GI-Path- Neoplastic Diseases of the Large and Small Bowel

Question 1

Polyps are most common in the but may occur in the esophagus, stomach, or small intestine.

• Those without stalks are referred to as

Answer 1

colon

sessile.

pedunculated

Question 2

The most common neoplastic polyp is the , which has the potential to progress to cancer.

• Nonneoplastic colonic polyps can be further classified as 3 types:

Answer 2

adenoma

inflammatory, hamartomatous, or hyperplastic

Question 3

Concerning inflammatory polyps:

• The rectal ulcer syndrome is associated with a purely inflammatory polyp.
• Patients present with the clinical triad of rectal bleeding, mucus discharge, and an inflammatory lesion of the rectal wall.

Answer 3

solitary

anterior

Question 4

Concerning solitary rectal ulcer syndrome:

The underlying cause is impaired relaxation of the anorectal sphincter, creating a sharp angle at the rectal shelf.

• This leads to recurrent abrasion and ulceration of the overlying rectal mucosa.
• Chronic cycles of injury and healing produce a mass composed of inflamed and reactive mucosal tissue.

Answer 4

anterior

polypoid

Question 5

polyps occur sporadically and as components of various genetically determined or acquired syndromes

Hamartomas are disorganized, growths composed of mature cell types normally present at the site at which the polyp develops.

• Hamartomatous polyposis syndromes are rare, but they are important to recognize because of associated intestinal and extraintestinal manifestations, and the need to screen family members.

Answer 5

Hamartomatous

tumorlike

Question 6

What is the most common type of hamartomatous polyp?

They may be or syndromic.

Answer 6

• Juvenile polyps

sporadic

Question 7

Sporadic juvenile polyps are usually , but the number varies from 3 to as many as 100 in individuals with the autosomal dominant syndrome of juvenile polyposis.

• The vast majority of juvenile polyps occur in children younger than years of age.
• Juvenile polyps characteristically are located in the and most manifest with rectal bleeding.**

Answer 7

solitary*

5

rectum

Question 8

Dysplasia occurs in a small proportion of (mostly syndrome- associated) juvenile polyps, and the juvenile polyposis syndrome is associated with an increased risk for development of within the colon and at other sites.

• may be required to limit the hemorrhage associ­ated with polyp ulceration in juvenile polyposis.

Answer 8

adenocarcinoma

Colectomy

Question 9

Individual sporadic and syndromic juvenile polyps often are

• They typically are pedunculated, smooth-surfaced, reddish lesions that are less than 3 cm in diameter and display characteristic spaces on cut sections.
• Microscopic examination shows the spaces to be dilated glands filled with mucin and inflammatory debris.

Answer 9

indistinguishable.

cystic

Question 10

What is a rare autosomal dominant disorder defined by the presence of multiple gastrointestinal hamartomatous polyps and mucocutaneous hyperpigmentation, that carries an increased risk for development of several malignancies, including cancers of the colon, pancreas, breast, lung, ovaries, uterus, and testes, as well as other unusual neoplasms?

Answer 10

Peutz-Jeghers syndrome

Question 11

Concerning Peutz-Jeghers Syndrome:

Germ line loss-of-function mutations in the gene are present in approximately half of the patients with the familial form of Peutz-Jeghers syndrome, as well as a subset of patients with the sporadic form.

• encodes a tumor suppressive protein kinase that regulates cellular metabolism.

Answer 11

LKB1/STK11

LKB1/STK11

Question 12

Intestinal PJ polyps are most common in the , although they may also occur in the stomach and colon and, rarely, in the bladder and lungs.

• On gross evaluation, the polyps are large and with a lobulated contour

Answer 12

small intestine

pedunculated

Question 13

Concerning Peutz-Jeghers Syndrome (a form of hamartomutous polyp)

Histologically there is an network of connective tissue, smooth muscle, lamina propria, and glands lined by normal-appearing intestinal epithelium.

Answer 13

arborizing

Question 14

What are common epithelial proliferations that typically are discovered in the sixth and seventh decades of life?

-formation of these lesions is thought to result from decreased epithelial cell turnover and delayed shedding of surface epithelial cells, leading to a “pileup” of goblet cells.

Answer 14

Colonic hyperplastic polyps

Question 15

Concerning Colonic hyperplastic polyps:

These lesions have severe/no malignant potential, they must be distinguished from sessile serrated adenomas, histologically similar lesions that do have malignant potential

Answer 15

no

Question 16

Hyperplastic polyps are most commonly found in the and typically are less than 5 mm in d.

• They are smooth, nodular protrusions of the mucosa, often on the of mucosal folds.
• They may occur singly but more frequently are multiple, particularly in the colon and rectum.

Answer 16

left colon

crests

sigmoid

Question 17

Histologically, hyperplastic polyps are composed of mature and absorptive cells.

• The delayed shedding of these cells leads to crowding that creates the

surface architecture, the morphologic hallmark of these lesions

Answer 17

goblet

serrated

Question 18

The most common and clinically important neoplastic polyps are colonic , benign polyps that give rise to a majority of colorectal adenocarcinomas.

• Most adenomas, however, do/do not progress to adenocarcinoma.
• Colorectal adenomas are characterized by the presence of epithelial

Answer 18

adenomas

do not

dysplasia.

Question 19

Because these (adenoma) polyps are precursors to colorectal cancer, current recommendations are that all adults in the United States undergo screening colonoscopy starting at years of age.

• Because individuals with a family history are at risk for developing colon cancer earlier in life, they are typically screened at least 10 years before the youngest age at which a relative was diagnosed

Answer 19

50

Question 20

Typical adenomas range from cm in diameter and can be pedunculated or sessile, with the surface of both types having a texture resembling velvet, due to the abnormal epithelial growth pattern

Answer 20

0.3 - 10

Question 21

Histologically, the cytologic hallmark of epithelial dysplasia is nuclear

, elongation, and stratification.

• These changes are most easily appreciated at the surface of the adenoma, because the epithelium fails to as cells migrate out of the crypt.

Answer 21

hyperchromasia

mature

Question 22

can be classified as tubular, tubulovillous, or villous on the basis of architecture.

Answer 22

Adenomas

Question 23

The histologic features of sessile serrated adenomas, overlap with those of polyps and lack typical cytologic features of dysplasia.

• Sessile serrated adenomas, which are most common in the colon, have a malignant potential similar to that of conventional adenomas.

Answer 23

hyperplastic

right

Question 24

What is an autosomal dominant disorder marked by the appearance of numerous colorectal adenomas by the teenage years?

• It is caused by mutations of the adenomatous polyposis coli gene (APC).

Answer 24

Familial adenomatous polyposis (FAP

Question 25

A count of at least polyps is necessary for a diagnosis of classic FAP, and as many as several thousand may be present.

• These growths are morphologically indistinguishable from sporadic

Answer 25

100

adenomas

Question 26

Colorectal develops in 100% of pts with untreated FAP, often before 30 years of age.

• As a result, prophylactic is standard therapy for individuals carrying APC mutations.
• Patients remain at risk for extraintestinal manifestations, including neoplasia at other sites.

Answer 26

adenocarcinoma

colectomy

Question 27

Specific APC mutations are associated with the development of FAP variants such as Gardner syndrome and syndrome

Answer 27

Turcot

Question 28

In addition to intestinal polyps, clinical features of syndrome may include osteomas of the mandible, skull, and long bones; epidermal cysts; desmoid and thyroid tumors; and dental abnormalities, including unerupted and supernumerary

Answer 28

Gardner

teeth.

Question 29

Turcot syndrome (a type of FAP) is rarer and is characterized by intestinal adenomas and tumors of the 
• 2/3 of patients with Turcot syndrome have APC gene mutations and develop

• The remaining 1/3 have mutations in one of several genes involved in DNA repair and develop

Answer 29

CNS.

medulloblastomas.

glioblastomas

Question 30

• Originally was described as familial clustering of cancers at several sites including the colorectum, endometrium, stomach, ovary, ureters, brain, small bowel, hepatobiliary tract, and skin.
• tend to occur at younger ages than do sporadic colon cancers and often are located in the right colon.

Answer 30

Hereditary nonpolyposis colorectal cancer (HNPCC)(AKA, Lynch syndrome)

Question 31

Adenomas are/are not present in HNPCC, but excessive numbers (i.e., polyposis) is not.

• In many cases, adenomas are associated with HNPCC, and mucin production may be a prominent in the subsequent adenocarcinomas

Answer 31

are

sessile serrated

Question 32

Answer 32

Question 33

HNPCC is caused by inherited germ line mutations in genes that encode

responsible for the detection, excision, and repair of errors that occur during DNA replication.

• At least five such mismatch repair genes have been recognized, but a majority of HNPCC cases involve either or MLH1

Answer 33

proteins

MSH2

Question 34

Patients with HNPCC inherit one mutated DNA repair gene and one

allele.

• When the second copy is lost through mutation or epigenetic silencing, defects in mismatch repair lead to the accumulation of mutations at rates up to 1000 times higher than normal, mostly in regions containing short repeating DNA sequences referred to as DNA.*

Answer 34

normal

microsatellite

Question 35

• Adenocarcinoma of the colon is the most common malignancy of the

tract and is a major contributor to morbidity and mortality worldwide.

• In contrast, the intestine, which accounts for 75% of the overall length of the gastrointestinal tract, is an uncommon site for benign and malignant tumors.*

Answer 35

GI

small

Question 36

Colorectal cancer incidence peaks at 60 to yrs of age, with less than 20% of cases occuring before age 50

Answer 36

70

Question 37

The dietary factors most closely associated with increased rates of colorectal cancer are low intake of vegetable fiber and high intake of carbohydrates and fat

Answer 37

unabsorbable

refined

Question 38

Concerning Adenocarcinoma:It is thought that reduced fiber content leads to decreased stool bulk and altered composition of the intestinal

• This change may increase synthesis of potentially toxic by-products of bacterial metabolism, which would be expected to remain in contact with the colonic mucosa for longer periods of time as a result of reduced stool bulk.
• High fat intake also enhances hepatic synthesis of cholesterol and bile acids, which can be converted into by intestinal bacteria.

Answer 38

microbiota.

oxidative

carcinogens

Question 39

Several epidemiologic studies suggest that or other NSAIDs have a protective effect against colorectal carcinoma.

this effect is mediated by inhibition of the enzyme cyclooxygenase-2 (COX-2), which is highly expressed in 90% of colorectal carcinomas and 40%-90% of adenomas.

• COX-2 is necessary for production of , which promotes epithelial proliferation, esp. after injury

Answer 39

aspirin

PGE2

Question 40

What are the two genetic pathways described concerning adenocarcinoma pathology;

Answer 40

APC/β-catenin pathway

microsatellite instability pathway

Question 41

The classic adenoma-carcinoma sequence, accounts for up to 80% of

colon tumors and typically includes mutation of APC early in the neoplastic process.

• For adenomas to develop, one/both copies of the APC gene must be functionally inactivated, either by mutation or epigenetic events.

Answer 41

sporadic

both

Question 42

APC is a key regulator of β-catenin, a component of the WNT signaling pathway.
• The APC protein normally binds to and promotes degradation of

• With loss of APC function, β-catenin accumulates and translocates to the , where it activates the transcription of genes, such as those encoding MYC and cyclin D1, that promote proliferation

Answer 42

negative

β-catenin.

nucleus

Question 43

Concerning adenocarcinoma:

Loss of APC is followed by additional mutations, including activating mutations in , which also promote growth and prevent apoptosis.*

• Neoplastic progression also is associated with mutations in other tumor suppressor genes such as SMAD2 and SMAD4 , which encode effectors of signaling.**
• The tumor suppressor gene is mutated in 70-80% of colon cancers but is uncommonly affected in adenomas, suggesting that TP53 mutations also occur at late stages of tumor progression.***

Answer 43

KRAS

TGF-β

TP53

Question 44

The microsatellite instability pathway - In patients with DNA mismatch repair deficiency (due to loss of mismatch repair genes), mutations accumulate in microsatellite , a condition referred to as microsatellite instability

Answer 44

repeats

Question 45

Concerning adenocarcinoma:

Some microsatellite sequences are located in the coding or promoter regions of genes involved in regulation of cell growth, such as those encoding the type II TGF-β receptor and the pro-apoptotic protein .

Answer 45

BAX

Question 46

Concerning adenocarcinoma:

Tumors in the colon often grow as polypoid, exophytic masses that extend along one wall of the largecaliber cecum and ascending colon; these tumors often/rarely cause obstruction.

By contrast, carcinomas in the colon tend to be annular lesions that produce “napkin ring” constrictions and luminal narrowing, sometimes to the point of obstruction.

• Both forms grow into the bowel wall over time and may be palpable as firm masses.

Answer 46

proximal

rarely

distal

Question 47

Answer 47

All adenocarcinoma

Middle: fibrosis, desmoplastic lesion

right: apple core or napkin ring lesion

Question 48

Concerning adenocarcinoma:

Most tumors are composed of tall cells that resemble dysplastic epithelium found in adenomas.

• The invasive component of these tumors elicits a strong stromal desmoplastic response, which is responsible for their characteristic firm consistency.

Answer 48

columnar

stromal

Question 49

Answer 49

Adenocarcinoma

A: abundant mucin- poor prognosis

B-signet ring cells (similar to gastric cancer)

Question 50

and other right-sided colon cancers most often are called to clinical attention by the appearance of fatigue and weakness due to iron-deficiency anemia.

• Thus, it is a clinical maxim that the underlying cause of -deficiency anemia in an older male or postmenopausal female is gastrointestinal cancer until proven otherwise.

-sided colorectal adenocarcinomas may produce occult bleeding, changes in bowel habits, or cramping left lower-quadrant discomfort.

Answer 50

Cecal

iron

Left

Question 51

Answer 51

Adenocarcinoma metastatses in lung and liver

Question 52

The most common tumor of the appendix is the tumor.

• It usually is discovered incidentally at the time of surgery or on examination of a resected appendix.
• This neoplasm most frequently involves the distal tip of the appendix, where it produces a solid bulbous swelling up to 2 to 3 cm in diameter.
• Although intramural and transmural extension may be evident, nodal metastases are very frequent/infrequent, and distant spread is exceptionally rare.

Answer 52

carcinoid

infrequent

Question 53

Conventional adenomas or non–mucin-producing also occur in the appendix and may cause obstruction and enlargement that mimics the changes of acute appendicitis.

• , a dilated appendix filled with mucin, may simply stem from an obstructed appendix containing inspissated mucin or may be a consequence of mucinous cystadenoma or mucinous cystadenocarcinoma

Answer 53

adenocarcinomas

Mucocele

Question 54

In mucinous invasion through the appendiceal wall can lead to intraperitoneal seeding and spread.

• In women, the resulting peritoneal implants may be mistaken for mucinous ovarian tumors.
• In the most advanced cases, the abdomen fills with tenacious, semisolid mucin, a condition called peritonei.
• This disseminated intraperitoneal disease may be held in check for years by repeated debulking, but ultimately is in most instances.

Answer 54

cystadenocarcinoma

pseudomyxoma

fatal