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Gastrointestinal tract disorders II

Development Anomalies

Idiopathic Inflammatory Bowel Disease:

Crohn disease.Chronic ulcerative colitis.

Benign and malignant neoplasms.

Objectives

1. Define Meckel's diverticulum and Hirschsprung's disease and identify their pathologic processes.

2. Correlate the different pathogenic mechanisms for the development of diarrhea with histologic/laboratory findings.

3. Recognize the importance of antibiotics in initiation of clostridium difficile colitis (pseudomembranous colitis).

4. Differentiate Crohn's disease from ulcerative colitis.

5. Describe the precursor lesion in colonic carcinoma.

6. Explain the multi-hit concept of pathogenesis.

7. Name the cell of origin and the most common location of carcinoid tumors.

Key words: Meckel's Diverticulum, Hirschprung's Disease, Ganglion Cells, Ischemia, Infarction, Diverticulosis, Diverticulitis, Diarrhea, Malabsorption, Celiac Sprue, Gluten, Villous Atrophy, Whipple's Disease

Clinical objectives

1. Describe the following aspects of ischemic bowel disease pathology: gross and microscopic features, complications (gangrene, perforation, peritonitis).

2. Describe the following aspects of carcinoid tumors of the small intestine: pathology (gross and microscopic features), clinical features of the carcinoid syndrome.

3. Compare and contrast Crohn disease and ulcerative colitis with respect to:

a. clinical features and extraintestinal manifestations

b. pathogenesis

c. pathology (gross and microscopic features)

d. complications (especially adenocarcinoma preceded by dysplasia)

4. Describe the pathogenesis of IBD.

5. Adenomatous polyps of the colon: know the classification of intestinal tumors (small intestine and colon)

6. Compare adenomatous polyps and hyperplastic polyps with respect to pathology (gross and microscopic features).

7. Know the three subtypes of adenomatous polyps, eg, tubular adenoma, villous adenoma, tubulovillous adenoma.

8. Describe the adenomatous polyp-cancer sequence and the features associated with risk of malignancy, eg, polyp size, histologic architecture, and severity of epithelial dysplasia.

9. Colon cancer: Compare the pathology (gross and microscopic features), and clinical features of right-sided colonic adenocarcinoma and left-sided colorectal adenocarcinoma.

Development Anomalies

Meckel's Diverticulum

Common (2%)

Usually asymptomatic (95%)

True (all layers present) diverticulum--deriving from failure of involution of the omphalomesenteric duct

Located around 2 feet from the ileocecal valve on the antimesenteric border

Hirschsprung's Disease

Failure of caudal migration of neural crest cells results in a segment of aganglionic bowel beginning at the anus

There is functional obstruction and progressive distention of the colon proximal to the affected segment

Males predominate 4:1 and there is an association with other congenital anomalies

Idiopathic Inflammatory Bowel Disease

Idiopathic inflammatory bowel disease is a set of chronic inflammatory conditions resulting from inappropriate and persistent activation of the mucosal immune system, driven by the presence of normal intraluminal flora. The two disorders known as inflammatory bowel disease (IBD) are Crohn disease (CD) and ulcerative colitis (UC). These diseases share many common features but have distinctly different clinical manifestations. Both CD and UC are chronic, relapsing inflammatory disorders of obscure origin. CD is an autoimmune disease that may affect any portion of the gastrointestinal tract from esophagus to anus, but most often involves the distal small intestine and colon. UC is a chronic inflammatory disease limited to the colon and rectum. Both exhibit extraintestinal inflammatory manifestations.

Etiology and pathogenesis

A remarkable attribute of the normal gastrointestinal tract is that the mucosal immune system is always poised to respond against ingested pathogens but is unresponsive to normal intestinal microflora. In IBD, this state of homeostasis is disrupted, leading to two key pathogenic abnormalities-strong immune responses against normal flora, and defects in epithelial barrier function. The basis of these abnormalities is still not established, which is why both CD and UC are considered idiopathic diseases. However, recently, extensive investigations of animal models, and more limited analyses of lesions from patients, have led to some important conclusions about the pathogenesis of IBD. It is postulated that IBD results from unregulated and exaggerated local immune responses to commensal microbes in the gut, in genetically susceptible individuals. Thus, as in many other autoimmune disorders, the pathogenesis of IBD involves failure of immune regulation, genetic susceptibility, and environmental triggers, specifically microbial flora. Below we summarize some salient points about each of the factors that contribute to IBD.

Crohn's

When first described by Crohn, Ginsburg, and Oppenheimer in 1932, this idiopathic disorder was thought to be limited to the terminal ileum, hence the designation terminal ileitis. Recognition that sharply delineated bowel segments might be affected, with intervening unaffected ("skip") areas, led to the alternative name regional enteritis. Predominant involvement of the colon gave rise to the term granulomatous colitis. It is now clear that any level of the alimentary tract may be involved and that there are systemic manifestations; thus, the eponymic name Crohn disease is preferred. When fully developed, Crohn disease is characterized pathologically by

Involves any area of the gastrointestinal tract--terminal ileum most common

Transmural inflammation with fissure and fistula formation

Skip areas

Granulomas

Risk of carcinoma less than ulcerative colitis `

Morphology. In CD, there is gross involvement of the small intestine alone in about 40% of cases, of small intestine and colon in 30%, and of the colon alone in about 30%. CD may involve the duodenum, stomach, esophagus, and even mouth, but these sites are distinctly uncommon. In diseased bowel segments, the serosa is granular and dull gray, and often the mesenteric fat wraps around the bowel surface (creeping fat). The mesentery of the involved segment is also thickened, edematous, and sometimes fibrotic. The intestinal wall is rubbery and thick, as a consequence of edema, inflammation, fibrosis, and hypertrophy of the muscularis propria. As a result, the lumen is almost always narrowed; in the small intestine this is evidenced on x-ray as the "string sign," a thin stream of barium passing through the diseased segment. Strictures may occur in the colon but are usually less severe. A classic feature of CD is the sharp demarcation of diseased bowel segments from adjacent uninvolved bowel.

When multiple bowel segments are involved, the intervening bowel is essentially normal ("skip" lesions).

A characteristic sign of early disease is focal mucosal ulcers resembling canker sores (aphthous ulcers), edema, and loss of the normal mucosal texture. With progressive disease, mucosal ulcers coalesce into long, serpentine linear ulcers, which tend to be oriented along the axis of the bowel. As the intervening mucosa tends to be relatively spared, the mucosa acquires a coarsely textured, cobblestone appearance. Narrow fissures develop between the folds of the mucosa, often penetrating deeply through the bowel wall and leading to bowel adhesions and serositis. Further extension of fissures leads to fistula or sinus tract formation, either to an adherent viscus, to the outside skin, or into a blind cavity. Free perforation or localized abscesses may also develop.

The characteristic histologic features of CD are:

• Mucosal inflammation. The earliest lesion in CD appears to be focal neutrophilic infiltration into the epithelial layer, particularly overlying mucosal lymphoid aggregates. As the disease becomes more established, neutrophils infiltrate isolated crypts; when a sufficient number of neutrophils have traversed the epithelium of a crypt (both in the small and large intestines), a crypt abscess is formed, usually with ultimate destruction of the crypt.

• Chronic mucosal damage. The hallmark of inflammatory bowel disease, both CD and UC, is chronic mucosal damage. Architectural distortion is manifested in the small intestine as variable villus blunting; in the colon, crypts exhibit irregularity and branching. The degree of the glandular architectural distortion in CD is usually less severe than in UC. Crypt destruction leads to progressive atrophy, particularly in the colon. The mucosa may undergo metaplasia: This may take the form of gastric antral-type glands (pyloric metaplasia) or the development of Paneth cells in the distal colon, where they are normally absent (Paneth cell metaplasia).

• Ulceration. Ulceration is the usual outcome of severe active disease. Ulceration may be superficial, may undermine adjacent mucosa in a lateral fashion, or may penetrate deeply into underlying tissue layers. There is often an abrupt transition between ulcerated and adjacent normal mucosa.

• Transmural inflammation affecting all layers. Chronic inflammatory cells suffuse the affected mucosa and, to a lesser extent, all underlying tissue layers. Lymphoid aggregates are usually scattered throughout the bowel wall.

• Noncaseating granulomas. In about half of the cases, sarcoid-like granulomas may be present in all tissue layers, both within areas of active disease and in uninvolved regions of the bowel

Granulomas have been documented throughout the alimentary tract, from mouth to rectum, in patients with CD limited to one bowel segment. Conversely, the absence of granulomas does not preclude the diagnosis of CD.

Other mural changes. In diseased segments, the muscularis mucosa usually exhibits reduplication, thickening, and irregularity. Fibrosis of the submucosa, muscularis propria, and mucosa eventually leads to stricture formation. Less common findings are mucosal and submucosal lymphangiectasia, hypertrophy of mural nerve fibers, and localized vasculitis.

Clinical Features. The clinical manifestations of Crohn disease are extremely variable. They are generally more subtle than those of UC. The disease usually begins with intermittent attacks of relatively mild diarrhea, fever, and abdominal pain, spaced by asymptomatic periods lasting for weeks to many months. Often the attacks are precipitated by periods of physical or emotional stress. During this lengthy, chronic disease, complications may arise from fibrosing strictures, particularly of the terminal ileum, and fistulas to other loops of bowel, the urinary bladder, vagina, or perianal skin, or into a peritoneal abscess. Extensive involvement of the small bowel, including the terminal ileum, may cause marked loss of albumin (protein-losing enteropathy), generalized malabsorption, specific malabsorption of vitamin B12 (resulting in pernicious anemia), or malabsorption of bile salts, leading to steatorrhea.

Extraintestinal manifestations of this disease include migratory polyarthritis, sacroiliitis, ankylosing spondylitis, erythema nodosum, and clubbing of the fingertips. Hepatic primary sclerosing cholangitis occurs, but the association is not as strong as in UC. Any of these manifestations can develop before onset of intestinal symptoms. Deranged systemic immunity is thought to underlie these related disorders. Uveitis, nonspecific mild hepatic pericholangitis, and renal disorders secondary to trapping of the ureters in the inflammatory process sometimes develop. Systemic amyloidosis is a rare late consequence.

Ulcerative Colitis

Ulcerative colitis is an ulceroinflammatory disease limited to the colon and affecting only the mucosa and submucosa except in the most severe cases. Unlike CD, UC extends in a continuous fashion proximally from the rectum. Well-formed granulomas are absent. Like CD, UC is a systemic disorder associated in some patients with migratory polyarthritis, sacroiliitis, ankylosing spondylitis, uveitis, hepatic involvement (pericholangitis and primary sclerosing cholangitis;, and skin lesions.

Begins in rectum and proceeds proximally in continuity

Approximately half of the cases limited to the left colon

Inflammation limited to the mucosa, pseudopolyps common

Greater risk of dysplasia and adenocarcinoma than Crohn's

Association with primary sclerosing cholangitis

Morphology. Ulcerative colitis involves the rectum and extends proximally in a retrograde fashion to involve the entire colon ("pancolitis") in the more severe cases. It is a disease of continuity, and "skip" lesions such as occur in Crohn disease are not found. In the course of colonic involvement with UC, the mucosa may exhibit slight reddening and granularity with friability and easy bleeding. With fully developed severe, active inflammation, there may be extensive and broad-based ulceration of the mucosa in the distal colon or throughout its length. Isolated islands of regenerating mucosa bulge upward to create pseudopolyps.

Ulcerative Colitis

•U.C., pseudopolyp.

•Another characteristic finding is the pseudopolyp which is formed by an inflammatory granulation tissue response thickening the mucosa which is accentuated by loss or partial loss of the adjoining ulcerated mucosa.

Often the undermined edges of adjacent ulcers interconnect to create tunnels covered by tenuous mucosal bridges. As with CD, the ulcers of UC are frequently aligned along the axis of the colon, but rarely do they replicate the linear serpentine ulcers of CD. With indolent chronic disease or with healing of active disease, progressive mucosal atrophy leads to a flattened and attenuated mucosal surface. Unlike CD, mural thickening does not occur in UC, and the serosal surface is usually completely normal. Only in the most severe cases of ulcerative disease (UC, CD, and other severe inflammatory diseases) does toxic damage to the muscularis propria and neural plexus lead to complete shutdown of neuromuscular function. In this instance the colon progressively swells and becomes gangrenous (toxic megacolon) The mucosal alterations in UC are similar to those of colonic CD, with inflammation, chronic mucosal damage, and ulceration.

Ulcerative Colitis

•The arrow marks a typical crypt abcess

•The crypt lumen is filled with polys and the lining epithelium is partially necrotic with the remaining epithelium being flattened and having degenerative changes

•This lesion is strongly supportive of, but not pathognomonic of a diagnosis of ulcerative colitis

•The lamia propria also shows a marked infiltrate of polys

First, a diffuse, predominantly mononuclear inflammatory infiltrate in the lamina propria is almost universally present, even at the time of clinical presentation. Neutrophilic infiltration of the epithelial layer may produce collections of neutrophils in crypt lumina (crypt abscesses). These are not specific for UC and may be observed in CD or any active inflammatory colitis. Unlike CD, there are no granulomas, although rupture of crypt abscesses may incite a foreign body reaction in the lamina propria. Second, further destruction of the mucosa leads to outright ulceration, extending into the submucosa and sometimes leaving only the raw, exposed muscularis propria. Third, with remission of active disease, granulation tissue fills in the ulcer craters, followed by regeneration of the mucosal epithelium. Submucosal fibrosis and mucosal architectural disarray and atrophy remain as residua of healed disease.

Ulcerative Colitis

•An acute inflammatory process is present with polys infiltrating lamina propria and crypt walls

•The glands show evidence of an underlying chronic process with the wide spacing of crypts indicating loss of crypts and the distorted "Y" shaped crypt giving evidence of previous damage and repair

•This combination of findings indicates an active phase of chronic inflammatory bowel disease

A key feature of UC is that the mucosal damage is continuous from the rectum and extending proximally. In CD, mucosal damage in the colon may be continuous but is just as likely to exhibit skip areas. It should be noted that quiescent UC, particularly treated disease in which active neutrophilic inflammation is not present, may appear virtually normal histologically. This does not preclude risk for dysplasia, as now described. Particularly significant in ulcerative colitis is the spectrum of epithelial changes signifying dysplasia and the progression to frank carcinoma. Nuclear atypia and loss of cytoplasmic differentiation may be present in inflamed or uninflamed colonic mucosa. Epithelial dysplasia is referred to as being low-grade or high-grade; cytologic features are the key to evaluating dysplasia. Distinguishing between regenerative changes and dysplasia can be very difficult and sometimes impossible. Pathologists are allowed some latitude in noting atypical changes that may not be definitive for a diagnosis of dysplasia. Plaque-like dysplastic lesions, overt polypoid dysplasia (adenomas), or invasive carcinoma are the ultimate lesions arising from flat dysplasia. It should be noted that elderly patients with UC are also at risk for sporadic adenomas. Distinction between IBD-associated dysplasia and a coexistent incidental adenoma may be difficult.

Clinical Features. Ulcerative colitis typically presents as a relapsing disorder marked by attacks of bloody mucoid diarrhea that may persist for days, weeks, or months and then subside, only to recur after an asymptomatic interval of months to years or even decades. In the fortunate patient, the first attack is the last. At the other end of the spectrum, the explosive initial attack may lead to such serious bleeding and fluid and electrolyte imbalance as to constitute a medical emergency. In most patients, bloody diarrhea containing stringy mucus, accompanied by lower abdominal pain and cramps usually relieved by defecation, is the first manifestations of the disease. In a small number of patients, constipation may appear paradoxically, due to disruption of normal peristalsis. Often the first attack is preceded by a stressful period in the patient's life. Spontaneously, or more often after appropriate therapy, these symptoms abate in the course of days to weeks. Flare-ups, when they do occur, may be precipitated by emotional or physical stress and rarely by concurrent intraluminal growth of enterotoxin-forming C. difficile. Sudden cessation of bowel function with toxic dilatation (toxic megacolon) rarely develops with severe acute attacks; perforation is a potentially lethal event.

Diverticulosis

Acquired (false) diverticula most common in sigmoid colon

Low fiber diets with small bulk require increased luminal pressure for propulsion of stool

The increased pressure forces mucosa through weak areas in the wall (where vessels perforate the muscle alongside the taeniae)

Most cases are asymptomatic but cramping pain, bleeding, and perforation occur

Tumors

Epithelial tumors of the intestines are a major cause of morbidity and mortality worldwide. The colon (including the rectum) is host to more primary neoplasms than any other organ in the body. Colorectal cancer ranks second only to bronchogenic carcinoma among the cancer killers in North America. Adenocarcinomas constitute the vast majority of colorectal cancers and represent 70% of all malignancies arising in the gastrointestinal tract. Curiously, the small intestine is an uncommon site for benign or malignant tumors despite its great length and vast pool of dividing mucosal cells.

Tumors of the Small Intestine and Colon

|Non-neoplastic (Benign) Polyps |

|Hyperplastic polyps |

|Hamartomatous polyps |

|Juvenile polyps |

|Peutz-Jeghers polyps |

|Inflammatory polyps |

|Lymphoid polyps |

|Neoplastic Epithelial Lesions |

|Benign |  |

|Adenoma* |

|Malignant |  |

|Adenocarcinoma* |

|Carcinoid tumor |

|Anal zone carcinoma |

|Mesenchymal Lesions |

|Gastrointestinal stromal tumor (GIST) (gradation from benign to malignant) |

|Other benign lesions |

|Lipoma |

|Neuroma |

|Angioma |

|Kaposi sarcoma |

|Lymphoma |

Polyps (epithelial)

Hyperplastic

No malignant potential

Adenomas

Dysplastic precursors to adenocarcinoma

40-50% prevalence after age 60

Familial predisposition to sporadic adenomas

Risk of carcinoma dependent mostly on size

Familial Polyposis Syndromes

28. Familial adenomatous polyposis (FAP)-5q21--mutation of APC tumor suppressor gene which encodes a protein believed to be important in cell adhesion

29. Hereditary nonpolyposis colorectal cancer (HNPCC)--Inherited mutation to a DNA repair gene

30. Increased risk other cancer, endometrial

Morphology.

Hyperplastic Polyps. These are small (usually ................
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