon, with

half being found in the rectosigmoid area. Most adenomas are clinically silent (and therefore candetected by screening colonoscopy). Larger adenomatous polyps can sometimes cause occult ble

patients presenting with anemia.

Adenomas are regarded as pre-malignant, and a fraction of them will progress to colorectal ade

Although most adenomas do not progress to colorectal cancer, there is currently no way of dist

between those that would progress towards malignancy and those that would not progress. It is t

generally recommended that adults screen for these lesions by surveillance colonoscopy startin

at least 10 years earlier if there is a significant family history). Polyp size, architecture and degreedysplasia are the main determinants of malignancy risk in these polyps

SCREENING FOR COLON CANCER

Colorectal cancers develop insidiously and may therefore go undetected for long periods. The

of endoscopic screening combined with the recognition that most carcinomas arise within ad

presents a unique opportunity for cancer prevention. Studies have demonstrated that regulasurveillance colonoscopy with polyp removal reduces the incidence of colon cancer.



**Despite the risk differences between villous and tubular

adenomas, these factors do not carry much clinical

significance by themselves. Other factors such as size, number

of polyps & grade of dysplasia carry more significance.

This particular tubular adenoma has a “stalof normal colonic mucosa (white arrows), mentire lesion easy to resect endoscopically

Adenomas can be further subclassified according to

architectural features:

• Tubular adenomas: The most common types of

adenomas. They can be pedunculated or sessile & are

composed mainly of rounded or tubular glands

• Villous adenomas: These are generally sessile, larger

(than tubular adenomas) & covered by long slender

villous projections.The gross figures on the right show

a large cauliflower-like mass in the rectosigmoid area

and the cut surface of a villous adenoma showing the

finger-like projections. These tumors secrete mucous

rich in potassium & protein. They are less commonthat tubular adenomas but have a higher risk of

developing into adenocarcinoma

• Tubulovillous adenomas: Contain mixed villous &

tubular features.

Normal

stalk

Aden

Villous adeno

Tubular adenoma

Vi

COLON ADENOMAS MICROSCOPIC FEATURES (HIGH PO



COLON ADENOMAS: MICROSCOPIC FEATURES (HIGH PO

Fle

ht

e/

Normalcrypts

Microscopically, by definition, all adenomas contain at

least low-grade (mild) dysplasia. This is characterized by:1. Nuclear hyperchromasia (darker colour)

2. Nuclear elongation and pseudostratification, with partial loss of

nuclear polarity.3. Paucity or absence of goblet cells (compare to normal crypts

that have numerous goblet cells)

The dysplasia shown in these images is classified as low grade. In higher

grade dysplasia, the nuclei are larger, show more atypia and loss of nuclear

basal polarity (see next page). Most adenomas have low grade dysplasia.

Normal

crypt Dysplasticcrypts

Nuclear pseudostratification



Histologic features of high grad

in colonic adenomas:

• Loss of nuclear polarity

• Increased nuclear atypia (also nucl

“rounder”)

• Marked nuclear pleomorphism

• Increased crowding of glands (note

glands are back-to-back)

• The atypical cells are still confined

basement membrane and do not i

lamina propria (If the cells invade t

propria, the lesion is upgraded to aadenocarcinoma)

By definition, all adenomas contain at least low-grade (mild) dysplasia. Dysplasia in adenomas

classified as low (mild, moderate) or high grade (severe, including carcinoma in situ). The grad

determined by cytologic and architectural features. High grade lesions have a much higher ris

adenocarcinoma.

Ad



Adenoma w

grade dy

Low grade

dysplasia



Sessile serrated adenomas (SSA), also called sessile

serrated polyps (SSPs) and are also considered

premalignant polyps. They predominantly arise in thececum and ascending colon. However, unlike the

conventional adenomas, they generally don’t show any

nuclear abnormalities like hyperchromasia and

pseudostratification. Instead, their microscopic appearance

more closely resembles hyperplastic polyps and can easily

be misdiagnosed as hyperplastic polyps.

They are thought to transform into colorectal carcinomas

through an alternative pathway called the “serrated

pathway”. Like conventional adenomas, their presence

warrants increased surveillance, and follows the same

guidelines.



Low-risk patients Follow-up colonoscopy in 5-10 yr. Based partially on clinical judgment, patient comfort, and

High-risk patientsFollow-up colonoscopy in 3 yr, assuming polypectomy was not piecemeal and adenomas w

removed. If follow-up endoscopy is normal or reveals only 1 to 2 small low-grade tubular a

exam in 5 years.

Small hyperplasticrectal polyps

Repeat colonoscopy in 10 yr, as in average risk guidelines.

Guidelines for Post-polypectomy Surveillance after Initial Colon(assuming no malignancy & that colonoscopy was thoroug

Low Risk features High Risk features1. No adenomatous polyps

2. 1-2 small (<1 cm) tubularadenomas w/low-grade

dysplasia

1. 3 to 10 adenomas

2. Any adenoma > 1 cm

3. Adenoma w/villous features

4. Adenoma with high-grade dysplasia

Although most adenomas do not p

adenocarcinomas, there is curren

distinguishing between those that

towards malignancy and those thaHowever, features such as size, ar

degree of epithelial dysplasia can

malignanct potential. These facto

used to guide clinical managemenVillous adenomas have a higher risk of malignancy, especially when greater than

4 cm, whereas tubular adenomas have a lower risk, especially if < 1 cm.



CARCINOMAS OF THE COLON

COLORECTAL CANCER



The majority of colon cancers are adenocarcinomas. It is the most common malignancy of the G

a major contributor to morbidity and mortality worldwide. In Barbados, colorectal cancer is re

for approximately 4 % of deaths. By contrast, the small intestine is an uncommon site for benig

malignant tumours.

CLINICAL PRESENTATION: Most early colorectal cancers are asymptomatic: Outcomes are best when colorectal cancers are

while patients are still asymptomatic. Most common symptoms include hematochezia , melena,

pain, iron def. anemia and/or a change in bowel habits.

Left-sided tumours present sooner by causing obstruction as fecal material is more solid at that p

complain of changes in bowel habits, cramping, constipation or left lower quadrant discomfort.

Right-sided tumours present later because the fecal material is more liquid at that point in transdon’t cause obstruction. Patients more commonly present with fatigue and weakness due to iron

anemia. It is a clinical maxim that the underlying cause of iron deficiency anemia in an older m

postmenopausal woman is colon cancer until proven otherwise.

Hematochezia is more likely with rectal cancers but occult colonic bleeding is more common wit

ascending colon cancers.

1/5 patients with CRC present with metastatic disease. Most common sites: regional lymph no

to the portal circulation), lungs, & peritoneum. Population screening of asymptomatic individu

colorectal cancer therefore significantly reduces incidence and mortality from colorectal carcin

COLORECTAL CANCER



RISK FACTOR/PROTECTIVE FACTORSRelative Risk

Colorectal Ca

Family history (first degree relative) 1.8

Physical inactivity (less than 3 hours/week) 1.7

Inflammatory bowel disease (Crohn's, ulcerative colitis) 1.5

Obesity 1.5

Red meat 1.5 Smoking 1.5

Alcohol (more than 1 drink/day) 1.4

High vegetable consumption 0.7

Oral contraceptive use (5 or more years of use) 0.7

Multivitamins & folic acid 0.5

Th ibl l f i t l f t i t d b th hi h i id f t



SYNDROME Gene DefectColorectal cancer

Carriers

Familial adenomatous polyposis (FAP) APC >90% by 40 yr

Attenuated familial adenomatouspolyposis APC <90% by 70 yr

Juvenile polyposis syndrome SMAD4, BMPRIA

Peutz-Jeghers syndrome STK/LKB

Hereditary nonpolyposis colorectal

cancer (HNPCC)(Lynch syndrome)

MLH1, MSH2, PMS2,

MSH6 50%-90% by 70 yr

CANCER RISK IN GENETIC SYNDROMES ASSOCIATED WITH COLORECTA

The possible role of environmental factors is suggested by the high incidence of t

industrialized countries and among emigrants from low-risk to high-risk regions.

animal fats and low in indigestible fiber have been implicated as risk factors.

Adenocarcinoma pathology



Adenocarcinoma pathologyGrossly, colorectal cancers resemble adenocarcinomas

elsewhere in the gut. They tend to be polypoid and

ulcerating or infiltrative. They may also form annular and

constrictive lesions. Polypoid cancers are more common in

the right colon, particularly in the cecum, where the large

caliber of the colon allows unimpeded intraluminal growth.

Annular constricting tumours are more common in the

distal colon. Ulceration of tumours, regardless of growth

pattern, is common. About 25% of colon carcinomas are

located in the cecum or ascending colon.

Polypoid

Exophytic

This specimen from the left colon shows an annular,encircling, and constricting cancer, presenting with

symptoms of obstruction.

Spot radiogra

enema showi

adenocarcino

with circumfe

of the lumen

“apple core le



In addition to the classic tubular architecture, colorectal adenocarcinom

can have other morphologies (e.g. papillary, mucinous, etc.

Tubular Papillary

Mucinous features



Mucinous featuresSome colerectal tumours are composed of large amounts of mucin due to excessive secretion

malignant cells and are referred to as “mucinous adenocarcinomas” Note how the cells appe

floating in large pools of mucin (the white areas). The mucous secreting cells have large cytop

vacuoles filled with mucin and are often referred to as signet ring cells (such as the signet rin

Linitis plastica/diffuse type adenocarcinomas of the stomach.

Signet Ring

cells

Low magnification Intermediate magnification High magnification



THE Liver is the most common site of systemic metastasis in

patients with colorectal adenocarcinoma

MEDICAL MANAGEMENT OF COLON CANCER:



MEDICAL MANAGEMENT OF COLON CANCER:The only curative treatment for colorectal cancer is resection. Small pedunculated polyps can sometim

removed endoscopically as long as they don’t have certain features (see panel below). However large le

require segmental resection. The goal of a (partial) colectomy for colon cancer is to achieve complete r

the tumor, its major vascular supply & the regional lymph nodes and associated lymphatic drainage. Re

mesenteric lymph nodes include those nodes along the course of major mesenteric vessels and the vas

of the marginal artery, as well as those adjacent to the colon along its mesocolic border.

The blood vessels are divided at their origin in order to obtain a wide resection and maximize the num

nodes removed. Ideal margins are usually at least 5 cm from the tumor. Tumours close to the anal sphi

often excised with closer margins to preserve sphincter function. Patients may require post-operative

chemotherapy and/or radiotherapy, depending on the findings in the serugical specimen (i.e. the stging

MANAGEMENT OF SMALL MALIGNANT POLYPS REMOVED

ENDOSCOPICALLY: Small endoscopically removed polyps can

sometimes be removed entirely endoscopy without further

treatment. However, if they have any of the features listed

below, surgery is generally recommended.

• The cancer is poorly differentiated (Grade III)

• There is evidence of vascular or lymphatic invasion

• If there are close (<2 mm) or positive resection margins, or

polyp was removed in multiple pieces, preventing easyassessment of margins.

Lymp

Invas

an un

histol

Note

lthe l

vesse

SURGICAL MANAGEMENT OF COLON CANCE



SURGICAL MANAGEMENT OF COLON CANCE

Blood supply to the colon originates from the superior mesenteric artery and inferior mesenteric arte

Appropriate surgical resection for an adenocarcinoma in the cecum or ascending colon will include rthe regional draining lymph nodes and division of the vascular bed supplying the region, as shown ab

MANAGEMENT OF RECTAL ADENOCARCINOMAS



Rectal tumours are generally associated with higher morbidity than right-sided tumors. The traditiona

tumors close to the anal verge has been an abdominal –perineal resection (APR), which involves the re

sigmoid colon , rectum and anus, and construction of a permanent colostomy. Because of the substant

of these procedures, local excision, rather than standard cancer resection, may be justified, to preserve

function.

Traditional APR involves resection ofthe sigmoid colon, rectum & anus

Rectal cancers have higher morbidity

to the anal sphincters. Aggressive T4

invade adjacent structures like the v

the vaginal wall and rectovaginal septhe prostate and seminal vesicles in

Alternatives to APR for Rectal Carcinomas



An APR is favored over a sphincter sparing procedure when there is:

• Disease involvement of the anal sphincter musculature or rectovaginal septum.• Poor continence preoperatively, or diarrheal disorders, where a low anastomosis would lead to feca

Local excision, transanal approach

Sphincter-sparing procedure with a

colonic J pouch

Sphincter-sp

procedure as

alternative toThe construc

serves as a re

Newer surgical techniques that preserve the anal sphincter, are becoming more popular, but are genera

recommended if the tumour is low in the rectum and involves the anal sphincter or the rectovaginal se

females. Also, the use of neoadjuvant chemotherapy and radiotherapy (neo= before surgery) improves

prognosis with these tumours.

MEDICAL MANAGEMENT OF COLON CANCER (co



MEDICAL MANAGEMENT OF COLON CANCER (co

CHEMOTHERAPY AND RADIATION FOR COLON CANCER

• For patients who have undergone potentially curative resection of a c

cancer, postoperative (adjuvant) chemotherapy is recommended,

especially with patients with stage III (node-positive) diseases.

• Most patients presenting with systemic metastasis are not surgical

candidates, and palliative chemotherapy is instead recommended. Ho

surgical resection may occasionally be performed for selected patient

limited metastatic disease in the liver or lung.

• The most important indicator of outcome following surgery, is the

pathologic stage. In the absence of systemic (organ) metastasis the

presence or absence of lymph node metastasis (N) is the best predic

prognososis, followed by depth of tumour invasion (T).

CLINICAL MANAGEMENT OF COLORECTAL CANCER IS GENERALLY DEPEND

CLINICAL AND PATHOLOGIC STAGE WHICH DETERMINE PROGNOSIS



CLINICAL AND PATHOLOGIC STAGE WHICH DETERMINE PROGNOSIS

TUMOUR (T)

Tis In situ dysplasia or intramucosal carcinoma

T1 Tumour invades submucosa

T2 Tumour invades into, but not through, muscularis propriaT3 Tumour invades through muscularis propria

T4a Tumour invades adjacent organs or structures.

T4b Tumour invades visceral peritoneum (serosa)

Lymph nodes (N)_

NX Lymph node cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis in one to three regional lymph nodes

N2 Metastasis in four or more regional lymph nodesDistant Metastasis (M)

MX Distant metastasis cannot be assessed

M0 No distant metastasis

M1 Distant metastasis or seeding of abdominal organs

Tumour-Node-Metasta

(TNM) Criteria

STAGE T N MI T1, T2 N0 M0

IIA T3 N0 M0

IIB T4 N0 M0

IIIA T1, T2 N1 M0

IIIB T3, T4 N1 M0

IIIC Any T N2 M0

IV Any T Any N M1

. CLINICAL STAGING

Clinical stage is determined by pathologic staging. For example, a tumour that invades into but not thro

propria and has metastasis in one regional lymph node gets the pathologic stage of T2 N1 MX , which t

clinical stage IIIA. These patients have a 5 year survival of 73%. The clinical stage helps determine howtherapy should be. In the absence of distal metastasis, nodal status is the next most important predict

as shown in the table.

Adapted from Robbins, Basic Path

PATHLOGIC TNM STAGING

TUMOUR T STAGING



In adenocarcinomas, the T stage in (TNM staging) is based

primarily on the depth of invasion of the tumour.

Tis/ Clinical stage 0

T1 tumor invades submucosa

T2 tumor invades into but not

the muscularis propria.

Tis: Adenocarcinomas that invade the lamina propria but do

not invade the submucosa are called intramucosal

adenocarcinomas. Even though these tumors are invasive,

they are assigned the same T grade as in situ neoplasms Tis),

and get the clinical stage of 0, because their likelihood ofsystemic and regional node metastasis is extremely low.

TUMOUR STAGING SHOWING DIFFERENT DEPTHS OF TUMOUR INVAS



T3 tumor invades through

muscularis propria into subserosa

or into nonperitonealized pericolic

or perirectal tissues (adventitia).

Muscularis

propria


The adjacent microscopic figure

shows a T3 invasive adenocarcinoma

invading through the muscularis

propria, gaining access to vascular

channels (arrow) leading to

hematogenous dissemination

T4b tumor involvinperitoneum (seros

T4a tumor directly

adjacent loop of bo

Tumour

Muscularis

propria

T3

ROLE OF MOLECULAR DEFECTS IN THE DEVELOMPMENT OF COLORECTAL CANCER





As shown in the table below, approximately 90% of colon cancers arise due to sporadic

and ~ 10% are due to familial (inherited defects). There are two major pathways: The

APC/WNT pathway, which appears to be responsible for ~ 80% of colorectal carcinomas

the DNA mismatch repair pathway that is responsible for 15-20% of colorectal carcinom

GENETIC PATHWAYS TO COLORECTAL CANCER



In 85% of cases of colorectal carcinoma, it has been estimated that at least 8 to 10 mutational events m

accumulate before an invasive cancer with metastatic potential develops. This process is initiated in his

normal mucosa, proceeds through an adenomatous precursor stage and ends as invasive adenocarcino

APC/WNT PATHWAY (most common)

MISMATCH REPAIR DEFECT PATHWAY



MISMATCH REPAIR DEFECT PATHWAY

LOH = Loss of heterozygosity

The APC/WNT and the MISMATCH REPAIR PATHWAY



MISMATCH REPAIR PATHWA

This pathway involves defects in the g

MLH1, MSH6, PMS2) which encode mproteins required during DNA replicat

In 15% of colorectal cancers, DNA repa

leading to defective correction of spon

replication errors, particularly in simple

sequences (microsatellites), resulting i

instability (MSI). MMR defects can be

sporadic:

• In hereditary Warthin-Lynch syndro

germline mutation in an MMR gene i

loss of heterozygosity (LOH) later in l

• In a sporadic form, hypermethylatio

promoter of the MMR gene MLH1 , in

transcription of the gene.

THE APC/WNT pathway

The early event in this pathway involves a defect in the

APC (Adenomatous polyposis coli) gene. This defect can

either be inherited or occur somatically as an epigenetic

event (typically by methylation of its promoterThe APC gene is a putative tumour suppressor gene that

appears to play an important role in the early development

of most colorectal epithelial neoplasms (adenomas &

adenocarcinomas). It normally functions as a negative

regulator of Beta-catenin by preventing it from activating

key proliferative genes such as Cyclin D1 and MYC. Mutant

APC, however, allows Beta-catenin to accumulate in thenucleus, thus leading to increased activation of cell-cycle

promoters.

Evidence of the importance of APC:

• Most sporadic colorectal cancers have APC mutations.

• Somatic APC mutations appear to precede the

development of sporadic adenomas.

• FAP (familial adenomatous polyposis) patients havegermline APC mutations.



OTHER IMPORTANT GENES INVOLVED IN DOWNSTREAM EVENT

Ras ONCOGENE:

Activating mutations of the ras proto-oncogene occur early in tubular adenomas

DCC (“DELETED IN COLON CANCER”) GENE:

A putative tumour suppressor gene often deleted in colorectal cancers.

P53 GENE

P53 mutations are a late event in the carcinogenic pathway and appear to play an

important role in the transition from adenoma to carcinoma .

Familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal canc



FAP, also termed adenomatous p

(APC), accounts for less than 1% o

cancers. It is caused by a germlin

the APC gene. Most cases are fam

30%-50% reflect new mutations.

FAP is characterized by hundredsof colorectal adenomas. Polyps st

during childhood, but the mean a

occurrence of symptoms is 36 ye

time cancer is often already pres

Carcinoma of the colon and rectu

inevitable, with a mean age of o

years. Total colectomy before thecancer is curative.

FAMILIAL ADENOMATOUS POLYPOSIS (FAP)

FAP colon with thousands of adenomas.


(HNPCC) are the most common forms of familial colon cancer. FAP and HNPCC typify

pathways of neoplastic transformation and progression that also contribute to

the majority of sporadic colon cancers.

HEREDITARY NON-POLYPOSIS COLORECTAL CANCER (H





HNPCC, or Warthin-Lynch syndrome, is an autosomal dominant inherited

disease caused by mutations in a mismatch repair (MMR) protein. It accou

3% to 5% of all colorectal cancers. It is characterized by:1.Cancer at a young age,

2.Few adenomas (hence “non-polyposis”),

3.A high frequency of carcinomas proximal to the splenic flexure (70%)

4.Multiple synchronous or metachronous colorectal cancers5.Extracolonic cancers, including endometrial and ovarian cancers;

adenocarcinomas of the stomach, small intestine and hepatobiliary tract

transitional cell carcinomas of the renal pelvis and ureter.

Generally colorectal cancers should be tested for the MMR defects if diag

in patient under 50, or having any of the above characteristics.

HEREDITARY NON POLYPOSIS COLORECTAL CANCER (H

Microsatellite instability (MSI), mismatch repair (MMR) genColorectal Carcinoma and HNPCC



Microsatellites are ubiquitous compon

genome comprised of tandemly repeated

sequence motifs (e.g. AAAAAAAAA, GTCG

CTAGCTAGCTAG, etc.) that can sometime

100x. These tandem repeats are highly vu

strand slippage during the reannealing ste

replication. In the absence of functional M

this slippage is not properly repaired.

Microsatellites are typically located in no

regions, so most of the insertions & delet

result from strand slippage are silent.

However, some microsatellites are locate

coding and promoter regions of genes tha

growth, like the gene encoding the type II

receptor. TGF-β normally inhibits colonic

proliferation, and mutants of this gene ca

to uncontrolled growth.

(HNPCC) is caused by germline mutations in one of

the mismatch repair genes hMSH2, hMLH1, hMSH6

or PMS2.

Mismatch repair defects during DNA replication lead

to microsatellite instability (MSI), in which areas rich

in microsatellite repeats are at increased risk of

developing insertion or deletion mutations. These

patients are at increased risk of having colon cancer. In

general, patients <50 presenting with colon cancer

should be screened for mismatch repair defects. If

they turn out to have a germline defect, then family

members should be tested and regularly screened

from an early age where applicable.

15-20% of sporadic colorectal cancers have

microsatellite instability: Patients who don’t have

familial HNPCC can acquire sporadic defects in one of

the MMR proteins. This most commonly happens by

promoter methylation of the MLH1 locus, whichprevents transcription of MLH1.

Microsatellite instability (MSI), mismatch repair (MMR) genColorectal Carcinoma and HNPCC

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Mechanism of strand slippage: Strand slippage

insertions or deletions that are multiples of the

being repeated. e.g.. dinucleotide or trinucleoti

produce insertions or deletions that are multipl

three, respectively. In patients with MMR gene

there will be a high number of these insertions

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Tumors should be tested for Microsatellite ins

in the following situations:

1. Colorectal cancer is diagnosed in a patient < 50 y

2. Presence of synchronous, metachronous colorectHNPCC-associated tumors, regardless of age.

3. Colorectal cancer with the MSI-High-like histology

patient > 60 years of age (Usually tumours due to M

a specific histologic appearance)

4. Colorectal cancer diagnosed in a patient with one

degree relatives with an HNPCC-related tumor, with

cancers being diagnosed under age 50 years.

5. Colorectal cancer diagnosed in a patient with two2nd-degree relatives with HNPCC-related tumors, re

NON NEOPLASTIC DISEASES OF THE





NON-NEOPLASTIC DISEASES OF THE

LARGE INTESTINE

• Inflammatory Bowel disease (IBD)Ulcerative Colitis

Crohn Disease (Includes small intestine)

• Toxic Megacolon

•Microscopic Colitis

• Irritable Bowel Syndrome (IBS)

• C.Difficile/Pseudomembranous colitis

• Diverticulosis/Diverticulitis

• Ischemic Colitis and Enteritis

CONGENTICAL/PEDIATRIC

• Hirschsprung’s

• Necrotizing enterocoliti

INFLAMMATORY BOWEL DISEASE



• Inflammatory bowel disease (IBD) is a chronic condition resulting from inappropria

mucosal immune activation. It comprises two different diseases: Crohn disease an

Ulcerative colitis. The distinction between the two is based, in a large part on the

distribution of affected sites and morphologic features.• The cause(s) of IBD remains uncertain. However, most investigators believe that IB

from a combination of the following:

Abnormal host interactions with intestinal microbes,

Intestinal epithelial dysfunction

Aberrant mucosal immune responses.• One theory involves the “Hygiene hypothesis” which proposes that a reduced freq

enteric infections due to improved hygiene has resulted in inadequate developme

regulatory processes that limit mucosal immune responses. As a result, exposure o

susceptible individuals to normally innocuous microbes later in life triggers inappro

immune responses.

• Immunosuppressive & immunomodulatory agents are the mainstays of IBD therap

ULCERATIVE COLITIS CROHN DISEASE

Ulcerative Colitis vs. Crohn disease



ULCERATIVE COLITIS CROHN DISEASE

Only the colon is affected (& occasionally a small portion

of terminal ileum due to “backwash ileitis) The rectum is

the most often affected site

Can affect anywhere from the mouse to anu

ileum is most often involved

Only small intestine affected in ~40% of case

Colon only in ~30% of cases

Both small intestine & colon: ~30% of cases

Diffuse, continuous disease Segmental disease/”skip lesions”

Rectum most often involved Terminal ileum most often involved

Disease worse distally Variable disease severity

No fissures or fistulas

Fissures, sinuses, fistulous tracts (eg. Entero

rectovaginal fistulas, entero-vesicular fistula

Inflammation only involves the mucosa and submucosa. Transmural inflammation

Microscopic: Superficial acute & chronic inflammation,

crypt-abscess, mucosal ulceration, inflammatory polyps &

pseudopolyps

Epithelioid granulomas unrelated to rupture

Serious complications: Toxic megacolon, Colorectal

adenocarcinoma. Cancer risk: 5-30%.

Serious Complications: Obstruction, Fistulas,

abscesses (e.g. peri-rectal). Colon cancer risk



CHRON DISEASE V

ULCERATIVE CO



SYMPTOMS: Characterized by relapsing, bloody mucoid diarrhea with pain/cramps

relieved by defecation; Symptoms can last for days or months and are followed by p

remission lasting months to years.DIAGNOSIS: Definitive diagnosis is made by noting diffuse disease limited to the col

disease shows rectal involvement and extends proximally in a continuous manner.

Unlike Crohn, there are no skip lesions, fissures, sinus tracts or granulomas. Microsc

disease is superficial and limited to the mucosal layer. This contrasts with Crohn dis

which has transmural involvement.

Ulcerative colitis is characterized by chronic diarrhea and rectal bleeding with a

exacerbations and remissions and with the possibility of serious local and syste

complications. Symptoms usually begin in early adulthood, with diffuse diseas

usually begins in the most distal part of the rectum and extends proximally wit

CLINICAL PRESENTATION

ULCERATIVE COLITIS: Gross features

Ul ti liti i h t i d b i fl d d



Ulcerative colitis is characterized by an inflamed and

damaged mucosa. The lesions are continuous and first extend

in the rectum and extend proximally. Therefore, in the vast

majority of cases, the severity of inflammation in ulcerative

colitis gets progressively worse going from proximal to distal.

The rectum is almost always involved in patients with

ulcerative colitis. However, there are a few exceptions

characterized by absence or decreased rectal involvement

relative to the rest of the colon, referred to as “rectal sparing”.

In some cases, this is a result of the use of topicl treatements

with 5-aminosalicylic acid (ASA) administered as a rectal

suppository or the use of steroid enemas. In both cases, therectum is most likely to benefit from this form of

administration. The other reasons for rectal sparing are less

well understood, but they appear to happen more often in

pediatric patients.

The adjacent total colectomy shows a diffusely inflamed mucosa

often described as a “cobblestoned appearance”. Note that thececum has the least inflammation in this example. o

Endcoscopic appearance of ulceshowing a granular erythematoumore severe forms, the mucosa and pseudopolyps will be presen

SEVERE ULCERATIVE COLITIS WITH NUMEROUS PSEUDOP



The “pseudopolyps” characteristically s

severe ulcerative colitis are not real poly

represent islands of inflamed mucosa th

yet been eroded. The flat surrounding a

represent areas where the mucosal laye

eroded down to the muscularis mucosa

Areas of completely

eroded mucosa

Pseudopolyps

ULCERATIVE COLITIS: MICROSCOPIC FEATURESMicroscopic features of



(Left) Mucosal biopsy of th

low power: The crypts are

architecturally distorted a

previous injury. (Right)

Crypt distortion

Microscopic features of

ulcerative colitis include

1. Mucosal congestion, e

microscopic hemorrha

2. A diffuse chronic inflainfiltrate in the lamina

3. Damage and distortio

Architectural changes

for the diagnosis of IB

are consistent with ch

ULCERATIVE COLITIS: MICROSCOPIC FEATURES: high pow



The lamina propria shows an increase in

acute and chronic inflammatory cells. A

mucosal crypt is distended by a

collection of neutrophils, known as a

crypt abscess. The presence ofneutrophils in damaged crypt is a sign of

active inflammation.

Crypt abs

COMPLICATIONS AND EXTRA-INTESTINAL MANIFESTATIONS OF ULCERAT

EXTRA INTESTINAL MANIFESTATIONS ACUTE & CHRONIC COMPLICATIONS OF



• Colorectal Cancer: Individuals with long-sta

have a much higher risk of colorectal cance

increased risk). Therefore, patients with UC

regular cancer surveillance. Some will even

require a prophylactic total proctocolectom

• Severe diarrhea and electrolyte disturbanc

• Hemorrhage, with or without resulting ane

• TOXIC MEGACOLON with perforation leadi

possible sepsis and death. Toxic megacolonsetting of fulminant colitis and is characteri

marked dilatation of the colon, thinning of

wall, and deep ulcers. Histologically, thre is

inflammation in all layers of the colon with

degrees of degeneration & necrosis. Patien

are at greatest risk for developing toxic meearly in their disease

EXTRA INTESTINAL MANIFESTATIONS

• Arthritis is seen in 25% of patients

with ulcerative colitis

•

Eye inflammation (mostly uveitis )and skin lesions develop in about

10% of patients. The most common

cutaneous lesions are erythema

nodosum and pyoderma

gangrenosum

•

Hepatobiliary disease occurs inabout 4% of patients, most

commonly primary sclerosing

cholangitis .

• Thromboembolic phenomena (e.g.

DVTs of the lower extremities)

ACUTE & CHRONIC COMPLICATIONS OF

One of the most feared long-term complications of IBD is the development of neoplasia. This risk is mo

h l l h d d b d l h h d l l



Ulcerative colitis patients with flat dysplasia (low or

high grade) are at a high risk of developing

adenocarcinomas. High grade flat dysplasia is often

an indicator for total colectomy.

Flat dysplasia is more concerning than the more

common polypoid dysplasia (e.g. tubular adenomas).

These areas cannot be identified grossly and are

generally only picked up during random surveillance

biopsies in IBD patients.

If a lesion in a UC patient is biopsied and found to

have an area of dysplasia, the dysplastic focus can be

treated like a typical adenoma and removed via

endoscopic polypectomy. However, if the lesion is

not polypoid then the recommendation is to treat it

like an area of flat dysplasia, which often requires a

colectomy

Flat Dysplasia in Ulcerative ColitisDysplasia in a area (flat dysp

ULCERATIVE COLITIS SHOWING CRYPT DISTORTION, INFLAMMATION AND FLAT DYSPLASIA

Non-dysplasticcrypts

patients with ulcerative colitis. The cancers are preceded by dysplasia, which tends to arise in multiple

sites. The risk of cancer is highest in patients with pancolitis of ten or more years duration. Their cancer

30 X higher than the general population.

CROHN DISEASECrohn’s disease is aserious, chronic, progressive inflammatory disorder of the lower intestinal

i l i th t i l ti f th il d h t i d b f i ht l f



Essentials of Rubin’s Pathology

A schematic representation of the major features of Crohndisease in the small intestine.

Unlike ulcerative colitis, Crohn disease can inv

in the GI tract. It most commonly affects the i

cecum. Grossly, it is characterized by thickeniwall, strictures, fistula formation, and fat wra

The bowel wall is usually firm and stiff becaus

combination of fat wrapping, submucosal fibr

hypertrophy of the muscularis propria.

Fat wrapping, or “creeping fat,” is the term us

adherence of mesenteric adipose tissue to th

and is usually associated with transmural inflathe underlying bowel segment. Bowel loops f

adhere to one another via mesenteric fat. Wh

fistula tracts can extend from one segment to

other abdominal organs.

It is especially common to find a diseased seg

to a normal segment of bowel. Enlarged mese

nodes are usually noted as well.

involving the terminal portion of the ileum and characterized by nausea, fever, weight loss, fre

of diarrhea, abdominal pain, ulceration, and fibrous tissue buildup.

CROHN DISEASE: Clinical featuresClinical manifestations of Crohn disease are extremely variable. In most patients disease begins with in



attacks of relatively mild diarrhea, fever & abdominal pain. ~ 20% of pts present acutely with right low

pain, fever & bloody diarrhea that may mimic acute appendicitis or bowel perforation. Periods of activ

typically interrupted by asymptomatic periods lasting weeks to months. Various external triggers, inclu

emotional stress, specific dietary items & cigarette smoking are associated with disease re-activation.

OTHER CLINICAL FINDINGS:

• Nutritional deficiencies : Iron-deficiency anemia (if there is colonic disease). Extensive sm. bowel dise

in serum protein loss, hypoalbuminemia, general nutrient malabsorption, or malabsorption of vit B12

• Fibrosing strictures, particularly of the terminal ileum, are common and require surgical resection. D

recurs at the site of anastomosis, and up to 40% of patients require additional resections within 10 ye

• Fistulae develop between loops of bowel and may also involve the urinary bladder, vagina (e.g. recto

fistulas), and abdominal or perianal skin (enterocutaneous fistulas) . Perforations and peritoneal absc

common.

• Extraintestinal manifestations: Uveitis, migratory polyarthritis, ankylosing spondylitis, erythema nod

clubbing of fingertips. Pericholangitis and primary sclerosing cholangitis occur in Crohn disease with

frequency. However, the relationship with PSC is more striking with pateints who have ulcerative colit

AFFECTED INDIVIDUALS: Female > males, caucasions> non-caucasions. The age distributionis bimodal d

Peak occurences between ages 10 & 30 and ages 50 &70.

TREATMENT: Anti-TNF antibodies have revolutionized treatment of Crohn disease.

Crohn's disease



This portion of terminal ileum demonstrates the gross findings withCrohn's disease. Though any portion of the gastrointestinal tract may be

involved with Crohn's disease, the small intestine--and the terminal ileum

in particular--is most likely to be involved. The specimen is a section of

thickened ileum, The intestinal wall is thick, the result of edema,

inflammation, fibrosis, and hypertrophy of the muscularis propria. Linear

ulcers are typically present in the diseased segment of bowel. Note the

area of normal adjacent intestinal mucosa.

“String sign” sh

narrowing of te

CROHN DISEASE: Gross features

Gross specimen of Crohn’s colitis showing deep ulcers extending along the longitudin

bowel, with a cobblestone appearance of t



Serositis with creeping fat.

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Area of colonic stenosis in Crohn

Linear Fissures

FISTULA FORMATION IN CROHN DISEASE

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FISTULA FORMATION IN CROHN DISEASE

CROHN COLITIS HISTOLOGY



Microscopically, Crohn's disease is characterized by transmural inflammation. Here, inflammatory cells

infiltrates) extend from mucosa through submucosa and muscularis and appear as nodular infiltrates inor serosal surface with pale granulomatous centers. Fissures extending into the submucosa is also seen

Fissu

Aggreg

inflam

cells in

subse

muscu

propri



GRANULOMA in CROHN, HIGH POWER

Summary of microscopic findings in Cro



• Transmural inflammation: Extending from

subserosa.

• Abundant neutrophils that infiltrate and da

epithelium, sometimes forming crypt absce

• Fistulous tracts

• Non-caseating granulomas: When making t

distinction between Crohn and ulcerative co

endoscopic biopsy, this is often a helpful clu

most endoscopic biopsies are too superficia

the other characteristic Crohn’s findings.

• Repeated cycles of crypt destruction and re

lead to distortion of mucosal architecture;

straight and parallel crypts take on bizarre b

shapes and unusual orientations to one ano

similar to the crpt distortion seen in Ulcerat

IBD: Genetics and pathogenesisRisk of disease is increased when there is an affected family

b d i C h di th d t f



member, and in Crohn disease, the concordance rate for

monozygotic twins is approximately 50%. By contrast, concordance

of monozygotic twins for ulcerative colitis is only 16%, suggesting

that genetic factors are less dominant in this form of IBD. Both

diseases are more common in Caucasians .NOD2 ASSOCIATION WITH CROHN DISEASE

One of the genes most strongly associated with Crohn disease is

NOD2 (nucleotide oligomerization binding domain 2).

NOD2 encodes a protein that binds to intracellular bacterial

peptidoglycans and subsequently activates the NF-κB cell signalling

pathway.

It has been postulated that disease associated NOD2 variants are

less effective at recognizing and combating luminal microbes, which

are then able to enter the lamina propria and trigger inflammatory

reactions

**Despite the increase in risk attributable to NOD2 polymorphisms, it should

be remembered that < 10% of individuals carrying risk associated NOD2

variants develop disease. Thus, as is the case with all IBD-associated genes,

any one gene confers only a small increase in the risk of developing thesediseases.

Host-microbial interactions abe ritical to the pathogenesis

From Ro

Cotran,



,

The most widely used criteria for the clinical diagnosis of toxic

megacolon is

TOXIC MEGACOLON



Plain abdominal radiographs are critical for dia

megacolon and for following its course. The ab

shows dilated bowel loops due to toxic megaco

the transverse colon is most dilated with a bow

greater than 6 cm & sometimes up to 15 cm. M

fluid levels are also common.

Toxic megacolon is most commonly associated

ulcerative colitis, but it can also be associated

inflammatory and infectious conditions (espec

colitis)

Toxic megacolon

megacolon is

1. The presence of radiologic distension,

2. Any three of the following: Fever >38ºC / Heart rate >120 beats

per min/ Neutrophilic leukocytosis >10,500 per microL/ Anemia

3. At least one of the following: Dehydration/ Altered

sensorium/Electrolyte disturbances/ Hypotension

Prolonged treatment with antibiotics (such as Clindamycin) can

d t th b l f l i t ti l fl ll i th f

PSEUDOMEMBRANOUS COLITIS



destroy the balance of normal intestinal flora, allowing overgrowth of

Clostridium difficile. C. difficile organisms The organism is not invasive

but produces toxins that damage the colonic mucosa leading to

formation of “pseudomembrane” similar to that caused by

Corynebacterium diphtheriae in the larynx. Only 2% to 3% of healthyadults harbour the organism whereas 10% to 20% of those recently

treated with antibiotics are infected.

SYMPTOMS:

Diarrhea, abdominal pain, leucocytosis, and fever are the most

symptoms.

Borody, T. J. & Khoruts, A. (2011)

Macroscopically, the colon shows raised yellowish plaques up to 2 cm

in diameter, which adhere to the underlying mucosa. The intervening

mucosa appears congested and edematous but is not ulcerated. In

severe cases, plaques coalesce into extensive pseudomembranes.

Necrosis of the superficial epithelium is believed to be the initial

pathologic event, followed by crypt disruption and expansion (bymucin and neutrophils)

PSEUDOMEMBRANOUS COLITIS



Classic “volcano” l

(“explosive crypt”)

pseudomembrane

of fibrin, mucin, ne

and debris of necro

epithelial cells.

Pseudomembranes

occasionally in oth

infections involving

Candida & E. coli .

PseudomembraneExplosive

crypt

STANDARD TREATMENT:

A ti i bi l ( i ll V i d t id

PSEUDOMEMBRANOUS COLITIS: TREATMIllustration



Antimicrobials (especially Vancomycin and metronidaz

with supportive fluid and electrolyte therapy. This trea

effective in most cases. However, Since 2000, new virule

difficile have emerged due to antibiotic resistance, maki

harder to eradicate these organisms.

LESS CONVENTIONAL TREATMENT

FMT also called fecal transplant has been proposed as m

treating patients with recurrent C., Difficile infections th

eradicated with antibiotics. It involves transplanting feca

from a healthy individual via a nasogastric tube or an en

is restoration of the colonic flora by introducing healthy

through infusion of stool, obtained from a healthy huma

A randomized study published in the NEJM in January 20

94% cure rate of pseudomembranous colitis caused by C

difficile, by administering fecal microbiota transplant com

31% treated with vancomycin.

Other recent studies suggest that FMT can be useful in t

conditions such as ulcerative colitis, constipation, irritab

syndrome & neurologic diseases like Parkinson's.

of fecal

transplant

DIVERTICULAR DISEASEA “diverticulum” is a blind pouch protruding from the alimentary tract that communicates with the lum

“True” diverticula (e g Meckel’s) contain all 3 gut wall layers in the outpouching Most acquired divert



Divertiula

True diverticula (e.g. Meckel s) contain all 3 gut wall layers in the outpouching. Most acquired divert

actually “false” diverticula, because they lack or have an attenuated muscularis externa.

Diverticular disease refers to two acquired entities: a condition termed diverticulosis and an inflamma

complication called diverticulitis . They tend occur in areas were the vasa recta perforate the muscular

because these are areas of weakness. The sigmoid colon is the most common site (> 90% of cases)

Pathology, the Big picture

Colon segment opened longitudinally to reveal the ostia(opening) of numerous diverticula (>20)

DIVERTICULAR DISEASECLINICAL PRESENTATION:

f l h f



• Common in ~ 50% of people over the age of 6

• Caused by increased intraluminal pressure an

weakness in colonic wall

•Associated with diets low in fibre and high incarbohydrates and meats.

• The sigmoid colon is the most common site fo

• Most patients are asymptomatic or have vag

discomfort. it is a common cause of chronic

hematochezia..

COMPLICATIONS• Diverticulitis and associated complications

• Fistula formation.

Note the significantly attenuated muscularis

propria layer around the diverticulum

Formation of colonic diverticuli

The most commonly known co



y

diverticuli are pseudo divertic

composed of only mucosa on

side and serosa externally.Colonic diverticuli resemble h

sense that they occur at sites

mucosal arteries as they pass

muscularis this represents a w

that leads to a diverticulum in

of high colonic intraluminal pr

during straining). Usually dive

adjacent to the taenia coli, co

to the entry site of blood vess

.In this case, the perforating branches of the

mesenteric artery branches are the area susceptible

to formation of diverticuli

DIVERTICULOSIS Multiple diverticula on benema



Segment of resected sigmoid colon with

numerous diverticula

DIVERTICULITISDIVERTICULITIS: Develops when a diverticulum becomes impacted by faecal material



CLINICAL PRESENTATION:

• Left lower quadrant pain, fever, leucocytosis +/-

occult blood or hematochezia.

COMPLICATION

• Perforation, leading to peritonitis and/or abscess

formation.• Bowel stenosis,

• Colovesical fistulas (fistula with bladder), which

can result in pneumaturia.

TREATMENT:

• Antibiotics and bowel rest, or resection of

affected area.

by infection and erosion through the serosa, leakage or perforation & development of

localized inflammatory mass. Erosion into a blood vessel may produce profuse haemo

although this is uncommon.

DIVERTICULITIS: perforation



h t t p : / / l i b r a r

y . m e d . u t a h . e

d u / W e b P a t h / G I H T M L

Ruptureddiverticulum

This diverticulum has become infla

has ruptured outward, and seen as

brown irregular tract extending dow

the mucosal surface. The erosion o

mucosa by the stool in the divertic

produce inflammation and hemorr

MICROSCOPIC COLITISThe tern Microscopic colitis encompases idiopathic

diseases that present with chronic, nonbloody, watery

diarrhea without weight loss The endoscopic and



diarrhea without weight loss. The endoscopic and

radiologic studies are usually normal, and the

pathologic findings are generally only apparent at the

microscopic level. There are two types of microscopic

colitis:

Collagenous colitis: This occurs mainly in older women

and is characterized by the presence of a thick

subepithelial collagen layer, increased #s of

intraepithelial lymphocytes, and a mixed inflammatory

infiltrate within the lamina propria.

Lymphocytic colitis: Similar to collagenous colitis, but

without thickening of the subepithelial collagen layer.

Lymphocytic colitis shows a strong association with

celiac disease and autoimmune diseases, including

thyroiditis, arthritis & autoimmune gastritis

In some cases, collagenous and lymphocytic colitis may

precede a diagnosis of inflammatory bowel disease

COLLAGENOUS CO

Thick subepithelial collagen

IBS is characterized by chronic, relapsing abdominal pain, bloating & changes in bowel ha

usually in the setting of normal gross & microscopic findings It is most commonly diagnos

IRRITABLE BOWEL SYNDROME (IBS)



usually in the setting of normal gross & microscopic findings. It is most commonly diagnos

females (esp. age 20-40) and has a 5-10% prevalence in developed countries, although diag

criteria often varies.

Most physicians use the following criteria to establish diagnosis:

• Occurrence of abdominal pain or discomfort at least 3 days/month over 3 months; sym

often relieved with defacation.

• A change in stool frequency or form

• Patients often report extraintestinal symptoms such as fibromyalgia, backache, headac

symptoms, dyspareunia, lethargy, & depression.

Before a diagnosis of IBS is made, other possible causes of symptoms, such as microscopic

colitis, celiac disease, giardiasis, lactose intolerance, small bowel bacterial overgrowth, bile

malabsorption, colon cancer, and inflammatory bowel disease must be excluded.

The pathogenesis of IBS is not well understood, but there appears to be an interplay betwe

psychologic stressors, diet, and abnormal GI motility. Disturbances in intestinal motility and

sensory function suggest a neurologic component.

SMALL AND LARGE INTESTINAL (MESENTERIC) ISCHEACUTE MESENTERIC ISCHEMIA:Acute mesenteric ischemia is caused by the sudden onset of intestinal hypoperfusion. It can be du



occlusive causes such as thrombotic or embolic occlusion of arterial blood supply or venous outflo

a non-occlusive reduction in arterial blood supply (such as during hypovolemia, cardiac failure, et

Atherosclerosis is a major risk factor. Rapid diagnosis is imperative since the clinical consequence

catastrophic, including bowel infarction, sepsis and death.

CHRONIC MESENTERIC ISCHEMIA

Chronic mesenteric ischemia is usually due to atherosclerotic narrowing of the arteries that sup

intestines. It is usually associated with intermittent abdominal pain, termed intestinal (abdomina

Characteristically, the pain begins within a half hour of eating and lasts for a few hours. Patients u

complain of recurrent abdominal pain after eating, which is due to an inability to increase blood f

the demand of the intestine postprandially. Consequently, these patients develop food fear and caconsiderable amount of weight.

In general, chronic ischemic syndromes are less common, due to the widely anastomosing blood s

(ie..collateral circulation), of the intestine, which provide alternative routes when one vessel is oc

collateral circulation allows the intestines to tolerate situations where there is a slowly progressiv

loss of blood supply from one artery. Therefore, most cases of bowel infarction are due to acute e

than chronic events. Chronic intestinal ischemic syndromes also generally require the severe com

two or more major arteries.

Occlusive arterial obstruction (Up to 75% of cases): Sudden occlusion of a large artery by thrombo

embolization leads to bowel infarction before collateral circulation comes into play. The superior mesenter

involved in the majority of cases. Depending on the size of the artery, infarction may be segmental or may

TYPES/CAUSES OF MESENTERIC ISCHEMIA



j y p g y, y g y

gangrene of virtually the entire sm. bowel. Atherosclerosis is a major risk factor. Other risk factors: Hyperco

bacterial endocarditis (source of septic emboli)

Non-occlusive ischemia (20-30% of cases). Most often due to general or localized hypoperfusion.

• Generalized hypoperfusion: 2⁰ to shock, cardiac failure & dehydration: The colonic circulation is particu

to hypoperfusion relative to the small intestine since it receives relatively less blood flow compared w

the GI tract. The Watershed areas of the colon are most vulnerable.

• Localized hypoperfusion due to surgical procedures such as coronary artery bypass surgery or aortic abd

aneurysm repair. In the latter, the rectum is vulnerable due to compromise of both of its arterial blood so

Venous thrombosis (5-10% of cases): Uncommon, but can result from hypercoagulable states (eg. Pre

use, genetic causes, etc), neoplasms, cirrhosis, abdominal trauma, or compression from an abdominal mass

presence of inflammation (phlebitis) are added risk factors. Nearly all cases involve the superior mesenteriuncommon, it accounts for most cases of small bowel ischemia in young adults.

Extrinsic/Mechanical causes: Both arterial and venous occlusion can occur from twisting of the bowel

around a fixed attachment (such as an adhesion, mesenteric defect) or incarceration and strangulation of int

contents within a hernia. Also, patients with excessive bowel distention from bowel obstruction can get hyp

increased venous pressure and/or venous thrombosis of the involved segment of intestine.

Other causes: Systemic vasculitis disorders, NEC, Radiation enterocolitis (radiation-induced vascular injury

infection, especially in immunocompromised individuals (due to viral tropism for endothelial cells)



Arterial supply of

the small intestine

Venous drainage of the smal



The blood supply to the small intestine is derived primarily from the

SMA, which primarily supplies the sm. Intestine & right colon. The

SMA gives rise to the inferior pancreaticoduodenal a., the middle colic

a., right colic a., ileocolic a. and many jejunal and ileal branches. The

celiac artery primarily supplies the stomach, liver, spleen & pancreas.

However, it also communicates with the SMA mainly via the junction

of the superior & inferior pancreaticoduodenal arteries, thus providing

a source of collateral flow when blood flow in the SMA is reduced.

The mesenteric veins parallel their

arteries. The superior mesenteric v

small intestine, cecum, ascending a

colon via the jejunal, ileal, ileocolic,

middle colic veins. The SMV joins t

to drain into the portal vein.

MESENTERIC ISCHEMIA DIAGNOSIS: CLINICAL SIGNS AND SYMPTOMSThe diagnosis of mesenteric ischemia depends upon a high level of clinical suspicion. Rapid diagnosis is essent

the potential for intestinal infarction. However, in early stages of disease, the typical physical signs or symptom

absent or mild. Therefore, if there is a high index of suspicion based on other factors (such as age, cardiovascu



Abdominal pain is the most common presenting symptom, classically described as: “abdominal pain out of propophysical examination”. Ischemia due to an arterial embolic occlusion typically presents with a sudden onset of sev

pain, often with nausea & vomiting. Thrombotic mesenteric artery occlusion may also have pain that is intensified

posprandial period. Mesenteric venous thrombosis may be more insidious.

In cases of non-occlusive mesenteric ischemia, the severity of the pain is more variable and is sometimes over

precipitating disorders (e.g. a mycocardial infarction).

Patients with acute colonic ischemia tend to have less severe abdominal pain. They typically present with sudd

cramping, left lower abdominal pain (corresponding to watershed areas), a desire to defecate & passage of blo

diarrhea. There is usually tenderness over the affected bowel

Marked abdominal distension

Absent bowel sounds

Rectal bleeding and hematochezia are classically seen in cases of colonic ischemia. Mild to moderate amounts of r

bloody diarrhea typically develop within 24 hrs of the onset of abdominal pain. In cases of small intestinal ischemia

to manifest later in disease. Occult blood may be present in early cases of small bowel ischemia.

Presence of peritoneal signs Rebound, guarding, etc

Dehydration and shock Indicates a deteriorating clinical course.

then additional more invasive testing may be required to establish an early diagnosis.

SIGNS AND SYMPTOMS OF ACUTE MESENTERIC ISCHEMIA

MESENTERIC ISCHEMIA DIAGNOSISLABORATORY STUDIES : Labs are nonspecific and may be normal. Common findings marked left-shift

hemoconcentration or metabolic acidosis.

COLONOSCOPY: For patients with suspected large intestinal ischemia the colonoscopy is the best dia



IMAGING: . Plain abdominal radiographs are often performed in suspectedcases of acute small intestinal ischemia. However, the findings are relatively

nonspecific and in early cases of ischemia, the film may be normal. CT scans

are more sensitive and specific. Also, in cases of suspected vascular

occlusion, CT angiography may be necessary.

X-ray findings that should raise suspicion include of acute bowel ischemia:

• Presence of an ileus with distended loops of bowel

•

Bowel wall thickening (especially in acute mesenteric venousthrombosis)

• Pneumatosis intestinalis (air in the wall of the intestine).

• Free intraperitoneal air: A non-specific finding, but suggests perforation

and requires immediate abdominal exploration.

LAPAROTOMY: In some cases of small intestinal ischemia, an exploratory

laparotomy is required to make the diagnosis and to identify the segment of

affected bowel.

COLONOSCOPY: For patients with suspected large intestinal ischemia, the colonoscopy is the best dia

Biopsies can also be taken to confirm the diagnosis histologically. Imaging teqniques such as CT scans ar

for diagnosis acute ischemia of the small intestine.

Small bowel ischemia: Aof the abdomen showingof small bowel with wall(arrow), consistent with

the bowel wall.

Infarcted bowel is edematous and has a diffuse dark/red to purple appearance, as shown in the figure (yellow

Compare to the pale pink colour of the normal bowl (blue arrow). The demarcation between infarcted bowel

normal tissue is usually sharp, although In mesenteric venous thrombosis, arterial blood continues to flow for



The dark red infarcted small intestine (yellow arrows) contrasts with the light pink viable bowel

(blue arrow). The forceps extends through an internal hernia in which a loop of bowel and

mesentery has been caught, undergoing infarction. This is one complication of adhesions from

previous surgery.

resulting in a less abrupt transition from affected to normal bowel.

The mucosa and submucosa usually show extensive haemorrhage especially prominent in mesenteric vein t

Later, blood-tinged mucus or frank blood accumulates in the lumen and the wall becomes edematous, thicke

rubbery. Coagulative necrosis of the muscularis propria develops within 1 to 4 days, the wall of the intestine and distended and bubbles of gas (pneumatosis) may be present in the bowel wall and mesenteric veins. Pe

occur in the infarcted areas.

OTHER COMPLICATIONS: Dysfunction and/or necrosis of

smooth muscle in the ischemic bowel interferes with peristalsis

and leads to an ileus, in which the bowl proximal to the lesion is

dilated and filled with fluid.

Intestinal organisms my pass through the damaged wallcausing peritonitis or septicemia

If the patient survives the episode of hypoperfusion, the bowel

may be completely repaired, or it may heal with granulation

tissue and fibrosis, with eventual stricture formation

Intestinal capillaries run alongside the inte

from crypt to surface, before making a hai



Early ischemia of the colon showing characteristic atrophy and mucin depletion of the epithelium. The

superficial crypts are usually the first to undergo ischemic changes because they have the most distal

the surface to empty into the postcapillary

configuration allows oxygenated blood to s

which contain the epithelial stem cells, bu

surface epithelium vulnerable to ischemic low flow states. Therefore, ischemic bow

characterized by atrophy or necrosis of th

epithelial cells (arrow) with preservation

sometime hyperproliferation) of the cryp

As the mucosal barrier breaks down, bacte

circulation and sepsis can develop; the mo

may exceed 50%.In both acute and chronic ischemia, bacte

superinfection & enterotoxin release may

pseudomembrane formation resembling

infection



OTHER DISEASES OF THE LARGE INTESTINE

• Angiodysplasia is defined as arteriovenous malformations of the inte



g y p

occurs in the cecum and right colon. It is common in individuals over

presenting with multiple episodes of rectal bleeding. Angiodysplasia

associated with Osler-Weber-Rendu and CREST Treatment is surgical

resection

• Melanosis Coli: Black pigmentation of the colon due to the ingestion

laxative pigment by macrophages in the mucosal and submucosa. Mo

seen in the setting of chronic laxative abuse.

• Infectious diseases , including opportunistic infections in immunosup

patients (such as CMV colitis)

• Iatrogenic: NSAID colitis, Graft-versus-host disease, Radiation colitis,

colitis

PERITONITISThis is inflammation of the peritoneum, associated with pain and tenderness. It may be localized (e.g.

over an inflamed appendix) or generalized, with the latter being more concerning.

A f t d t l d t li d it iti ( l i ll d b d lik i idit f th bd



A perforated gut leads to generalized peritonitis (classically and causes board-like rigidity of the abdom

instances, perforation may cause a localized peritonitis, such as with perforated colonic diverticula.

SIGNS OF PERFORATION AND GENERALIZED PERITONITIS:

• Peritoneal signs; Board-like rigidity of the abdomen

• Elevated white cell count.

• Hypovolemia, due to marked loss of fluid and protein from the gut into the peritoneal cavity in cas

perforation.

• A plain radiograph may show free air if the peritonitis was due to perforation

• Elevated amylase levels: Perforation of upper GI tract can lead to elevation of serum amylase, due

amylase-rich duodenal contents into the peritoneum, when then get reabsorbed into the circulatioAcute pancreatitis, when severe, can lead to marked increase in serum amylase levels, which can c

generalized peritonitis.

MANAGEMENT

Rapid fluid resuscitation is important (marked loss of fluid and protein into the peritoneal cavity will in

hypovolaemia). Generally, urgent surgical intervention is appropriate. Antibiotic therapy should be for

coverage, including Gram negative organisms.



CONGENITAL DISORDERS OF THE

LARGE INTESTINE

HIRSCHSPRUNG DISEASE (HD)Hirschsprung disease (also known as “congenital megacolon” results from the congenital absence of ganglion cells

Auerbach and Meissner’s plexuses , due to failure of neural crest cell migration. The resulting aganglionic segment

fails to relax, causing a functional obstruction. In most patients, it affects a short segment of the distal colon, with

zone in the rectosigmoid colon In others it involves longer segments of colon In ~5% of cases the entire colon is



zone in the rectosigmoid colon. In others, it involves longer segments of colon. In 5% of cases, the entire colon is

rare cases the small bowel may also be involved. It is estimated to occur in 1 in 5,000 lives, and 80% of the patient

Barium e

with Hirs

the trans

the lower

and norm

CLINICAL PRESENTATION:

• The majority of patients with HD are diagnosed as neonates. There may also be a history of oligohydramniosduring pregnancy.

• Infants present with symptoms of distal intestinal obstruction, including bilious emesis, abdominal distension

& constipation.

• ~ 95% of neonates with HD fail to pass meconium within the 1st 48 hours of life. A digital rectal exam can

sometimes trigger an explosive expulsion of gas and stool (“blast sign”), which may relieve the obstruction

temporarily.

• The most serious complication is an enterocolitis which can casue necrosis and ulceration of the dilated

proximal segment of the colon and may extend into the small intestine.DIAGNOSIS:

• Imaging reveals dilated portions of colon proximal to the aganglionic segment. The “transition zone” and

areas distal to the transition zone should be biopsied to look for ganglion cells. There is also a striking increase

in nonmyelinated cholinergic nerve fibbers in the submucosa (neural hyperplasia). The presence of

acetylcholinesterase-positive fibers in the muscularis mucosae and lamina propria along with absence of

ganglion cells in supports the diagnosis of Hirschsprung’s disease.

TREATMENT:

• Surgical resection of the aganglionic area.

HIRSCHSPRUNG DISEASE (HD)



Stenotic

aganglionic

segment

GENETICS:At least eight genetic mutations have been identified in

patients with HD, The predominant gene affected is the RET

proto-oncogene which encodes a tyrosine kinase. RET

malfunction accounts for at least 50% of familial and 20% of

sporadic cases . There is also a strong association between HD

and Down syndrome and MEN2

Dilatedsegment

Resection

case of sh

HIRSCHS

a dilated

narrow a

segment



NECROTIZING ENTEROCOLITIS (NEC)

Necrotizing enterocolitis is one of the most



Necrotizing enterocolitis is one of the most

common acquired surgical emergencies in

newborns. It is particularly common in premature

infants (due to decreased immunity) after oral

feeding and is likely related to an ischemic event

involving the intestinal mucosa. Ischemia is

followed by bacterial colonization, which can

proceed to necrosis, gangrene and perforation of

the bowel.

Approximately 50% of infants who survive NEC havelongterm complications, including Intestinal

strictures and short gut syndrome (malabsorption

syndrome resulting from removal of excessive or

critical portions of the small intestine).

NECROTIZING ENTEROCOLITIS (NEC): DIAGNO

A Plain radiograph of the abdomen is



usually the best diagnostic tool. Findings

include

Dilated loops of bowel (yellow arrow) Thickened bowel walls

Portal venous gas

Pneumatosis intestinalis: Linear

lucencies consistent with air in the bowel

wall (white arrow). This is

pathognomonic of NEC in newborn Abdominal free air; This is an ominous

sign, indicating perforation.

Air in the bowel wall

(pneumatosis intestinalis)

PATHOLOGY OF THE ANUS



COMMON ANAL POLYPOID LESIONS

HemorrhoidsHemorrhoids are dilated anal & perianal collateral vessels that connect the portal and caval ve

system. They affect about 5% of the general population and develop secondary to persistently

venous pressure within the hemorrhoidal plexus. The most frequent predisposing influences



straining at defecation due to constipation (straining increases intra-abdominal and venous pr

and 2. venous stasis of pregnancy.

Hemorrhoids may also develop in association with portal hypertension. The pathogenesis ofhaemorrhoids (anal varices) in portal hypertension is similar to that of esophageal varices, alt

varices are both more common and much less serious.

There are two types of haemorrhoids

• Internal haemorrhoids, which arise from the su

hemorrhoidal plexus above the pectinate line.

• External hemorrhoids which are located below

anorectal line.


Microscopically, hemorrhoids consist of

walled, dilated, submucosal vessels that

b th th l t l

Hemorrhoids



Hemorrhoid: Note marked vascular dilatation &

thrombosis.

beneath the anal or rectal mucosa.

In their exposed position, they are subje

trauma and tend to become inflamed,thrombosed, and, in the course of time,

recanalized.

Prolapsed hemorrhoids (right ) may become irreducible, and

strangulated. Main symptoms are itching, pain and bleeding,

which can cause iron deficiency anemia.. A prolapsed hemor

ANAL NEOPLASMS




Low and high power views of a condyloma, showing a papillary architecture and

acanthosis of the squamous epithelium.

Carcinomas of the anal canal can be either glandular (adenocarcinomas) or squamous. Pure squamous

carcinomas are often associated with HPV infections and can arise in precursor lesions such as condylo

accuminatum (“anal wart”)

pdf large intestine pathology aug 2015

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