tbl 4 pathology readings

Question 1

[Sigmoid Diverticulitis]

In general, diverticular disease refers to ___________ of the colonic mucosa and submucosa. Such colonic diverticula are rare in individuals younger than 30 years of age, but the prevalence approaches 50% in Western adult populations older than 60 years of age. Diverticula generally are multiple, and the condition is referred to as diverticulosis. This disease is much less common in developing countries, probably because of dietary differences.

Colonic diverticula tend to develop under conditions of _____________ in the sigmoid colon. This is facilitated by the unique structure of the colonic muscularis propria, where nerves, arterial vasa recta, and their connective tissue sheaths penetrate the inner circular muscle coat to create discontinuities in the muscle wall. In other parts of the intestine, these gaps are reinforced by the external longitudinal layer of the muscularis propria, but in the colon, this muscle layer is discontinuous, being gathered into three bands termed taeniae coli. High luminal pressures may be generated by ________________, with spasmodic sequestration of bowel segments that may be exacerbated by diets low in fiber, which reduce stool bulk.

Answer 1

acquired pseudodiverticular outpouchings;

elevated intraluminal pressure; exaggerated peristaltic contractions;

Question 2

[Sigmoid Diverticulis]
omically, colonic diverticula are small, flasklike outpouchings, usually 0.5 to 1 cm in diameter, that occur in a regular distribution in between the ___________. They are most common in the _____________, but other regions of the colon may be affected. Colonic diverticula have a thin wall composed of a flattened or atrophic mucosa, compressed submucosa, and
attenuated muscularis propria—often, this last component is totally absent . Obstruction of diverticula with stasis of contents, leads to inflammatory changes, producing ____________________. Because the wall of the diverticulum is supported only by the muscularis mucosa and a thin layer of subserosal adipose tissue, inflammation, increased pressure, and mucosal ucleration within an obstructed diverticulum can readily result in perforation. With or without perforation, recurrent diverticulitis may cause __________, fibrotic thickening in and around the colonic wall, or stricture formation.

Most individuals with diverticular disease remain asymptomatic throughout their lives. About 20% of those affected develop complaints including ____________, continuous lower abdominal discomfort, constipation, and diarrhea. Longitudinal studies have shown that while diverticula can regress early in their development they often become more numerous and larger over time. Whether a high-fiber diet prevents such progression or protects against diverticulitis is unclear. Even when diverticulitis occurs, it most often resolves spontaneously or after antibiotic treatment, and relatively few patients require surgical intervention.

Answer 2

taeniae coli;

sigmoid colon;

diverticulitis and peridiverticulitis;

segmental colitis;

intermittent cramping

Question 3

Inflammatory bowel disease (IBD) is a chronic condition resulting from complex interactions between intestinal microbiota and host immunity in genetically predisposed individuals resulting an inappropriate mucosal immune activation. IBD encompasses two entities, Crohn disease and ulcerative colitis . The distinction between ulcerative colitis and Crohn disease is based, in large part, on the distribution of affected sites and the morphologic expression of disease at those sites. Ulcerative colitis is limited to the _____________ and extends only into the __________. By contrast, Crohn disease, also referred to as regional enteritis (because of frequent ileal involvement), may involve any area of the gastrointestinal tract and is frequently __________.

Both Crohn disease and ulcerative colitis frequently present during ____________________, although some studies suggest a second, smaller peak in the incidence of both diseases after the fifth decade. In Western industrialized nations, IBD is most common among whites and, in the United States, occurs three to five times more often among eastern European (Ashkenazi) Jews. This predilection is at least partly due to genetic factors, as discussed below. The geographic distribution of IBD is highly variable, but it is most prevalent in North America, northern Europe, and Australia. The incidence of IBD worldwide is on the rise and it is becoming more common in regions in which the prevalence was historically low. The _____________ , first applied to asthma, says that childhood and even prenatal exposure to environmental microbes resets the immune system in a way that prevents excessive reactions. Extrapolated to IBD, it suggests that a reduced frequency of enteric infections due to improved hygiene has resulted in inadequate development of regulatory processes that limit mucosal immune responses early in life. While attractive and commonly stated, firm evidence is lacking and hence the increasing incidence of IBD remains mysterious.

Answer 3

colon and rectum;

mucosa and submucosa;

transmural;

adolescence or in young adults;

hygiene hypothesis;

Question 4

[IBD Pathogenesis: Genetics]

Risk for disease is increased when there is an affected family 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.

Molecular linkage analyses of affected families have identified ________________ as a susceptibility gene in Crohn disease which encodes a protein that binds to _________________ and subsequently activates NF-κB. Some studies suggest that the disease-associated form of NOD-2 is ineffective at defending against intestinal bacteria. The result is that bacteria are able to enter through the epithelium into the wall of the intestine, where they trigger inflammatory reactions. It should, however, be recognized that disease develops in less than 10% of individuals carrying specific NOD2 polymorphisms, and these polymorphisms are uncommon in African and Asian patients with Crohn disease.

The search for IBD-associated genes using genome-wide association studies (GWAS) that assess single-nucleotide polymorphisms (SNPs) as well as high throughput sequencing and other approaches have yielded a rich harvest of over 200 genes associated with IBD. Among these, NOD2, discussed above, and two autophagy–related genes are of particular interest. They are ___________________ and ________________ genes. Both are part of the autophagosome pathway and, like NOD-2, are involved in host cell responses to intracellular bacteria, supporting the hypothesis that inadequate defense against luminal bacteria may be important in the pathogenesis of IBD. None of these genes is associated with ulcerative colitis.

Answer 4

NOD2 (nucleotide oligomerization binding domain 2);

intracellular bacterial peptidoglycans;

ATG16L1 (autophagy-related 16–like-1);

IRGM (immunity-related GTPase M)

Question 5

[IBD Pathogenesis: Mucosal Immune Response]

Although the mechanisms by which mucosal immunity contributes to the pathogenesis of ulcerative colitis and Crohn disease are still being deciphered, immunosuppressive and immunomodulatory agents remain mainstays of IBD therapy. Polarization of helper T cells to the _________ is well recognized in Crohn disease, and some data suggest that TH17 T cells also contribute to disease pathogenesis. Consistent with this, certain polymorphisms of the __________ confer protection from Crohn disease and ulcerative colitis (IL-23 is involved in the development and maintenance of TH17 cells). However, agents that block IL-17 or its receptor have provided no benefit, whereas an antibody that inhibits both TH 1- and TH17-inducing cytokines is effective, suggesting that the two T cell subsets may have a synergistic role in the disease. Some data suggest that mucosal production of the TH2-derived cytokine _____ is increased in ulcerative colitis, and, to a lesser degree, Crohn disease. Defects in regulatory T cells, especially the IL-10-producing subset, are believed to underlie the inflammation especially in Crohn disease. Mutations in the IL-10 receptor are associated with severe, early-onset colitis. Thus, some combination of excessive immune activation by intestinal microbes and defective immune regulation likely is responsible for the chronic inflammation in both forms of IBD.

Answer 5

TH1 type;

IL-23 receptor;

IL-13 ;

Question 6

[IBD Pathogenesis: Epithelial defects]
A variety of epithelial defects have been described in Crohn disease, ulcerative colitis, or both. For example, defects in intestinal epithelial tight junction barrier function occur in patients with Crohn disease and a subset of their healthy first-degree relatives. This barrier dysfunction cosegregates with specific disease-associated NOD2 polymorphisms, and experimental models demonstrate that barrier dysfunction can activate innate and adaptive mucosal immunity and sensitize subjects to disease. Interestingly, the _________, which contain anti-microbial peptides that can affect composition of the luminal microbiota, are abnormal in patients with Crohn disease carrying ATG16L1 mutations, thus providing one potential mechanism in which a defective feedback loop between the epithelium and microbiota could contribute to disease pathogenesis.

Answer 6

Paneth cell granules

Question 7

[IBD Pathogenesis: Microbiota]
The quantity of microbial organisms in the gastrointestinal lumen is enormous, amounting to as many as 10^12 organisms/mL of fecal material in the colon (50% of fecal mass). There is significant interindividual variation in the composition of this microbial population, which is modified by diet and disease. Microbial transfer studies are able to promote or reduce disease in animal models of IBD, and clinical trials suggest that probiotic (or beneficial) bacteria or even fecal microbial transplants from healthy individuals may benefit IBD patients.

One model that unifies the roles of intestinal microbiota, epithelial function, and mucosal immunity suggests a cycle by which _____________ of luminal bacterial components activates innate and adaptive immune responses. In a genetically susceptible host, the subsequent release of TNF and other immune signals directs epithelia to increase tight junction permeability, which further increases the flux of luminal material. These events may establish a self-amplifying cycle in which a stimulus at any site may be sufficient to initiate IBD.

Answer 7

transepithelial flux

Question 8

[Crohn Disease Morphology]
Crohn disease, also known as regional enteritis, may occur in any area of the gastrointestinal tract but the most common sites involved at presentation are the ____________________. Disease is limited to the small intestine alone in about 40% of cases; the small intestine and the colon both are involved in 30% of patients; and the remainder of cases are characterized by colonic involvement only. Infrequently, Crohn disease may involve the esophagus or stomach. The presence of multiple, separate, sharply delineated areas of disease, resulting in _________, is characteristic of Crohn disease and may help in differentiation from ulcerative colitis. _______ are common.

The earliest lesion, the _____________, may progress, and multiple lesions often coalesce into elongated, ____________ oriented along the axis of the bowel. Edema and loss of normal mucosal folds are common. Sparing of interspersed mucosa results in a coarsely textured, __________ in which diseased tissue is depressed below the level of normal mucosa. Fissures frequently develop between mucosal folds and may extend deeply to become sites of perforation or fistula tracts. The intestinal wall is thickened as a consequence of __________, inflammation, submucosal fibrosis, and hypertrophy of the muscularis propria, all of which contribute to stricture formation. In cases with extensive transmural disease, mesenteric fat frequently extends around the serosal surface (creeping fat).

Answer 8

terminal ileum, ileocecal valve, and cecum;

skip lesions;

Strictures;

aphthous ulcer;

serpentine ulcers;

cobblestone appearance;

transmural edema;

Question 9

[Crohn’s Disease: Morphology]

The microscopic features of active Crohn disease include abundant neutrophils that infiltrate and damage crypt epithelium. Clusters of neutrophils within a crypt are referred to as a ____________ and often are associated with crypt destruction. Ulceration is common in Crohn disease, and there may be an abrupt transition between ulcerated and normal mucosa. Repeated cycles of crypt destruction and regeneration lead to distortion of mucosal architecture; the normally straight and parallel crypts take on bizarre branching shapes and unusual orientations to one another .

Epithelial metaplasia, another consequence of chronic relapsing injury, often takes the form of ____________ (pseudopyloric metaplasia).

Paneth cell metaplasia may occur in the ___________, where Paneth cells are normally absent. These architectural and metaplastic changes may persist, even when active inflammation has resolved. Mucosal atrophy, with loss of crypts, may follow years of disease. _________________, a hallmark of Crohn disease, are found in approximately 35% of cases and may arise in areas of active disease or uninvolved regions in any layer of the intestinal wall. Granulomas also may be found in ___________. Cutaneous granulomas form nodules that are referred to (misleadingly) as metastatic Crohn disease. The absence of granulomas does not preclude a diagnosis of Crohn disease.

Answer 9

crypt abscess;

gastric antral-appearing glands;

left colon;

Noncaseating granulomas;

mesenteric lymph nodes

Question 10

[Crohn Disease: Clinical Manifestations]

The clinical manifestations of Crohn disease are extremely variable. In most patients, disease begins with intermittent attacks of relatively mild diarrhea, fever, and abdominal pain. Approximately 20% of patients present acutely with _________________ pain and fever, which may mimic acute appendicitis or bowel perforation. Patients with colonic involvement may present with bloody diarrhea and abdominal pain, creating a differential diagnosis with some colonic infections. Periods of disease activity typically are interrupted by asymptomatic intervals that last for weeks to many months. Disease reactivation can be associated with a variety of external triggers, including physical or emotional stress, specific dietary items, ___________ use, and cigarette smoking.

_____________ may develop in individuals with colonic disease, while extensive small-bowel disease may result in serum protein loss and ______________, generalized nutrient malabsorption, or malabsorption of vitamin B 12 and bile salts. Fibrosing strictures, particularly of the terminal ileum, are common and require surgical resection. Disease often recurs at the site of anastomosis, and as many as 40% of patients require additional resections within 10 years. Fistulas develop between loops of bowel and may also involve the ____________, vagina, and abdominal or perianal skin. Perforations and peritoneal abscesses can also occur.

Extraintestinal manifestations of Crohn disease include uveitis, migratory polyarthritis, sacroiliitis, ankylosing spondylitis, erythema nodosum, and __________________, any of which may develop before intestinal disease is recognized. Pericholangitis and primary sclerosing cholangitis may occur in Crohn disease but are more common in ulcerative colitis. As discussed later, the risk for development of colonic adenocarcinoma is increased in patients with long-standing colonic Crohn disease.

Answer 10

right lower-quadrant; NSAID;

Iron-deficiency anemia; hypoalbuminemia;

urinary bladder;

clubbing of the fingertips

Question 11

[Ulcerative Colitis: Morphology]

Ulcerative colitis always involves the ______ and extends proximally in a continuous fashion to involve part or the entire colon that can be _________ ulcerated. Skip lesions are not seen (although focal appendiceal or cecal inflammation occasionally may be present in those with left-sided disease). Disease of the entire colon is termed pancolitis. Disease limited to the rectum or rectosigmoid may be referred to descriptively as ulcerative proctitis or ulcerative proctosigmoiditis . The small intestine is normal, although mild mucosal inflammation of the distal ileum, __________, may be present in severe cases of pancolitis.

On gross evaluation, involved colonic mucosa may be slightly red and granular-appearing or exhibit extensive broad-based ulcers. The transition between diseased and uninvolved colon can be abrupt. Ulcers are aligned along the long axis of the colon but typically do not replicate the serpentine ulcers of Crohn disease. Isolated islands of regenerating mucosa often bulge into the lumen to create small elevations, termed ___________ . Chronic disease may lead to mucosal atrophy and a flat, smooth mucosal surface lacking normal folds. Unlike in Crohn disease, mural thickening is absent, the serosal surface is normal, and strictures do not occur. However, inflammation and inflammatory mediators can damage the ___________ and disturb neuromuscular function leading to colonic dilation and ___________, which carries a significant risk for perforation.

Answer 11

rectum;

diffusely;

backwash ileitis;

pseudopolyps;

muscularis propria;

toxic megacolon

Question 12

[Ulcerative Colitis: Morphology]
Histologic features of mucosal disease in ulcerative colitis are similar to those in colonic Crohn disease and include inflammatory infiltrates, crypt abscesses, crypt distortion, and _____________. However, skip lesions are absent, and inflammation generally is limited to the ________________. This distinction may not be demonstrated by endoscopic biopsies, which typically sample the mucosa and little or no submucosa. In severe cases, mucosal damage may be accompanied by ulcers that extend more deeply into the submucosa, but the muscularis propria is rarely involved. Submucosal fibrosis, mucosal atrophy, and distorted mucosal architecture remain as residua of healed disease, but the histologic pattern also may revert to near normal after prolonged remission. Granulomas are not present.

Some extraintestinal manifestations of ulcerative colitis overlap with those of Crohn disease, including migratory polyarthritis, sacroiliitis, ankylosing spondylitis, uveitis, skin lesions, pericholangitis, and ___________________.

Answer 12

epithelial metaplasia;

mucosa and superficial submucosa;

primary scleros­ing cholangitis

Question 13

[Ulcerative Colitis: Clinical Features]
Ulcerative colitis is a relapsing disorder characterized by attacks of bloody diarrhea with expulsion of __________________ and lower abdominal pain and cramps that are temporarily relieved by defecation. These symptoms may persist for days, weeks, or months before they subside, and occasionally the initial attack may be severe enough to constitute a medical or surgical emergency. More than half of patients have mild disease, but almost all experience at least one relapse during a 10-year period. _______________ cures intestinal disease, but extraintestinal manifestations may persist.

The factors that trigger ulcerative colitis are not known; infectious enteritis precedes disease onset in some cases. The onset of symptoms can occur shortly after smoking cessation in some patients, and smoking may partially relieve symptoms. Unfortunately, studies of nicotine as a therapeutic agent have been disappointing.

Answer 13

stringy, mucoid material;

Colectomy

Question 14

[Colitis-Associated Neoplasia]
One of the most feared long-term complications of ulcerative colitis and colonic Crohn disease is the development of neoplasia. This process begins as dysplasia, which, just as in Barrett esophagus and chronic gastritis, is a step along the road to full-blown carcinoma. The risk for development of dysplasia is related to several factors:

• Duration of disease. Risk increases beginning ________ after disease initiation.
• Extent of involvement. Patients with _______ are at greater risk than those with only left-sided disease.
• Inflammation. Greater frequency and severity of active inflammation (characterized by the presence of ____________) may increase risk. This is another example of the enabling effect of inflammation on carcinogenesis.

To facilitate early detection of neoplasia, patients typically are enrolled in surveillance programs approximately 8 years after diagnosis of IBD. An important exception to this approach is in patients with _______________, who are at markedly greater risk for development of dysplasia and generally are enrolled for surveillance at the time of diagnosis. Surveillance requires regular and extensive mucosal biopsy, making it a costly practice. In many cases, dysplasia occurs in flat areas of mucosa that do not appear abnormal by eye. Thus, advanced endoscopic imaging techniques are being developed to try to enable the detection of early dysplastic changes

Answer 14

8 to 10 years;

pancolitis;

neutrophils;

primary sclerosing cholangitis

Question 15

Polyps are most common in the colon but may occur in the esophagus, stomach, or small intestine. Those without _______ are referred to as sessile. As sessile polyps enlarge, proliferation of cells adjacent to the polyp and the effects of traction on the luminal protrusion may combine to create a stalk. Polyps with stalks are termed _____________. In general, intestinal polyps can be classified as nonneoplastic or neoplastic. The most common neoplastic polyp is the ________, which has the potential to progress to cancer. Nonneoplastic colonic polyps can be further classified as inflammatory, hamartomatous, or hyperplastic.

Answer 15

stalks;

pedunculated;

adenoma

Question 16

[Inflammatory Polyps]
The solitary 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 anterior rectal wall. The underlying cause is impaired relaxation of the __________________, creating a sharp angle at the anterior rectal shelf. This leads to recurrent abrasion and ulceration of the overlying __________. Chronic cycles of injury and healing produce a _________ composed of inflamed and reactive mucosal tissue.

Answer 16

anorectal sphincter; rectal mucosa; polypoid mass

Question 17

[Hamartomatous Polyps]
Hamartomatous polyps occur sporadically and as components of various genetically determined or acquired syndromes. As described previously, hamartomas are disorganized, tumorlike 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.

Individual sporadic and syndromic juvenile polyps often are indistinguishable. They typically are __________, smooth-surfaced, reddish lesions that are less than 3 cm in diameter and display characteristic cystic spaces on cut sections. Microscopic examination shows the spaces to be dilated glands filled with ____________________. Some data suggest that mucosal hyperplasia is the initiating event in polyp development, and this mechanism is consistent with the discovery that mutations in pathways that regulate cellular growth, such as _____________ signaling, are associated with autosomal dominant juvenile polyposis.

Answer 17

pedunculated;

mucin and inflammatory debris;

transforming growth factor-β (TGF-β)

Question 18

[Peutz-Jeghers Syndrome]

Peutz-Jeghers syndrome is a rare autosomal dominant disorder defined by the presence of multiple gastrointestinal hamartomatous polyps and _______________________ 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. Germ line loss-of-function mutations in the ___________ 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. LKB1/STK11 encodes a tumor suppressive protein kinase that regulates cellular metabolism, yet another example of links between alterned metabolism, abnormal cell growth, and cancer risk. Intestinal polyps are most common in the small intestine, 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 pedunculated with a ___________ contour. Histologic examination demonstrates a characteristic _________ network of connective tissue, smooth muscle, lamina propria, and glands lined by normal-appearing intestinal epithelium

Answer 18

mucocutaneous hyperpigmentation;

LKB1/STK11 gene;

lobulated;

arborizing

Question 19

[Hyperplastic Polyps]
Colonic hyperplastic polyps are common epithelial proliferations that typically are discovered in the sixth and seventh decades of life. The pathogenesis of hyperplastic polyps is incompletely understood, but formation of these lesions is thought to result from decreased ___________ and delayed shedding of surface epithelial cells, leading to a “pileup” of goblet cells. Although these lesions have no malignant potential, they must be distinguished from sessile serrated adenomas, histologically similar lesions that have malignant potential, as described later.

Hyperplastic polyps are most commonly found in the left colon and typically are less than 5 mm in diameter. They are smooth, nodular protrusions of the mucosa, often on the crests of mucosal folds. They may occur singly but more frequently are multiple, particularly in the _______________. Histologically, hyperplastic polyps are composed of mature goblet and absorptive cells. The delayed shedding of these cells leads to crowding that creates the __________ surface architecture, the morphologic hallmark of these lesions .

Answer 19

epithelial cell turnover;

sigmoid colon and rectum

serrated

Question 20

[Adenomas]

The most common and clinically important neoplastic polyps are colonic adenomas, benign polyps that give rise to a majority of _______________. Most adenomas, however, do not progress to adenocarcinoma.

Colorectal adenomas are characterized by the presence of ___________. These growths range from small, often pedunculated polyps to large sessile lesions. There is no gender predilection, and they are present in nearly 50% of adults living in the Western world beginning at age 50. Because these polyps are precursors to colorectal cancer, current recommendations are that all adults in the United States undergo screening colonoscopy starting at 50 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. While adenomas are less common in Asia, their frequency has risen (in parallel with an increasing incidence of colorectal adenocarcinoma) as Western diets and lifestyles become more common.

Typical adenomas range from 0.3 to 10 cm in diameter and can be pedunculated or sessile, with the surface of both types having a texture resembling velvet or a raspberry, due to the abnormal epithelial growth pattern. Histologically, the cytologic hallmark of epithelial dysplasia is ______________, elongation, and stratification. These changes are most easily appreciated at the surface of the adenoma, because the epithelium fails to mature as cells migrate out of the crypt. Pedunculated adenomas have slender fibromuscular stalks containing prominent blood vessels derived from the submucosa. The stalk usually is covered by ________________—, but dysplastic epithelium is sometimes present.

Answer 20

colorectal adenocarcinomas;

epithelial dysplasia;

nuclear hyperchromasia;

nonneoplastic epithelium

Question 21

[Adenomas: Morphology]

Adenomas can be classified as tubular, tubulovillous, or villous on the basis of their architecture. These categories, however, have little clinical significance in isolation. Tubular adenomas tend to be small, _______________ composed of small, rounded, or tubular glands. By contrast, villous adenomas, which often are larger and sessile, are covered by slender villi . Tubulovillous adenomas have a mixture of tubular and villous elements. Although foci of invasion are more frequent in villous adenomas than in tubular adenomas, villous architecture alone does not increase cancer risk when polyp size is considered.

The histologic features of sessile serrated adenomas, which are also referred to as sessile serrated polyps, overlap with those of hyperplastic polyps and lack typical cytologic features of dysplasia. Nevertheless, sessile serrated adenomas, which are most common in the _________, have a malignant potential similar to that of conventional adenomas. The most useful histologic feature that distinguishes sessile serrated adenomas from hyperplastic polyps is the presence of serrated architecture throughout the full length of the glands, including the ___________, associated with crypt dilation and lateral growth, in the former. By contrast, serrated architecture typically is confined to the surface of hyperplastic polyps.

Although most colorectal adenomas behave in a benign fashion, a small proportion harbor invasive cancer at the time of detection. Size is the most important characteristic that correlates with risk for malignancy. For example, while cancer is extremely rare in adenomas less than 1 cm in diameter, some studies suggest that nearly 40% of lesions larger than 4 cm in diameter contain foci of invasive cancer. In addition to size, high-grade dysplasia is a risk factor for cancer in an individual polyp (but not other polyps in the same patient).

Answer 21

pedunculated polyps;

right colon;

crypt base;

Question 22

[Familial Adenomatous polyps]
Familial adenomatous polyposis (FAP) is an autosomal dominant disorder marked by the appearance of numerous colorectal adenomas by the teenage years. It is caused by mutations of the _____________. A count of at least 100 polyps is necessary for a diagnosis of classic FAP, and as many as several thousand may be present. Except for their remarkable numbers, these growths are morphologically indistinguishable from sporadic adenomas. Colorectal adenocarcinoma develops in 100% of patients with untreated FAP, often before 30 years of age. As a result, _______________ is standard therapy for individuals carrying APC mutations. However, patients remain at risk for extraintestinal manifestations, including neoplasia at other sites.

Specific APC mutations are also associated with the development of other manifestations of FAP and explain variants such as Gardner syndrome and Turcot syndrome . In addition to intestinal polyps, clinical features of Gardner syndrome, a variant of FAP, may include __________ of the mandible, skull, and long bones; epidermal cysts; desmoid and thyroid tumors; and dental abnormalities, including unerupted and supernumerary teeth.

Turcot syndrome is rarer and is characterized by intestinal adenomas and tumors of the central nervous system. Two-thirds of patients with Turcot syndrome have APC gene mutations and develop _______________. The remaining one-third have mutations in one of several genes involved in DNA repair and develop _____________. Some patients with hundreds of adenomas lack APC mutations but instead have mutations of the base excision repair gene MUTYH (also called MUTYH polyposis). The role of these genes in tumor development is discussed later.

Answer 22

adenomatous polyposis coli gene (APC);

prophylactic colectomy;

osteomas;

medulloblastomas; glioblastomas

Question 23

[Hereditary Nonpolyposis Colorectal Cancer]
Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, 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. Colon cancers in patients with HNPCC tend to occur at younger ages than do sporadic colon cancers and often are located in the right colon. Adenomas are present in HNPCC, but excessive numbers (i.e., polyposis) is not. In many cases, ____________ are associated with HNPCC, and mucin production may be a prominent in the subsequent adenocarcinomas.

Just as identification of APC mutations in FAP has provided molecular insights into the pathogenesis of a majority of sporadic colon cancers, dissection of the defects in HNPCC has shed light on the mechanisms responsible for most of the remaining sporadic cases. HNPCC is caused by inherited germ line mutations in genes that encode proteins 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 ___________. Patients with HNPCC inherit one mutated DNA repair gene and one normal 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 microsatellite DNA. The human genome contains approximately 50,000 to 100,000 microsatellites, which are prone to undergo expansion during DNA replication and represent the most frequent sites of mutations in HNPCC. The consequences of mismatch repair defects and the resulting ___________ are discussed next in the context of colonic adenocarcinoma.

Answer 23

sessile serrated adenomas;

MSH2 or MLH1;

microsatellite instability

Question 24

[Adenocarcinoma]
Adenocarcinoma of the colon is the most common malignancy of the gastrointestinal tract and is a major contributor to morbidity and mortality worldwide. By contrast, the small intestine, which accounts for 75% of the overall length of the gastrointestinal tract, is an uncommon site for benign and malignant tumors. Among malignant small-intestinal tumors, adenocarcinomas and _____________ tumors have roughly equal rates of occurrence, followed by lymphomas and sarcomas.

Each year in the United States, there are more than 130,000 new cases and nearly 50,000 deaths from colorectal adenocarcinoma. This represents nearly 15% of all cancer-related deaths, second only to lung cancer. Colorectal cancer incidence peaks at 60 to 70 years of age; less than 20% of cases occur before 50 years of age. Males are affected slightly more often than females. Colorectal carcinoma is most prevalent in the United States, Canada, Australia, New Zealand, Denmark, Sweden, and other (so-called) developed countries that share lifestyles and diet. The incidence of this cancer is as much as 30-fold lower in India, South America, and Africa. In Japan, where incidence was previously very low, rates have now risen to intermediate levels (similar to those in the United Kingdom), presumably as a result of changes in lifestyle and diet.

The dietary factors most closely associated with increased colorectal cancer rates are low intake of unabsorbable vegetable fiber and high intake of refined carbohydrates and fat. In addition to dietary modification, pharmacologic chemoprevention has become an area of great interest. Several epidemiologic studies suggest that ________________ have a protective effect. This is consistent with studies showing that some NSAIDs cause polyp regression in patients with FAP in whom the rectum was left in place after colectomy. It is suspected that this effect is mediated by inhibition of the enzyme ________________, which is highly expressed in 90% of colorectal carcinomas and 40% to 90% of adenomas and is known to promote epithelial proliferation, particularly in response to injury.

Answer 24

carcinoid (neuroendocrine);

aspirin or other NSAIDs;

cyclooxygenase-2 (COX-2)

Question 25

[Adenocarcinoma Pathogenesis]
Studies of colorectal carcinogenesis have provided fundamental insights into the general mechanisms of cancer evolution. The combination of molecular events that lead to colonic adenocarcinoma is heterogeneous and includes genetic and epigenetic abnormalities. At least two distinct genetic pathways, the APC/β-catenin pathway and the microsatellite instability pathway, have been described. In simplest terms, mutations involving the APC/β-catenin pathway lead to increased _________, whereas those involving the ____________ pathway are associated with defects in DNA mismatch repair). Both pathways involve the stepwise accumulation of multiple mutations, but the genes involved and the mechanisms by which the mutations accumulate differ. Epigenetic events, the most common of which is ___________, may enhance progression along both pathways.

• The APC/β-catenin pathway. The classic adenoma-carcinoma sequence, which accounts for as much as 80% of sporadic colon tumors, typically involves mutation of the APC tumor suppressor early in the neoplastic process. For adenomas to develop, both copies of the APC gene must be functionally inactivated, either by mutation or epigenetic events. APC is a key negative regulator of β-catenin, a component of the WNT signaling pathway. The APC protein normally binds to and promotes degradation of β-catenin. With loss of APC function, β-catenin accumulates and translocates to the nucleus, where it activates the transcription of genes, such as those encoding _____________, that promote proliferation. This is followed by additional mutations, including activating mutations in KRAS, which also promote growth and prevent apoptosis. The conclusion that mutation of KRAS is a late event is supported by the observations that mutations are present in fewer than 10% of adenomas less than 1 cm in diameter, 50% of adenomas greater than 1 cm in diameter, and 50% of invasive adenocarcinomas. Neoplastic progression also is associated with mutations in other tumor suppressor genes such as _______________ , which encode effectors of TGF-β signaling. Because TGF-β signaling normally inhibits the cell cycle, loss of these genes may allow unrestrained cell growth. The tumor suppressor gene TP53 is mutated in 70% to 80% of colon cancers but is uncommonly affected in adenomas, suggesting that TP53 mutations also occur at late stages of tumor progression. Loss of function of TP53 and other tumor suppressor genes is often caused by chromosomal deletions, highlighting chromosomal instability as a hallmark of the APC/β-catenin pathway. Alternatively, tumor suppressor genes may be silenced by methylation of ___________, a 5′ region of some genes that frequently includes the promoter and transcriptional start site. Expression of telomerase also increases as lesions become more advanced.

Answer 25

WNT signaling; microsatellite instability; methylation-induced gene silencing

MYC and cyclin D1;

SMAD2 and SMAD4;

CpG islands

Question 26

[Adenocarcinoma: Pathogenesis]
•The microsatellite instability pathway. In patients with DNA mismatch repair deficiency (due to loss of mismatch repair genes, as discussed earlier), mutations accumulate in ____________, a condition referred to as microsatellite instability. These mutations generally are silent, because microsatellites typically are located in noncoding regions, but other microsatellite sequences are located in the coding or promoter regions of genes involved in regulation of cell growth, such as those encoding the ________ and the pro-apoptotic protein ____. Because TGF-β inhibits colonic epithelial cell proliferation, type II TGF-β receptor mutants can contribute to uncontrolled cell growth, while loss of BAX may enhance the survival of genetically abnormal clones.

• CpG island hyper­methylation phenotype (CIMP). In a subset of colon cancers with microsatellite instability, there are no mutations in DNA mismatch repair enzymes. These tumors demonstrate the CpG island hypermethylation phenotype (CIMP). In these tumors, the MLH1 promoter region is typically hypermethylated, thereby reducing MLH1 expression and repair function. Activating mutations in the _____________ are common in these cancers. In contrast, KRAS and TP53 are not typically mutated. Thus, the combination of microsatellite instability, BRAF mutation, and methylation of specific targets, such as MLH1, is the signature of this pathway of carcinogenesis.

Answer 26

microsatellite repeats; type II TGF-β receptor; BAX

BRAF oncogene

Question 27

[Adenocarcinoma: Morphology]
Overall, adenocarcinomas are distributed approximately equally over the entire length of the colon. Tumors in the proximal colon often grow as _________________ that extend along one wall of the large-caliber cecum and ascending colon; these tumors rarely cause obstruction. By contrast, carcinomas in the distal colon tend to be ____________ 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). The general microscopic characteristics of right- and left-sided colonic adenocarcinomas are similar. Most tumors are composed of tall columnar cells that resemble dysplastic epithelium found in adenomas. The invasive component of these tumors elicits a strong _____________ response, which is responsible for their characteristic firm consistency. Some poorly differentiated tumors form few gland. Others may produce abundant mucin that accumulates within the intestinal wall, and these carry a poor prognosis. Tumors also may be composed of signet ring cells similar to those in gastric cancer.

Answer 27

polypoid, exophytic masses;

annular lesions;

stromal desmoplastic;

Question 28

[Adenocarcinoma: Clinical features]
The availability of endoscopic screening combined with the recognition that most carcinomas arise within adenomas presents a unique opportunity for cancer prevention. Unfortunately, colorectal cancers develop insidiously and may therefore go undetected for long periods. Cecal and other right-sided colon cancers most often are called to clinical attention by the appearance of _______________ due to iron-deficiency anemia. Thus, it is a clinical maxim that the underlying cause of iron-deficiency anemia in an older male or postmenopausal female is gastrointestinal cancer until proven otherwise. Left-sided colorectal adenocarcinomas may produce __________, changes in bowel habits, or cramping __________ discomfort.

Although poorly differentiated and mucinous histologic patterns are associated with poor prognosis, the two most important prognostic factors are depth of invasion and the presence or absence of lymph node metastases. The most important distinctions are:

• Depth of invasion . Tumors limited to the submucosa (i.e., those that do not cross the muscularis mucosae) have 5-year survival rates approaching 100%, while invasion into the submucosa or muscularis propria reduces 5-year survival to 95% and 70% to 90%, respectively (for tumors limited to the primary site). Invasion through the visceral serosal surface or into adjacent organs and tissues reduces survival further.
• The presence of lymph node metastases further compromises survival. As a result, most cases with lymph node metastases receive radiation or chemotherapy. In some cases, these treatments may be administered prior to primary tumor resection, a process termed ____________. Molecular characterization of the tumor can be helpful in guiding the specific therapeutic approach.
• Distant metastases to lung, liver , or other sites also limits survival, and only 15% or fewer of patients with tumors at this stage are alive 5 years after diagnosis. Because of the ____________, the liver is the most common site of metastatic lesions. However, the rectum does not drain by way of the portal circulation, and metastases from carcinomas of the anorectum region often circumvent the liver.

Regardless of stage, however, some patients with small numbers of metastases do well for years after resection of distant tumor nodules. This is particularly true of metastases to liver or lung and emphasizes the clinical and molecular heterogeneity of colorectal carcinomas

Answer 28

fatigue and weakness;

occult bleeding; left lower-quadrant

neoadjuvant therapy;

portal drainage