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Digestive Pathology Lecture 3
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LSUHSC-New Orleans, 2015
Last updated on September 24, 2015
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Intestine II
5. Diverticular disease6. Mechanical obstruction
7. Tumors of the small and large intestine
8. Appendix
Colonic diverticula (diverticulosis)
Outpouchings (generally multiple) of mucosa and submucosa (false diverticula) through weak points, alongside the taeniae coli, where the vasa rectapenetrate the inner circular layer
Diverticular disease
Two kinds:
– Mostly confined to the left colon
• Associated with increased intraluminal pressure, hypertrophy of muscularis propria
• Complicated by inflammation (diverticulitis) and perforation
– Distributed throughout the colon
• A connective tissue abnormality proposed
• Complicated by bleeding (connective tissue provides inadequate support for blood vessels)
Diverticula, epidemiology, risk factors
More frequent in western industrialized countries than in Asia and non-industrialized countries
In the West, more frequent in the sigmoid and descending colon
In Asian populations, higher prevalence of diverticula in the right colon
Associated with:
– Aging
– Diets low in fiber
– Low physical activity
– Obesity
– Constipation
Diverticula, symptoms, complications
Most are asymptomatic or cause vague symptoms referred to the left lower abdomen
10-25% become symptomatic:
– Inflammation (diverticulitis):
• Related to age, obesity, red meat consumption
• Perforation, peritonitis, pericolonic abscesses, fistulae
– Hemorrhage (more common in the right colon)
Intestine II
5. Diverticular disease
6. Mechanical obstruction7. Tumors of the small and large intestine
8. Appendix
Mechanical intestinal obstruction
The syndrome:
– Colic
– Distention
– Vomiting
– Failure to pass feces or gas (flatus)
Four entities account for 80% of cases:
– Hernias
– Intestinal adhesions
– Intussusception
– Volvulus
Hernias
Protrusion through a weak point in the peritoneal wall, into a peritoneum-lined pouch called hernial sac
Hernias Inguinal
– Men (9:1)– Indirect : along the inguinal canal (75%)– Direct: above the inguinal ligament
Umbilical– Most are congenital, small, close spontaneously by age 4-5
• About equal sex distribution, more common in blacks
– In adults: multiparous women, cirrhotic patients
Femoral (femoral canal)– Women almost exclusively, prone to strangulation
Obturator (obturator canal)– Women (6:1), not visible externally
Incisional hernia– Breakdown of an incision closure
Hernias, classified as:
Reducible (spontaneously or manually)
Incarcerated, no longer reducible
Strangulated, with compromise of the vascular supply
Adhesions
Bands of fibrous tissue among bowel segments or between bowel segments and the abdominal wall
Adhesions
Rarely congenital (Ladd bands)
Most are secondary to:
– Previous surgeries
– Infection
– Endometriosis
Can result in:
– Trapping, obstruction, volvulus, strangulation
Adhesions are the most common cause of intestinal obstruction in the US
Intussusception
A segment of intestine telescoped into an immediately distal segment
HUJI
Intussuscipiens
Intussusceptum
Intussusception
Most common cause of intestinal obstruction in infants
Most common in boys, 3-12 months
– Lymphoid hyperplasia as leading point
Terminal ileum (ileo-ileal, ileo-colic)
Colic, “currant jelly” stools
Rare in adults
– Intraluminal polyps or tumors as leading points
Result in obstruction, strangulation
In young children may be treated (reduced) with radiologic contrast medium or air enemas
Volvulus
Complete twisting of a loop of bowel about its mesenteric axis
Results in obstruction and infarction
Volvulus
Volvulus
Gastric
– Adults
– Paraesophageal (rolling) hiatal hernias
Small intestine
– Neonates and infants• Malrotation (mid-gut volvulus), the most common volvulus
• Meckel diverticulum
– Adhesions
Colonic (sigmoid, cecum)
– Elderly
– Constipation (impacted feces)
Intestine II
5. Diverticular disease
6. Mechanical obstruction
7. Tumors of the small and large intestine
– Polyps, adenomas
– Colorectal carcinoma
– Carcinomas of the anal canal
– Carcinoids
– Lymphoma8. Appendix
Polyps
Polyp: a mass that protrudes into the lumen– Sessile: lacking a pedicle
– Pedunculated
Multiple types– Inflammatory
– Hamartomatous• Juvenile/retention
• Peutz Jeghers
– Hyperplastic
– Serrated
– Adenomatous
Polyps, sessile, pedunculated
Inflammatory polyps (pseudopolyps)
Mucosal erosion
Inflammation
Granulation tissue proliferation
Reactive epithelial hyperplasia
Fibrosis of the lamina propria
Inflam
mato
ry p
oly
ps
(pse
udopoly
ps)
••
Juvenile (retention) polyps
Hamartomatous
– Cystically dilated glands
– Glands and stroma in disarray
Large, ulcerated, inflamed
Smooth, rounded contour
Pedunculated
Juvenile (retention) polyps
Juvenile (retention) polyps
Most are sporadic and single
– Have no malignant potential
– Most occur in the rectum
– Majority occur in children < 5 y/o
• Bright red bleeding during or after bowel movement
When more than 5
– Juvenile polyposis syndrome
– Autosomal dominant
– Carry a risk of colorectal adenocarcinoma
Peutz-Jeghers polyps
Hamartomatous
– Arborizing proliferation of the muscularis mucosae
Pedunculated, large, lobulated
More common in the small intestine
Peutz-Jeghers polyps
Peutz-Jeghers polyps
Peutz-Jeghers polyps
May be:– Single or few and sporadic or
– Part of the autosomal dominant Peutz-Jeghers syndrome:
• Mutation in the LKB1/STK11 tumor suppressor gene
• Multiple polyps in: jejunum, ileum, colon, stomach, duodenum
• Pigmented macules around the lips, oral mucosa, face, genitalia, palms and soles (lentigines, lentiginosis)
Peutz-Jeghers syndrome
Peutz-Jeghers syndrome
Increased risk of carcinomas
Most commonly outside the GI tract:
– breast, ovary, uterus, cervix, testicle, lung, pancreas
Increased risk of esophageal and gastrointestinal cancer also
Polyps may have malignant potential
Hyperplastic polyps
Usually small (<5 mm) and sessile
Histologically:
– Crypt hyperplasia
– Serrated crypt profiles
– Serrated architecture is limited to the upper half of the crypts
Hyperplastic polyps
Hyperplastic polyps
Hyperplastic polyps
Common
Most are asymptomatic, incidental
Mirror the demographics, risk factors and anatomic distribution of adenomatous polyps
More common in men
Prevalence increases with age
More common in the left colon
No significant malignant potential
Sessile serrated adenomas
Similar to hyperplastic polyps
Serrated architecture extending to the crypt base
Crypt dilatation and branching
Larger
More common in the right colon
Have premalignant potential (associated with microsatellite instability pathway of colorectal carcinogenesis)
Sessile serrated adenomas
Adenomatous polyps (adenomas) Dysplastic: low-grade or high-grade dysplasia
– Variable nuclear enlargement, hyperchromasia, pseudostratification
– Variable architectural disarray
Sessile or pedunculated
Three subtypes:
– Tubular (the most common): tubular glands
– Villous: long villous projections
– Tubulovillous: a mixture of both
Adenomatous polyps (adenomas)
Tubular adenomas
Villous adenoma
Tubulovillous and villous adenomas
Adenomatous polyps, location, demographics
Most are colonic
Infrequent in the small intestine except for periampullary region
Left colon: younger and white
Right colon: older and black
More common in men than in women
Prevalence increases with age
Adenomatous polyps, symptoms
Most are asymptomatic
May produce occult bleeding
Rare protein-losing enteropathy
Adenomatous polyps, cancer risk
Risk is proportional to polyp:
– Size
– Amount of villous component
– Cancer, rare in tubular adenomas < 1 cm
– Common in villous adenomas > 4 cm
– Presence of high-grade dysplasia
Tubular adenoma with high-grade dysplasia
Adenoma-carcinoma sequence
Familial adenomatous polyposis
Autosomal dominant
Defect in APC gene
Numerous adenomatous polyps– A minimum of 100 necessary for diagnosis
Polyps also present in the stomach and small intestine (particularly in the periampullary region)
Risk of progression to adenocarcinoma close to 100%
Prophylactic colectomy is necessary
Adenomatous polyposis coli
Variants of FAP
Attenuated APC (AAPC):
– Fewer polyps, lesser risk of cancer
Gardner syndrome:
– Osteomas
– Desmoid tumors
– Epidermal cysts
– Other
Turcot syndrome:
– Central nervous system tumors (medulloblastomas, other)
Colorectal ADENOCARCINOMA
Colorectal carcinoma, risk factors
Old age: peak incidence 60 to 79 years
Smoking
Alcohol
Obesity, type 2 diabetes
Reduced physical activity
High intake of read meat and processed meats
Decreased intake of folate and calcium
Urbanization
High socioeconomic status
Inflammatory bowel disease
Chromosomal abnormalities, polyposis syndromes
Colorectal carcinoma, prevention
Primary prevention
– NSAIDS (aspirin, piroxicam, sulindac)
• Prevent polyps and cause them to regress
– Regular physical activity
– Postmenopausal hormonal supplementation with estrogen AND progesterone
– Removal of adenomatous polyps
• Most carcinomas originate in adenomatous polyps
• Carcinogenesis is slow, allow early detection
– Fiber, fresh fruits and vegetables (inconclusive)
Adenoma/carcinoma surveillance
Recommendations for people at average risk:
– Colonoscopy at age 50
– If no adenoma/carcinoma found, repeat in 10 years
– If 1-2 small (<1 cm) tubular adenomas, no high-grade dysplasia, repeat in 5-10 years
– If 3-10 adenomas, any with villous component, any ≥ 1cm, or any with high-grade dysplasia, repeat in 3 years
– If >10 adenomas, repeat in < 3 years, consider possibility of familiar syndrome
– More intensive surveillance when: significant family historyor personal risk factors such as IBD
– Polyps must be completely removed, when in doubt repeat in 3-6 months
Adenomatous polyps and cancer
The prevalence is comparable
The anatomic distribution is comparable
The peak incidence of polyps antedates that of colorectal cancer
Early invasive carcinoma is often surrounded by adenomatous tissue
The risk of cancer is related to the number of polyps
Removal of polyps reduces the incidence of colorectal cancer
Adenoma-carcinoma sequence
“Multi-hit” concept of carcinogenesis
Cumulative alterations in the genome lead to transition from adenomatous polyps with low-grade dysplasia to high-grade dysplasia and invasive carcinoma
The APC/Beta-catenin (suppressor) pathway
Loss of APC gene
Beta-catenin mutations
Activation of K-ras gene
Loss of DCC, SMAD2 and SMAD4 genes
Loss of TP53 gene
Activation of telomerase
The microsatellite instability pathway
Hereditary nonpolyposis colorectal cancer (HNPCC) syndrome (Lynch syndrome)
– Autosomal dominant
– Associated with extraintestinal cancers, particularly endometrial cancer
Defect of DNA mismatch repair genes
– 90% of mutations involve hMSH2 and hMLH1
Tumors tend to be proximal to the hepatic flexure, mucinous
Association with serrated adenomas
CpG island Methylator phenotypes (CIMP)
Individuals susceptible to hypermethylation of CpG islands
– Cytosine-phosphate-Guanine dinucleotide rich regions
CpG islands are located in the promoter regions of many critical genes involved in carcinogenesis
Colorectal cancer incidence
More common in men than women
More common in blacks than in whites
Decreasing incidence greater among whites than among blacks
Colo
rect
al ca
nce
r IN
CID
EN
CE
Colorectal cancer incidence by sub-site
Incidence has declined among whites in all regions of the colon, but greater decline has occurred in the sigmoid and rectum
Right-sided carcinomas
– Incidence increases with age
– More common among blacks
Colorectal cancer mortality
Greater among men than among women
Greater among blacks than among whites
Decreasing rates greater among whites than among blacks
Colo
rect
al ca
nce
r M
ORTALIT
Y
Location, morphology and symptoms
In the proximal colon
– Exophytic
– Obstruction is uncommon
– Major manifestation: anemia (occult blood loss)
In the distal colon:
– Infiltrative, annular (apple core, napkin ring)
– Obstruction and changes in bowel habits are common
– Gross bleeding is frequent
Iron deficiency anemia in older men and postmenopausal women: gastrointestinal cancer until proven otherwise
Colorectal cancer, RIGHT vs. LEFT
Intramucosal vs. invasive carcinoma
Cancer limited to the mucosa (intramucosal carcinoma) has no metastatic potential
Invasion beyond the muscularis mucosae carries the risk of lymphatic invasion and metastases
Secondary prevention (early detection)
Fecal occult blood tests
Fecal DNA test, detects exfoliated malignant cells with mutations commonly found in adenomas and colorectal cancer
Digital rectal examination
Colorectal carcinoma
Carcinoembryonic antigen (CEA)
– Used for monitoring patients with resected colorectal cancer
The most important prognostic indicator is the extent of the tumor spread:
– Depth of invasion
– Lymph node or distant metastases
Liver is the most common site of metastatic involvement
Carcinomas of the anal canal
Squamous cell carcinomas, distally, associated with HPV infection
Adenocarcinomas, proximally
Transitional (basaloid) carcinomas, originate in the transitional epithelium between the squamous and the columnar epithelium
Anal transitional zone
Carcinoids
Originate in neuroendocrine cells
Can arise in many organs but the majority occur in the GI tract
– Most occur in appendix and ileum
– Less often in stomach, colon and rectum
In the stomach, associated with hypergastrinemia
In the appendix, located at the tip
Characteristic gross yellow-tan appearance
Carcinoids, microscopy
Commonly submucosal
Cells are very uniform
Carcinoid, serotonin
Carcinoids, behavior
The average age at diagnosis 61.4 years
Indolent growth
Size ( 2 cm) and deep local penetration correlates with metastases
Appendiceal carcinoids almost never metastasize
Small bowel carcinoids are the most often associated with metastases
Carcinoid syndrome
Carcinoids elaborate serotonin and other histamine-like substances
Normally, the liver metabolizes (inactivates) serotonin
Carcinoid syndrome occurs when:
– The liver metabolic capacity is overwhelmed or bypassed
• Large primary tumors
• Extensive liver metastases
• Carcinoids outside the portal vein system (extraintestinal)
Carcinoid syndrome
Clinical features:
– Vasomotor disturbances:
• flush
– Intestinal hypermotility:
• diarrhea, cramps, nausea, vomiting
– Bronchoconstrictive attacks
– Endocardial fibrosis, right ventricle
– Pulmonic and tricuspid valves thickening and stenosis
Carcinoids, prognosis
Carcinoids without associated metastases:
– Excellent prognosis
With hepatic metastases and carcinoid syndrome:
– Survival for 10-15 years is not unusual
Gastrointestinal lymphoma
Lymphomas of mucosa-associated lymphoid tissue (MALTOMAS)
The gut is the most common location for extranodal lymphomas
Most occur in the stomach and small bowel
Most are of B-cell type (>95%)
Rare T-cell tumors:
– Almost always occur in patients with celiac sprue
Lymphoma
Lymphoma, risk factors
Helicobacter pylori infection:
– Gastric lymphomas
– Dependent on cytokines produced by H. pylori-reactive T helper cells
Campylobacter jejuni infection:
– Small intestinal (Mediterranean) lymphoma
Celiac disease (T-cell lymphomas)
Immunodeficiency
Lymphoma, outcome
Gastrointestinal lymphomas have a better prognosis than nodal lymphomas
Gastric lymphomas have a better prognosis than those of the small or large bowel
T-cell lymphomas have poor prognosis
The histologic grade and stage of dissemination are the major determinants of prognosis
Mediterranean lymphoma
Endemic in Middle-East and Mediterranean
Immunoproliferative small intestinal disease IPSD:– Massive infiltration of the proximal small intestine
by lymphocytes and plasma cells
– Overt B-cell lymphoma
Truncated IgA heavy chain (alpha H chain disease)
Associated with Campylobacter jejuni
Sometimes regresses after antibiotic therapy
IPSD
Intestine II
5. Diverticular disease
6. Mechanical obstruction
7. Tumors of the small and large intestine
8. Appendix
– Appendicitis
– Mucocele
– Appendiceal tumors
Acute appendicitis
Obstruction of the appendiceal lumen, usually by a fecalith
Lower frequency in cultures with high fiber diets
More common in:
– Teenagers and young adults, but incidence is increasing in older adults
– Men
Acute appendicitis
Acute appendicitis
The histologic criterion: neutrophilic infiltration of the muscularis propria
Acute appendicitis
Acute appendicitis
Complications:
– Rupture and peritonitis
– Pylephlebitis, thrombosis, portal hypertension, liver abscesses
Mucocele of the appendix
Cystic dilatation of the appendix by inspissated mucus
Caused by:
– Obstruction of the lumen, rare
– Focus of mucin-producing hyperplastic epithelium
Appendiceal mucocele
Cystadenoma, cystadenocarcinoma
Mucinous cystadenoma:
– Possible extravasation of mucin with or without tumoral cells into the abdominal cavity (no malignant cells)
Mucinous cystadenocarcinoma:
– Common extravasation of mucin and malignant cells into the abdominal cavity
Mucinous cystadenoma
Mucinous cystadenomaExtravasation of mucus
Mucinous cystadenomaExtravasation of mucus and cells
Mucinous cystadenocarcinomaextravasation of mucus and malignant cells
Pseudomyxoma peritonei
Any condition in which the abdominal cavity is filled with extracellular mucin
Some use the term exclusively for the condition associated with mucinous cystadenocarcinoma (malignant neoplastic cells identified in the mucinous fluid)
