Large Intestine (Colon)

With increased availability of total colonoscopy and flexible sigmoidoscopy, pathologists can expect an ever-increasing number of colorectal biopsy specimens. The pathologist plays a critical role in the diagnosis and management of patients with colitis and suspected colitis. When evaluating a colorectal biopsy specimen, it is useful to scan the tissue at low magnification and ask several questions. Are abnormalities present? If present, are the changes diffuse or focal? Is the luminal border of the specimen straight or irregular? Is intraepithelial mucin (the goblet cell population) preserved or depleted? If intracellular mucin is depleted, is this change focal or diffuse? Are inflammatory cells increased in the lamina propria or epithelium? Is this increase diffuse or focal? What kind of inflammatory cells are they? Is the lamina propria obliterated by fibrous or fibromuscular tissue? Are crypt abscesses present? Are colonic tubules straight? Do the colonic tubules reach the muscularis mucosae or are they short, branched, or budded? With careful consideration of the features outlined earlier, one can often recognize a pattern of abnormality that when coupled with clinical and endoscopic information can lead to a fairly specific diagnosis in a large number of patients. The following patterns of inflammation can be identified in mucosal biopsy specimens: chronic colitis, diffuse active colitis, focal active colitis, ischemic-type injury, trauma-related change, apoptotic colopathy, and intraepithelial lymphocytosis. Identification of an inflammation pattern can be helpful in assessing patients by creating a clinically relevant differential diagnosis. Quiescent UC best typifies the chronic colitis pattern of injury. The predominant features are mucosal atrophy and architectural distortion ( Fig. 23-56 ). 322. , 323. , 324. , 325. The luminal border is often irregular and the number of crypts decreased. The remaining crypts typically appear short (i.e., they do not touch the muscularis mucosae), they lose their parallel arrangement, and they become branched and budded. The goblet cell population is usually preserved. Chronic inflammatory cells including plasma cells are increased in the lamina propria. Paneth cells may be present. The muscularis mucosae is usually hypertrophied. The foregoing changes, although consistent with a diagnosis of chronic UC, must be interpreted in light of the clinical, radiologic, and endoscopic findings because similar changes can be seen in focal, healed, or healing areas of other chronic colitides such as Crohn's disease, ischemia, chronic irradiation injury, tuberculosis, and schistosomiasis. Figure 23-56 ▪ Quiescent ulcerative colitis. The predominant feature is the loss of the crypt parallel arrangement. The luminal border is irregular. The remaining crypts are atrophic, shortened, branched, and budded. Quiescent ulcerative colitis. The predominant feature is the loss of the crypt parallel arrangement. The luminal border is irregular. The remaining crypts are atrophic, shortened, branched, and budded. Care must be taken when interpreting biopsy specimens obtained from the normal mucosa adjacent to lymphoid follicles, from normal mucosa containing the innominate groove, and from the lower portion of the rectum near the transition zone. These areas normally show some loss of crypt parallelism and should not be misinterpreted as evidence of chronic colitis. 2. , 7. Conversely, histologically normal biopsy specimens must not be reported as showing “chronic nonspecific inflammation” consistent with UC. Unless one or more of the features discussed in the preceding paragraph are also present, it is a good rule not to diagnose primary IBD based only on an evaluation of inflammatory cells within the lamina propria. The term active colitis describes inflammatory conditions in which neutrophils are present within the lamina propria, within epithelial cells (cryptitis), or within the lumen of crypts (crypt abscesses). Included under this heading are UC in an active phase, most examples of Crohn's disease, and infectious colitis or acute self-limited colitis. 326. , 327. UC in an active phase represents the prototype diffuse active colitis. Biopsy specimens usually demonstrate diffuse abnormalities, meaning that changes are of approximately the same intensity in all areas of the tissue submitted from a particular region of the colon. The luminal border of the mucosa is irregular. 323. , 324. , 325. , 326. , 327. , 328. , 329. Increased numbers of chronic inflammatory cells are present in the lamina propria and may occasionally spill over into the superficial portion of the submucosa. Intracellular mucin in goblet cells is diffusely depleted. 330 Cryptitis and crypt abscess formation are often prominent ( Fig. 23-57 ). It is surprising that even in UC of extremely short overt clinical duration, atrophy, branching, and budding of crypts are already apparent in many specimens. 7. , 324. , 325. , 326. , 327. , 328. , 329. This crypt distortion coupled with basal plasmacytosis, which is defined as increased plasma cells in the lower fifth of the mucosa, has been proposed as the most useful histologic criterion to differentiate primary IBD from infectious colitis or acute self-limited colitis. 323. , 326. , 327. , 328. Figure 23-57 ▪ Ulcerative colitis in an active phase showing architectural distortion, diffuse goblet cell depletion, basal plasmacytosis, and crypt abscess formation. Ulcerative colitis in an active phase showing architectural distortion, diffuse goblet cell depletion, basal plasmacytosis, and crypt abscess formation. Remember, the most a pathologist can conclude from a biopsy specimen showing this pattern of injury is that the changes are consistent with UC in an active phase. The diffuse active colitis pattern of injury can also be seen in some examples of Crohn's disease 324. , 328. and in some cases of documented infectious colitis, 331 although we think it is likely that these cases represent an infectious exacerbation of an underlying, albeit clinically latent, primary IBD. The diffuse active colitis pattern of injury has been reported in a form of colitis associated with diverticular disease. 332 However, this entity can be distinguished from classic UC by virtue of its rectal sparing and the presence of inflammation only in areas of diverticula. The focal active colitis pattern of injury refers to the patchy distribution of architectural or acute inflammatory change in mucosal biopsy specimens. Chronic colitis showing diffuse chronic changes as described earlier, coupled with patchy acute inflammation, is not considered focal active colitis but is classified as chronic colitis showing mild activity . The focal active colitis pattern consists of limited areas of increased inflammatory cells sometimes coupled with focal minimal architectural distortion ( Fig. 23-58 ). Characteristically, some areas of the biopsy specimen from a region of the colon must maintain an essentially normal appearance. The focal active colitis pattern of injury is usually not seen with UC and when present suggests Crohn's disease, 7. , 333. , 334. injury related to nonsteroidal anti-inflammatory drugs (NSAIDs), or infectious colitis or acute self-limited colitis (see later). 7. , 323. , 327. , 330. , 334. , 335. The focal active colitis pattern of injury, however, can be seen in resolving UC under active medical management. 330. , 336. Areas previously involved in the colon and rectum in UC can return to an almost normal histologic appearance with therapy. Figure 23-58 ▪ Focal active colitis pattern of injury. The focal area of cryptitis is associated with no architectural change in this example. Focal active colitis pattern of injury. The focal area of cryptitis is associated with no architectural change in this example. Granulomas typically found in Crohn's disease should be sought in all biopsy specimens, but especially those showing the focal active pattern. Although serial sectioning of biopsy specimens is advocated by some investigators for the detection of granulomas, 337 in our experience, granulomas are rarely missed. That said, germinal centers, tangential cuts of blood vessels, tangential cuts of the pericryptal fibroblastic sheath, and an inflammatory reaction to extravasated mucin (so-called mucin granulomas) are often misinterpreted as the granulomas of Crohn's disease. In the absence of true granulomas, biopsy specimens from patients with Crohn's disease often show the focal active colitis pattern of injury without neutrophils in the lamina propria. Some examples of Crohn's colitis can be indistinguishable from resolving mucosal UC in biopsy specimens. 323. , 328. A fibrinopurulent exudate in the specimen overlying but separate from the mucosa is always abnormal. The clinician should be informed that ulcers are likely to be present in a more proximal location in the bowel. On a practical note, all inflammatory exudates should be examined under high magnification for trophozoites of Entamoeba histolytica, because this is their preferred location and these organisms are easy to overlook. The definitive classification of colonic inflammation depends on clinical pathologic correlation. In our opinion, the task of the pathologist is to convey the histologic pattern of injury to the clinician who then collates that information with the clinical history and data obtained from endoscopic, radiologic, and laboratory examination. Antineutrophil cytoplasmic antibodies (ANCAs) have been identified in patients with IBD. 338. , 339. , 340. The immunofluorescence pattern (perinuclear) differs from the diffuse cytoplasmic reaction detected in patients with Wegener's granulomatosis. Although initially thought to be specific for UC, ANCAs more likely reflect inflammatory conditions involving the colon. In one study, up to 70% of patients with presumed UC had ANCA positivity with a 46% prevalence in patients with colonic Crohn's disease and a 5% prevalence in patients with infectious-type colitis. 328 Another antibody, anti– Saccharomyces cerevisiae antibody (ASCA), has been closely linked to Crohn's disease. ASCAs can be identified in up to 60% to 70% of patients with Crohn's disease, as opposed to 10% to 15% in UC and 5% of controls. 341. , 342. Some investigators have proposed the use of ANCA and ASCA together to increase specificity. 343 These tests clinically have demonstrated low sensitivity (≈50% to 60%) but have been reported to be highly disease specific. These tests may have value in classification of indeterminate colitis but this remains to be proved. 344 The following histologic appearances have been described in culture-proved or toxin-proved infectious colitis: normal colon, nonspecific increases in chronic inflammatory cells, the diffuse active colitis pattern of injury 331 (although these likely represent infectious exacerbations of an underlying primary IBD), ischemic-like changes, 345. , 346. and the focal active colitis pattern of injury. Although colonic mucosal biopsy appearance in infectious colitis can vary greatly, many specimens have the focal active colitis pattern. In general, invasive organisms cause greater changes in morphology than those producing their effects by toxins. Histologic evaluation, although helpful in suggesting infection and ruling out primary IBD, can only rarely suggest a specific cause. The definitive diagnosis of infectious colitis requires laboratory identification of the serologic features of the offending organism. Even after extensive microbiologic workup, a subset of patients presumed clinically to have infectious colitis will experience spontaneous recovery in less than 6 months and will have biopsy specimens that demonstrate the focal active colitis pattern of injury without an identifiable infectious cause. The term acute self-limited colitis has been used to describe such patients. 326. , 327. , 328. , 330. We prefer the term infectious-type colitis to acute self-limited colitis because some examples of acute self-limited colitis may not be self-limited. 7 Other investigators prefer the term nonrelapsing colitis . 327. , 329. The characteristic pattern of acute ischemic-type injury consists of hemorrhage into the lamina propria associated with superficial epithelial coagulative necrosis, with relative sparing of the deep portions of the crypts ( Fig. 23-59 ). 3. , 346. , 347. These changes can occasionally be associated with more extensive necrosis of epithelium with inflammatory pseudomembrane formation. Surprisingly, acute and chronic inflammatory cells, especially plasma cells, are typically scant in ischemic-type damage and this feature can help differentiate ischemic-type damage from primary IBD. Figure 23-59 ▪ Acute ischemic pattern of injury showing hemorrhage into the lamina propria associated with coagulative necrosis of the surface epithelium and inflammatory pseudomembrane formation. Regenerative changes are present at the crypt bases. Acute ischemic pattern of injury showing hemorrhage into the lamina propria associated with coagulative necrosis of the surface epithelium and inflammatory pseudomembrane formation. Regenerative changes are present at the crypt bases. The differential diagnosis of ischemic-type damage is wide and includes all causes of true ischemia such as inadequate perfusion, narrowing of blood vessels, obstructing lesions of the bowel, and bowel distention. Ischemic-type change is also associated with a variety of drugs, including vasopressors, oral contraceptives, NSAIDs, cocaine, and glutaraldehyde, which is sometimes used to clean endoscopes. 348. , 349. , 350. , 351. Some infectious agents typically cause ischemic-type damage, including cytomegalovirus (CMV), Clostridium difficile , Clostridium septicum, and the enterohemorrhagic Escherichia coli (EHEC). 346 Trauma-type histologic changes frequently coexist clinically with mucosal ulcers or erosions. The characteristic trauma-type histologic pattern is found in the mucosa adjacent to ulcers or in polypoid mucosa areas and consists of fibromuscular proliferation within the lamina propria associated with mucosal architectural distortion and intramucosal capillary ectasia ( Fig. 23-60 ). 352. , 353. , 354. , 355. The trauma-type histologic features can be seen in the solitary rectal ulcer syndrome, localized colitis cystica profunda, inflammatory cloacogenic polyp, the mucosa adjacent to orifices of colonic diverticula, 356 and inflammatory cap polyposis 357 and are frequent findings adjacent to neoplasia and in the vicinity of the ileocecal valve. 358 Figure 23-60 ▪ Solitary rectal ulcer syndrome showing the traumatic pattern of injury. Sections show fibromuscular obliteration of the lamina propria associated with mucosal architectural changes, inflammation, and capillary ectasia. Solitary rectal ulcer syndrome showing the traumatic pattern of injury. Sections show fibromuscular obliteration of the lamina propria associated with mucosal architectural changes, inflammation, and capillary ectasia. Surface colonic epithelial apoptosis and karyorrhectic debris within the superficial lamina propria are commonly seen in mucosal biopsy specimens and are widely attributed to bowel preparation. Apoptotic bodies in the deep crypt are only rarely seen (<1 per 20 crypts) outside of pathologic conditions. Increased deep apoptotic bodies can be seen in ischemic-type damage, CMV infection, chemotherapy or radiation, and in association with mycophenolate mofetil (CellCept) ( Fig. 23-61 ). 359 Although associated with a variety of injurious agents, apoptosis is the characteristic form of cell death in cell-mediated immune cytotoxicity as demonstrated in graft-versus-host disease (GVHD), 360 other immune deficiency syndromes 361. , 362. and thymic neoplasia. 363 Many patients with AIDS with diarrhea demonstrate deep apoptosis in the absence of pathogens, a finding suggesting that primary immune-mediated apoptotic colopathy may cause some of the diarrhea and wasting seen in AIDS. 364. , 365. Figure 23-61 ▪ Acute graft-versus-host disease, grade 2, showing numerous apoptotic bodies and scattered crypt abscesses. Acute graft-versus-host disease, grade 2, showing numerous apoptotic bodies and scattered crypt abscesses. The term collagenous colitis, first coined by Lindström in 1976, 366 describes a distinct clinicopathologic syndrome causing watery diarrhea, predominantly in middle-aged or older (mean age, 59 years) women (male-to-female ratio, 1 : 7.5). 367. , 368. Results of colonoscopic and barium enema examination in these patients are usually normal. Therefore, diagnosis depends on recognition of characteristic changes in biopsy specimens. The primary histologic change of collagenous colitis consists of a patchy increase in the thickness of the subepithelial collagen plate ( Fig. 23-62 ). 367. , 368. The normal colonic epithelial collagen layer measures approximately 5 µm in thickness, but in collagenous colitis it may increase to 10 µm or more. We use 15 µm as a morphologic cutoff point for collagenous colitis. A mild to moderate increase in chronic inflammatory cells including plasma cells and eosinophils expands the lamina propria. Patchy injury to the surface epithelium characterized by increased numbers of intraepithelial lymphocytes, epithelial degeneration, and sloughing also occur. Atrophy, mucosal architectural distortion, and acute inflammation are usually not present or are minimal. 367. , 369. , 370. Figure 23-62 ▪ Collagenous colitis. Sections show benign colonic mucosa without architectural distortion. Increased numbers of inflammatory cells including plasma cells and eosinophils are present within the lamina propria. Surface epithelial lymphocytosis is evident. The subepithelial collagen plate is increased in thickness. Collagenous colitis. Sections show benign colonic mucosa without architectural distortion. Increased numbers of inflammatory cells including plasma cells and eosinophils are present within the lamina propria. Surface epithelial lymphocytosis is evident. The subepithelial collagen plate is increased in thickness. Read and colleagues 371 introduced the term microscopic colitis to describe patients with chronic watery diarrhea of unknown origin occurring in middle-aged (mean, 54 years) patients. As in collagenous colitis, the colonoscopic appearance and the barium enema were usually described as normal. Biopsy specimens demonstrated increased inflammatory cells in a pattern not specific for any established entity. 371 Since this initial report, investigators have refined the clinical and especially the histologic diagnostic criteria of lymphocytic colitis. 370. , 372. The histologic changes include increased chronic inflammatory cells in the lamina propria and surface epithelium, degenerative changes of the surface epithelium, minimal architectural change, and minimal acute inflammation ( Fig. 23-63 ). The changes of lymphocytic colitis in general resemble the surface epithelial and lamina propria changes of collagenous colitis, and indeed changes identical to lymphocytic colitis are seen in biopsy specimens from patients with collagenous colitis when areas where the collagen plate is not well developed are sampled. Figure 23-63 ▪ Lymphocytic colitis. The sections show little architectural change but a marked increase in inflammatory cells within the lamina propria and within the surface epithelium. Lymphocytic colitis. The sections show little architectural change but a marked increase in inflammatory cells within the lamina propria and within the surface epithelium. The similarities between lymphocytic colitis and collagenous colitis are striking. They share similar symptoms and endoscopic findings. The histologic similarities include increased intraepithelial lymphocytes, surface epithelial damage, and increased chronic inflammatory cells within the lamina propria. 369. , 370. , 373. Both collagenous colitis and lymphocytic colitis can be associated with other autoimmune phenomena such as thyroid disease, enteropathic arthritis, rheumatoid arthritis, myasthenia gravis, and celiac sprue. 374. , 375. Some cases of lymphocytic colitis demonstrate thickening of the subepithelial collagen plate, and distinguishing lymphocytic colitis from collagenous colitis may not be so clear-cut in all cases. 373 It appears likely that lymphocytic colitis and collagenous colitis are either the same or very similar conditions, perhaps representing different morphologic phases of one disease process. 370. , 374. Some minor differences between lymphocytic colitis and collagenous colitis deserve mention, however. Collagenous colitis has been reported predominantly in women, whereas lymphocytic colitis affects men and women equally. 370. , 376. Differences in human leukocyte antigen (HLA) haplotypes between collagenous colitis and lymphocytic colitis have been described. 376 Finally, collagenous colitis and lymphocytic colitis differ histologically with the presence of the thickened collagen plate. Lymphocytic colitis and collagenous colitis are associated with net fluid secretion in the colon that is responsible for the diarrhea. 377 Several investigators could find no association between the thickness and extent of the collagen plate and the amount of diarrhea. 373 Therefore, most investigators conclude the damage to the surface epithelial cells and the inflammation, rather than the collagen deposits, cause diarrhea. The presence and thickness of the subepithelial collagen plate appear unrelated to the patient's age or the duration of disease. 373 Some patients have also demonstrated evidence of small bowel dysfunction such as salt wasting, fatty acid malabsorption, small bowel net secretion, and rarely a small bowel villous lesion that resembles celiac sprue (see later). 376 Spontaneous resolution of collagenous and lymphocytic colitis has occurred, thus rendering evaluation of therapeutic regimens difficult. 378 A few patients with these colitides have presented with relatively mild diarrhea and have achieved medical control with dietary restriction (elimination of caffeine and lactose-containing foods), bulking agents, and antimotility drugs (loperamide hydrochloride, diphenoxylate hydrochloride, atropine). A trial of bismuth compounds is worthwhile. Many times, symptomatic therapy has failed, thus necessitating the addition of anti-inflammatory agents. Approximately 80% to 90% of patients eventually respond to therapy with sulfasalazine, prednisone, or budesonide. 368. , 378. , 379. NSAIDs and ticlopidine have been linked to some occurrences of collagenous colitis, 380. , 381. and lymphocytic colitis has been reported in patients receiving Ruscus extract (Cyclo 3 Fort), 382 ranitidine, 383 ticlopidine, and flutamide. 381 However, most cases cannot be linked to drug ingestion and the bulk of the evidence suggests that lymphocytic and collagenous colitis share common immune-mediated etiology and pathogenesis. Both conditions have a striking histologic similarity to celiac sprue, a condition known to be autoimmune and possibly having a viral or infectious trigger. 370 In addition, both lymphocytic and collagenous colitis have been linked to other conditions thought to have autoimmune pathogenesis such as Crohn's disease, hypothyroidism, hyperthyroidism, inflammatory arthropathies, pernicious anemia, small bowel villous atrophy, iritis, diabetes mellitus, and myasthenia gravis. 374. , 384. , 385. Both conditions respond dramatically to anti-inflammatory agents. 378. , 379. The finding of “lymphocytic colitis–like” histologic features reported in an epidemic outbreak of Brainerd diarrhea linked to a water tank aboard a cruise ship supports an infectious trigger for some cases of lymphocytic colitis (see later). The association between lymphocytic colitis or collagenous colitis and celiac sprue and spruelike lesions deserves special attention. In the experience of DuBois and associates 386 and Wolber and colleagues, 387 approximately 25% of patients with “celiac sprue” who had colonic biopsies also showed changes of lymphocytic colitis. Colonic microscopic abnormalities in patients with celiac sprue occur after experimental exposure to wheat or gliadin enemas, a finding suggesting that the entire intestinal tract may be susceptible to gluten-induced injury. It is possible that in some patients with true celiac sprue (responsive to gluten withdrawal), occult dietary gluten reaches the colon and induces the histologic changes of lymphocytic colitis. However, approximately one half of the patients with spruelike small bowel lesions and lymphocytic colitis have not responded to gluten withdrawal. The term lymphocytic enterocolitis has been coined to describe this refractory spruelike condition associated with colonic intraepithelial lymphocytosis. 386 As more cases are investigated, it is not unusual to see variations in histologic pattern commingled with the classic changes of lymphocytic and collagenous colitis. These variations include architectural change, cryptitis, Paneth cell metaplasia, ulcers, and inflammatory membranes. 388. , 389. , 390. , 391. Approximately one third of patients demonstrate cryptitis. Rarely, one encounters inflammatory pseudomembranes. Neither histologic pattern correlates strongly with infection. Approximately 2% of patients have ulcers, and architectural abnormalities have been reported in 5% of patients. Paneth cell metaplasia is seen in 14% to 44% of patients, most often in collagenous colitis in which it may correlate with increased severity of diarrhea. Acute inflammation is seen with increased frequency in patients taking antibiotics. Ulcers have been linked with concomitant NSAID usage. Some investigators have suggested that the “stiff” colon seen in collagenous colitis could be at increased risk for the development of ulcers and perforation during colonoscopy. 388 Other variants with subepithelial giant cells have been described ( Fig. 23-64 ). 392 Histologic features, aberrant or otherwise, do not seem to correlate with symptoms, results of medical treatment, or outcome. 393 No patient with unusual histologic features, including architectural change and Paneth cell metaplasia, has yet to develop primary IBD (e.g., Crohn's disease or UC). Figure 23-64 ▪ Lymphocytic colitis with subepithelial giant cells. Lymphocytic colitis with subepithelial giant cells. The term Brainerd diarrhea has been applied to outbreaks of diarrhea of unknown origin characterized by acute onset and prolonged duration. 394 The disease was named after Brainerd, Minnesota, where in 1984 122 residents developed watery diarrhea after drinking unpasteurized milk. A second outbreak occurred in Henderson County, Illinois in 1987, when 72 people developed watery diarrhea associated with drinking contaminated well water at a roadside restaurant. In each outbreak, patients underwent extensive diagnostic evaluations including comprehensive microbiologic studies of their stool and the implicated exposure site. Despite the workup, no causative agent was identified. The clinical and epidemiologic characteristics were typical of point-source epidemic infectious diarrhea. However, unlike in typical infectious diarrhea, these patients developed a chronic watery diarrhea syndrome with symptoms lasting longer than 6 months and often lasting for years. In general, the small bowel biopsy specimens from patients with Brainerd diarrhea were histologically normal. Colonic biopsy specimens revealed surface epithelial lymphocytosis without distortion of mucosal architecture, surface degenerative changes, or thickened subepithelial collagen plate. The degree of surface epithelial lymphocytosis was similar to that seen in cases of collagenous and lymphocytic colitis. 370. , 394. , 395. Many experts believe that patients with the clinical syndrome of chronic watery diarrhea of unknown origin and patients reported as having lymphocytic colitis represent a heterogeneous group that may contain persons with unrecognized Brainerd diarrhea. With long-term follow-up, cases of Brainerd diarrhea appear to be self-limited, and patients recover in less than 3 years. From a practical standpoint, surface epithelial lymphocyte counts should be performed on all colonic biopsy specimens from patients with chronic diarrhea, especially chronic watery diarrhea. Currently, Brainerd diarrhea cannot be recognized outside the setting of an epidemic. The solitary rectal ulcer syndrome, localized colitis cystica profunda, inflammatory cloacogenic polyp, prolapsing mucosal folds in areas of diverticular disease, and inflammatory cap polyposis are closely allied conditions that have been linked to large bowel mucosal prolapse and trauma. 352. , 353. , 354. , 355. , 356. , 396. , 397. , 398. , 399. , 400. Affected patients with solitary rectal ulcer, localized colitis cystica profunda, and inflammatory cloacogenic polyp often demonstrate abnormal function of the anal and pelvic floor musculature during defecation 352. , 401. , 402. that leads to rectal mucosal prolapse or even intussusception. The resulting trauma is thought to cause the clinical symptoms and the pathologic changes. The term solitary rectal ulcer syndrome is quite a misnomer because the ulcers are often multiple, a preulcer polypoid phase is reported, and similar lesions occur in the anal canal and proximal colon. 352. , 356. , 396. , 397. The terms colitis cystica profunda and inflammatory cloacogenic polyp are also misnomers. Because all three conditions share a common histologic appearance, clinical presentation, clinical course, and pathogenesis, we prefer to consider them together under the heading mucosal prolapse syndromes . Patients with mucosal prolapse syndrome range in age from 10 to 83 years with the majority presenting in the third and fourth decades of life. The condition occurs more commonly in women. All patients report difficulties in defecation. Other common symptoms include rectal bleeding, passage of mucus, anal and abdominal pain, and intermittent bowel habits in which periods of constipation interrupt bouts of loose stools. Furthermore, surprising numbers of patients admit to the use of digital manipulation, spoons, or other instruments to assist in rectal evacuation. The diagnosis of mucosal prolapse syndromes can be difficult because the history often suggests primary inflammatory or ischemic bowel disease. In addition, mucosal prolapse is often covert requiring special techniques such as evacuation cine proctography and defecography to demonstrate abnormalities in these patients. 352. , 356. , 401. , 403. Ulcers, when present, typically occur on the anterior or anterolateral wall of the rectum, are irregular in shape, and often appear well demarcated. In patients without ulceration, the mucosa appears polypoid, roughened, or erythematous. Inflammatory cloacogenic polyp 398. , 399. involves the lower rectum and anal transition zone. The clinical impression in patients with mucosal prolapse syndromes is often incorrect and includes ulcer, Crohn's disease, nonspecific proctitis, carcinoma, and villous adenoma. 355 The characteristic histopathologic changes are found in the mucosa adjacent to the ulcers or in the polypoid areas and consist of fibromuscular obliteration of the lamina propria associated with mucosal architectural distortion often with a hyperplastic or villiform appearance (see Fig. 23-60 ). 352. , 353. , 354. , 355. , 397. Inflammation is typically mild or absent and mucosal capillaries can be ectatic. Superficial erosions occasionally occur and can be associated with acute inflammation and the formation of inflammatory pseudomembranes. On occasion, colonic glands may be misplaced into the muscularis mucosae or submucosa, a histologic pattern referred to as localized colitis cystica profunda . Submucosal vessels may also be ectatic and hyalinized. The histologic features of specimens obtained from ulcerated areas appear nonspecific and usually show fibrinopurulent debris, fibrosis, and granulation tissue. Differential diagnostic considerations include mucinous adenocarcinoma, chronic UC, Cowden's disease, and ulcers resulting from ergotamine suppositories. The misplaced glands of mucosal prolapse syndrome (colitis cystica profunda) simulate pseudoinvasion seen in adenomas; these glands can be associated with dissecting mucous pools and easily can be mistaken for invasive mucinous adenocarcinoma. Table 23-2 illustrates histologic features that aid in this differential diagnosis. The mucosal abnormalities of mucosal prolapse syndrome also closely mimic chronic UC. Knowledge of the clinical picture and recognition of the characteristic fibromuscular obliteration of the lamina propria (not usually present in IBD) are helpful in this distinction. The histologic appearance of colorectal polyps from patients with Cowden's disease appears identical to the histologic features seen in mucosal prolapse syndrome. 304 Mucosal prolapse syndrome and Cowden's disease must be separated on clinical grounds. Clinical history is also required to separate the rectal ulcers associated with the use of ergotamine suppositories from mucosal prolapse. These lesions can be grossly and microscopically identical to those seen in mucosal prolapse syndrome. 404 The few studies with long-term follow-up report a chronic, stable appearance to the lesions. 352. , 396. , 405. Most patients with mucosal prolapse syndrome tolerate their symptoms following reassurance that they do not have cancer, the addition of fiber to the diet, and instruction to reduce straining and to avoid digital manipulation. The rare patient with severe bleeding or obstruction requires excisional therapy. Medical remedies such as sulfasalazine, local or systemic corticosteroids, and antibiotics are useless. 352. , 355. , 396. Unusual patients with severe, incapacitating symptoms have been treated by resection, diverting colostomy, or rectal prolapse repair. Results of these operations have varied and because approximately 100 different operations have been described for mucosal prolapse syndrome, comparisons are difficult. Inflammatory conditions of the colon can be caused by specific agents or conditions, such as bacteria or ischemia, or can be nonspecific. After specific causes of colitis have been ruled out, one is left with a group of diseases referred to as nonspecific or primary IBD . These include UC, Crohn's disease, and IBD type indeterminate (unclassified colitis). In most cases, careful examination of gross and microscopic features will allow categorization of these nonspecific IBDs into either UC or Crohn's disease. 406 Approximately 10% of cases will cause significant differential diagnostic problems by illustrating ambiguous features. These cases are best classified as IBD type indeterminate (see later). Evolving surgical techniques have changed the pathologist's role in the analysis of IBD. Patients with UC have several surgical options that either create continence through ileostomy (Kock ileostomy) or preserve anal sphincter function and restore continuity to the bowel (ileal pouch–anal anastomosis). 406. , 407. , 408. These operations have in common the creation of a pouch or reservoir formed by interconnecting loops of terminal ilium. In general, these pouch procedures are contraindicated in patients with Crohn's disease because of increased morbidity such as fistula and abscess. 409 Furthermore, complications requiring pouch removal can result in loss of considerable lengths of small bowel, sometimes enough to cause short-bowel syndrome. In our experience, there is nothing quite like a pouch to bring out the Crohn's disease in someone. These cases highlight the limitations of the current pathologic classification especially in the setting of fulminant clinical disease. Accurate pathologic diagnosis of colonic IBD contributes greatly to patient care. In patients who have had subtotal colectomy, relaxed and thorough pathologic examination of the colectomy specimen to rule out Crohn's disease is possible. A staged resection of the large bowel is still the safest and most advisable approach for patients with severe or fulminant colitis, even though it requires an additional operation to remove the rectum and a period with a temporary ileostomy. Although pathologic assessment and interpretation are more difficult in fulminant disease, the two-stage procedure still allows for a complete examination of the colectomy specimen before any contemplated pouch construction with ileal-anal anastomosis. Some surgeons do not consider two-stage proctocolectomy necessary for selected patients with colonic IBD. The one-stage operative approach therefore requires accurate preoperative diagnosis and emphasizes the importance of clinical evaluation, radiologic examination, endoscopic analysis, and proper interpretation of mucosal biopsy specimens (see earlier). 406 Pouch complications include inflammation, fistula, obstruction, incontinence, and anastomotic leaks. 406. , 407. Although many complications result from surgical and mechanical difficulties, and others relate to the development of “primary” inflammation in the pouch (see “Pouchitis,” later), some of these complications represent pouch recurrence of initially unrecognized Crohn's disease. These cases illustrate the inability to differentiate UC from Crohn's disease reliably in severe colitis, even after thorough examination of the colectomy specimen. 410 All reports of surgical experience with ileal pouch–anal anastomosis for presumed UC contain approximately 2% to 7% of patients in whom the final diagnosis proves to be Crohn's disease. 406. , 409. , 410. , 411. , 412. We recommend use of a three-tiered classification system for primary IBD in colon resection specimens: UC, Crohn's disease, and IBD of indeterminate type. The definitive diagnosis of UC requires all the following features: diffuse disease limited to the large intestine, involvement of the rectum, more proximal colonic disease occurring in continuity with an involved rectum (i.e., no gross or histologic skip lesions), the absence of deep fissural ulcers, the absence of mural sinuses, and the absence of transmural lymphoid aggregates or granulomas ( Fig. 23-65 ). 406. , 413. , 414. The definitive diagnosis of Crohn's disease requires histologic verification with the demonstration of transmural lymphoid aggregates in an area not deeply ulcerated or the presence of non-necrotizing granulomas ( Figure 23-66 ▪ , Figure 23-67 ▪ ). 406. , 413. , 414. , 415. , 416. When the gross and clinical features suggest Crohn's disease by the presence of skip lesions, linear ulcers, cobblestoning, fat wrapping, or terminal ileal inflammation, extensive histologic sampling to find the definitive histologic features of Crohn's disease is suggested ( Fig. 23-68 ). Figure 23-65 ▪ Ulcerative colitis in a resection specimen. The distal margin is involved by the inflammatory process. More proximal inflammation occurs in continuity with an involved rectum. No skip areas, no deep ulcers, and no mural sinuses are present. Figure 23-66 ▪ Colonic Crohn's disease showing transmural lymphoid aggregates in an area not deeply ulcerated. Figure 23-67 ▪ A non-necrotizing granuloma in a patient with Crohn's disease. Figure 23-68 ▪ Resection specimen of colonic Crohn's disease. The cobblestoning within the descending colon gives way to patchy areas of ulcer with intervening normal mucosa in the right colon. Ulcerative colitis in a resection specimen. The distal margin is involved by the inflammatory process. More proximal inflammation occurs in continuity with an involved rectum. No skip areas, no deep ulcers, and no mural sinuses are present. Colonic Crohn's disease showing transmural lymphoid aggregates in an area not deeply ulcerated. A non-necrotizing granuloma in a patient with Crohn's disease. Resection specimen of colonic Crohn's disease. The cobblestoning within the descending colon gives way to patchy areas of ulcer with intervening normal mucosa in the right colon. The term primary IBD of an indeterminate type is used for cases of idiopathic colonic IBD that have ambiguous pathologic features in the resection specimen and are inconclusive for a diagnosis of UC or Crohn's disease. 406. , 410. , 413. , 414. , 415. , 416. , 417. , 418. These cases are usually accompanied by fulminant clinical colitis, a setting in which transmural inflammation and deep fissural ulcers (features usually associated with Crohn's disease) can be found in patients with a clinical course that indicates UC ( Figure 23-69 ▪ , Figure 23-70 ▪ ). Figure 23-69 ▪ Fulminant primary inflammatory bowel disease of an indeterminate type showing deep linear ulcers and areas of serositis. Figure 23-70 ▪ Fulminant primary inflammatory bowel disease, type indeterminate. Deep ulcers extend into the muscularis externa and are associated with transmural lymphoid aggregates. Fulminant primary inflammatory bowel disease of an indeterminate type showing deep linear ulcers and areas of serositis. Fulminant primary inflammatory bowel disease, type indeterminate. Deep ulcers extend into the muscularis externa and are associated with transmural lymphoid aggregates. The classification system has prognostic significance. The pouch failure rate in indeterminate colitis (≈19%) is intermediate between that seen with Crohn's disease (≈48%) and that reported in UC (≈8%). Even so, patients without clinical, endoscopic, or radiologic evidence suggestive of Crohn's disease in whom the final pathologic results are indeterminate generally are considered suitable for ileal pouch–anal anastomosis. 406. , 414. , 418. , 419. , 420. , 421. , 422. , 423. Colon and rectum surgically placed out of circuit acquire histologic changes associated with defunctioning alone, regardless of the original reason for diversion. 424. , 425. , 426. , 427. The changes reflect a physiologic response to stasis and the loss of trophic factors in the feces, most notably short-chain fatty acids. 428 Most patients are asymptomatic. The mucosa of the diverted segment appears erythematous, granular, and friable ( Fig. 23-71 ). Histologic changes include marked lymphoid hyperplasia with germinal center formation, usually accompanied by mild colitis with crypt abscess formation ( Fig. 23-72 ). These changes may be indistinguishable from follicular proctitis (ulcerative proctitis or localized UC). 429 With time, the muscularis mucosae hypertrophies, the submucosa shows fatty and fibrous tissue infiltration, the muscularis propria thickens, and the lumen becomes progressively smaller. 406 The mucosal lymphoid hyperplasia may be accompanied by lymphoid aggregates scattered in the deep submucosa and muscularis externa and may occur in diverted segments in patients without IBD. Care must be taken not to base a diagnosis of primary IBD, especially Crohn's disease, solely on the histologic changes seen in diverted specimens. In many patients, the rectum is placed out of circuit during an operation for primary IBD. In these instances, the rectum can show changes of both IBD and diversion. The histologic changes in a defunctioned rectum do not correlate with the original diagnosis or clinical outcome. 430 Figure 23-71 ▪ Defunctioned rectum showing an erythematous and granular mucosa with mural thickening. Figure 23-72 ▪ Microscopic sections from defunctioned rectum showing mucosal architectural distortion and marked mucosal lymphoid hyperplasia. Defunctioned rectum showing an erythematous and granular mucosa with mural thickening. Microscopic sections from defunctioned rectum showing mucosal architectural distortion and marked mucosal lymphoid hyperplasia. A late complication of Kock pouch and ileal pouch–anal anastomosis is the development of “primary” inflammation in the pouch with its associated clinical syndrome termed pouchitis . 431. , 432. The reported incidence ranges from 8% to 46%. This wide range may be the result of the lack of an accepted case definition of pouchitis. Patients generally experience nausea, vomiting, malaise, fever, and abdominal cramping. The increased effluent/stool from the pouch may be watery, foul smelling, or grossly bloody. Patients frequently become incontinent. Pouch bacterial ecology is often altered and many patients respond to antibiotics such as metronidazole and ciprofloxacin, a finding that suggests a bacterial cause in some cases. Some patients have required 5-aminosalicylates, sulfasalazine, corticosteroids, immunomodulators, or even pouch excision to manage symptoms. 432 Pouch biopsy may be performed to confirm the presence of inflammation or to evaluate the possibility of Crohn's disease. 433 Pouch biopsy specimens from nondysfunctional pouches can show mild villus shortening and increased chronic inflammation with augmented crypt proliferation. Most specimens from pouches that are functioning well resemble normal terminal ileum. A few neutrophils within surface epithelium and within the lamina propria are commonly seen in pouches that are functioning well. 432. , 433. , 434. , 435. , 436. In contrast, pouches with classic pouchitis show decreased epithelial mucin and decreased or absent lymphoid follicles. The most consistent finding in this classic form of pouchitis has been ulcers with granulation tissue and patchy accumulations of neutrophils within crypt epithelium and within the lamina propria with deep crypt abscess formation. 432. , 433. , 435. , 437. , 438. To define pouchitis more precisely, Sandborn proposed the Pouchitis Disease Activity Index. 432. , 434. In this system, up to 12 points are awarded for various clinical and endoscopic findings. The amount of neutrophilic infiltration and the degree of ulceration are graded on a scale of 1 to 3 points each. Histologic findings are weighted in this system because pouchitis is diagnosed in patients who have 7 or more points. Many investigators report an inconsistent relationship between endoscopic and histologic changes in the pouch and patients’ symptoms. Therefore, many clinicians diagnose pouchitis on clinical criteria and reserve endoscopic examination with biopsy for those patients with refractory pouchitis or possible Crohn's disease. 432. , 433. , 439. , 440. Unfortunately, no reliable endoscopic or histologic criteria are available to differentiate most examples of pouchitis from a new onset or recurrence of Crohn's disease in the pouch. Confusion over pouchitis is easily understood when one considers that the clinical syndrome of pouchitis probably represents at least six different conditions ( Table 23-8 ). 406. , 432. , 433. TABLE 23-8 Pouchitis Syndromes: Proposed Classification Antibiotic-Responsive Pouchitis Syndromes Classic pouchitis Proximal jejunal bacterial overgrowth Chronic and Refractory Pouchitis Syndromes Irritable pouch syndrome Short-strip (segment) pouchitis Crohn's disease (refractory pouchitis with Crohn's-like histology) Chronic primary refractory pouchitis Pouchitis Syndromes: Proposed Classification The two variants of antibiotic-responsive pouchitis syndromes are classic pouchitis and jejunal bacterial overgrowth. 432. , 433. , 441. Classic pouchitis is associated with endoscopic and histologic findings that support the pouch as the source of clinical symptoms. 431. , 432. , 433. , 434. , 436. , 439. Patients with classic pouchitis usually respond to antibiotics such as metronidazole and ciprofloxacin. Occasional patients with clinical symptoms of pouchitis have had endoscopically and histologically negative pouches but have responded to antibiotics. 431. , 432. Although rare, some of these patients have had proximal jejunal bacterial overgrowth, 442 probably as a result of pouch distention causing an ileal brake phenomenon that decreases motility in the proximal intestine. 442. , 443. This decreased motility may predispose some individuals to proximal small bowel bacterial overgrowth. Pouchitis syndromes refractory to antibiotic therapy include irritable pouch syndrome, short-strip pouchitis (“cuffitis”), Crohn's disease, and chronic primary refractory pouchitis. 432. , 433. Patients with irritable pouch syndrome may have severe clinical symptoms but demonstrate normal pouch endoscopy and histology. Some of these patients respond to dietary fiber supplements and antidepressant therapy. 432 To obtain a better-functioning pouch, many surgeons have abandoned rectal mucosectomy in the ileal pouch–anal anastomosis procedure. 432. , 444. In short-strip pouchitis, clinical symptoms may be caused by exacerbation of UC in the small retained rectal segment. 432. , 445. Many patients with this form of pouchitis have responded to topical corticosteroids or mesalamine. Although debated, 446 missed Crohn's disease is likely to manifest as a late pouch fistula or abscess rather than as refractory pouchitis. In occasional reported cases of refractory pouchitis, pouch biopsy specimens contained granulomas or the excised pouch showed histologic criteria for Crohn's disease. 414. , 433. , 436. Invariably, the original colectomy showed either missed Crohn's disease or colitis of an indeterminate type. 414 These cases are best classified as Crohn's disease. 406. , 414. , 433. Patients with chronic pouchitis should be investigated with endoscopy and biopsy to rule out Crohn's disease or CMV infection, which has been linked to some cases of refractory pouchitis. 432. , 447. Routine biopsy specimens of the pouch should be examined as well as biopsy specimens of the afferent limb. Afferent limb ulcers tend to correlate with Crohn's disease and, in patients who do not have Crohn's disease, with the use of NSAIDs. 448 We have seen cases of refractory pouchitis requiring surgical removal of the pouch. After careful pathologic evaluation, no specific infection and no criteria for Crohn's disease can be found in either the excised pouch or the original colectomy specimen. 414. , 433. , 436. These cases are best categorized as primary refractory pouchitis . The causes of classic pouchitis and primary refractory pouchitis are unknown but are probably related to a combination of stasis, bacterial overgrowth, the abnormal immune response of patients with IBD, or perhaps associated colonic-type metaplasia, which is reported to occur in a minority of pouches (see later). 432. , 433. , 449. Some investigators have identified histologic patterns of mucosal adaptation in pouches. 450. , 451. , 452. Approximately 50% to 60% of patients exhibit what has been called type A mucosa with normal small bowel biopsy histology or only mild mucosal atrophy with no or minimal inflammation. Type B mucosa, characterized by transient atrophy with temporary moderate to severe inflammation followed by normalization of intestinal mucosa, is seen in 30% to 40% of patients. Type C mucosa with permanent persistent atrophy and severe inflammation occurs in up to 10% of pouches. Colonic-type features have been reported at least focally in pouches of all types by routine morphology, mucin histochemistry, immunohistochemistry, lectin binding, or electron microscopy. This colonic-type change is best developed in type C mucosa but is not complete. All pouches seem to retain mostly small bowel properties regardless of mucosal type or the duration of the pouch. With long-term follow-up, it appears that epithelial dysplasia can rarely develop in the pouch. This extremely rare complication seems to be limited to the subgroup of patients (<10%) in whom refractory pouchitis and colonic-type metaplasia develop (type C mucosa). 450. , 451. , 452. Most investigators suggest yearly pouch surveillance once type C mucosa is established. However, until further information on cancer risk is available, it would seem prudent to survey types A and B mucosa as well, perhaps every other year. 433. , 453. Dysplasia can also develop in the small retained rectal segment (often incorrectly referred to as the anal transition zone) in patients who have had restorative proctocolectomy and stapled ileal pouch–anal anastomosis. 454 Annual endoscopic surveillance with biopsy for these retained rectal segments seems prudent. The incidence of dysplasia is rare (<3% of patients), correlates with the original colectomy specimen containing dysplasia or cancer, and can be safely treated by completion mucosectomy. 454. , 455. , 456. Specimens from colostomy revisions usually show changes associated with trauma and mucosal prolapse such as erosions, ulcers, hemorrhage, acute and chronic inflammation, and fibromuscular obliteration of the lamina propria. One often encounters peri-intestinal fibrosis and suture granulomas. Inflammatory polyps can be seen as well. Infiltration of the large intestine by large numbers of eosinophils can be seen in eosinophilic gastroenteritis . These patients usually show peripheral blood eosinophilia and have a clinical history of atopy. 457. , 458. , 459. , 460. The entity that has been termed allergic proctitis is in our opinion a form of UC. 461 Whenever large numbers of eosinophils are encountered in a colorectal biopsy specimen, this finding should prompt thorough search for parasites, especially Strongyloides species. The most common form of allergic proctitis or colitis occurs in infants as a result of dietary protein–related allergy. These children present typically with rectal bleeding, sometimes with diarrhea. 462. , 463. Colorectal biopsy specimens show increased numbers of eosinophils within the lamina propria, occasionally with focal active colitis. Biopsy specimens that contain more than 60 eosinophils per 10 high-power fields are suggestive of this disease. 463 Allogeneic bone marrow transplantation can be complicated by acute or chronic GVHD. 360. , 464. , 465. , 466. , 467. The changes of acute GVHD (apoptotic colopathy) in mucosal biopsy have been described and various grading systems for acute GVHD are used. 360. , 466. , 467. Grade 1 acute GVHD correlates with increased apoptosis alone. Grade 2 changes include crypt abscesses as well as apoptotic bodies (see Fig. 23-61 ). Total necrosis of crypts is classified as grade 3, whereas denudation of areas of bowel is considered grade 4. 360 Biopsy specimens should be carefully examined for CMV infection. CMV may also cause apoptotic change that can mimic GVHD and occasionally both conditions can coexist. 467 Apoptosis is seen with damage associated with chemotherapy and irradiation. Patients receiving bone marrow transplantation for malignant conditions are prepared with chemotherapy and irradiation; therefore, distinguishing the effects of therapy from GVHD without a clinical history is impossible. Histologic changes associated with chemotherapy and irradiation typically resolve in 7 to 10 days. 464. , 466. Apoptotic colopathy identical to grade 1 GVHD can be seen in immunodeficiency syndromes, in patients receiving mycophenolate mofetil, and in primary AIDS-related colitis. Grade 4 GVHD cannot be distinguished from ischemic damage without a clinical history. Chronic GVHD usually spares the colon but a few examples have been described. The pathologic changes include submucosal fibrosis, mucosal calcification, and fibrosis of the lamina propria. 360. , 464. , 467. Chronic colitis–like changes have been seen in a subset of patients with GVHD; the relationship between this condition and chronic GVHD requires more study. 468 A localized form of UC with a better prognosis has been described as mucosal proctosigmoiditis, follicular proctitis, or ulcerative proctitis . 469. , 470. , 471. The gross and endoscopic mucosal appearance resembles that seen with more extensive forms of UC. Mucosal biopsy specimens typically show changes of UC but some have shown prominent mucosal lymphoid aggregates (follicular proctitis) ( Fig. 23-73 ). 429 Most patients respond to the local administration of corticosteroids or 5-aminosalicylates; approximately 10% of patients develop more extensive colitis. 469. , 470. Some evidence suggests that patients with prominent lymphoid follicles are less likely to respond to treatment. 429 Figure 23-73 ▪ Follicular proctitis showing typical changes of ulcerative colitis (crypt distortion, mucin depletion, and crypt abscesses) along with prominent mucosal lymphoid aggregates. Follicular proctitis showing typical changes of ulcerative colitis (crypt distortion, mucin depletion, and crypt abscesses) along with prominent mucosal lymphoid aggregates. Inflammatory changes are relatively common in patients with diverticular disease and are often related to trauma or prolapse. 356 IBD and diverticular disease are both common and occasionally coexist. UC-like inflammation in association with diverticular disease has been described. 332 Crohn's disease and diverticular disease share similar features such as focal mucosal inflammation, stricture, and fistula. Frequently, the pathologist will ascribe all the changes to one disease (usually diverticular disease) and overlook the concurrent IBD (usually Crohn's disease). Features that suggest Crohn's disease in this setting are the presence of fissural ulcers, patchy active mucosal inflammation outside diverticula, granulomatous inflammation, and internal fistulas other than colovesical or colovaginal fistula. Approximately 15% to 20% of patients develop other bowel lesions of IBD on follow-up. 472. , 473. , 474. , 475. , 476. , 477. Systemic mastocytosis is a rare disorder characterized by the infiltration of mast cells and eosinophils in the skin, bones, lymph nodes, and other organs such as the GI tract. 478. , 479. , 480. One group of investigators suggested that colorectal biopsy specimens showing more than 20 mast cells per high-magnification field as highlighted by CD117 or mast cell tryptase immunostain should be diagnosed as mastocytic enterocolitis, a disease best treated with antihistamines or mast cell stabilizers. 481 This controversial study did not control for thickness of immunohistochemically stained sections and lacked a treatment control group, thus making such conclusions premature. Mast cells coexpressing CD25 usually indicate neoplastic mast cells. 480 Patients with long-standing UC are at increased risk for colorectal carcinoma. 322 The prevalence of colorectal cancer in patients with UC is estimated to be 3.7% overall and 5.4% for those with pancolitis. 482 Those at greatest risk are patients with extensive colitis 483. , 484. who have been afflicted for more than 8 to 10 years. The cumulative risk of cancer in a patient with UC is approximately 2% at 10 years, 8% at 20 years, and 18% at 30 years. 482. , 485. Early age at onset of colitis, family history of colorectal cancer, histologic evidence of active inflammation, and sclerosing cholangitis may also increase the risk. 483. , 484. , 485. , 486. , 487. , 488. , 489. , 490. , 491. , 492. , 493. , 494. , 495. Colitis-associated carcinoma makes up only a small proportion of total colorectal cancer cases, but these tumors are particularly bothersome to the medical community. They frequently occur in young patients and often develop insidiously even while the patient is under active medical care. Many times the carcinomas are not clinically apparent until distant spread has occurred. 488. , 489. Colitis-associated carcinomas are often flat and infiltrative and difficult to visualize with standard radiographic and endoscopic techniques. 1 Because the symptoms associated with carcinoma mimic those of colitis, diagnosis is often delayed. The estimated risk of carcinoma complicating UC varies considerably. However, epidemiologic data suggest that patients with UC have 6 to 8 times the risk of developing carcinoma when compared with the general population, and looking at the subgroup of patients with UC who have extensive colitis, the risk is 15- to 19-fold. 483. , 490. This increased risk poses a management dilemma for physicians caring for patients not sick enough to require colectomy. Several management options are available. First, the physician can ignore the risk. Many physicians prefer this approach when dealing with an older patient or a patient who is not otherwise a surgical candidate, especially if the actual cancer risk is believed to be low. 491 A second management approach is prophylactic colectomy in patients with colitis for longer than 8 to 10 years. 491 This may be the best approach when dealing with a young patient because of the expected long duration of cancer risk and the possibility that surveillance can fail. 489 Furthermore, the results of ileal pouch–anal anastomosis are better in young patients. Although prophylactic colectomy theoretically eliminates the cancer risk, several factors have made this approach generally unacceptable. Patients with extensive colitis for more than 8 to 10 years are often asymptomatic or have only mild disease. Such patients often find it difficult to accept the risks associated with major surgery, the possible morbidity associated with mobilizing the rectum, or the social implications of a permanent ileostomy (in the event of a pelvic pouch failure). Besides, most studies suggest that prophylactic colectomy would have been unnecessary in the majority of patients because they would not have developed carcinoma. 1. , 484. A third option is colonoscopic surveillance with biopsy. The strategy of such surveillance is to identify a marker that signals a subgroup of patients with colitis who are at increased risk for carcinoma or the detection of carcinoma in an early, curable phase. 1. , 484. , 491. Currently, recognition of dysplasia in surveillance biopsy specimens is used as such a marker. Dysplasia, the presumed precancerous epithelial change, has been regularly recognized in colectomy specimens both adjacent to and distant from colitis-associated carcinomas. 1. , 322. Circumstantial evidence suggests that dysplasia may not only be the marker for carcinoma but also may itself be the carcinoma in a preinvasive phase. 1. , 322. Dysplastic epithelium can occur in grossly flat mucosa, in mucosa with a villous or plaquelike configuration, or in a nodular growth resembling adenoma ( Fig. 23-74 ). 1 Dysplasia is recognized by histologic examination of biopsy specimens using well-defined cytologic criteria that include nuclear enlargement with hyperchromasia, increased mitotic figures, and decreased intracellular mucin. 1. , 322. Most colitis-associated dysplasia resembles adenomas seen in patients without colitis. Figure 23-74 ▪ Adenoma-like dysplasia lesion in ulcerative colitis. An invasive adenocarcinoma was discovered on histologic examination of the central ulcerated area. Adenoma-like dysplasia lesion in ulcerative colitis. An invasive adenocarcinoma was discovered on histologic examination of the central ulcerated area. The pathologist should use the term dysplasia only as a synonym for intraepithelial neoplasia and not in reference to reactive or reparative changes seen with active inflammation. The distinction between repair and dysplasia can be difficult, requires experience, and in certain instances can be impossible. In general, cytologic abnormalities seen in the presence of active inflammation must be interpreted with caution. 1. , 322. Similar features can be seen in repair and dysplasia and no one histologic feature is absolute in making the distinction. 1 Both conditions are associated with nuclear enlargement and hyperchromasia, increased mitotic figures, and decreased intracellular mucin. Some features favor repair over dysplasia. Although cells undergoing repair demonstrate nuclear enlargement with hyperchromasia, these nuclei are often evenly spaced and not crowded, round to oval with a smooth external nuclear contour, contain granular chromatin with a single or multiple chromocenter or nucleoli, and are remarkably similar to one another in size and appearance. In contrast to dysplasia, the nuclear-to-cytoplasmic size ratio of regenerative cells is often actually decreased, especially in cells adjacent to ulcerated areas. During this phase, the cell cytoplasm is often eosinophilic. Nearby crypt abscesses or neutrophils within epithelium (cryptitis) help to confirm the diagnosis of repair. As a general rule, reparative epithelial change is limited to or accentuated in the crypt base and will not extend onto the surface of the crypt. Features that favor dysplasia over repair are variable nuclear hyperchromasia, nuclear pleomorphism, irregular external nuclear contours, nuclear stratification with irregular nuclear crowding and overlap, and a loss of nuclear polarity. The changes of dysplasia usually extend onto the surface of the crypt. Major distortions of mucosal architecture also favor dysplasia. The Inflammatory Bowel Disease–Dysplasia Morphology Study Group proposed a three-tiered classification for biopsy interpretation in IBD: positive, negative, and indefinite for dysplasia. 322 Our experience has shown that this classification is useful and reasonably reproducible. 1. , 492. Biopsy specimens negative for dysplasia include normal colon and those biopsy specimens showing changes of active or quiescent UC. Positive biopsy specimens are reported as showing high-grade dysplasia or low-grade dysplasia. Most dysplasias histologically resemble adenomas seen in patients without colitis, although some do not. 1 Dysplasias in this latter group are easy to miss. In low-grade dysplasia, nuclear changes such as crowding, pleomorphism, hyperchromasia, and increased mitotic figures are present, but in general, the nuclei are limited to the basal half of the cell ( Fig. 23-75 ). Usually, intracellular mucin is decreased, but on occasion intracellular mucin can be increased. Dystrophic or signet ring–type goblet cells are common in dysplasia although not pathognomonic. The general mucosal architecture should not be greatly disturbed. Figure 23-75 ▪ Low-grade dysplasia in ulcerative colitis. The nuclei show variable hyperchromasia and pleomorphism but the nuclei for the most part maintain a basal orientation. Low-grade dysplasia in ulcerative colitis. The nuclei show variable hyperchromasia and pleomorphism but the nuclei for the most part maintain a basal orientation. The distinction between low-grade dysplasia and high-grade dysplasia is made largely on the degree of cytologic and architectural change. In high-grade dysplasia, hyperchromasia and pleomorphism are marked ( Fig. 23-76 ). Stratification with loss of nuclear polarity is often present. Nuclei may be found in the luminal portions of the cells. High-grade dysplasia is often associated with a distortion of mucosal architecture, most often taking the form of a villous growth similar to villous adenomas seen in patients without colitis. Figure 23-76 ▪ High-grade dysplasia in ulcerative colitis showing a high degree of cytologic abnormality with full-thickness stratification of nuclei and with nuclei in the luminal portions of the cells. High-grade dysplasia in ulcerative colitis showing a high degree of cytologic abnormality with full-thickness stratification of nuclei and with nuclei in the luminal portions of the cells. Biopsy specimens are classified as showing changes indefinite for dysplasia when cytologic abnormalities are seen but these changes are of insufficient degree to warrant a diagnosis of true dysplasia. Indefinite changes are usually encountered in a background of active inflammation in which atypical epithelial changes could represent repair or regeneration rather than dysplasia. The indefinite category also includes odd mucosal patterns of growth that have not yet been observed to give rise to carcinoma (e.g., sessile serrated polyp–like change [ Fig. 23-77 ], epithelial changes that resemble gastric foveolar epithelium). The category, indefinite for dysplasia, is a legitimate diagnosis alerting the treating physician that worrisome changes are present that may place a patient in a higher risk category that requires more frequent surveillance. The Inflammatory Bowel Disease–Dysplasia Morphology Group originally subdivided indefinite dysplasia into three groups: probably inflammatory, probably dysplastic, and unknown. 322 Obviously, in a category that is already uncertain, subcategorization is cumbersome, subjective, and associated with marked interobserver and intraobserver variation. Therefore, subdivision of biopsy specimens in the indefinite category is not recommended. 1 Figure 23-77 ▪ This sessile serrated polyp–like lesion in ulcerative colitis is best classified as indefinite for dysplasia. This sessile serrated polyp–like lesion in ulcerative colitis is best classified as indefinite for dysplasia. The use of 5-aminosalicylate compounds decreases the risk of cancer by 53% to 75%, 485. , 493. as does seeing the physician regularly and having more than one colonoscopy. 493 Most patients and physicians opt for lifelong annual or biannual colonoscopic surveillance. 1. , 485. Current practice guidelines recommend two to four biopsy specimens obtained every 10 cm throughout the diseased bowel in addition to special sampling of macroscopic lesions. 494 Compliance with this recommendation has been inadequate. 495. , 496. , 497. , 498. Patients whose biopsy specimens remain negative for dysplasia can probably safely continue regular surveillance. Most authorities recommend annual total colonoscopic examination for patients with extensive UC who have had their disease for more than 8 to 10 years. 1. , 322. , 492. , 497. The surveillance interval can be increased to 2 to 3 years for patients with negative initial colonoscopy because in only 2% to 4% of these patients has disease been shown to progress. 489 Patients demonstrating epithelial changes indefinite for dysplasia should have shorter follow-up (e.g., 6 months to 1 year). 488. , 498. They must not be ignored because 28% of patients in whom the initial biopsy results were indefinite progressed to high-grade dysplasia and 9% progressed to cancer. 489 Management recommendations for patients with low-grade dysplasia in a flat mucosa are difficult because of the paucity of long-term follow-up information. Some clinicians consider it safe to continue short-term follow-up (e.g., 3 to 6 months) for patients with low-grade glandular dysplasia; 488. , 498. if dysplasia persists 1. , 497. , 499. , 500. or is associated with any suspicious gross lesion or stricture (dysplasia-associated lesion or mass [DALM]), colectomy should be considered. 1. , 322. , 484. , 501. Forty-three percent of reported patients with DALM already had carcinoma in immediate colectomy specimens. 489. , 501. Increasing numbers of experts have advocated immediate colectomy for low-grade dysplasia. 487. , 488. , 489. , 502. These experts have stated that 19% of patients with low-grade dysplasia already had complicating carcinomas, and they also have cited a very high rate of progression to high-grade dysplasia or carcinoma with follow-up (54%, St. Marks, London; 53%, Mt. Sinai, New York; 33%, Mayo Clinic, Rochester, Minn). 485 These data are questioned because of case selection bias. 489 If high-grade dysplasia is encountered, then colectomy should be recommended because the risk of concurrent carcinoma is estimated to be as high as 42%. 1. , 489. Experience with surveillance biopsy interpretation has shown that truly negative results are rarely interpreted as dysplasia, and dysplasia, especially high-grade dysplasia, is rarely missed. 1. , 492. That said, variations in interpretation do occur, 1. , 322. , 500. , 502. , 503. , 504. and in general confirmation of a biopsy diagnosis of dysplasia is desirable before colectomy. 1. , 322. Any one or more of the following may be considered adequate confirmation: finding of dysplasia in a repeat biopsy from the same site, finding of dysplasia in one or more additional sites during the same endoscopic examination, or review and confirmation of the original dysplasia interpretation by another pathologist experienced with the classification system. 1. , 322. , 485. Surveillance endoscopy with biopsy has limitations. No compelling evidence proves that surveillance benefits the patient. 489. , 491. , 497. , 503. , 505. Participation in a surveillance program does not guarantee that lethal cancer will not develop. 488. , 489. , 491. , 497. , 500. , 505. , 506. Dysplasia is unusual and it is difficult for any one pathologist to acquire extensive experience. Therefore, errors in histologic interpretation can be expected. Dysplasia can be focal and is subject to tremendous sampling error. 1. , 488. , 492. Because most authorities consider dysplasia a neoplastic change, it is unlikely that it ever resolves spontaneously. Thus, a clinician should not be lulled into a false sense of security by negative follow-up biopsy results once true dysplasia has been identified. 1 Although not proved scientifically, it seems likely that patients benefit from surveillance programs because many carcinomas are detected in a curable phase. 1. , 488. , 497. , 498. , 500. , 505. In addition, the incidence of carcinoma in patients whose biopsy specimen results have remained negative is low. 489. , 497. , 498. It is unclear whether this benefit justifies the large cost of surveillance endoscopy. 489. , 507. Finally, surveillance programs are pointless unless the patient complies with regular surveillance and agrees to colectomy when the end point (dysplasia) has been reached. 507 Many groups have searched for other markers for precancer in UC. Sialomucins predominate in cancer and dysplasia in UC but the role of mucin histochemistry findings is debated. 508 Results of lectin binding, CEA immunohistochemical study, and immunohistochemical analysis for products of c- myc and ras oncogenes have produced variable results and could not reliably differentiate dysplasia from repair. 1 Several investigators described a correlation between DNA aneuploidy and dysplasia or carcinoma in UC. 509. , 510. , 511. However, only 80% to 90% of invasive carcinomas and 50% to 80% of dysplasia demonstrated DNA aneuploidy. This finding indicates that DNA analysis by flow cytometry could not be used alone in a cancer surveillance program. Many specimens (≥6%) interpreted as negative or indefinite for dysplasia showed DNA aneuploidy. 510. , 511. This finding can be interpreted in several ways. It could indicate technical problems linked to false-positive results including failure to disaggregate nuclear clumps, prolonged exposure of the sample to higher temperatures, and debris in the sample. 511. , 512. Alternatively, this test could identify a subgroup of patients different from the group identified by dysplasia that is showing objective chromosomal abnormalities in the absence of recognizable dysplasia. It is tempting to speculate that this DNA aneuploidy could be used as a marker of some carcinomas complicating UC, although other investigators concluded that the detection of DNA aneuploidy was not useful as a predictor of the presence of concurrent carcinoma in UC. 509. , 510. , 511. Until large prospective studies determine the usefulness of DNA aneuploidy in UC, histologic dysplasia is still the only reliable marker for cancer in a surveillance program. 1. , 513. , 514. DNA analysis could benefit some patients. Patients with diploid DNA content and no signs of dysplasia probably can be examined at longer surveillance intervals. 510. , 511. Approximately 90% of patients would fall into this category and a longer interval surveillance could save considerable amounts of money and time. A special problem concerns the occurrence of adenoma in patients with colitis. Colorectal adenomas and IBD are both relatively common. Therefore, there is probably no reason that both conditions could not coexist. Because most IBD-associated dysplasias resemble adenomas, 1 the distinction in practice is often impossible. Management of patients with UC and adenoma has been controversial. Does the lesion represent a harmless sporadic adenoma or is it a dangerous DALM? In general, a pathologic diagnosis of “adenoma” in a patient with IBD must be carefully evaluated by the treating physician and should at least prompt further consultation with the pathologist because the lesion could represent IBD-associated dysplasia, an ominous change that implies a substantial risk for the development of carcinoma or for coexisting cancer. 1. , 515. Dysplasia in IBD can be broadly classified endoscopically as flat or raised. Raised lesions can be further subdivided into adenoma-like (i.e., discrete, well-circumscribed sessile or pedunculated lesions that resemble sporadic adenomas [see Fig. 23-74 ]) or non–adenoma-like (i.e., irregular plaque or masslike) lesions ( Figure 23-78 ▪ , Figure 23-79 ▪ ). 1. , 516. Most experts recommend colectomy for flat high-grade dysplasia and endoscopically raised non–adenoma-like dysplasia lesions. Correct management of patients with UC who have endoscopically adenoma-like dysplasia is not clear. The differential diagnosis between conventional adenoma and dysplastic lesions in IBD has been the focus of several publications. Distinction based on pathomorphologic features has been proposed. 517. , 518. Although lesions can be classified histologically using this system, to date this approach has not been clinically validated. The study of Torres and colleagues 517 suggested that an admixture of normal and dysplastic glands at the surface of the lesion could be used to distinguish IBD-associated dysplasia from conventional adenoma. Several drawbacks to this study limit its clinical usefulness. An association with carcinoma or flat dysplasia was definitional for IBD-associated dysplasia in this study. Furthermore, the study had limited clinical follow-up to determine whether the distinction based on this feature (admixture of normal and dysplasia at the surface) was clinically relevant in patients not yet known to have other areas of dysplasia or carcinoma. Many authorities believe that admixtures of normal and dysplastic glands are so highly prevalent in sporadic adenomas that this criterion is not helpful in practice. Figure 23-78 ▪ Masslike dysplasia-associated lesion or mass (DALM) from a patient with ulcerative colitis. Figure 23-79 ▪ Histologically adenoma-like dysplasia in ulcerative colitis. This histologic pattern can be seen in any of the gross or endoscopic configurations of dysplasia. Masslike dysplasia-associated lesion or mass (DALM) from a patient with ulcerative colitis. Histologically adenoma-like dysplasia in ulcerative colitis. This histologic pattern can be seen in any of the gross or endoscopic configurations of dysplasia. Molecular analysis has been applied in an attempt to resolve this diagnostic problem. Odze and associates 519 reported a similar prevalence of 3p, APC, and p16 mutations in adenoma-like dysplasia lesions in UC and sporadic adenomas. However, non–adenoma-like dysplasia in UC showed significantly higher proportions of 3p and p16 mutation, a finding indicating different timing of molecular events in these lesions. 519 Although promising, these molecular approaches are technically difficult, are not generally available, and remain to be validated clinically. Immunohistochemistry has also been used in an attempt to discriminate between conventional adenoma and IBD-associated dysplasia. 520. , 521. p53 overexpression by immunohistochemical analysis that generally correlates with mutation of the corresponding tumor suppressor gene appears to be the most promising. p53 gene mutations reportedly occur earlier in IBD-associated dysplasia than in conventional adenoma or carcinoma. Therefore, strong p53 overexpression tends to correlate with IBD-associated dysplasia. Unfortunately, only 30% of IBD-associated dysplasias overexpress p53 (versus 5% of sporadic adenomas). 520. , 521. This p53 testing is probably not sensitive enough for routine practice. Combining p53 immunoreactivity with beta-catenin expression (which exploits the relatively low prevalence of APC gene mutation in IBD-associated dysplasia) or bcl-2 immunohistochemistry (which is more often overexpressed in sporadic adenomas) does not appear to improve the sensitivity or specificity of this approach. 520. , 521. Immunohistochemistry is clearly technically easier and more widely available. However, as with the molecular approaches outlined earlier, diagnoses based on immunohistochemistry have not been clinically validated. Pathomorphologic, molecular, or immunohistochemical testing could eventually separate harmless sporadic adenomas from the more ominous DALMs in patients with IBD but this remains to be proved. In the meantime, follow-up information is sufficient to guide a careful physician facing this dilemma. The most important criterion for stratification is the topographic relation of the adenoma-like lesion to areas of colitis. Adenoma-like lesions occurring in areas not affected by colitis histologically or endoscopically have not been associated with a high risk of concurrent or subsequent carcinoma. These lesions should be considered conventional adenomas and treated by polypectomy alone. 1. , 516. , 517. , 520. , 522. Management of adenoma-like lesions occurring in areas involved by colitis is more challenging. As many as two thirds of patients have had concurrent or subsequent invasive carcinoma at follow-up. 1. , 515. , 517. , 523. From a practical standpoint, we believe that it is prudent to consider all adenoma-like lesions occurring in areas involved by colitis as potentially IBD-associated dysplasia lesions. These lesions must be excised endoscopically and not merely sampled with biopsy. 523 The diagnosis of IBD-associated dysplasia alone in this unique setting (adenoma-like dysplasia in a macroscopic polyp) may not necessarily be an indication for immediate colectomy. 1. , 323. , 498. , 515. , 516. , 517. , 520. , 524. Endoscopic polypectomy alone may be adequate treatment provided that careful patient selection criteria are applied, including the following: (1) the patient is in an adenoma age group (>40 years of age), (2) the adenoma-like lesion is discretely defined macroscopically and can be excised in its entirety, (3) excision of the lesion appears complete to the endoscopist, (4) no flat dysplasia is identified in the colon, and (5) the colon is easy to survey (i.e., compliant patient without inflammatory polyposis). Current data suggest that the majority of patients managed in this fashion will follow a clinically benign course. 1. , 515. , 516. , 522. , 523. , 524. However, these patients must receive careful short-term surveillance. A 3- to 6-month initial surveillance interval can be increased to 6 months to 1 year following negative results of colonoscopy. 516 Colectomy should be recommended for patients not fulfilling these selection criteria. 515 Increasing epidemiologic and pathologic evidence suggests that patients with Crohn's disease are also at increased risk for the development of carcinoma. 1. , 525. , 526. , 527. Those patients who are younger than 21 years of age at the onset of Crohn's disease may be at even higher risk. 528 Colonic carcinomas in patients with Crohn's disease have in general developed after about 20 years of disease. 1. , 525. , 526. , 527. , 528. , 529. , 530. , 531. , 532. The diagnosis is usually made clinically because a gross intraluminal lesion can often be visualized ( Fig. 23-80 ). The colonic carcinomas have been better differentiated than their small bowel counterparts in Crohn's disease, with an increased prevalence of mucinous histologic features. 1. , 525. , 526. , 531. Figure 23-80 ▪ Colorectal adenocarcinoma in patients with Crohn's disease often produces luminal lesions. This small, plaquelike area of dysplasia and the underlying carcinoma that is associated with a stricture mimic the inflammatory fibrostenosing lesions of Crohn's disease. Colorectal adenocarcinoma in patients with Crohn's disease often produces luminal lesions. This small, plaquelike area of dysplasia and the underlying carcinoma that is associated with a stricture mimic the inflammatory fibrostenosing lesions of Crohn's disease. Reports using current histologic criteria almost invariably note dysplasia in the epithelium adjacent to small bowel and colonic carcinomas in Crohn's disease. 1. , 525. , 526. , 527. , 531. Dysplasia distant from carcinomas has also been encountered in specimens exhibiting both colonic carcinoma and Crohn's disease. These features suggest that the dysplasia-carcinoma sequence similar to that proposed for UC also occurs in Crohn's disease. 1. , 526. , 531. A practice-based surveillance study of 259 patients with Crohn's colitis affecting at least one third of the colon for more than 8 years found that 16% of patients developed dysplasia or cancer at 16 years. 533 Opinions vary regarding cancer surveillance in patients with long-standing Crohn's disease. 1. , 525. , 526. , 527. , 529. , 531. , 534. It is possible that surveillance could benefit an occasional patient with colonic Crohn's disease by detecting dysplasia or early carcinoma, but the safety, necessity, and benefit of regular cancer surveillance are questioned. 535 Colonoscopy may be technically impossible or dangerous in some patients with Crohn's disease. Retained rectal stumps are often strictured and inaccessible. The absolute number of colon carcinomas reported in Crohn's disease is still low, so again the expected yield of positive cases in a surveillance program would be quite small. Some experts advocate a UC-like surveillance strategy for patients with at least 8 years of Crohn's colitis involving at least one third of the colon. 485 Rather than ignoring the risk in Crohn's disease, options are available for a cautious clinician. 1. , 534. , 535. A patient with recrudescence of colitis-like symptoms and a background of long-standing inactive Crohn's colitis should be thoroughly investigated for carcinoma. 526 Yearly surveillance of an out-of-circuit rectum seems reasonable considering that approximately 20% of the reported cases of large bowel cancer in Crohn's disease have occurred in such segments. 534. , 535. It may, however, be better to advise removal of the defunctioned rectum, especially if reanastomosis is not planned, not possible, or contraindicated. The presence of dysplasia in a biopsy specimen from a patient with Crohn's disease must alert the physician to the possibility of coexistent invasive carcinoma. In this situation, management approaches similar to those proposed for dysplasia in UC are recommended. 1. , 321. , 526. Clinicians should also recognize that chronic fistula or anal stricture in Crohn's disease may be complicated by squamous carcinoma or adenocarcinoma. 1. , 530. Any abrupt change in the volume or nature of a fistula discharge or the development of an area of induration or mass near a fistula should be investigated with biopsy. 535 So-called left-sided colonic diverticular disease commonly affects middle-aged and older individuals and shows a characteristic muscular abnormality of the bowel wall. 536 The abnormality is characterized by marked thickening of the inner circular layer of the muscularis externa that results in a narrowed lumen and a mucosa thrown up into prominent accordion-like folds. The mucosal abnormality and associated diverticula are most prominent within the sigmoid colon but they may extend proximally for a variable distance and may even involve the entire colon. Diverticula are not seen in the rectum. The diverticula are usually still enveloped by an intact longitudinal muscle layer. Diverticula usually manifest in two longitudinally running rows situated between the mesenteric and two anti-mesenteric taeniae. In severe cases of diverticular disease, diverticula can also be found between the antimesenteric taeniae. Similar clinical signs and symptoms occur regardless of whether objective inflammatory changes are present; therefore, the term diverticular disease is preferred rather than routinely making the distinction between diverticulosis and diverticulitis. Diverticula are sometimes difficult to demonstrate in freshly resected specimens because of lost muscle tone and intraluminal pressure. As a result the diverticula often evert and are mistaken for polyps. The best way to demonstrate diverticula is to fix an intact specimen with formalin under pressure for at least 1 day before dissection ( Fig. 23-81 ). Figure 23-81 ▪ Diverticular disease showing a thickened muscularis externa, prominent mucosal folds, and areas of diverticula. Diverticular disease showing a thickened muscularis externa, prominent mucosal folds, and areas of diverticula. Complications of diverticular disease include inflammation within the diverticula (diverticulitis), perforation of diverticula, adhesion, fistula formation, pericolonic abscess with inflammatory mass, hemorrhage, and obstruction. 537 Although colovesical and colovaginal fistula can occur in diverticular disease, other fistula combinations must raise the suspicion of coexisting Crohn's disease. Any granularity or ulceration of the luminal mucosa that is accompanied by microscopic findings of crypt abscesses or deep lymphoid aggregates away from inflamed diverticula must also raise the possibility of coexisting Crohn's disease (see earlier). Likewise, features of colitis distal to the zone of diverticula (e.g., at the distal resection margin) must also raise the question of coexisting Crohn's disease. Right-sided diverticular disease is often isolated and usually unassociated with diverticula in the rest of the colon. Right-sided diverticula occur in younger patients and are frequently seen in Asians. 538. , 539. , 540. , 541. Clinically, right-sided diverticular disease manifests with symptoms that mimic acute appendicitis. Some authors classify these diverticula as congenital if the outpouching contains all layers of the bowel wall or acquired if the diverticula resemble those seen in the left-sided diverticular disease. Complications include inflammation, hemorrhage, pericolonic abscess, and peritonitis. These diverticula have been implicated in some solitary nonspecific ulcers of the cecum and right colon. The clinical diagnosis of ischemic bowel disease can be difficult. Patients usually present with nonspecific symptoms and routine radiographic examinations such as plain abdominal films or barium enemas are rarely of use. Even arteriography may not be helpful because of the poor correlation between angiographic findings and the ultimate diagnosis or clinical outcome. 542 Angiographic demonstration of patent mesenteric blood vessels does not exclude ischemia. Conversely, stenosis or occlusion of mesenteric arteries (even two of the three major vessels) does not establish a diagnosis of ischemia because these are frequent findings in asymptomatic patients. Therefore, the diagnosis of ischemic bowel disease requires a high index of clinical suspicion complemented by continued monitoring of clinical, laboratory, and radiographic information. The pathologist can play an important role in the diagnosis and management of ischemic bowel disease by recognizing the patterns of injury that suggest ischemia in biopsy and resection specimens. At first glance, intestinal ischemia seems simple, but in reality the topic is almost impossibly complex; the ultimate outcome of the patient depends on complicated interrelationships among temporal, anatomic, and physiologic factors. 543 For example, gradual occlusion of large vessels rarely causes ischemic damage because adequate collateral circulation (e.g., arc of Riolan, marginal artery of Drummond) will develop. In contrast, acute arterial occlusion is likely to result in infarct. Considering anatomic factors, occlusion of a large vessel does not often result in ischemic damage because collateral circulation is usually adequate to protect the bowel. However, occlusion of smaller end arteries frequently results in segmental ischemic damage and infarct. 544 Finally, the mere existence of an entity referred to as nonocclusive intestinal ischemia emphasizes the importance of physiologic considerations. Systemic hypotension and bowel distention lead to marked decreases in splanchnic blood flow caused by vasoconstriction and arteriovenous shunting in the bowel wall. 544. , 545. This phenomenon can result in widespread bowel infarct even in the presence of patent blood vessels. Ischemic injury to the GI tract occurs whenever the oxygen or vascular supply cannot meet the metabolic demands of the tissue. GI ischemia has many causes, including inadequate perfusion, narrowing of blood vessels from any cause, bowel obstruction and distention, drug effects, and infections that can mimic ischemic damage. The list of differential diagnostic possibilities often overwhelms the pathologist and clinician. Keeping the diagnostic considerations in their proper perspective, almost all cases of mesenteric ischemia result from systemic hypotension or occlusion of a major blood vessel. 544 Knowledge of these relative frequencies can be invaluable in decreasing the pathologist's anxiety and frustration when dealing with these types of specimens and when interacting with the concerned clinician, patient, and family. Most ischemic episodes result from nonocclusive ischemic bowel disease (low-flow states) and in these cases no vascular lesion or specific cause for ischemia can be demonstrated on pathologic examination. Superior mesenteric artery embolism or thrombosis is usually diagnosed by radiography or at operation. Almost all significant superior mesenteric artery occlusions occur in the proximal 1 cm to 2 cm of the artery, 544 an area not likely to be present in a resection specimen; such occlusive plaques, thrombi, or emboli are either bypassed surgically or removed and submitted separately to the pathology laboratory. Mesenteric venous thrombosis is also diagnosed and identified at laparotomy and treated with thrombectomy. Low-flow states, superior mesenteric artery occlusion, and mesenteric venous thrombosis account for more than 95% of major ischemic events. Ischemia can result in a wide range of pathologic changes depending on the cause, severity, and duration of the hypoxia. Thus, ischemia can cause little or no change, mucosal plaques or hemorrhages with erosion, discrete or serpiginous ulcers that mimic Crohn's disease, strictures, or at the severe end of the spectrum, hemorrhagic infarct with perforation. Any part or length of bowel can be affected depending on the cause and duration of hypoxia and the state of the collateral circulation. In general, those cases of ischemic bowel disease associated with narrowing of a blood vessel show pathologic changes in the bowel in the corresponding distribution. In contrast, nonocclusive intestinal ischemia causes patchy and irregular distribution of damage not necessarily corresponding to an area supplied by a specific blood vessel ( Fig. 23-82 ). Ischemic damage associated with reduced blood flow shows a propensity to affect “watershed zones” such as the splenic flexure, which is the boundary between the superior mesenteric and inferior mesenteric artery distributions. 3. , 347. Figure 23-82 ▪ Ischemic colitis caused by low flow. Areas of mucosa hemorrhage and ulcer with intervening edematous mucosa can mimic Crohn's disease and primary inflammatory bowel disease of an indeterminate type. The distribution of mucosal damage in this specimen does not correspond to an area supplied by a specific blood vessel. Ischemic colitis caused by low flow. Areas of mucosa hemorrhage and ulcer with intervening edematous mucosa can mimic Crohn's disease and primary inflammatory bowel disease of an indeterminate type. The distribution of mucosal damage in this specimen does not correspond to an area supplied by a specific blood vessel. Acute, organizing, and healed phases of ischemia can be recognized histologically. 347 Acute ischemic damage can be focal or diffuse. The characteristic pattern of acute injury consists of hemorrhage into the lamina propria associated with superficial epithelial coagulative necrosis, often with sparing of the deep portion of the intestinal crypt (see Fig. 23-59 ). 3. , 347. The mucosal distribution of these changes can be explained by the existence of a countercurrent exchange mechanism that has been suggested for intestinal mucosa. In the mucosa, a central arteriole carries blood luminally in a direction parallel to but opposite to the direction of blood flow in the draining mucosal venule. This situation causes a gradient in oxygen tension to form, with the luminal aspect of the bowel relatively hypoxic when compared with the crypt base. 546. , 547. The changes of acute ischemia can occasionally be associated with more extensive necrosis of the epithelium, often associated with an attached inflammatory pseudomembrane. Surprisingly, acute and chronic inflammatory cells are typically minimal in acute ischemic damage. This finding helps to differentiate ischemic damage from changes seen in primary IBD. Depending on the severity and duration of the hypoxia, the acute change can be reversible or can proceed to mucosal ulcers, at which point the histologic features become relatively nonspecific. 548 With increasing severity and duration, ischemia can lead to full-thickness infarct with hemorrhage and coagulative necrosis involving all bowel layers. Granulation tissue and fibrosis with plump fibroblasts predominate in the organizing phase of ischemic damage . The histologic change becomes nonspecific. Ischemia should be suspected when an ulcer or area of organizing inflammation in the bowel appears quite bland and is not associated with a marked increase in chronic inflammatory cells with plasma cells and lymphoid aggregates so characteristic of primary IBD. Often, the mucosa of the ulcer edge shows changes similar to those seen in acute ischemic damage, and extensive samplings of these areas can help in diagnostic problem cases. The presence of hemorrhage and hemosiderin deposits in the connective tissues, although not pathognomonic, strongly suggests an ischemic origin. During the healing phase, the colonic mucosa often assumes an architectural appearance similar (if not identical) to chronic UC with atrophy, shortened crypts, and branched and budded glands. 3. , 347. These changes usually have a patchy distribution in healed ischemic damage but are diffuse in UC. Ischemia usually does not show the basal plasmocytosis of primary IBD. Healed phases of ischemia are often complicated by fibrous stricture in which fibrosis can affect all the layers of the bowel wall including the muscularis externa. Fibrosis of the muscularis externa is distinctly unusual in primary IBD and its presence should raise the suspicion of ischemic bowel disease. Again, hemosiderin deposits can be a helpful clue in recognizing the ischemic nature of the injury. Most ischemic bowel lesions result from a combination of atherosclerosis and low-flow states and are referred to as nonocclusive ischemic bowel disease . 544 Specimens showing ischemic damage or infarct are usually resected on an emergency basis and include relatively short segments of mesentery. Large segments of infarct or ischemic damage are usually caused by an occlusive lesion in a proximal segment of a large artery or vein. In other words, the offending vessel is not likely to be present in the resection specimen. Although one is unlikely to see specific vascular abnormality in the resection specimen, the blood vessels should be carefully dissected and many cross sections examined microscopically to detect vascular lesions such as atherosclerosis, embolus, thrombosis, or inflammation (vasculitis). The significance of vascular inflammation in areas of active ulcer and infarct is questionable because this “vasculitis” may be secondary. However, acute inflammation in vascular walls associated with fibrinoid necrosis found in apparently viable areas separated from an ulcerated and necrotic area by a margin of normal tissue may indicate systemic vasculitis. Polyarteritis nodosa is a multisystem disease characterized by random necrotizing inflammation involving small and medium-sized arteries. Because the distribution and severity of the vascular lesions are haphazard, polyarteritis nodosa produces protean clinical manifestations without pathognomonic signs or symptoms. Abdominal pain, fever, leukocytosis, hypertension, and neuropathy are common in patients with polyarteritis nodosa. 549 According to the American College of Rheumatology, the presence of 3 of the following 10 criteria are considered diagnostic of the disease 550 : weight loss, livedo reticularis, testicular pain or tenderness, myalgia or myopathy, neuropathy, hypertension, renal impairment, hepatitis B infection, abnormal arteriogram, and positive biopsy results. The diagnostic histopathologic change of polyarteritis nodosa is necrotizing panarteritis with inflammation involving intima, media, and adventitia. The inflammatory infiltrate is composed of neutrophils, eosinophils, plasma cells, and lymphocytes and is often associated with a deposition of fibrin. 551. , 552. The vascular lesions are usually seen in various stages of development and healing. Disruption of the internal elastic lamina weakens the vascular wall and can lead to aneurysm formation, an important sign used in radiographic diagnosis. Of patients with polyarteritis nodosa, 14% to 70% have GI tract involvement 553 such as duodenal or gastric ulcer, melena, hematemesis, or small bowel infarcts. GI tract involvement is usually a manifestation of systemic polyarteritis nodosa. However, a growing body of literature has described polyarteritis nodosa apparently limited to one organ, most commonly the skin, gallbladder, or vermiform appendix. 551. , 552. , 553. , 554. , 555. Only a rare patient with polyarteritis nodosa that is initially diagnosed in the gallbladder or appendix develops systemic vasculitis 552. , 553. , 556. , 557. and those who do frequently have elevated serum rheumatoid factor or antinuclear antibodies. Phlebitis, Churg-Strauss angiitis, small vessel vasculitis, Buerger's disease, and giant cell arteritis can manifest initially in the GI tract and cause ischemic injury. 553. , 557. Phlebitis and small vessel vasculitis are frequently associated with drugs and medications and are often self-limited. 553. , 558. Special consideration should be given to an entity referred to as intra-abdominal (lymphocytic) phlebitis . Rare cases of ischemic damage to the colon have been linked to a curious form of phlebitis reported under numerous synonyms including lymphocytic phlebitis, necrotizing and giant cell granulomatous phlebitis, idiopathic myointimal hyperplasia of mesenteric veins, mesenteric inflammatory veno-occlusive disease, intramural mesenteric venulitis, and idiopathic colonic phlebitis. 553. , 558. , 559. , 560. , 561. , 562. , 563. , 564. , 565. , 566. , 567. , 568. Since the original descriptions, approximately 40 additional cases have been described. The patients have ranged in age from 30 to 77 years, and no gender predilection is apparent. Most cases involve the small intestine and colon but involvement of other organs such as the gallbladder, omentum, and stomach have been described. 553. , 568. Four patients received treatment with the drug rutoside. Microscopically, specimens show phlebitis and thrombophlebitis mostly involving the submucosal veins and venules ( Fig. 23-83 ). The most prominent lesion is infiltrative lymphocytic phlebitis. In approximately half of these patients, the phlebitis has been necrotizing, and in about one third a granulomatous component has been visible. In approximately half of the patients, myointimal proliferation has been described. 559 Some investigators have proposed that myointimal hyperplasia represents an end stage of lymphocytic phlebitis. 561 Figure 23-83 ▪ Intra-abdominal (lymphocytic) phlebitis. The submucosal vein demonstrates infiltration of its wall by lymphocytes with focal phlebothrombosis. The accompanying artery is normal. Intra-abdominal (lymphocytic) phlebitis. The submucosal vein demonstrates infiltration of its wall by lymphocytes with focal phlebothrombosis. The accompanying artery is normal. Immunohistochemical analysis has been performed on a few cases and demonstrates a mixture of T cells and B cells with a few macrophages. 559. , 565. Some of the T cells express the cytotoxic granule-associated protein TIA-1 and granzyme B, findings supporting the contention that the lymphocyte-mediated vascular damage is a central event in the pathogenesis. 565 So far, cases in the literature have had a favorable clinical outcome. The disease usually has been diagnosed and treated by resection in these patients. No patient to date has required repeat resection, nor has any patient developed systemic vasculitis. Some patients continue to have abdominal pain, and at least one report noted recurrent phlebitis documented by biopsy. 559 Other entities considered part of the spectrum of ischemic bowel disease include necrotizing enterocolitis of the neonate, neutropenic enterocolitis (typhlitis), intestinal Behçet's disease, late irradiation enterocolitis, uremic colitis, stercoral ulcer associated with bowel obstruction, potassium chloride–induced ulcer, stress ulcer and ulcers associated with drugs (e.g., NSAIDs and chemicals), certain infections such as Clostridium difficile –associated colitis, and EHEC infection. The pathologic features of these disorders resemble ischemic bowel disease and are generally indistinguishable without knowledge of clinical and laboratory information. Necrotizing enterocolitis is a serious form of intestinal injury that resembles ischemic bowel disease. Although many investigators think it part of the spectrum of ischemia, increasing evidence supports a role for infectious agents in the pathogenesis of the lesion. 569 Necrotizing enterocolitis of the neonate generally affects low-birth-weight or premature infants. The disease usually occurs in babies younger than 10 days of age and symptoms usually develop after feeding has begun. The lesions resemble acute ischemic damage. 569. , 570. Ulcers that can be patchy or diffuse occur and in general may affect any part of the GI tract. Preferred sites of involvement include the terminal ileum, right colon, and stomach. Histologically bland transmural necrosis occurs and may be associated with gas cysts within the bowel wall (pneumatosis cystoides intestinalis [PCI]) ( Fig. 23-84 ). Babies surviving the acute episode may later develop fibrous strictures. Figure 23-84 ▪ Necrotizing enterocolitis of the neonate demonstrating a combination of ischemic-type injury with the acute form of pneumatosis cystoides intestinalis. Necrotizing enterocolitis of the neonate demonstrating a combination of ischemic-type injury with the acute form of pneumatosis cystoides intestinalis. Neutropenic enterocolitis goes by numerous synonyms, including hemorrhagic necrosis of the GI tract, necrotizing enterocolitis, agranulocytic colitis, typhlitis, and the ileocecal syndrome. 571. , 572. , 573. , 574. The condition is fulminant segmental colitis that is often seen in patients with lymphoma or leukemia receiving immunosuppressive drug therapy, but it has also been seen in association with other chemotherapy-induced or non-neoplastic–induced neutropenias such as cyclic neutropenia. Many investigators consider this disorder a form of ischemic bowel disease, but increasing evidence implicates bacteria, especially Clostridium septicum, as causative agents. 575. , 576. , 577. , 578. The pathogenesis is unclear but is likely to be multifactorial with neutropenia, altered mucosal integrity, ischemia, and infection all playing a role. The lesion can occur anywhere in the GI tract, but the preferred sites are cecum, right colon, and terminal ileum. The histologic picture combines infarct necrosis with profound secondary bacterial or fungal overgrowth and is often associated with a paucity of acute inflammatory cells. The prognosis is grave; however, reports of successful surgical and medical management have been published. 571. , 572. , 574. , 575. , 579. Investigators have reported benign cecal ulcers and segmental necrosis of the right colon in which the pathologic features are nonspecific or resemble ischemia. 580. , 581. , 582. The cause of many of these ulcers remains unclear. 580 Some may represent inflammatory changes or bleeding vascular lesions in right-sided diverticula. 582. , 583. Many are associated with end-stage renal disease, hemodialysis, renal or cardiac transplantation, and corticosteroid therapy. Some are clearly related to ischemia caused by low-flow states, which are known to occur in patients undergoing hemodialysis. 581 However, a strong correlation exists among cecal and terminal ileal ulcers, renal or cardiac transplantation, immunosuppression, and CMV infection. 584 The possible role of CMV in these ulcers is unknown. The exact cause of many colonic ulcers cannot be determined at present. 585 NSAID use should also be investigated. 586 The term Behçet's disease describes the clinical triad of aphthous stomatitis, genital ulcers, and relapsing iritis. Behçet's disease is seen worldwide, but most cases have been reported from the Mediterranean basin, the Middle East, and Japan. 587 Male patients are twice as commonly affected as female patients and the mean age of onset is in the third decade. 587. , 588. Behçet's disease is a systemic disorder; only 10% to 15% of patients demonstrate GI tract involvement, 587. , 588. , 589. usually in the form of intestinal ulcers. The ulcers of intestinal Behçet's are described as multiple, deep, and punched-out with a preferential localization in the ileum and cecum. The ulcers often perforate. 588. , 589. , 590. , 591. The primary clinical differential diagnosis is Crohn's disease. Intestinal Behçet's disease differs from Crohn's disease in several ways. Behçet's disease is usually not associated with strictures or granulomas. Free perforation, common in Behçet's disease, occurs rarely in Crohn's disease. Details of histologic pattern in intestinal Behçet's are difficult to find. 590. , 591. The inflammatory infiltrate of Behçet's ulcer appears nonspecific. The lesions of so-called acute Behçet's ulcer closely resemble acute ischemic bowel disease. The chronic lesion of Behçet's disease resembles Crohn's disease except the transmural lymphoid aggregates in Behçet's disease contain more germinal centers, the bowel wall can be fibrosed, and granulomas are not usually encountered. Some authors have reported mononuclear cell infiltrates around capillaries and venules with some areas of fibrinoid necrosis. 588. , 590. Indeed, large vessel inflammation with occlusion and aneurysm formation have been described in 3% to 25% of patients with Behçet's disease. 591. , 592. Vasculitis may be the common underlying factor producing the GI lesions of Behçet's disease. 590 Late complications of irradiation can occur weeks to years after therapy and include colitis, stricture, ulcer, and fistula ( Fig. 23-85 ). 593. , 594. Many of these abnormalities may be related to ischemia as a result of the effect of radiation on blood vessels. Histologically, the mucosa appears atrophic and similar (often identical) to that seen in chronic UC. Having said that, the basal plasmacytosis in the lamina propria characteristic of primary IBD is usually but not always absent. Ectatic mucosal capillaries with thrombosis and hyalinization are important histologic signs that can point to irradiation effect ( Fig. 23-86 ). Irradiation may be associated with fibrosis of any of the layers of the bowel wall. The fibrosis can appear dense and hyalinized and may contain large, atypical radiation fibroblasts. Vascular changes are often prominent. Blood vessels may be ectatic in the mucosa and submucosa. More commonly, however, one encounters marked intimal fibroplasia with hyaline thickening of the blood vessel walls that leads to luminal stenosis. Figure 23-85 ▪ Chronic radiation proctocolitis. The mucosal atrophy, erythema, and granularity can simulate ulcerative colitis. The fibrous stricture present in the descending colon can mimic Crohn's disease. Figure 23-86 ▪ Radiation-induced proctitis in a patient treated for prostate adenocarcinoma. Capillary ectasia, fibrosis, and thrombosis are important histologic clues to radiation injury. Chronic radiation proctocolitis. The mucosal atrophy, erythema, and granularity can simulate ulcerative colitis. The fibrous stricture present in the descending colon can mimic Crohn's disease. Radiation-induced proctitis in a patient treated for prostate adenocarcinoma. Capillary ectasia, fibrosis, and thrombosis are important histologic clues to radiation injury. Sharply demarcated ulcers sometimes with secondary bacterial overgrowth can often be seen in the colon and rectum proximal to obstructing lesions such as invasive carcinoma, or they can be seen in patients with intractable constipation and fecal impaction. 544. , 595. , 596. , 597. The ulcer, bland in appearance, is thought to result from ischemia caused by a combination of pressure injury related to the hard fecal mass and the physiologic effects of bowel distention. 544. , 598. Many drugs or chemicals have been associated with ischemic-type changes in the colon, including hydrogen peroxide and glutaraldehyde (used to clean endoscopes), 349 NSAIDs, 350. , 586. , 599. cocaine, 350. , 600. , 601. oral contraceptives, and estrogen compounds. 348 Colitis can be caused by a host of bacteria including Campylobacter species, Shigella species, Salmonella species, Neisseria gonorrhoeae , Yersinia species, Mycobacterium species, and Aeromonas species. Although the histologic features of colonic mucosal biopsy specimens can vary greatly in these infections from essentially normal to lesions mimicking idiopathic IBD, large numbers of specimens show active colitis, as outlined earlier in the chapter, that when seen should suggest infectious-type colitis. 3. , 323. , 324. , 326. , 327. , 328. , 602. , 603. , 604. , 605. , 606. , 607. , 608. The histologic finding usually consists of the focal active colitis pattern of injury with relative preservation of mucosal architecture except for edema. The active inflammation is associated with little or no mucin depletion. Neutrophils can be present within the lamina propria and scattered cryptitis and crypt abscess formation, sometimes with luminal accentuation, can be seen. The definitive diagnosis of infectious colitis requires laboratory documentation by culture, PCR on the paraffin block, or serologic examination. Histologic evaluation, although helpful in suggesting infection, can only rarely point to a specific agent. True granulomas can be seen in tuberculosis, syphilis, Chlamydia species infection, and Yersinia pseudotuberculosis infection. Microgranulomas are described in infection with Salmonella species, Campylobacter species, and Yersinia enterocolitica . Isolated mucosal giant cells are nonspecific but have been described in Chlamydia trachomatis infection. 330. , 607. Some bacterial infections cause little inflammation but can be diagnosed by observation of adherent organisms such as with intestinal spirochetosis and adherent E. coli species. Although intestinal spirochetosis (infection with Brachyspira aalborgi or Brachyspira pilosicoli ) can be seen in patients with human immunodeficiency virus (HIV) infection or AIDS, 609. , 610. it is more frequently encountered in immunocompetent patients in whom its significance remains controversial. 609. , 611. , 612. , 613. , 614. The microscopic appearance is subtle, consisting of a thickening or accentuation of the colonic brush border that stains deeply with hematoxylin. This effect is caused by adherent spirochetes that align in parallel and embed themselves in the absorptive cells. Identification can be enhanced by use of a Warthin-Starry (or other silver) stain. The organism also cross-reacts with Treponema species immunostains. Adherent E. coli infections, described in HIV/AIDS under the term diarrheogenic bacterial enterocolitis, are discussed later. GI involvement with Mycobacterium avium-intracellulare complex (MAIC) is seen in HIV/AIDS usually as part of disseminated infection. The organism is easily cultured from stool and even blood. MAIC can affect any part of the GI tract, including the large bowel. 615. , 616. The characteristic histologic feature is infiltration of the lamina propria by foamy macrophages that can mimic muciphages. In addition, MAIC stains positive with PAS, a finding further adding to the possibility of misdiagnosis. MAIC is easily diagnosed with an acid-fast stain. Cryptosporidium parvum infection can occur in immunocompetent persons but is more often seen in HIV/AIDS 617. , 618. and occasionally can be seen in the colon ( Fig. 23-87 ). In biopsy specimens, cryptosporidial organisms are identified as basophilic dots measuring approximately 3 µm attached to the surface of the colonocyte. Immunocytochemical methods for identification have been described. 619 Figure 23-87 ▪ Active colitis associated with cryptosporidiosis. Note the numerous basophilic dots on the luminal surface of the colonocytes. Active colitis associated with cryptosporidiosis. Note the numerous basophilic dots on the luminal surface of the colonocytes. Amebiasis (infection with E. histolytica ) is quite common worldwide and is seen in HIV/AIDS. 620 Clinical disease varies widely from asymptomatic conditions to fulminant colitis. Early lesions consist of a slight mucosal depression and erosion with adherent exudate containing trophozoites of E. histolytica ( Fig. 23-88 ). Focal active colitis can also be seen. 608 More severe disease can cause ulcers that have been described as flask-shaped because they undermine the adjacent mucosa. E. histolytica is easily distinguished from the much larger Balantidium coli, which is only rarely seen in humans. 621 In addition, the trophozoite of B. coli is ciliated, the nucleus is much larger and kidney-shaped, and the cytoplasm contains vacuoles. Figure 23-88 ▪ Amebiasis. The adherent exudate contains trophozoites of Entamoeba histolytica . Amebiasis. The adherent exudate contains trophozoites of Entamoeba histolytica . Schistosoma species infestation is a major cause of colitis worldwide but is rarely seen in North America. The adult worms elicit no inflammatory response. The colitis and the symptoms are caused by the marked inflammatory response to the eggs that can lead to mucosal ulcers ( Fig. 23-89 ). Chronic colitis and inflammatory polyps can be seen in areas of endemic infection. 622 Figure 23-89 ▪ Schistosomiasis involving the colon demonstrating a fibrous and chronic inflammatory response to calcified eggs. Schistosomiasis involving the colon demonstrating a fibrous and chronic inflammatory response to calcified eggs. Strongyloidiasis is usually a self-limiting infection with adult worms residing in the proximal small bowel; the eggs develop into rhabdoid larvae in the lumen that pass in the stool. In immunocompromised patients, the rhabdoid larvae may develop into the infective filiform larvae. These infective larvae may invade intact colonic mucosa or perianal skin and set up a cycle of infection referred to as autoinfection . Many such infections are severe and often fatal. In colorectal biopsy specimens the infective larvae can be seen usually associated with marked infiltration of mucosa with the eosinophils ( Fig. 23-90 ). 622 Sometimes an eosinophilic and granulomatous reaction can be seen in biopsy and resection specimens. 623 Figure 23-90 ▪ Infective filiform larva of Strongyloides autoinfection within the colonic lamina propria. Infective filiform larva of Strongyloides autoinfection within the colonic lamina propria. Occasionally intraluminal worms are encountered in the colonic lumen and are removed at colonoscopy. These parasites are usually identified as Trichuris (whipworm) ( Fig. 23-91 ) or Enterobius (pinworm) by examination of the worm and egg morphology. 622 Figure 23-91 ▪ Trichuriasis diagnosed by removal of the adult female worm at endoscopy. Sections show a gravid uterus containing the typical egg morphology of Trichuris species (bipolar plugs). Trichuriasis diagnosed by removal of the adult female worm at endoscopy. Sections show a gravid uterus containing the typical egg morphology of Trichuris species (bipolar plugs). Common viral pathogens include adenovirus, rotavirus, coronavirus, echovirus, enterovirus, astrovirus, and Norwalk virus. Colorectal biopsy is rarely performed in the setting of viral gastroenteritis; therefore, histologic changes are not well documented. Norwalk virus and rotavirus are not known to cause morphologic changes in the colon. Adenovirus can cause diarrhea in HIV/AIDS. 608 Histologic changes affecting epithelial cells include cellular disorder with loss of orientation and degeneration. Eosinophilic viral intranuclear inclusions can be seen in surface goblet cells but are quite subtle. Immunohistochemical analysis can be performed as an aid to diagnosis. CMV infection is extraordinarily common in patients with HIV/AIDS and in other immunosuppressed patients such as those receiving transplants. The characteristic inclusions are seen in endothelial cells, fibroblasts, and smooth muscle cells and are only rarely encountered in epithelial cells. 624 Severe infection can lead to vascular thrombosis and ischemic-type damage with ulcers ( Figure 23-92 ▪ , Figure 23-93 ▪ ). Figure 23-92 ▪ Endoscopic view of cytomegalovirus-associated colitis with “punched-out” ulcers. Figure 23-93 ▪ Numerous intranuclear and cytoplasmic inclusion bodies of cytomegalovirus within the lamina propria. Endoscopic view of cytomegalovirus-associated colitis with “punched-out” ulcers. Numerous intranuclear and cytoplasmic inclusion bodies of cytomegalovirus within the lamina propria. Herpes simplex virus infection is associated with painful ulcers in the distal rectum and perianal skin. 625. , 626. The pathologic changes (ulcer, neutrophils in the lamina propria, cryptitis, and crypt abscess formation) may suggest infection; however, viral inclusions are not seen in the colon and rectum. Invasive candidiasis can be seen in severely debilitated patients and in patients with HIV/AIDS. This disorder is rarely encountered in colorectal biopsy specimens. Colorectal histoplasmosis can be seen in immunocompetent patients and in immunocompromised patients such as those with HIV/AIDS. 627. , 628. In disseminated forms one can see collections of foamy macrophages. Some patients demonstrate granulomatous inflammation, which is sometimes suppurative. Diagnosis can be made using Gomori methenamine silver or other fungal stains. Administration of any antibiotic that favors the growth of toxin-producing C. difficile can lead to pseudomembranous colitis. 629. , 630. Early studies linked clindamycin and lincomycin to pseudomembranous colitis, but in terms of absolute numbers, most cases are linked to ampicillin, penicillin, the cephalosporins, and the fluoroquinolones (especially the C-8-methoxyfluoroquinolones gatifloxacin, and moxifloxacin) because of their far more prevalent use. 630. , 631. Currently, the second- and third-generation cephalosporins and the fluoroquinolones are the leading instigators of C. difficile –associated colitis. 630. , 631. , 632. Pseudomembranous colitis has even been associated with antineoplastic chemotherapeutic agents that have antimicrobial activity. 633 In many cases, the source of Clostridium difficile infection is the patient's own gut flora. Alterations of the gut flora allow the patient's own C. difficile organisms to multiply. However, the spore-forming organism C. difficile is widely distributed in nature. Although cases may be acquired by these routes, increasing evidence indicates that C. difficile is often acquired in hospitals. 630. , 632. , 634. Indeed, reports of a previously uncommon strain of C. difficile, the NAP1 strain, showed that it is responsible for severe hospital outbreaks and serious disease in otherwise healthy individuals. 630. , 635. , 636. , 637. , 638. These reports of close-contact transmission, high recurrence rate, young age, bloody diarrhea, and lack of antibiotic exposure suggest changing epidemiologic features. Advanced age is a risk factor; patients who are older than 65 years old have an approximately 20 times greater risk of developing C. difficile infection. 630 Statistically, C. difficile is associated with only a minority of cases of antibiotic-associated diarrhea. In GI diseases other than primary IBD, isolation rates are about the same as in healthy adults. C. difficile is more frequently identified in patients with IBD and may be linked to exacerbations of IBD and fulminant colitis. 639. , 640. Symptoms of pseudomembranous colitis usually develop during the administration of antibiotics but in up to one third of patients, the onset of symptoms can be delayed for up to 4 to 6 weeks; occasionally, no antibiotic exposure has occurred. 630. , 636. , 641. , 642. The characteristic endoscopic and histologic lesion is found early in the course of the disease and only in some individuals. The surface of the mucosa is covered by a plaquelike, cream-colored to yellow pseudomembrane ( Fig. 23-94 ). The intervening mucosa frequently appears normal but can be hyperemic or edematous. 345 With increasing severity, the membranes can become confluent and linear ulcers can develop. Usually the pseudomembranes are evenly distributed throughout the colon but in up to one third of patients, the pseudomembranes can be confined to the right colon. This finding emphasizes the need for total colonoscopy to make an endoscopic diagnosis. Figure 23-94 ▪ Endoscopic view of Clostridium difficile –associated pseudomembranous colitis. Plaquelike, cream-colored pseudomembranes overlie erythematous mucosa and have become confluent in the foreground. Endoscopic view of Clostridium difficile –associated pseudomembranous colitis. Plaquelike, cream-colored pseudomembranes overlie erythematous mucosa and have become confluent in the foreground. Histologically, patchy necrosis of the superficial colonic crypts is evident that is not unlike that seen in ischemia. The affected crypts become dilated near the surface and an inflammatory exudate erupts from the surface aspect of the degenerating crypts in an explosive or mushroom-like configuration. The pseudomembrane may cover adjacent virtually normal colonic mucosa ( Fig. 23-95 ). The karyorrhectic debris and neutrophils in the pseudomembranes tend to orient in a curious linear fashion within the fibrin and mucus. Early lesions of C. difficile and occasionally the mucosa between diagnostic pseudomembranes can show the focal active colitis pattern of injury frequently described in acute infectious-type colitis (acute self-limited colitis). 326. , 327. , 345. Left untreated, some cases of C. difficile –associated colitis progress and can become indistinguishable from ischemic bowel disease. Toxic megacolon and perforation can occur. Figure 23-95 ▪ Exploding crypt lesion of Clostridium difficile –associated pseudomembranous colitis. The affected crypt is dilated with epithelial necrosis. The fibrin, karyorrhectic debris, and neutrophils orient in a curious linear fashion within the inflammatory pseudomembrane. Exploding crypt lesion of Clostridium difficile –associated pseudomembranous colitis. The affected crypt is dilated with epithelial necrosis. The fibrin, karyorrhectic debris, and neutrophils orient in a curious linear fashion within the inflammatory pseudomembrane. Treatment falls into three major categories: (1) nonspecific therapy, (2) specific therapy, and (3) therapies aimed at altering the gut flora. Nonspecific treatments include discontinuance of the offending antibiotic, supportive measures, enteric precautions to retard the spread of C. difficile outbreaks, and surgery. Surgical excision may occasionally be indicated 327 for patients too sick to take oral antibiotics (the specific therapy), as well as for some patients with relapses and for nonresponders. Toxic megacolon and perforation also require surgical treatment. Specific therapies include the oral administration of antibiotics such as vancomycin, metronidazole, bacitracin, and the toxin binder cholestyramine. Vancomycin, the preferred treatment, is relatively expensive. 630 Bacitracin and metronidazole appear to be as effective as vancomycin and are less expensive. Theoretical disadvantages to metronidazole therapy include stool levels of the drug that appear far lower than those of vancomycin and the finding that metronidazole has occasionally been implicated as a cause of pseudomembranous colitis. Treatment or prevention of pseudomembranous colitis by altering the gut flora with the introduction of such agents as Lactobacillus and Saccharomyces boulardii 630. , 643. , 644. has been studied. Saccharomyces boulardii was shown to decrease the incidence of antibiotic-associated diarrhea but did not change the rate of C. difficile colonization. Another provocative approach to prevention is to restrict the use of newer antibiotics such as third-generation cephalosporins and fluoroquinolones in the hospital setting. 632. , 638. Patients with C. difficile –associated pseudomembranous colitis who are treated specifically show a 95% to 100% response rate usually with defervescence in 1 to 2 days and resolution of diarrhea in 5 days. However, 5% to 50% of patients have a relapse and relapse treatment can be challenging. Most investigators recommend a second course of the same antibiotic (metronidazole or vancomycin) for 14 days. 645 For a second recurrence, tapered-pulsed vancomycin is advised. 630 For a third or subsequent recurrence, a probiotic or toxin binder is added to tapered-pulsed vancomycin therapy. Newer treatments for recurrences include passive immunoglobulin therapy, toxin receptor decoys (e.g., tolevamer), and active immunization against toxin A. 645 Stool culture for C. difficile is usually not recommended but some investigators report a significantly higher yield of positive results based on fecal culture followed by toxin assay on positive colonies. 646 Cell culture assay for toxin B is not routinely performed. Results of latex agglutination tests have been disappointing. 647 Enzyme-linked immunoassays (EIAs) that detect toxin A (Meridian Diagnostic, Vitec, BD, and Cambridge) or toxin A and toxin B are widely used. 630 These assays have a 90% to 95% positive correlation with cell culture assay. Commercially available tests that detect toxin A and toxin B are preferred because 1% to 2% of C. difficile strains produce only toxin B. 629. , 630. An alternative and more sensitive but slower approach is to perform an EIA for the detection of common antigen (a highly sensitive marker for C. difficile ) followed by a cytotoxic assay if the results of the EIA are positive. 630 Various gene probes and PCR techniques that detect toxin at the DNA level are available for research purposes. 648 The clinical syndrome of hemorrhagic colitis is characterized by abdominal cramping, bloody diarrhea, and either no fever or low-grade fever. 346. , 649. Patients typically demonstrate right-sided colonic edema, erosion, and hemorrhage and the absence of conventional enteric pathogens. In 1983, investigation of hemorrhagic colitis outbreaks occurring in Oregon and Michigan implicated a then-rare serotype of E. coli , O157:H7, as the cause of the syndrome. 650 Subsequently, investigations of several additional outbreaks confirmed the association between hemorrhagic colitis and the verocytotoxin-producing E. coli , the most important of which is E. coli O157:H7. 651 Patients with hemorrhagic colitis typically present with the sudden onset of crampy abdominal pain occurring 3 to 4 days after ingestion of contaminated food, usually undercooked hamburger. Outbreaks have also been linked to other foods, drinking water, and swimming pools. 652 Watery diarrhea, nausea, and vomiting follow within hours. One to 2 days later, grossly bloody diarrhea replaces the watery diarrhea. In almost all patients, the disease resolves spontaneously, usually within 8 days. Investigation of the epidemic outbreaks of E. coli O157:H7 infection revealed that not all patients acquire the full syndrome of hemorrhagic colitis. Rather, a clinical spectrum exists ranging from asymptomatic carrier or self-limited nonbloody diarrhea to severe cases complicated by hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura. 651. , 653. , 654. E. coli O157:H7 produces several toxins active against vero cells (verocytotoxins) and HeLa cells that have been termed Shiga-like toxins because their mode of action is similar to that of the toxin produced by Shigella dysenteriae type I. The toxins interact with the membrane receptor globotriosyl ceramide, are apparently absorbed into epithelial and endothelial cells, and cause damage or cell death by interfering with protein synthesis. 651. , 655. Colonic histologic features in EHEC infection are the best documented of the diarrheogenic E. coli organisms because EHEC infection can lead to hospitalization and it clinically mimics ischemia and primary IBD, thus prompting colonoscopy with biopsy. 346. , 656. , 657. Colonoscopy typically demonstrates patchy erythema, edema, and surface ulceration of the colon ( Fig. 23-96 ). The cecum and right colon are usually described as markedly abnormal, whereas the descending colon typically has mild or no changes. Histologically, specimens usually show hemorrhage and edema within the lamina propria. Specimens most often show focal necrosis associated with hemorrhage and acute inflammation within the superficial mucosa with preservation of the deep colonic crypts, similar to the pattern of injury described in acute ischemic colitis. Specimens from many patients show neutrophils infiltrating the lamina propria and crypts resembling the focal active colitis pattern of injury seen in infectious colitis or acute self-limited colitis ( Fig. 23-97 ). Rarely patients also demonstrate inflammatory pseudomembranes. This combination of ischemic-like and infectious-like injury with capillary thrombi should at least suggest EHEC-associated colitis in biopsy specimens. Figure 23-96 ▪ Endoscopic view of a patient with culture-proven Escherichia coli O157:H7 infection. Patchy erythema and a linear ulcer are visible on the mucosal surface. Figure 23-97 ▪ Enterohemorrhagic Escherichia coli infection showing the infectious-type colitis pattern of injury with focal active colitis and neutrophils infiltrating the lamina propria. Endoscopic view of a patient with culture-proven Escherichia coli O157:H7 infection. Patchy erythema and a linear ulcer are visible on the mucosal surface. Enterohemorrhagic Escherichia coli infection showing the infectious-type colitis pattern of injury with focal active colitis and neutrophils infiltrating the lamina propria. Routine stool culture media do not enable one to distinguish E. coli O157:H7 from other strains of E. coli normally found in the stool. Physicians suspecting hemorrhagic colitis caused by E. coli O157:H7 should specifically request that stools be screened for this organism. Specimens may be examined using sorbitol fermentation as a strain marker; unlike most E. coli organisms, E. coli O157:H7 strains test negative for sorbitol or have delayed positive results. 658 Colonies that test negative for sorbitol at 24 hours can be screened with commercial O157 antisera. Additional biochemical tests and H-antigen determinations can be performed later. 346 DNA hybridization techniques, PCR, direct immunofluorescence, and latex agglutination techniques have also been described for identification. Procedures for detection of free fecal verocytotoxin and more sensitive methods for screening stool cultures for verotoxin-producing E. coli using polymyxin B on colony sweeps have been reported. 651. , 652. E. coli organisms are the predominant components of the gut microflora. Although most of these organisms are harmless or even beneficial, at least six categories of E. coli intestinal pathogens are recognized ( Table 23-9 ). 659. , 660. TABLE 23-9 Escherichia coli Intestinal Pathogens Category Virulence Mechanisms Clinical Features Enterotoxigenic (ETEC) Heat-labile or heat-stable toxins Watery diarrhea in travelers and children Adherence Enteroinvasive (EIEC) Adherence and invasion Dysentery Enterohemorrhagic (EHEC) Shiga-like toxins Bloody diarrhea Adherence HUS/TTP Enteropathogenic (EPEC) Attachment and effacement Watery diarrhea in children Enteroaggregative (EAEC) Adherence, ? cytotoxin Watery or persistent diarrhea Children/developing countries, traveler's diarrhea, diarrhea in HIV-infected patients Diffusely adherent (DAEC) Adherence Acute or persistent diarrhea Children/developing countries HIV, human immunodeficiency virus; HUS/TTP, hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura. Escherichia coli Intestinal Pathogens HIV, human immunodeficiency virus; HUS/TTP, hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura. Much is known about the microbiology, pathogenic mechanisms, virulence factors, molecular genetics, and epidemiology of intestinal E. coli infections. However, surprisingly little is known about the histopathologic features of the human gut infection. Information remains scant because most infectious diarrheas, being self-limited, do not require specific treatment even when an infectious organism is identified. Therefore, sophisticated diagnostic tests such as organism identification, virulence factor determination, and endoscopy with biopsy are reserved for outbreaks or for cases with unusual features (e.g., severe or protracted diarrhea, systemic symptoms, need for hospitalization, or a differential diagnosis including serious diseases such as primary IBD or ischemia). Analysis of the information available yields limited numbers of reaction patterns in E. coli –associated infection that have been described in the human gut or inferred from in vitro models or from human infection with other organisms having similar virulence factors. These include the following: no histologic change (enterotoxigenic E. coli [ETEC]); observation of surface adherent organisms (enteropathogenic E. coli [EPEC], enteroaggregative E. coli [EAEC], possibly diffusely adherent E. coli [DAEC]; Fig. 23-98 ); mild, nonspecific inflammation (possibly all subtypes); ischemic-like change (EHEC); and acute infectious (self-limited) colitis (EHEC, enteroinvasive E. coli [EIEC], possibly ETEC). Figure 23-98 ▪ Adherent rod-shaped bacteria presumed to be Escherichia coli from a patient with human immunodeficiency virus infection/acquired immunodeficiency syndrome and bacterial enterocolitis. Adherent rod-shaped bacteria presumed to be Escherichia coli from a patient with human immunodeficiency virus infection/acquired immunodeficiency syndrome and bacterial enterocolitis. ETEC organisms are thought to adhere to and colonize the surface of the small bowel where they elaborate their toxins. 659 It is possible that a serendipitously obtained small bowel biopsy specimen may contain adherent surface bacteria. Histologic appearances of the small bowel and colon are inferred from ETEC's close relationship with Vibrio cholerae, which does not cause histologically recognizable lesions in the small bowel or the colon. Therefore, normal colon would be expected in ETEC-associated diarrhea. It is possible that ETEC could cause some acute self-limited colitis. Recognizing the difficulty in identifying pathogenic E. coli in routine stool culture, it is possible that EIEC and EHEC could otherwise be responsible for some cases of acute self-limited colitis. As stated earlier, diffuse active colitis was also seen in some examples of documented cases of infectious colitis. These infectious colitis cases were associated with an epidemic outbreak of Shigella dysentery. Because the pathogenic features of Shigella species are virtually identical to those of EIEC, it is possible that EIEC may on rare occasions cause the diffuse active colitis pattern of injury. That said, EIEC infection with this pattern of injury may represent an infectious exacerbation of underlying primary IBD. The ability to adhere to and colonize host enterocytes or colonocytes is requisite for human infection for all six recognized categories of diarrheogenic E. coli . However, EPEC, EAEC, and DAEC, which are traditionally referred to as the enteroadherent E. coli, are best differentiated on the basis of their adherence patterns to HEp-2 cells in culture. These patterns include localized adherence (EPEC), aggregative adherence (EAEC), and diffuse adherence (DAEC). 659 The human gut histopathologic features in EPEC in vivo have been described 661. , 662. and are similar to those seen in experimental animal models. 663 Jejunal biopsy specimens have demonstrated variable villous abnormalities without acute inflammation. 661. , 662. Adherent bacteria could be identified on routine H&E-stained sections on the luminal surface. Adherent surface bacteria have also been seen in colorectal biopsy specimens. 661 The characteristic attaching and effacing lesion can be recognized only by the use of electron microscopy. 659. , 661. , 662. The bacteria intimately adhere to the host cell by an attachment pedestal and cause effacement of the adjacent microvilli. Human histopathologic features associated with EAEC and DAEC infection can be inferred only from animal models and in vitro studies. 659. , 664. , 665. , 666. Presumably, bacteria adhere to the surface epithelium of the small intestine and the colon. 667 EAEC and DAEC infection may be associated with variable villous abnormalities. Electron microscopic study has shown adherent bacteria in cell culture with a normal microvillous structure. In the colon, EAEC produces cytotoxic effects ultrastructurally (microvillous vesiculation, enlarged crypt openings, creation of intercrypt crevices, and mucosal epithelial cell extrusion). 667 The most detailed description of human ileal and colorectal infection with EPEC, EAEC, and possibly DAEC probably is found in a published review of patients with AIDS. 668 Unfortunately, the exquisite light and electron microscopic descriptions of these diarrheogenic bacterial enterocolitides were not complemented by microbiologic studies. Therefore, identification of these organisms as E. coli rests on the pathologic similarity to other reported cases and preliminary isolation studies that have shown that at least some of these cases were caused by EAEC and DAEC. 668 The colonic histologic pattern showed surface epithelial degeneration with adherent bacteria (some extremely subtle) without colonic architectural distortion or significant inflammation. Electron microscopic examination demonstrated three patterns: (1) typical adhering and effacing lesions (as with EPEC), (2) a loosely adherent pattern with effacement (as with EAEC), and (3) an intercalated pattern with effacement in which vertically oriented bacteria were seen burrowing between intact microvilli. The intercalated pattern could be DAEC in vivo because it is similar to the pictures and descriptions of DAEC in other in vitro and animal models. 666

Normal large bowel gross anatomy and microscopic anatomy 1. , 2. , 3. are outlined here. The large bowel extends from the ileocecal valve to the anus and measures 120 cm to 150 cm in adults. It can be clinically useful to divide the large bowel into regions. The cecum, the most proximal saccular part of the large bowel, lies inferior to a horizontal line defined by the ileocecal valve. The cecum is completely invested by peritoneum and contains the opening of the vermiform appendix. The right colon, 15 cm to 20 cm in length, extends to the hepatic flexure. The right colon lacks mesentery and lies mostly in the retroperitoneum except for its anterior and right lateral serosa. The transverse colon averages 30 cm to 60 cm in length, runs from the hepatic flexure to the splenic flexure, and has a mesentery. The descending colon begins at the splenic flexure, becomes retroperitoneal, and extends for 20 cm to 25 cm. At the distal portion of the descending colon, the large bowel once again acquires a mesentery to become the sigmoid colon, which measures approximately 40 cm in length. The sigmoid colon arbitrarily becomes the rectum at approximately the level of the third sacral vertebra. The rectum, measuring 10 cm to 15 cm in length, ends at the anal canal. The upper one third of the rectum is covered by peritoneum; the lower two thirds lies in the retroperitoneum surrounded by the fatty mesorectum. Beneath the mesothelium-covered serosa lies a subserosal layer of fibroadipose tissue. The muscularis externa of the large bowel is composed of an inner circular layer and an outer longitudinally running layer of smooth muscle that condenses into three longitudinally running taeniae coli, the mesocolic taenia and two antimesenteric taeniae. The taeniae unite at the base of the vermiform appendix. They flare at the rectum and incorporate into its external muscular layer. The inner and outer layers of muscularis externa are separated by the myenteric plexus of Auerbach. Appendages of subserosal fat typically hang from the large bowel to form the epiploic appendices. Extending luminally from the muscularis externa lie the fibroadipose tissue, blood vessels, lymphatics, and nerves of the submucosa. The submucosa contains Meissner's plexus, which is usually found closely juxtaposed to the muscularis mucosae. The inner surface of the large bowel is characterized by horizontally oriented folds (plicae semilunares) and fine innominate grooves of the mucosa. The proximal colon to the splenic flexure derives its blood supply from the superior mesenteric artery through the ileocolic, right colic, and middle colic branches. The remainder of the colon is supplied by the left colic and sigmoid branches of the inferior mesenteric artery. The inferior mesenteric artery and iliac vessels provide blood to the rectum. Veins accompany the arteries and share their names. The large bowel venous drainage enters the portal circulation except for the distal rectum, which drains into the systemic circulation through the middle and inferior rectal veins. In portal hypertension, this area can serve as a portal-systemic shunt and can be a site of varices. The lymph node drainage is divided into those lymph nodes close to the bowel wall (e.g., pericolic, perirectal) and those that follow the blood vessels (e.g., mesenteric). The vagus nerves supply stimulatory nervous activity to the right colon and proximal transverse colon. The remainder of the large bowel is supplied by pelvic postganglionic parasympathetic nerves. The inhibitory nervous activity is derived from the superior and inferior mesenteric plexuses. The large bowel mucosa is composed of a single-cell layer of colorectal epithelium covering the lumen and lining the crypts, the supporting lamina propria and a small smooth muscle band referred to as the muscularis mucosae . The normal colorectal luminal surface of the mucosa is straight; the glands are made up of tubules (crypts) that are tightly packed, parallel, nonbranching, and closely approximating the muscularis mucosae ( Fig. 23-1 ). The appearance of the colonic tubules is similar to rows of test tubes placed in a rack. Goblet cells interspersed between colorectal absorptive cells line the colonic tubules. Scattered neuroendocrine cells can be observed usually near the base of the crypt and contain basally oriented eosinophilic cytoplasmic granules. The lamina propria contains a modest amount of mixed inflammatory cells including plasma cells, lymphocytes, eosinophils, mast cells, and macrophages. Intraepithelial lymphocytes are present normally but usually are fewer than 6 per 100 colorectal epithelial cells. The muscularis mucosae is arranged into two layers (an inner circular and outer longitudinally running layer) and is usually thin and regular. The submucosa is typically devoid of inflammatory cells. Scattered mucosal and submucosal lymphoid follicles are normally encountered, especially in younger individuals. In areas of mucosal lymphoid follicles, the mucosal architecture may be distorted and the muscularis mucosae can be incomplete. Flattened epithelial cells known as M cells overlie the mucosal lymphoid aggregates. The epithelium of the M-cell zone typically contains numerous intraepithelial lymphocytes. 1. , 2. , 3. Paneth cells with their basal nuclei and luminal cytoplasmic refractile red granules are seen in the base of colonic crypts but are considered normal only in the cecum and proximal right colon. 2. , 3. Figure 23-1 ▪ Normal colonic mucosa. The luminal surface is straight, and the colonic tubules are tightly packed, parallel, nonbranching, and closely approximating the muscularis mucosae. Normal colonic mucosa. The luminal surface is straight, and the colonic tubules are tightly packed, parallel, nonbranching, and closely approximating the muscularis mucosae. Mucosal biopsy interpretation can be hampered by changes associated with bowel preparation and with the trauma of the biopsy procedure itself. Changes ascribed to bowel preparation include decreased intraepithelial mucin, increased numbers of mitotic figures, surface apoptosis with karyorrhectic debris in the superficial lamina propria, and small numbers of neutrophils and eosinophils in surface or crypt epithelium. 2. , 3. , 4. , 5. , 6. , 7. Edema and recent hemorrhage into tissues not associated with other degenerative or inflammatory changes most likely represent biopsy-related trauma. Muciphages (foamy macrophages containing faintly periodic acid–Schiff [PAS]-positive material) are often present in the lamina propria of the large bowel, especially the rectum, where they most likely represent a nonspecific response to mucosal injury (i.e., trauma). 8. , 9. Muciphages should be distinguished from xanthelasma/xanthomatous polyp, which can also occur in the large intestine ( Fig. 23-2 ). Figure 23-2 ▪ A, Large bowel xanthelasma/xanthomatous polyp with foamy macrophages infiltrating the superficial lamina propria and submucosa. B, Large bowel xanthoma/xanthomatous polyp. The histiocytes are highlighted with a CD68 immunostain. A, Large bowel xanthelasma/xanthomatous polyp with foamy macrophages infiltrating the superficial lamina propria and submucosa. B, Large bowel xanthoma/xanthomatous polyp. The histiocytes are highlighted with a CD68 immunostain.

The term intestinal pseudo-obstruction describes a disorder in which patients present with signs and symptoms of intestinal obstruction and in whom no mechanical obstructive lesion can be demonstrated. 669 Intestinal pseudo-obstruction can be associated with a heterogeneous group of conditions some of which can affect the colon. 669. , 670. , 671. Systemic lupus erythematosus, dermatomyositis, and scleroderma can cause fibrosis of the muscularis externa. 669. , 671. Amyloid deposits can also affect colonic motility. 672 Visceral myopathies can occasionally be identified in the colon. Recognized variants of familial visceral myopathy demonstrate differences in the mode of inheritance (autosomal dominant versus recessive), site of gut involvement, clinical symptoms, and extraintestinal manifestations. Visceral myopathies also occur in sporadic form. 673 The intestinal pathologic changes of many familial and sporadic visceral myopathies are identical and consist of muscle cell degeneration, muscle cell loss, and fibrosis of the muscularis externa. The degenerative fibers appear swollen and rarified. Collagen may encircle the residual muscle fibers in areas of muscle fiber dropout and impart a vacuolated appearance. 671. , 673. , 674. These changes are often limited to, or are more severe in, the external layer of the muscularis externa. The differential diagnosis of these forms of visceral myopathy includes other entities that cause fibrosis of the muscularis externa and encompasses ischemia, tuberculosis, and scleroderma. Ischemia usually is associated with a fibrous stricture and hemosiderin deposits. Tuberculosis typically causes strictures and granulomas, often with central necrosis. Progressive systemic sclerosis is associated with more patchy bowel involvement than are the visceral myopathies. The fibrosis is often denser and replaces all the muscle layers of the muscularis externa or is accentuated in the inner layer ( Fig. 23-99 ). Vacuolar change is usually not seen with progressive systemic sclerosis. 671 Figure 23-99 ▪ Progressive systemic sclerosis showing atrophy and fibrosis of the inner circular layer of the muscularis externa (trichrome stain). Progressive systemic sclerosis showing atrophy and fibrosis of the inner circular layer of the muscularis externa (trichrome stain). The visceral neuropathies 675. , 676. , 677. , 678. , 679. , 680. , 681. form a complex group of unusual entities that vary in their pattern of inheritance, the extent of intestinal and extraintestinal involvement, and the nature of the histologic changes in the neural plexuses of the gut. Many of the neuronal and axonal changes are subtle; with the exception of inflammatory neuropathies 675 and some neuropathies associated with intranuclear or intracytoplasmic inclusions (e.g., red cytoplasmic inclusions in ganglion cells of mitochondrial neurogastrointestinal encephalomyopathy), 677 they cannot be recognized in routine H&E-stained sections. Difficult and unusual cases should probably be referred for consultation to pathology departments with particular expertise in the evaluation of visceral neuropathies. That said, referral is rarely indicated clinically. Some sporadic cases demonstrate mononuclear inflammation in the myenteric plexuses, and these cases can be identified by routine light microscopy. 678. , 679. Some of these cases are manifestations of paraneoplastic syndromes often linked to small cell carcinoma of the lung. 680 Others are postinfectious. 675 The inflammatory neuropathies can sometimes cause acquired aganglionosis and can be associated with circulating antibodies, such as anti-Hu, (ANNA-1, antineuronal nuclear antibody-1), anti-Ri, and anti-Yo (Purkinje cell cytoplasmic autoantibody). 680. , 681. An acquired form of hypoganglionosis associated with buserelin-induced formation of anti-GnRH (anti–gonadotropin-releasing hormone) antibodies has been reported. 682 Investigators now recognize the role interstitial cells of Cajal (ICCs) play as gut pacemakers and as mediators of neurotransmission. 683. , 684. ICCs stain specifically with the tyrosine kinase receptor c- kit . 685 Immunohistochemical analysis for c- kit (CD117) and for CD34 (which reacts with many c- kit receptors) represents a relatively easy way to study severe constipation and intestinal pseudo-obstruction. Streutker and colleagues 685 described completely absent or markedly reduced numbers of ICCs in some cases of intestinal pseudo-obstruction. Reduced volumes of ICCs have also been described in some patients with slow-transit constipation. 685. , 686. , 687. , 688. , 689. Although the observations could be an epiphenomenon, they could form the basis of an alternate classification system for these cases. Severe intestinal malabsorption for whatever reason (e.g., celiac sprue, cystic fibrosis) can be associated with dark brown or orange-brown discoloration of the bowel wall, 690. , 691. owing to deposits of a granular material that has the characteristics of lipofuscin in the smooth muscle of the muscularis externa and to a lesser degree the muscularis mucosae ( Fig. 23-100 ). This excessive accumulation of lipofuscin is termed ceroidosis or the brown bowel syndrome . Whether this pigment deposition adversely affects muscle function is debated; however, damage to smooth muscle mitochondria has been described, and several reports have linked ceroidosis to intestinal pseudo-obstruction. 692 Because of the name brown bowel syndrome , ceroidosis may be confused with melanosis coli (discussed in the next section). Figure 23-100 ▪ Ceroidosis. Note the deposits of brown-staining lipofuscin-like granules in the smooth muscle of the muscularis externa. Ceroidosis. Note the deposits of brown-staining lipofuscin-like granules in the smooth muscle of the muscularis externa. Melanosis coli is a condition in which macrophages filled with lipofuscin-like pigment are found within the lamina propria or deeper in the wall of the colon ( Fig. 23-101 ). 693. , 694. These macrophages may be of such numbers as to impart a brown or black color to the colonic mucosa ( Fig. 23-102 ). Melanosis coli has been associated with increased apoptosis, which is often linked to ingestion of purgatives of the anthracene group ( Cascara sagrada, aloe, rhubarb, senna, frangula). 695. , 696. , 697. Figure 23-101 ▪ Melanosis coli. Macrophages laden with lipofuscin-like pigment are present within the lamina propria. Figure 23-102 ▪ Specimen of resection performed for constipation shows severe melanosis coli imparting a black color to the mucosa. Melanosis coli. Macrophages laden with lipofuscin-like pigment are present within the lamina propria. Specimen of resection performed for constipation shows severe melanosis coli imparting a black color to the mucosa. One group of patients has severe and persistent constipation with no apparent cause (idiopathic constipation or morbid obstipation). These patients, usually women, can have as little as one bowel movement every 1 to 4 weeks, 673 and many of these patients are so uncomfortable that they require colectomy for relief. 698. , 699. , 700. , 701. Because these patients almost invariably take laxatives, melanosis coli is usually found. What is so frustrating to the pathologist is that by H&E staining, the neuronal plexus and smooth muscle in these patients appear normal. Distinctive abnormalities of the myenteric plexuses (e.g., loss of “argyrophilic” neurons) have been reported using special silver staining techniques. 673. , 693. , 701. , 702. These tests are best performed by pathology departments with expertise in this area. Reduced volumes of ICCs have been described in some patients with severe constipation. 685. , 689. Cathartic colon is the name given to end-stage idiopathic constipation in which the bowel can no longer contract effectively. The mucosa has the gross appearance of snakeskin and histologically shows melanosis coli. The muscularis propria is thin and atrophic, and neurons are decreased in Auerbach's plexus. Hirschsprung's disease (aganglionic megacolon) has a predilection for boys and men. Approximately 90% of patients present in infancy with constipation, abdominal distention, vomiting, and delay of meconium stool; diarrhea may occur 703 and some patients may even be affected by life-threatening enterocolitis. Reports suggest that many cases of Hirschsprung's disease have a genetic basis. Both Hirschsprung's disease and MEN2 are associated with mutations of the RET proto-oncogene. 704. , 705. , 706. In cases of MEN2, the mutations are activating and enhance the function of the coded protein, whereas in Hirschsprung's disease the mutations are inactivating. Several cases of familial Hirschsprung's disease have been linked to mutations of the endothelin receptor-B (ENDRB) gene. 707 At least nine additional genes have been implicated in the pathogenesis of Hirschsprung's disease: NTN (seen only with RET mutations), GDNF, EDN3, ECE-1, SOX10, PHOX2B, ZFHX1B, L1CAM, and 7DHCR . 706 Despite this progress, mutations of one or more of the known genes are detected in only half the patients with Hirschsprung's disease. In the typical clinical picture of Hirschsprung's disease, the anus is normal. The anal canal and rectum are usually small and devoid of stool. In classic cases, these physical findings are confirmed by barium enema study. The contrast material flows into an unexpanded distal segment, then passes through a cone-shaped area, and finally passes into the dilated proximal bowel ( Fig. 23-103 ). Figure 23-103 ▪ Hirschsprung's disease, resection specimen. The unexpanded aganglionic segment (left) merges with the cone-shaped hypoganglionated region that extends into the dilated ganglionated zone (right) . Hirschsprung's disease, resection specimen. The unexpanded aganglionic segment (left) merges with the cone-shaped hypoganglionated region that extends into the dilated ganglionated zone (right) . The pathologic change is aganglionosis. The narrowed distal segment shows loss of ganglion cells in both the submucosa and myenteric plexuses, usually accompanied by hypertrophy of the muscularis mucosae and muscularis externa and increased numbers of nerve fibers in the submucosa and between the muscle layers of the muscularis externa. 708 Hypertrophied nerve fibers (>40 µm) derived from the extrinsic and sensory fibers are observed in many but not all cases of Hirschsprung's disease. In the tapered or cone-shaped region, the number of ganglion cells may be decreased (hypoganglionosis). Historically, histologic diagnosis was based on full-thickness rectal biopsy specimens. However, this procedure requires general anesthesia and risks the development of stricture and perforation. Because the submucosal and myenteric plexuses stop at about the same level in Hirschsprung's disease, 708. , 709. suction biopsy that samples the mucosa and submucosa is now considered the method of choice for the diagnosis. All rectal biopsy specimens for suspected Hirschsprung's disease should be serially sectioned throughout the block and each section examined. 708. , 710. If no ganglion cells are found, then some comment should be made concerning the adequacy of the specimen. Biopsy specimens devoid of ganglion cells, but in which the amount of submucosa is less than the thickness of the mucosa, should be considered insufficient to diagnose Hirschsprung's disease. 708 If the biopsy specimen contains epithelium of the anal canal, this specimen should also be considered inadequate, because the anal canal and distal 2 cm of rectum are normally hypoganglionated or aganglionated. Many pathologists prefer to examine frozen section slides stained for acetylcholinesterase in addition to standard H&E-stained sections. In Hirschsprung's disease, examination using the acetylcholinesterase stain demonstrates increased acetylcholinesterase-positive nerve fibers in the lamina propria and muscularis mucosae. The utility of this technique as an adjunct to diagnosis is debated. False-positive and false-negative reactions have been reported, and the use of this method is a matter of personal preference. 711. , 712. , 713. Occasionally, ganglion cells may be difficult to identify using light microscopy alone, especially in the neonate. 708 In such cases, a positive immunohistochemical reaction for neuron-specific enolase can be valuable in documenting ganglion cells. 714 We have been successful in performing immunohistochemical analysis for neuron-specific enolase on sections after they have been stained with H&E and examined. Other immunostains such as cathepsin D, PGP 9.5 (protein gene product 9.5), RET, BMPR1A (bone morphogenetic protein receptor type 1A), and bcl-2 decorate ganglion cells. 710. , 715. Frozen section is often used as an adjunct to visual inspection to select the site for colostomy. However, use of the frozen section to establish a primary diagnosis of Hirschsprung's disease is best avoided because of the high rate of incorrect interpretations. 716 In 90% of patients with Hirschsprung's disease, the aganglionic segment of colon is less than 40 cm in length. The remaining patients have longer aganglionic segments that may extend even into the small intestine. 673 Microscopically, the hypertrophied nerve trunks of short-segment Hirschsprung's disease are absent, but increased numbers of acetylcholinesterase-positive mucosal nerve fibers are usually but not always seen. 717 Ultrashort-segment Hirschsprung's disease (segments <2 cm) reportedly exists but is impossible for a pathologist to document by routine H&E stains of the rectal mucosa and submucosa alone because this segment of the colon is relatively hypoganglionated or aganglionated even in physiologically normal individuals. Rectal manometry may be used in the diagnosis of this lesion. Recognition of acetylcholinesterase nerve abnormalities similar to those seen in Hirschsprung's disease may complement that study. Some patients may have internal sphincter achalasia with abnormalities of nitric oxide–induced sphincter relaxation. Regardless of pathogenesis, some patients benefit from sphincterotomy. Hypoganglionosis is regularly observed in the cone-shaped transition zone between normal and aganglionic bowel in Hirschsprung's disease. 673 Some authors believe that diffuse hypoganglionosis of the colon may give rise to megacolon similar to that observed in Hirschsprung's disease. 708. , 718. No accepted definition of hypoganglionosis exists; however, guidelines were offered by Meier-Ruge. 717 This study suggested that a decrease by a factor of 10 in the number of ganglion cells per centimeter of bowel as compared with normal (40 to 80 myenteric plexus neurons/cm bowel) is diagnostic of hypoganglionosis. 717 Other investigators have accepted much higher numbers of ganglion cells as evidence of hypoganglionosis. 719 In general, the condition has not been well characterized and many reports lack quantitation. 673 Diverse abnormalities have been described by special silver staining in cases that would have been called hypoganglionosis by H&E staining results, 720 and some cases of “hypoganglionosis” may be similar to those cases reported as severe idiopathic constipation or cathartic colon. Intestinal neuronal dysplasia is characterized by hyperplasia of the myenteric plexuses, increased acetylcholinesterase activity in nerves of the lamina propria and submucosa, and increased numbers of ganglion cells with the formation of giant ganglia. 719. , 721. , 722. , 723. These giant ganglia, typically containing more than 7 to 10 neurons (normal ganglia contain 3 to 5), make up only 3% to 5% of all ganglia seen in a given case and are usually not seen in the distal 7 cm of the rectum. 724 Occasionally, ganglion cells may be found within the lamina propria but this feature should not be considered diagnostic for intestinal neuronal dysplasia because it can be seen in physiologically normal individuals. 725. , 726. The condition may give rise to signs and symptoms similar to those seen in Hirschsprung's disease. Intestinal neuronal dysplasia may occur in a localized or disseminated form. Similar lesions sometimes referred to as ganglioneuromatosis can be observed in patients with von Recklinghausen's disease or MEN2B. 673. , 722. , 723. Although some clinicians diagnose intestinal neuronal dysplasia based on abnormal acetylcholinesterase staining in specimens containing ganglion cells, others believe that one cannot rely on acetylcholinesterase staining alone for the diagnosis. 727 Diagnostic criteria for intestinal neuronal dysplasia and even its very existence are challenged 727. , 728. because 95% of infants so diagnosed experience normalization of gut motility within 1 year. Therefore, many of the observed “abnormalities” could be within normal range and in general the diagnosis should be reserved for florid pathologic cases. 729 In zonal aganglionosis or skip-segment Hirschsprung's disease, ganglion cells are found distal to one or more aganglionic segments. 729. , 730. , 731. Evidence suggests that zonal aganglionosis is rare and is likely to be acquired by ischemia (e.g., necrotizing enterocolitis), viral infection, or some other (e.g., immunologic) injury. The problem is that a rectal biopsy specimen may yield ganglion cells in spite of an authentic Hirschsprung's disease–like aganglionic lesion. Immaturity of ganglion cells 673. , 717. and hypogenesis of myenteric plexuses 717. , 718. have been reported to cause signs and symptoms similar to those seen in Hirschsprung's disease. Immunostains for bcl-2 may be helpful in detecting immature ganglion cells. 719

The GI tract is a common site for amyloid deposits; such deposition has been documented in 70% of primary amyloidosis cases and in half of secondary cases. 672. , 732. , 733. Occasionally the deposition is symptomatic and causes ischemic manifestations such as bleeding diarrhea or infarct, sometimes referred to as amyloid colitis . On rare occasions, the deposits can be localized and form a tumor. 734 The AA (secondary) type of amyloid primarily deposits in the lamina propria and walls of blood vessels; the AL (primary or myeloma-associated) type tends to accumulate preferentially in blood vessel walls and in the muscularis externa. 672. , 735. Amyloid can be subtyped using immunohistochemical analysis. 736 Although subcutaneous biopsy or aspiration is an easy way to obtain tissue for diagnosis, rectal biopsy is still widely used to diagnose amyloidosis. 735. , 737. The term pneumatosis cystoides intestinalis (PCI) describes the occurrence of gas-filled cysts within the bowel wall. The large intestine is a common site of involvement; benign and fulminant forms have been described. 738. , 739. The fulminant form of PCI is most often seen in infants as a complication of ischemia. PCI in this setting is caused by mural invasion by gas-forming bacteria and subsequent formation of cysts (see Fig. 23-84 ). The fulminant form can be seen in adults sometimes in association with drugs such as antineoplastic chemotherapeutic agents or in pseudomembranous colitis. 739 Histologically, one sees ischemic change, bacterial overgrowth, and gas cysts predominantly within the submucosa. It is easy to dismiss the gas cysts as cutting artifact because an endothelial or histiocytic lining is rarely seen in this form of PCI. The benign form of PCI is most often seen in adults and is usually asymptomatic, 738 although diarrhea, constipation, and rectal bleeding have been documented. 738. , 740. Benign PCI is often seen with comorbid conditions that either increase intraluminal pressure or provide a breach in mucosal integrity by which the gas can enter the bowel wall. These conditions include chronic obstructive pulmonary disease, emphysema, diverticular disease, appendicitis, cholelithiasis, peptic ulcer disease, abdominal trauma, Crohn's disease, and GI tract surgery. 738. , 739. At endoscopy, mucosal broad-based elevations that are sometimes semitranslucent have been described. Resection specimens often show crepitance. Microscopic analysis demonstrates occasional tears in the submucosal connective tissues, but more often one sees dilated spaces lined totally or partially by endothelium, inflammatory cells, histiocytes, and marked foreign body giant cell reaction ( Fig. 23-104 ). 741 Figure 23-104 ▪ The benign form of pneumatosis cystoides intestinalis showing a submucosal dilated space lined by histiocytes and a foreign body giant cell reaction. The benign form of pneumatosis cystoides intestinalis showing a submucosal dilated space lined by histiocytes and a foreign body giant cell reaction. The principal differential diagnostic consideration is the entity referred to as pseudolipomatosis . 742. , 743. Pseudolipomatosis resembles fatty infiltration of the lamina propria but ultrastructural study convincingly demonstrates that the spaces are, in fact, gas cysts ( Fig. 23-105 ). Pseudolipomatosis has been associated with air inflation used to distend the bowel during colonoscopy. Some investigators have implicated cleaning agents used to disinfect colonoscopes. Figure 23-105 ▪ Pseudolipomatosis. The lamina propria contains small gas cysts that resemble adipose tissue. Pseudolipomatosis. The lamina propria contains small gas cysts that resemble adipose tissue. The term fibrosing colopathy has been applied to colonic strictures seen in some patients with cystic fibrosis. 744. , 745. The pathologic change is submucosal fibrosis, which can sometimes extend into the muscularis externa. Fibrosing colopathy has been linked to administration of high-dose pancreatic replacement therapy. Large bowel agenesis and atresia are extremely rare. 746. , 747. Congenital atresia and stenosis are associated with failure to pass meconium, abdominal distention, and vomiting. These conditions are often seen on a background of other congenital anomalies. Pathologically, one can see an imperforate septum, a portion of the colon replaced by fibrous cord, or the absence of a segment of colon and associated mesentery. Colonic malrotation occurs with malrotation of the small bowel and is associated with abnormal anatomic relationships and fibrous bands; it may predispose patients to volvulus. 747. , 748. Mispositioning of the cecum and appendix may lead to delayed diagnosis of acute appendicitis. Congenital duplications and diverticula are located within the mesentery and often occur in combination with other congenital malformations. 749. , 750. Sometimes, the duplications are tubular, represent doubling of the bowel, and run parallel to the colon and rectum. Other duplications can become cystic and are often referred to as enterogenous cysts . Patients may have associated spine abnormalities. We classify tubular duplications that communicate with the lumen at one end as congenital diverticula . Small duplications and diverticula are usually asymptomatic. Larger ones may cause mass lesions, abdominal pain, constipation, or bleeding. Hindgut duplications may be associated with complex genital and urinary tract abnormalities. Duplications and congenital diverticula usually have organized layers of smooth muscle sometimes with a nerve plexus within their walls. Mucosal linings if present resemble colon, respiratory epithelium, or gastric mucosa. As lesions enlarge to become cystic, the lining and the wall can become atrophic. 751 The retrorectal space is a relatively common location for developmental cysts that can become symptomatic in adults. 752. , 753. , 754. Epidermoid or dermoid cysts are unilocular, are lined by squamous epithelium, and may contain adnexal structures (dermoid cyst) and lack smooth muscle in the wall. Rectal duplications can become cystic. Rectal duplications are also unilocular, are lined by colonic, gastric, or respiratory epithelium, and have an organized muscular wall that recapitulates the muscularis externa. The retrorectal cystic hamartoma is often referred to as a tailgut cyst . This lesion manifests as a multilocular cystic and solid tumor ( Fig. 23-106 ). The variably sized cysts can be lined by squamous, transitional, or glandular epithelium. Disorganized bundles of smooth muscle are found within the wall. Inflammatory changes such as a foreign body giant cell reaction are quite common. Developmental cysts in the retrorectal space are susceptible to infection and fistula, and associated malignancy has been reported. 754 Therefore, total excision is recommended. Figure 23-106 ▪ Tailgut cyst. These retrorectal cystic lesions are typically multilocular. The cysts can be lined by squamous, transitional, or glandular epithelium. Tailgut cyst. These retrorectal cystic lesions are typically multilocular. The cysts can be lined by squamous, transitional, or glandular epithelium. The histologic changes associated with acute chemotherapy- or radiation-induced colitis are similar. Necrosis, ulcer, and inflammation occur usually within 2 weeks of the cessation of therapy. 593. , 755. , 756. Epithelium lining the colonic tubules often shows marked enlargement with large atypical nuclei and loss of intracellular mucin ( Fig. 23-107 ). Apoptotic bodies similar to those seen with grade 1 GVHD may be prominent. 757 Typically, the acute changes subside in 1 to 2 months. 755. , 758. Figure 23-107 ▪ Acute irradiation change. Sections show marked epithelial atypia. Features that favor radiation effect include the bizarre atypia, the maintenance of tubular structures, the relatively low nuclear-to-cytoplasmic size ratio despite the cellular gigantism, and the paucity of mitotic figures. Acute irradiation change. Sections show marked epithelial atypia. Features that favor radiation effect include the bizarre atypia, the maintenance of tubular structures, the relatively low nuclear-to-cytoplasmic size ratio despite the cellular gigantism, and the paucity of mitotic figures. The epithelial atypia seen as a result of acute irradiation and chemotherapy can be alarming and may mimic the appearance of glandular dysplasia and carcinoma. Features favoring chemotherapy or radiation effect over dysplasia or carcinoma include (1) overall preservation of mucosal architecture, (2) bizarre atypia, (3) maintenance of a relatively low nuclear-to-cytoplasmic size ratio despite cellular enlargement and nuclear atypia, (4) a paucity of mitotic figures, (5) recognition of similar atypia in nearby fibroblast and endothelial cells, and (6) lack of an infiltration pattern in tumor desmoplasia. 759 The taxanes can cause epithelial changes that can mimic high-grade glandular dysplasia 760 similar to the changes seen with colchicine toxicity. 761 The histologic changes include increased apoptosis, increased mitotic figures, and “ringed” mitotic figures that correlate with metaphase arrest ( Fig 23-108 ). The nuclear stratification and loss of polarity can mimic dysplasia. 760. , 761. Figure 23-108 ▪ Colchicine effect within a colonic hyperplastic polyp. Note the numerous apoptotic bodies and the “ringed” mitoses. The nuclear stratification can mimic dysplasia. Colchicine effect within a colonic hyperplastic polyp. Note the numerous apoptotic bodies and the “ringed” mitoses. The nuclear stratification can mimic dysplasia. Late complications of radiation-induced change are better documented than are antineoplastic chemotherapy effects and may occur weeks to years after therapy. 593 These late complications of radiation include chronic colitis, stricture, ulcers, and fistula. 594 The histologic pattern resembles that of ischemic damage with mucosal atrophy and architectural change. Mucosal and submucosal blood vessels can become ectatic. Fibrosis occurs and often resembles hyalin. Fibrosis can affect any bowel layer, including the muscularis externa. Atypical radiation-type fibroblasts can persist for years. Other vascular changes include intimal fibroplasia, accumulation of foamy macrophages in blood vessel walls, and luminal stenosis. Epiploic appendices are pedunculated, serosa-covered accumulations of adipose tissue seen on the lateral aspects of the colon. They can become very large in obese individuals. The pedicles of epiploic appendices are thin and prone to torsion, a feature that can cause infarct and even amputation. Infarcted epiploic appendices can appear as fine, gray-white nodules attached to the bowel or even can be found loose within the abdomen at surgery. These appearances can mimic metastatic carcinoma or foreign body. The subsequent biopsy specimen can be confusing to the pathologist who is asked to identify the frozen section. Microscopically, these lesions show a central zone of infarct with mummification of the adipose tissue surrounded by a variable amount of fat necrosis and calcification. The outermost portion usually shows fibrosis. 762 Pacinian corpuscles occur in many areas of the body. Although most are noted in the skin, they occur in the base of the mesentery. For unknown reasons, these intra-abdominal pacinian corpuscles can enlarge up to 1.0 cm or more and thus can mimic tumor implants or carcinomatosis. 763. , 764. They also may be a source of confusion to the surgical pathologist asked to identify them at frozen section and are often misinterpreted as nematodes. Histologically, this specialized end organ resembles its cutaneous counterpart. A central blood vessel and nerve are surrounded by tortuous, roughly concentric lamellae ( Fig. 23-109 ). Figure 23-109 ▪ Hyperplastic pacinian corpuscle. Microscopically, hyperplastic pacinian corpuscles can mimic a parasite. The histologic pattern, however, shows a central blood vessel surrounded by edematous concentric lamellae. Hyperplastic pacinian corpuscle. Microscopically, hyperplastic pacinian corpuscles can mimic a parasite. The histologic pattern, however, shows a central blood vessel surrounded by edematous concentric lamellae. Extravasation of barium sulfate used in radiologic examination outside the lumen of the colon and rectum may elicit an inflammatory response often referred to as a barium granuloma . These lesions are usually encountered coincidentally in resection specimens in biopsies performed for IBD. Rarely, this inflammatory reaction can produce a polypoid mass or ulcerated lesion that mimics neoplasm. 765 Microscopically, barium sulfate appears olive green and is refractile, especially with the microscopic condenser lowered ( Fig. 23-110 ). The small granular crystals do not bend polarized light and coalesce within connective tissue and macrophages. Water-soluble contrast media such as Gastrografin (sodium amidotrizoate and meglumine amidotrizoate) tend not to cause an exuberant inflammatory response. Gastrografin morphologically is composed of larger rectangular or rhomboidal light tan to pale yellow crystals. Figure 23-110 ▪ Barium granuloma. Macrophages are present that contain olive green refractile extravasated barium sulfate. Barium granuloma. Macrophages are present that contain olive green refractile extravasated barium sulfate.

We wish to acknowledge and thank Michele Dover for her tenacity and help in transcribing this manuscript. We also thank Drs. Jeff Kneile and Amber Petrolla for their contributions.

FAP is inherited as an autosomal dominant trait. Bussey recognized that 100 or more colorectal adenomas (recognized grossly) phenotypically identified patients with FAP and distinguished them from patients with multiple adenomas in whom inheritance was not seen. 243. , 244. In typical FAP, hundreds to thousands of adenomas develop within the colon ( Fig. 23-42 ). The adenomas begin to appear in the second or third decades of life and are surprisingly asymptomatic considering their usually large numbers. Symptomatic patients present with signs and symptoms of increased bowel motility and the passage of blood or mucus, or both, which often heralds the onset of carcinoma. The average age of patients with colon cancer and FAP is 39 years. 66 Two thirds of patients with these so-called propositus cases present with carcinoma and nearly one half of them have more than one carcinoma in the colon. This high risk of invasive cancer in symptomatic patients forms the basis for polyposis registries and the extensive screening of asymptomatic kindred at risk for FAP. Figure 23-42 ▪ Familial adenomatous polyposis syndrome in resection specimen. The mucosa is carpeted by thousands of adenomas. Familial adenomatous polyposis syndrome in resection specimen. The mucosa is carpeted by thousands of adenomas. Screening recommendations have evolved with increased genetic information. Genetic testing should be considered for FAP, attenuated FAP, and mutY homologue (MYH)–associated polyposis (MAP) when 10 or more colorectal adenomas are found in a patient during a single examination or over time. 66 Screening of first-degree relatives of affected individuals should begin at the age of 10 years. 63 In the absence of genetic testing, endoscopic screening is still useful to detect FAP. All affected patients have adenomas within the range of a flexible sigmoidoscope. It is therefore recommended that screening sigmoidoscopy begin at age 14 years with re-examination every 2 years. The diagnosis of FAP must be confirmed with biopsy because lymphoid polyposis and hyperplastic polyposis can mimic FAP grossly and endoscopically. Once a diagnosis of FAP has been established, prophylactic proctocolectomy is recommended. Most investigators recommend sigmoidoscopy for mutation-negative kindred at age 12 years just in case the genetic test is erroneous. Thyroid examination for associated thyroid lesions (usually papillary carcinoma with cribriform pattern 245 ) and determination of serum alpha fetoprotein (to screen for hepatoblastoma) are recommended. Regular upper endoscopy should also be performed. Gastric and duodenal polyps develop in 30% to 90% of patients with FAP. 246 The gastric lesions are usually fundic gland polyposis, whereas the duodenal polyps are usually adenomas. The fundic gland polyps can develop a peculiar surface epithelial atypia called foveolar dysplasia, 247 but progression to carcinoma is extremely rare. 229 The incidence of duodenal adenomas in FAP increases with increasing age. Duodenal adenomas have a propensity to develop in the periampullary region. Adenomas anywhere in the GI tract can proceed through the dysplasia-carcinoma sequence. The relative risk of duodenal or periampullary carcinoma in patients with FAP is approximately 125 to 350 times that seen in the general population, and duodenal or periampullary carcinoma has become the major cause of morbidity and mortality in patients with FAP in the post–prophylactic colectomy era. 248 The gene responsible for FAP ( APC gene) has been localized to the long arm of chromosome 5 (5q21-q22) and has been cloned. 249. , 250. , 251. , 252. , 253. Some APC gene mutation–negative cases may be caused by mutation of MYH (see later). 254 Mutation in most patients with FAP creates a stop codon resulting in a truncated protein product. The APC gene is a tumor suppressor gene and the APC protein is part of the Wnt-signaling pathway 66. , 255. involved in cell growth control. When the APC gene is mutated, beta-catenin accumulates, thus altering expression of certain genes affecting proliferation, differentiation, migration, and apoptosis. 256 Most patients are now diagnosed by DNA sequencing, which has largely replaced the assay to detect the truncated APC protein (PTT). 63. , 256. Monoallelic mutation analysis (MAMA) examines the two APC alleles independently and can detect more than 95% of patients with FAP. Another test, multiplex ligation-dependent probe amplification (MLPA), is useful in detecting large deletions. 256 More than 700 disease-causing APC gene mutations have been reported. 256 Localization of mutations within the APC gene locus correlates with phenotype. For example, germline mutations between codon 1250 and codon 1464 are associated with very large numbers of colonic adenomas, whereas mutations elsewhere, especially near the 5′ end or the 3′ end of the APC gene and an area of exon 9, yield lesser numbers of colonic adenomas (see the later discussion of attenuated FAP). 63. , 256. , 257. , 258. In Gardner's variant, in addition to colonic adenomas and upper GI polyps, patients can exhibit extraintestinal manifestations such as osteomas, epidermal inclusion cysts and other benign skin tumors, desmoid tumors of the abdomen or abdominal wall, fibrosis of mesentery, dental abnormalities, carcinoma of the periampullary region or duodenum, and carcinoma of the thyroid. Patients with Gardner's syndrome have APC gene mutations; however, no particular APC mutation distinguishes FAP from Gardner's variant. Even within a “Gardner's family,” Gardner's stigmata can be variably expressed and can skip generations. 253 Therefore, some unknown disease-modifying factors are required for phenotypic expression of the extraintestinal manifestations. Turcot's syndrome has been the subject of some controversy. In many investigators’ zeal to publish, the phenotypic spectrum has been unduly broad with colonic manifestations ranging from a single adenoma to a virtual carpeting of the colonic mucosa with polyps. Furthermore, the brain tumors have comprised almost every histologic type. Molecular studies done on 14 families with Turcot's syndrome have clarified the situation. 259 Families with Turcot's syndrome and germline mutations of the APC gene have a typical FAP colonic phenotype and develop medulloblastomas. Other patients originally thought to have Turcot's syndrome have mutations in the DNA MMR genes that are characteristic of Lynch's syndrome. The brain tumors in this group have varied, with many reported as glioblastoma. Mutations of the APC gene near the 5′ end and 3′ end and in a particular region of exon 9 66 result in fewer adenomas (<100; average, 30), a tendency for the adenomas to be macroscopically flat, and a propensity for these adenomas to cluster in the right colon. Originally reported as hereditary flat adenoma syndrome, this form is now more accurately referred to as attenuated FAP (AFAP). 63. , 258. As in typical FAP, these patients can develop fundic gland polyposis, duodenal adenomas, and periampullary carcinoma. The risk of colorectal carcinoma is increased in these patients albeit to a lesser degree than in the other form of FAP and the cancers tend to occur later in life (average age, 49 years). Inherited variants of a base-excision repair gene MYH have been associated with colorectal polyposis with an autosomal recessive mode of inheritance. 254. , 260. , 261. Some cases phenotypically resemble FAP or attenuated FAP and are referred to as MYH polyposis or MAP. 254 Of those patients with a phenotype typical of FAP or suspected AFAP in whom an APC gene mutation is not found, 10% to 20% will have mutation of the MYH gene. 66 Approximately 80% of affected persons have one of two specific MYH mutations (Y165C or G382D). If one is found, then sequencing is done to find the mutation on the other allele because MAP is biallelic. 66 These patients should be treated and followed similarly to patients with FAP. Juvenile polyps can occur in a sporadic form or can be part of juvenile polyposis syndrome. In the sporadic form, juvenile polyps have their peak prevalence in children between 1 and 7 years of age. Some evidence indicates that juvenile polyps once formed can regress; they can certainly be seen in adults. Sporadic juvenile polyps typically occur singly but patients can have up to five, usually located in the rectum. Juvenile polyps typically range in size up to 2 cm and can be associated with overt prolapse ( Fig. 23-43 ). 262 Because these polyps are often attached by a small pedicle, they are prone to autoamputation. Histologically, typical juvenile polyps consist of a hamartomatous overgrowth of the lamina propria accompanied by elongation and cystic dilatation of colonic crypts lined by nondysplastic colonic epithelium ( Fig. 23-44 ). 66 Osseous and cartilaginous stromal metaplasia can occur ( Fig. 23-45 ). The inflammatory component of juvenile polyps can be quite prominent with neutrophils and lymphoid follicles within the lamina propria. Frequently, the distinction between juvenile polyps and inflammatory polyps of primary IBD cannot be made on histologic grounds alone and requires clinical correlation. Nonsyndromatic juvenile polyps appear to have no malignant potential. 263 Figure 23-43 ▪ Endoscopic photograph of a sporadic juvenile polyp. The polyp head is erythematous with scattered surface exudate and is attached to the bowel by an elongate pedicle. Figure 23-44 ▪ Sporadic juvenile polyp showing the edematous and inflammatory expansion of the lamina propria with glandular cyst formation. Figure 23-45 ▪ Area of stromal bone formation within the lamina propria of a juvenile polyp. Endoscopic photograph of a sporadic juvenile polyp. The polyp head is erythematous with scattered surface exudate and is attached to the bowel by an elongate pedicle. Sporadic juvenile polyp showing the edematous and inflammatory expansion of the lamina propria with glandular cyst formation. Area of stromal bone formation within the lamina propria of a juvenile polyp. Juvenile polyposis syndrome can be familial or nonfamilial and usually becomes clinically apparent within the first decade of life with painless rectal bleeding, prolapse, iron deficiency anemia, or passage of an autoamputated polyp. 244 Patients are considered to have juvenile polyposis syndrome if they have six or more juvenile polyps in the colon and rectum, have juvenile polyps throughout the GI tract, or have any number of juvenile polyps in association with a positive family history. 262. , 264. In the nonfamilial forms of juvenile polyposis syndrome (≈30% of the total), patients frequently have associated abnormalities, such as cardiac defects, hydrocephalus, gut malrotation, undescended testes, and skull abnormalities. 244 Patients with the familial forms usually lack these extraintestinal manifestations. Inheritance has varied although almost all are considered autosomal dominant with variable penetrance. 244 Familial forms of juvenile polyposis syndrome appear to be associated with an increased risk of colorectal carcinoma. 264 Prophylactic colectomy may be prudent in juvenile polyposis syndrome. Patients may also have an increased risk of gastric, small intestinal, and pancreatic carcinoma. 265 Juvenile polyposis syndrome coexisting with HHT (Osler-Weber-Rendu syndrome) is rarely reported. 265 The number of polyps in juvenile polyposis syndrome typically ranges from a few dozen to several hundred ( Fig. 23-46 ). Phenotypically, juvenile polyposis syndrome appears to occur in three varieties: (1) polyps limited to the colon, (2) polyps limited to the stomach, and (3) polyps throughout the entire GI tract. 266. , 267. , 268. The mucosal polyps found in the context of juvenile polyposis syndromes are often unusual histologically. In addition to the typical juvenile polyps described earlier, one can find juvenile polyps with atypical features such as more epithelium than lamina propria. In addition, mixture polyps (juvenile polyps with areas of adenoma or dysplasia) are quite frequent. 244. , 264. A family showing an autosomal dominant inheritance of atypical juvenile polyps, adenomas, hyperplastic polyps, and polyps showing a mixture of all three types (hereditary mixed polyposis syndrome) 269 may have a variant of juvenile polyposis or they may have MAP. 265. , 270. , 270a. Figure 23-46 ▪ Resection specimen of juvenile polyposis syndrome. Although some polyps grossly resemble sporadic juvenile polyps, many have an unusual frondlike configuration. Resection specimen of juvenile polyposis syndrome. Although some polyps grossly resemble sporadic juvenile polyps, many have an unusual frondlike configuration. Two genes have been identified to cause familial juvenile polyposis syndrome, MADH4 (mothers against decapentaplegic homologue 4, also known as SMAD-4 [18q21.1] and DPC-4 ) seen in approximately 15% of patients and BMPR1A (bone morphogenetic protein receptor type 1A [10q22.3]) 265. , 271. , 272. , 273. seen in 25% of cases. One should consider genetic testing for juvenile polyposis syndrome when three or more juvenile polyps have occurred in one individual or when juvenile polyps are found outside the colon. 66 MADH4 and BMPR1A are both components of the signaling pathway for transforming growth factor-β and the bone morphogenetic proteins. Patients with MADH4 gene mutation are more likely to have gastric juvenile polyposis. 265. , 274. , 275. Juvenile polyps can be found in patients with other hamartomatous syndromes of the colon, such as intestinal ganglioneuromatosis or ganglioneurofibromatosis (see later), 276. , 277. , 278. although some of these syndromes are now best classified as PTEN (phosphatase and tensin homologue) syndrome (see later). Patients can sometimes be managed with endoscopy and polypectomy (every 1 to 3 years); however, colectomy must be considered for patients with large numbers of polyps or polyps with dysplasia or for patients with complications (e.g., bleeding, obstruction). Screening colonoscopy every 3 years should commence with symptoms or in the early teenage years in an asymptomatic patient. 66. , 279. Upper endoscopy is also recommended in patients with juvenile polyposis syndrome. Esophagogastroduodenoscopy and small bowel examination (every 2 years) should begin at age 15 years. 66. , 279. Ruvalcaba-Myhre-Smith syndrome consists of macrocephaly, mental deficiency, unusual craniofacial appearance, pseudopapilledema, pigmented macules on the penis, and hamartomatous polyps in the GI tract. The syndrome appears to be passed on as an autosomal dominant condition. 280 The GI polyps have been indistinguishable from juvenile polyps and in rare instances intestinal ganglioneuromatosis has also been described. The syndrome has been linked to mutations or deletions in the PTEN gene (10q23.3) 267. , 271. , 281. and with Cowden's syndrome and can be considered as one of the PTEN polyposis syndromes. 265 Peutz-Jeghers polyps can be found throughout the GI tract, either sporadically or as part of the Peutz-Jeghers syndrome. 1. , 282. , 283. The polyp itself is characterized by fairly normal epithelium and lamina propria lining an abnormal arborizing network of smooth muscle that represents hamartomatous overgrowth of the muscularis mucosae ( Fig. 23-47 ). 1. , 282. , 284. Peutz-Jeghers syndrome, usually inherited as an autosomal dominant trait, is the combination of skin hyperpigmentation and Peutz-Jeghers polyps in the GI tract. The diagnosis of Peutz-Jeghers syndrome is considered definitive if the patient has a Peutz-Jeghers polyp and at least two of the following criteria: (1) family history, (2) mucocutaneous hyperpigmentation, and (3) small bowel polyposis. 265. , 283. The pigmentation consists of clusters of brown or black freckles about the lips, buccal mucosa, and perianal and genital region. Pigmented areas can occasionally be seen on the fingers and toes. The spots appear in the first year of life and tend to fade toward middle age. The polyps usually number only in the dozens and can be found throughout the GI tract. These polyps have a propensity to form in the small intestine where they often cause intussusception. In rare kindred, Peutz-Jeghers polyps have been limited to the large bowel. Cases of complicating GI carcinoma have been reported. 285. , 286. Approximately 5% of female patients with Peutz-Jeghers syndrome have a peculiar ovarian tumor, sex cord tumor with annular tubules (SCTAT). 287 The rate of detection may increase if the ovaries are carefully examined, 287. , 288. and some tumors may be associated with sexual precocity. 289 Male patients with Peutz-Jeghers syndrome occasionally have unilateral or bilateral Sertoli cell tumors of the testes. 290. , 291. Adenoma malignum and pancreaticobiliary tract carcinomas are reported to occur at increased rates. 292 Figure 23-47 ▪ Colonic Peutz-Jeghers polyp illustrating the arborizing hamartomatous overgrowth of the muscularis mucosae. Colonic Peutz-Jeghers polyp illustrating the arborizing hamartomatous overgrowth of the muscularis mucosae. The Peutz-Jeghers syndrome has been linked to the STK11 (serine/threonine-protein kinase 11, also known as LKB1 ) gene on chromosome 19p13.3 293. , 294. , 295. , 296. and can be demonstrated in 70% of cases. 265 This is a tumor suppressor gene involved in transduction of intracellular growth signals. 66 Investigators have suggested that genetic testing be considered for Peutz-Jeghers syndrome when any Peutz-Jeghers polyps or typical perioral pigmentations are found. 66 Meta-analysis of cancer risk in an evaluation of patients with known mutations of the STK11 gene have shown increased lifetime risk for cancer of the esophagus, stomach, small bowel, colon, pancreas, and breast. 283. , 297. Putting this into perspective, the risk for breast cancer in Peutz-Jeghers syndrome is similar to the risk seen in individuals with germline mutations of BRCA1 and BRCA2 and Peutz-Jeghers syndrome is the strongest known risk factor for pancreatic carcinoma except for hereditary pancreatitis. 283 Screening at-risk individuals (first-degree relatives of a patient with Peutz-Jeghers syndrome) should begin at birth with an annual history and physical examination to look specifically for melanotic spots, precocious puberty, and testicular tumors. Asymptomatic at-risk individuals without stigmata by age 8 years should be tested for STK11/LKB1 gene mutations. If mutation is not found in the family, small intestinal contrast radiography every 2 years until age 25 years is recommended. Other investigators suggest that upper and lower endoscopy with small bowel series should be done at ages 12, 18, and 24 years. 283 Esophagogastroduodenoscopy and upper GI radiographic series with small bowel follow through are recommended in patients with Peutz-Jeghers syndrome commencing at age 8 years and repeated every 2 years thereafter. 283. , 298. Colonoscopy every 3 years is recommended starting with symptoms or by age 18 years if symptoms have not occurred. 66. , 283. Testicular examination, pelvic examination by age 20 years, mammographic examination by age 25 years, and endoscopic ultrasound examination of the pancreas by age 25 to 30 years have been recommended. 229. , 283. Annual transvaginal ultrasound examination and serum CA-125 determination are also recommended commencing at age 25 years. 283 Intestinal ganglioneuromatosis is defined as proliferation of ganglion cells, neurites, and supporting cells that can affect any layer of the GI wall ( Fig. 23-48 ). 280 These proliferations often manifest as mucosal polyps in the colon. Although these lesions most often occur as an isolated phenomenon, the importance of intestinal polypoid ganglioneuromatosis is in recognizing the other settings in which it can occur, such as von Recklinghausen's disease ( NF1 gene mutation), MEN2B ( RET gene mutation), Cowden's syndrome ( PTEN mutation), Ruvalcaba-Myhre-Smith syndrome ( PTEN mutation), and tuberous sclerosis ( TSC1 [9q34] or TSC2 [16p13] mutation). 299. , 300. , 301. , 302. , 303. Intestinal ganglioneuromatosis can coexist with juvenile polyps although these patients may be better classified as having PTEN polyposis. 276. , 277. , 278. Figure 23-48 ▪ Colonic ganglioneuroma is composed of ganglion cells, neurites, and supporting cells. Colonic ganglioneuroma is composed of ganglion cells, neurites, and supporting cells. Cowden's syndrome describes an autosomal dominant multiple hamartoma syndrome in which patients have multiple orocutaneous hamartomas (e.g., facial trichilemmomas, mucosal papillomas, acral keratosis, subcutaneous lipomas), fibrocystic disease of the breast, an increased risk of breast carcinoma, thyroid abnormalities, and hamartomatous polyps in the stomach, small intestine, and colon. Polyps of the GI tract, when described, often have shown an abnormal proliferation of the smooth muscle in the lamina propria and generally have resembled the polypoid variant of solitary rectal ulcer syndrome. 304 Some juvenile polyp–like proliferations have been described. 265 Intestinal ganglioneuromatosis has also been reported. 302 Other associated abnormalities include macrocephaly, high arched palate, hypoplastic mandible and maxilla, microstomia, supernumerary nipples, pectus excavatum, hemangiomas, ovarian cysts, and uterine leiomyomas. 265. , 303. The gene (PTEN) for Cowden's disease has been mapped to chromosome 10 (10q22-23). 272. , 305. , 306. Cowden's syndrome and Ruvalcaba-Myhre-Smith syndrome are sometimes referred to as the PTEN polyposis syndromes . Genetic testing is suggested when features of this syndrome are present. 66 Esophagogastroduodenoscopy and small bowel examination every 2 years beginning at age 15 years is recommended. 66 Cronkhite-Canada syndrome is an acquired nonfamilial syndrome characterized by intestinal polyposis, dystrophic changes of the fingernails, alopecia, and cutaneous hyperpigmentation. 307. , 308. Patients first present with diarrhea, abdominal pain, and anorexia that progresses to weight loss and protein-losing enteropathy. Many patients complain of loss of taste (hypogeusia) and loss of smell. As a rule, the ectodermal changes occur weeks to months after the other symptoms. The nail dystrophy consists of thinning, splitting, and separation from the nail bed (onycholysis). Onychomadesis (complete loss of the nail) can also occur. The hair loss is rapid and may be seen in the scalp, eyebrow, face, axilla, or pubic region. The cutaneous hyperpigmentation ranges from small macules to confluent areas of hyperpigmentation that can be 10 cm or more. Histologically, the pigmented macules result from increased melanin in the basal layer. Cronkhite-Canada polyps are found throughout the GI tract but are most commonly seen in the stomach and large bowel. Grossly, they are sessile; a few are pedunculated. The polyps tend to occur on a background of diffuse mucosal thickening ( Fig. 23-49 ). Histologically, the polyps themselves are identical to juvenile polyps. However, the mucosa between polyps is abnormal and shows edema, congestion, and inflammation (chronic inflammation often with prominent eosinophils) of the lamina propria coupled with glandular ectasia ( Fig. 23-50 ). Carcinomas of the colon and stomach have been described rarely in patients with Cronkhite-Canada syndrome. The malabsorption in this syndrome is usually progressive and with no specific therapy available, the prognosis is generally poor. Death results from anemia, septic shock, bleeding, or postoperative complications. Treatment consists of supportive therapy, antibiotics, corticosteroids, and surgery. Within the stomach, Cronkhite-Canada syndrome closely mimics Ménétrier's disease. Ménétrier's disease, however, is confined to the stomach and has no associated ectodermal changes. Figure 23-49 ▪ Endoscopic photograph of the colon from a patient with Cronkhite-Canada syndrome. The broad-based sessile polyps are situated on a background of diffuse mucosal thickening, nodularity, and exudate. Figure 23-50 ▪ Cronkhite-Canada syndrome polyps resemble juvenile polyps because they are composed of edematous and inflammatory expansion of the lamina propria with glandular cyst formation. In contrast to juvenile polyps, the adjacent nonpolypoid mucosa shows similar lamina propria abnormalities and mucosal atrophy. Endoscopic photograph of the colon from a patient with Cronkhite-Canada syndrome. The broad-based sessile polyps are situated on a background of diffuse mucosal thickening, nodularity, and exudate. Cronkhite-Canada syndrome polyps resemble juvenile polyps because they are composed of edematous and inflammatory expansion of the lamina propria with glandular cyst formation. In contrast to juvenile polyps, the adjacent nonpolypoid mucosa shows similar lamina propria abnormalities and mucosal atrophy. Heterotopic gastric, pancreatic, sebaceous, and salivary gland tissues have been described in the colon and rectum. These ectopic tissues can be found throughout the GI tract but are most often seen in the rectum where they can cause a plaque, polyp, or mass ( Fig. 23-51 ). 309. , 310. , 311. Figure 23-51 ▪ Endoscopic view of gastric heterotopia. This photograph taken with the endoscope retroflexed for a view of the rectum shows a plaquelike area of erythema. Endoscopic view of gastric heterotopia. This photograph taken with the endoscope retroflexed for a view of the rectum shows a plaquelike area of erythema. Inflammatory fibroid polyp is most commonly found in the stomach but can be encountered throughout the GI tract including the colon and rectum. 1. , 312. , 313. , 314. Symptoms include abdominal pain and bleeding. The polyp is usually solitary. It can be sessile or pedunculated and typically has a solid pale tan cut surface. Microscopically one sees a loose myxoid fibrous tissue background containing regularly distributed blood vessels, some of which show hyalin change in their walls. The fibrous tissue can layer in a whorl-like fashion around these vessels in an onion-skin pattern. Most lesions are rich in inflammatory cells including plasma cells and eosinophils ( Fig. 23-52 ). Scattered macrophages and Touton-type giant cells can also be seen. The stroma in most lesions is positive for CD34 but negative for CD117. Mutations in platelet-derived growth factor receptor alpha gene have been described. 314a The mucosa overlying these typically submucosal tumors can be ulcerated, presumably by trauma, and can show areas of inflamed granulation tissue. The ulcerated surface can contain bizarre stromal cells, which are also seen in a variety of inflammatory polyps with chronic ulceration (e.g., IBD, trauma or prolapse, and radiation injury). The inflammatory fibroid polyp is benign and typically does not recur. Figure 23-52 ▪ Inflammatory fibroid polyp. The lesion is histologically composed of loose myxoid fibrous tissue and blood vessels. The fibrous tissue is layered around the vessels and contains inflammatory cells. Inflammatory fibroid polyp. The lesion is histologically composed of loose myxoid fibrous tissue and blood vessels. The fibrous tissue is layered around the vessels and contains inflammatory cells. Malakoplakia, an abnormal immune response to gram-negative bacteria, can cause a tumor or polyp in any site of the GI tract, including the large bowel. Histologically, it is characterized by xanthogranulomatous inflammation accompanied by the pathognomonic Michaelis-Gutmann body ( Fig. 23-53 ). 1 The partially digested bacteria accumulate in macrophages and lead to deposition of calcium and iron on the residual bacterial glycolipids. 315 An association between colorectal malakoplakia and colorectal neoplasia may exist. 315 Figure 23-53 ▪ Malakoplakia. The xanthogranulomatous inflammatory reaction contains numerous Michaelis-Gutman bodies. Malakoplakia. The xanthogranulomatous inflammatory reaction contains numerous Michaelis-Gutman bodies. Defined as the presence of endometrial glands or stroma usually with hemorrhage and hemosiderin deposits in an extrauterine location, endometriosis tends to affect sites closest to the female genital tract such as the sigmoid colon and rectum. 1 Symptoms include episodic abdominal pain. Hematochezia can occur with mucosal involvement. Endometriosis usually involves the serosa and muscularis externa and can cause smooth muscle proliferation and stricture. Mucosal and submucosal involvement can cause mucosal polyps. 316 Endometriosis must be distinguished from müllerian adenosarcoma and endometrial stromal sarcoma. The glandular component can be confused with colitis cystica profunda and adenocarcinoma. Immunohistochemical analysis for CD10, which highlights endometrial stromal cells, can be helpful in the differential diagnosis as can recognition of ciliated epithelial cells. Differential cytokeratin immunostaining can also help because endometriosis commonly stains positive for CK7, whereas colorectal epithelium usually expresses CK20. Examples of malignant transformation (mostly endometrioid carcinoma and clear cell carcinoma) in endometriosis have been reported. 316 Injection of materials containing lipid bases into the lower rectum and anus can cause a mass or polyp referred to as an oleogranuloma . The lesion is composed of lipid-containing cysts surrounded by a foreign body giant cell reaction. 1 Benign fibroblastic polyps and perineurioma have been described in the colon and rectum where they may represent the same or a similar lesion. 317. , 318. , 319. These mucosal polyps are usually solitary but can be multiple and have been reported throughout the GI tract, most commonly in the colon and rectum. Histologically, these polyps contain proliferations of small tightly packed spindle cells within the lamina propria that often orient themselves parallel to the muscularis mucosae. This lesion frequently coexists with hyperplastic polyp–like epithelial proliferations, and indeed the polyp could represent a trauma-related change seen in the otherwise typical hyperplastic polyp or sessile serrated polyp ( Fig. 23-54 ). The spindle cells test negative for immunoreactive S-100 protein and other neuromarkers; they can express immunoreactive epithelial membrane antigen by immunohistochemical analysis. Figure 23-54 ▪ Benign fibroblastic polyp/colorectal perineurioma. The lesion is composed of small, tightly packed spindle cells within the lamina propria. Note the alignment of the superficial spindle cells parallel to the muscularis mucosae. Mucosal hyperplastic polyp–like changes are often present in these lesions. Benign fibroblastic polyp/colorectal perineurioma. The lesion is composed of small, tightly packed spindle cells within the lamina propria. Note the alignment of the superficial spindle cells parallel to the muscularis mucosae. Mucosal hyperplastic polyp–like changes are often present in these lesions. Areas of increased elastin fibers in the submucosa and muscularis mucosae are referred to as elastosis or elastofibromatous change and can cause polyps in the colon and rectum. Histologically, the elastosis appears as finely granular or fibrillar amphophilic material usually with a fibrous component and is often centered around prominent blood vessels ( Fig. 23-55 ). The change could also be a manifestation of mucosal trauma or prolapse. Elastosis can be confused with amyloid deposits but results of Congo red stains have been negative. 320 Figure 23-55 ▪ Elastofibromatous change can be seen within mucosal polyps of the colon and rectum. The finely granular and fibrillar eosinophilic material is often centered around blood vessels. Elastofibromatous change can be seen within mucosal polyps of the colon and rectum. The finely granular and fibrillar eosinophilic material is often centered around blood vessels. Benign spindle cell proliferations that express immunoreactive S-100 protein can manifest as mucosal polyps in the colon and rectum and are usually termed mucosal neuromas 1 or Schwann cell hamartomas . Care must be taken not to overlook ganglion cells, which would indicate a ganglioneuroma. These lesions can be seen in patients with neurofibromatosis but most occur sporadically and are unassociated with syndromes. 321