Textbook of Gastroenterology
4th Edition

INFLAMMATORY DISORDERS OF THE COLON (Table 142-3)
TABLE 142-3 Types of Colitis
An important function of biopsy is to establish the presence and type of colitis in various possible inflammatory disorders of the colon. It is important to emphasize that an isolated increase in the numbers of lymphocytes, plasma cells, and macrophages in the lamina propria is not by itself diagnostic of colitis. There is a wide normal variation in round cell content of the lamina propria. Numerous isolated eosinophils may be seen in the normal mucosa, especially in the right colon, in children,116 or in patients from the southern latitudes, even within the U.S.117 The diagnosis of colitis requires alterations in the epithelial cells or in the crypt architecture in addition to an increase in inflammatory cells in the lamina propria. These changes include infiltration of surface, or crypt epithelium by neutrophils, eosinophils, and lymphocytes; decreased mucus secretion (goblet cell depletion); distortion of crypt architecture and reactive nuclear changes, such as enlargement, vesicular chromatin, and prominent nucleoli.
Three causes of bloody diarrhea that may be confused with one another are idiopathic ulcerative colitis (Fig. 142-50), Crohn’s disease (Fig. 142-51), and acute self-limited colitis (Fig. 142-52). The term idiopathic inflammatory bowel disease (IIBD) refers to both ulcerative colitis and Crohn’s disease. These are both chronic diseases in contrast to acute self-limited colitis which is often of known infectious origin and is both relatively acute and self-limited. The most common reason to biopsy the colon is to help differentiate between these three diseases because their prognoses and responses to treatment are very different.
FIGURE 142-50. Ulcerative colitis. A: The biopsy specimen shows disease in which the inflammatory infiltrate varies in intensity and the distortion of the crypt architecture is mild; the crypt seen in the center of the biopsy sample is branched and contains neutrophils infiltrating its epithelium and lumen. B: A biopsy specimen from a patient with severe disease with diffuse inflammation, distortion of the crypt architecture, and basal lymphoplasmacytosis. C: Atrophic mucosa in a patient with inactive ulcerative colitis; there is distortion of the crypt architecture but no inflammation.
FIGURE 142-51. Crohn’s disease of the colon. A: This biopsy specimen contains a discrete epithelioid granuloma (arrows) composed of multinucleated giant cells and epithelioid histiocytes. B: View at higher magnification power. Although inflammation surrounds the granuloma and involves some of the lamina propria, the mucosa at the left side of A is essentially normal, emphasizing that Crohn’s colitis is commonly focal in distribution.
FIGURE 142-52. Acute self-limited colitis in a patient with salmonellosis. A: Normal mucosa for comparison with (B) the histological appearance of the mucosa in acute self-limited colitis. In acute self-limited colitis, there is no distortion of crypt architecture, and this differentiates it from idiopathic inflammatory bowel disease. The crypts remain as straight, evenly spaced tubules, but there is a mixed inflammatory infiltrate in the lamina propria in which neutrophils predominate over round cells. Accumulation of neutrophils within the crypt lumen to form crypt abscesses is evident, but this is a nonspecific finding seen in all kinds of colitis, as is the absence of mucus secretion in the actively inflamed mucosa.
While both ulcerative colitis and Crohn’s disease undoubtedly are at some point in time truly “acute,” at the time of onset of the bloody diarrhea there are virtually always histological features of chronicity, even when the duration of symptoms is quite short.118 From a diagnostic standpoint, the presence of these features of chronicity is often more important than the acute neutrophilic inflammatory component since, in an acute inflammatory background, evidence of chronicity suggests an active IIBD (see Fig. 142-2) rather than an infectious acute self-limited colitis (see Fig. 142-52). In endoscopically normal or near-normal segments of bowel, the presence of histologically detected chronic IIBD changes (see Fig. 142-50) can be crucial to the distinction between ulcerative colitis and Crohn’s disease, and thus these apparently “normal” areas must also be biopsied. Histologically a completely normal segment between abnormal segments is more suggestive of segmental Crohn’s disease, whereas the presence of residual distortion of crypt architecture in endoscopically normal-appearing areas is in favor of ulcerative colitis which is more often a diffuse process.
The following features suggest chronicity (see Fig. 142-50): crypt architectural distortion, Paneth cell metaplasia (distal to the right colon), and basal lymphoplasmacytosis. Irregularities of crypt shape include branching, foreshortening, and loss of parallelism. Abnormal branching must be differentiated from normal innominate grooves. In the former, two branches of the crypt join to empty at the surface; in the latter, all crypts open independently on the surface of the innominate groove. An occasional branched gland in an otherwise normal mucosa is of no significance, as is branching adjacent to a lymphoid follicle or in proximity to the anus. Foreshortening refers to glands that fail to extend down to a level seen in normal mucosa (i.e., to nearly touch the muscularis mucosae). Loss of parallelism refers to the lack of a “rack of test tubes” architecture seen in optimally oriented normal colonic mucosa.
Marked variation in size and irregular spacing of glands are sometimes best appreciated on portions of specimens tangentially oriented parallel to the surface. Small cross-sectional glands immediately adjacent to mid- and large-size glands suggest crypt architectural distortion.
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Crypt architectural distortion may accompany “diversion” colitis following mechanical diverting of the fecal stream and in “pouchitis” within an ileal pouch following ileoanal-pouch anastomosis after total proctocolectomy. Crypt distortion may also be seen in rare infections that linger for a prolonged period of time such as amoebic colitis, occasional cases of Campylobacter jejuni, Salmonella, Shigella, and in radiation (Fig. 142-53) or chemotherapeutic damage or chronic ischemia. A segmental colitis mimicking ulcerative colitis but limited to the sigmoid colon may occur in patients with sigmoid diverticular disease.119 Thus, the pathologist should indicate that the changes likely represent an IIBD, but if the clinical context is not completely known, a “consistent with” modifier is appropriate. Finally, patients with IIBD are at increased risk of infection with the usual bacterial and viral pathogens. These are usually diagnosed clinically through appropriate stool pathogen cultures. One pathogen that may only be detected morphologically is CMV and it should be sought in all IIBD biopsies, particularly those with marked inflammatory activity.
FIGURE 142-53. Colitis after therapeutic radiation. A: After radiation the chronic changes in the mucosa are atrophic and may resemble inactive ulcerative colitis. B: Fibrosis of the lamina propria and hyalinization of vascular walls are shown (arrows). These ectatic vessels with hyalinized walls serve to distinguish radiation colitis from inactive ulcerative colitis. The surface epithelium in this biopsy sample is eroded; this may be an artifact because it is not a consistent finding in radiation colitis. Acute radiation changes, not shown here, may be indistinguishable from ischemia.
Ulcerative Colitis
In the past ulcerative colitis was believed to virtually always affect the colonic mucosa in a diffuse and circumferential manner. The disease usually involves the rectum in continuity with a variable length of colon, and when the entire large bowel is inflamed, the appendix and terminal ileum may be affected as
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well. There are now numerous reported exceptions to the conventional wisdom regarding the diffuse nature of the disease in ulcerative colitis. In up to one third of cases, patients with well-documented ulcerative colitis may have patchy or focal segmental inflammation.120,121 (see Fig. 142-50A) This is usually seen in patients whose disease is or has at one time been in remission.
The pathological findings are essentially restricted to the mucosa and upper submucosa unless there is extensive ulceration, as in fulminant colitis, in which case the inflammation may extend through the bowel wall. Paradoxically, large and deep ulcers are not typical of ulcerative colitis except when the disease is fulminant. A pronounced chronic inflammatory infiltrate consisting of many plasma cells, lymphocytes, and variable numbers of macrophages and eosinophils occupies the lamina propria and may form aggregates near the base of the mucosa (basal lymphoplasmacytosis) (see Fig. 142-50B). In contrast, the neutrophils in active ulcerative colitis tend to be localized to crypt epithelium (“cryptitis”) or lumen (“crypt abscess”) or marginating in capillaries; they are not found in large numbers in the lamina propria unless crypts are perforated. Numerous eosinophils, however, may be found within the lamina propria or epithelium in IIBD. In active ulcerative colitis, the goblet cell mucin is usually markedly diminished or depleted, even in crypts that are not infiltrated by neutrophils. The crypt epithelium may be hyperplastic with large, hyperchromatic, crowded and stratified nuclei that may closely resemble those seen in dysplastic epithelium, except that the nuclear changes generally mature toward the surface (see Fig. 142-2).
During the resolution phase of active inflammation in ulcerative colitis, the inflammatory infiltrate within the lamina propria may resolve in an irregular manner so that the biopsy shows what appears to be a focal inflammatory process.120,121 With quiescence, the neutrophilic infiltrate disappears and the intensity of chronic inflammation gradually diminishes. Biopsies taken during the inactive stage may show a characteristic appearance referred to as “atrophy” and are characterized by reduced numbers of crypts with distorted architectures best recognized by branching (see Fig. 142-50C), or they may be normal, as previously mentioned. The base of the crypt may be separated from the underlying muscularis mucosae by a long distance, and the muscularis mucosae itself may be quite thickened and its bundles of muscle separated from each other by fibrosis. The picture of “atrophic” mucosa is highly characteristic of ulcerative colitis and is seldom seen in Crohn’s disease. A closely similar picture may occur in healed ischemia and radiation (see Fig. 142-53) or chemotherapy-induced colitis, so that clinical correlation is important.
Frequently there is a lack of correlation between the endoscopic appearance of the mucosa and its histological appearance. For this reason, the endoscopist should be encouraged to biopsy endoscopically normal-appearing mucosa to document that it is, in fact, normal. In children with ulcerative colitis, focal inflammation or rectal sparing may be present at the initial diagnostic evaluation.122 Patients presenting with fulminant ulcerative colitis may also have gross and histological rectal sparing. In cases with atypical distributions, particular attention should be given to all of the patient’s biopsies, especially those from early on in their disease, as time or treatment may influence disease distribution in ulcerative colitis.
Crohn’s Disease
Crohn’s disease may affect any part of the GI tract from the mouth to the anus. The small bowel alone is affected in about 30% of cases and the small and large bowel together in about 55%.123 The colon is said to be affected by itself in 15% of cases, but this is probably overestimated. In the most common pattern of involvement, the disease affects the terminal ileum and proximal colon together. Inflammatory lesions of the anus are particularly characteristic of Crohn’s disease and may occur even in the absence of inflammation of the colon. In contrast to ulcerative colitis, which it may mimic clinically, Crohn’s disease usually affects the colon and the rest of the bowel in a discontinuous
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manner (see Fig. 142-51). In about half of patients who have colonic involvement by Crohn’s disease, the rectum is spared both endoscopically and histologically. Large, linear or serpiginous ulcers surrounded by normal-appearing mucosa are characteristic, as are small, punctate erosions surrounded by a zone of hyperemia (aphthae).
True epithelioid granulomas are the most dependable criterion for the diagnosis of Crohn’s disease (see Fig. 142-51). Typically, they are relatively small, compact aggregates of epithelioid histiocytes that contain variable numbers of giant cells. Not infrequently, giant cells cannot be identified. In some granulomas, the epithelioid histiocytes do not form compact nodules but rather “loose” aggregates. Such loose granulomas are more difficult to recognize and are more often related to foreign material, such as mucus, than are compact granulomas. The reported frequency with which granulomas can be identified in biopsies varies markedly between various studies. Possible explanations for this marked variation include the definition of granulomas used, whether or not isolated giant cells are mislabeled granulomas, the number of biopsies obtained, and the number of sections examined. Serial sectioning will significantly increase the yield of granulomas.124,125 Microgranulomas are quite small, consisting only of a few histiocytes, and can be easily overlooked. The cytoplasm of epithelioid histiocytes has a typical ground-glass appearance revealed on fine focusing at high power; this appearance reflects the excess cytoplasmic smooth endoplasmic reticulum (E.R.) in epithelioid histiocytes revealed at the higher magnifications of electron microscopy. One must be cautious about what is diagnosed as an epithelioid granuloma in colorectal biopsies. Ruptured crypts release mucin into the lamina propria, and this commonly induces a granulomatous reaction.126 Such mucin granulomas usually include mature macrophages and foreign body–type giant cells. They can be recognized because of their predominance of giant cells and their orientation about perforated crypts. Mucin granulomas are nonspecific, and they may be seen in Crohn’s disease, ulcerative colitis, infections, diverticulitis, and adenomas, among other conditions. Isolated giant cells in the lamina propria occur in similar settings and should likewise not be considered as evidence of granulomatous inflammation in the colon; if located in the basal portion of the mucosa, they are characteristic of IIBD but may be seen in both ulcerative colitis and Crohn’s disease. Biopsies from patients with Crohn’s disease may also demonstrate aphthous lesions. In the absence of another known cause of aphthous lesions (e.g., Yersinia enterocolitica), their presence is very suggestive of the diagnosis of Crohn’s disease.
Aphthous-like lesions may also be seen endoscopically in patients who have received sodium phosphates orally or by enema. Histologically, these are prominent lymphoid follicles with reactive changes in the adjacent mucosa. These do not indicate colitis and are a bowel preparation artifact.
Normal areas of colonic mucosa alternating with focal areas of inflammation favors Crohn’s disease over ulcerative colitis but ulcerative colitis can become patchy over time, especially with remission and with new immunosuppressive therapies. A variant of untreated ulcerative colitis that must not be confused with Crohn’s disease is the “cecal patch” of colitis in which the cecum is discontinuously involved.121 Occasionally, clinically typical Crohn’s disease shows diffuse inflammation that is indistinguishable from ulcerative colitis; unless typical epithelioid granulomas are present, this colitis must be classified as IIBD of indeterminate type. The latter is a diagnosis that we make infrequently. Correlation of clinical activity with biopsy appearance in Crohn’s disease is even less dependable than that seen in ulcerative colitis and the typical atrophic appearance of quiescent ulcerative colitis is not often seen in Crohn’s disease.
The pathology of postoperative ileoanal pouches in ulcerative colitis overlaps substantially with that of Crohn’s disease, and Crohn’s like complications are also seen. This does not mean that the original diagnosis of ulcerative colitis was incorrect.
Acute Self-Limited Colitis
Colorectal mucosal biopsy plays an important role in the management of patients with the acute onset of often bloody diarrhea. The endoscopic appearance of acute self-limited colitis is indistinguishable from that of ulcerative colitis. In marked contrast to the histological appearance of acute self-limited colitis (see Fig. 142-52), when a patient with the initial symptoms of IIBD is seen for the first time, even if symptoms have only been present for a few days, the characteristic distortion of crypt architecture and marked, chronic inflammation of the lamina propria are present in colorectal biopsies (see Fig. 142-2).118,127,128 The absence of these key features signifies that the disease process will probably pursue an acute, self-limited course and is, therefore, most likely infectious.118,128 In the characteristic picture of acute self-limited colitis crypt architecture is well preserved, and polymorphonuclear leukocytes predominate in a lamina propria that lacks the prominent chronic inflammatory infiltration of IIBD.118,128 As in ulcerative colitis, goblet cell mucin may be diminished or absent, neutrophilic infiltration of the crypt epithelium (cryptitis) may be present, and crypt abscesses may be seen. Crypt abscesses associated with a prominent infiltrate of macrophages, producing the appearance of granulomatous inflammation, suggest C jejuni infection or Salmonella. Pseudomembranes are most commonly seen with Clostridium difficile-induced colitis, but are nonspecific and may be seen in other types of colitis, including E coli 0157:H7.129,130 The latter may produce an appearance that is indistinguishable from ischemic colitis (Fig. 142-54). The changes include, in addition to the other characteristic features of acute self-limited colitis, mucosal hemorrhage, capillary thrombosis, and necrosis.
FIGURE 142-54. Ischemic colitis. A: The upper part of the mucosa is necrotic whereas the deeper portion remains viable. The dark band along the surface of the mucosa represents hemorrhage. The arrow points to a crypt basement membrane devoid of epithelial cells because they have become necrotic and sloughed off (crypt ghost). Notice the relatively mild inflammatory infiltrate. B: The eroded surface epithelium, superficial hemorrhage, and crypt ghosts (arrow) are seen at higher power.
In about half of patients who have acute self-limited colitis that is presumably infectious, the stool cultures and examination for ova and parasites are negative. Thus, the biopsy is quite helpful in determining whether the patient with acute bloody diarrhea has a self-limited process or chronic IIBD. In the general population of the United States, the most common enteric pathogens cultured in the acute self-limited colitides are C jejuni, Salmonella species, E coli 0157:H7, and Shigella species. Cultures are essential for planning appropriate treatment. When none of these pathogens is identified, the causative organism may be an invasive E coli that cannot be distinguished from nonpathogenic E coli without tissue culture assays or DNA probing.
Ischemic Colitis
Ischemic colitis from vascular hypoperfusion can have a wide variety of causes.131,132 Clinically its diagnosis can be difficult
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and biopsy often is required. In patients with acute ischemic injury, the bowel wall may be friable, but biopsy specimens can be taken safely if done carefully. Black or dusky bowel which may be infarcted should not be biopsied.
The histological hallmarks of ischemic colitis include necrosis of the upper part of the mucosa with sloughing of epithelial cells from the surface and upper regions of the crypts, while the epithelium in the deeper part of the mucosa may remain intact (see Fig. 142-54). A superficial zone of hemorrhage corresponds approximately to the region of necrosis of epithelial cells. Pericryptal basement membranes from which the epithelium has sloughed are called crypt ghosts. Capillary thrombi are prominent. Inflammatory cells, including mostly neutrophils but with a few mononuclear cells, are present but in relatively small numbers unless infection supervenes. The submucosal edema typical of ischemic colitis may produce a bleb that is occasionally removed like a polyp and submitted for histological examination. Such blebs are responsible for the “thumbprints” seen on roentgenograms. In patients with transitory mucosal ischemia, regeneration rapidly occurs and produces changes in the epithelial cells that can be misinterpreted as dysplasia or carcinoma. Ischemic colitis most commonly occurs in the absence of an occlusive vascular lesion.133
Patients who develop ischemic lesions of the intestine without vascular occlusion do so because of hypoperfusion of the mesenteric vasculature.132,134 The hypoperfusion can be due to a wide variety of causes, but the most common are cardiac failure or arrhythmias, digitalis toxicity, shock, and septicemia.133 The physiology of the mesenteric circulation is such that a countercurrent exchange mechanism reduces oxygen content in the upper portion of the mucosa while it remains normal in the lower.135 Consequently, the upper mucosa, which is relatively hypoxic under normal conditions, is particularly vulnerable to the effects of hypoperfusion and may become necrotic while the lower mucosa remains intact.
Ischemic lesions are more common in the colon than in the small bowel, probably because of the vast collateral network in the small bowel. Ischemic colitis may follow three courses depending upon the duration of the ischemic episode and the extent and depth of the lesion. If the ischemia is transitory, only superficial necrosis is produced, and spontaneous healing with no sequelae may occur. Following more prolonged ischemic episodes, the necrosis extends deeper into the bowel wall so that the muscularis propria may be affected. Recovery is usually accompanied by prominent submucosal fibrosis with stricture formation. After prolonged acute ischemia, necrosis of the full thickness of the bowel wall develops, and perforation, peritonitis, and sepsis result in a high mortality rate. Morphologically, one may see all stages at the same time in different biopsies, with necrosis restricted to the superficial mucosa, various depths of mucosal destruction, and ulcers.
Ischemic colitis developing in a younger person or in a patient without apparent predisposing factors, such as cardiac failure or arrhythmia, should suggest a vascular occlusive lesion, such as arteritis, intravascular coagulation, atheroembolism, amyloidosis, volvulus, or thromboangiitis obliterans.136,137 Several examples of ischemic colitis that were apparently induced by cocaine have been reported.138 The mechanism of this ischemia is probably related to the potentiating action of cocaine on norepinephrine. Venous stenosis due to a spectrum of lesions ranging from various types of phlebitis to myointimal hyperplasia may also occur in young people.139,140 These mesenteric venoocclusive lesions are of unknown etiology and appear to have a favorable prognosis after resection. Ischemia in young persons taking NSAIDs has been described, as has ischemic colitis in young women taking oral contraceptive agents. In some young patients with
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ischemic colitis, no apparent cause for the decreased blood flow is ever found. A group of other colitides that probably arise on an ischemic basis and which morphologically resemble ischemic colitis includes: E coli 0157:H7, some forms of pseudomembranous colitis, uremic colitis, radiation colitis, and colitis that accompanies some obstructive lesions.134,141,142 and 143
Infectious Colitides
Sexually transmitted rectal infections include gonorrhea, herpes simplex, chlamydia, syphilis, amebiasis, and the various other enteric pathogenic bacteria.144 The persisting opportunistic infections in AIDS each have characteristic organisms: Cryptosporidia which may involve the small and large bowel (see Fig. 142-44), MAC, and rotavirus in children. CMV, HSV, tubercle bacilli (Fig. 142-55), and Histoplasma species (Fig. 142-56) also are seen. Schistosomal colitis (Fig. 142-56) is an important and extremely common problem in the rest of the world but is only occasionally seen in foreigners or international travelers in the United States. It is diagnosed by finding the characteristic eggs, often within epithelioid granulomas. A section through the edge of a granuloma may miss the egg and be confused with Crohn’s colitis, but inspection of serial sections can overcome this problem. Amebic colitis (Fig. 142-57) in nonendemic areas of the U.S. is seen mostly in travelers, migratory workers, and homosexual men. When amebic colitis is suspected, special care must be taken while obtaining and handling the biopsy specimen to avoid removing adherent mucus containing the amebae. Do not orient such specimens; just drop them into fixative and let the technician attempt orientation after fixation.
FIGURE 142-55. Colonic tuberculosis in a patient with acquired immunodeficiency syndrome (AIDS). A: The biopsy specimen shows inflammation of the colonic mucosa with multiple, large, confluent granulomas. The arrow points to a focus of necrosis within a granuloma. B: This shows the same biopsy specimen as in panel A, at higher power. Necrosis within granulomas should always suggest an infectious agent. C: Ziehl-Neelsen stain in which acid-fast bacilli of Myobacterium tuberculosis are evident. The tissue response to Myobacterium avium complex differs in that granulomas and diffuse granulomatous inflammation with discrete aggregates of epithelioid histiocytes are not seen; rather, there is diffuse infiltration of macrophages with foamy cytoplasm filled with acid-fast bacilli (see Fig. 142-41).
FIGURE 142-56. A: Colonic histoplasmosis in a patient with disseminated histoplasmosis in acquired immunodeficiency syndrome (AIDS). Distorted glandular architecture and an inflammatory infiltrate in the lamina propria are shown. B: Inspection of the inflamed lamina propria at higher power reveals a foamy or bubbly appearance caused by numerous Histoplasma organisms within the cytoplasm of macrophages. The organisms are seen as clear vacuoles, many of which contain a dark central dot representing the nucleus. C: Biopsy specimen from a patient with schistosomiasis. The ovum is clearly identified in the lamina propria and can be diagnosed as a schistosome, but speciation is not possible except in the rare circumstance in which the plane of section passes through a lateral spine of Schistosoma mansoni.
FIGURE 142-57. Amebic colitis. A: The mucosa shows diffuse inflammation of the lamina propria and an eroded surface. The material adherent to the surface includes erythrocytes and numerous amebic organisms. B: These are seen at high power. The organisms are large cells, measuring approximately 30 μm in diameter. They have a relatively small nucleus compared with the cytoplasmic volume. Phagocytized red blood cells are visible as black round structures within several of the amebae.
The most common antibiotic-related colitis is caused by overgrowth of C difficile, which secretes specific toxins. Although colitis caused by C difficile usually is called pseudomembranous colitis (Fig. 142-58), only 50% of patients have pseudomembranes at the time of biopsy and pseudomembranes are also seen in other colitides. With or without pseudomembranes, the histological pictures may be indistinguishable from acute self-limited colitis.
FIGURE 142-58. Pseudomembranous colitis caused by Clostridium difficile. A: This biopsy specimen shows features of an acute self-limited colitis with active inflammation of the lamina propria, erosion of the surface epithelium, and adherent fibrinopurulent exudate (pseudomembrane), but preservation of the crypt architecture. Most of the inflammatory cells are neutrophils. B: The erosion of the surface epithelium, the pseudomembrane, and the predominantly neutrophilic infiltration are well illustrated at high-power magnification. This picture has features also seen in ischemic colitis.
Collagenous Colitis
In collagenous colitis there is troublesome, often persistent watery diarrhea, for as long as 15 years, frequently in older women with a normal colonoscopy.145 On biopsy there is a thickened collagen plate (≥15 microns, the diameter of two red cells) located beneath the surface epithelium but not around the crypts (Fig. 142-59). It has a spiculated and irregular appearance due to an incorporation of capillaries and inflammatory cells within the collagen and due to projections of collagen into the underlying lamina propria. This produces a striking contrast to the normal basement membrane which has a uniform straight lower border. These qualitative changes in the collagen plate may be as important as the absolute thickness of the subepithelial collagen in establishing the diagnosis of collagenous colitis.146 The collagen deposition may be diffuse or patchy and tends to be least prominent in the distal sigmoid and rectum. The superficial lamina propria may be expanded by increased numbers of round cells. Occasionally the rectum is not involved and colonoscopy with more proximal sampling may be necessary for diagnosis. The crypt architecture is almost always well preserved and about half of patients have a focal, mild neutrophilic infiltration of the crypt epithelium which tends to be observed early in the course of disease rather than later. If the neutrophils are prominent, bacterial infection must be ruled out. Lymphocytosis of the surface and crypt epithelium may be present and surface cell damage may be prominent. Collagenous colitis does not have enough inflammatory change or architectural distortion to resemble IIBD. Patchy collagenous thickening however can occasionally be seen in IIBD, ischemic colitis, and other conditions. Rarely amyloid may mimic collagenous colitis.
FIGURE 142-59. Collagenous colitis. A: This biopsy specimen shows normal glandular architecture, a possible increase in the number of plasma cells in the upper portion of the lamina propria, and a markedly thickened subepithelial collagen plate. The surface epithelium is abnormal and infiltrated by lymphocytes. B: These changes are seen better at higher power. Observe the lacy or reticulated appearance of the thickened subepithelial collagen table, which incorporates inflammatory cells and capillaries.
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Lymphocytic Colitis
This is an entity in which patients have diarrhea and other symptoms and a normal appearance on colonoscopy.147 It is remarkably similar symptomatically to collagenous colitis. However histologically there is no excessive collagen but rather a prominent lymphocytic infiltration of the surface and crypt epithelium with expansion of the lymphocytic content of the lamina propria. Like collagenous colitis, lymphocytic colitis is idiopathic and has preservation of the crypt architecture, so the histological picture is not likely to be confused with IIBD.
The term “microscopic” colitis148 is applied to both collagenous and lymphocytic colitis as well as to patients with chronic diarrhea of unknown origin in general who have no endoscopic
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abnormalities. These patients may have mild inflammation on biopsy and are a heterogenous group that has only chronic diarrhea, normal endoscopy, and mild histological inflammation in common. Other causes are various drug-induced injuries. Thus, the term does not refer to a specific disease entity and should be replaced by more specific terminology whenever possible.
Patients with chronic, watery diarrhea and histological findings similar to lymphocytic colitis have been described in an epidemic of diarrhea traceable to a point source.149 Thus, the histological features of lymphocytic and collagenous colitis seen in patients with chronic, watery diarrhea may reflect reaction patterns to a variety of injuries, rather than specific disease entities.
Other Colitides
There are a variety of other colitides. Diversion colitis usually is a mild colitis that occurs when the colon is excluded from the fecal stream.150 Restoration of the fecal stream to the diverted colon reverses the process. Radiation colitis has an acute mucosal phase resembling acute ischemia and a more chronic mesenchymal phase with atypical fibroblasts, scarring, and telangiectatic capillaries that may have hyalinized walls.151 It is an unpredictable process that may become clinically manifest at any time from months to years after irradiation.
Finally, a number of colitides are iatrogenic. Endoscopes may be inadequately rinsed after use of sterilizing solutions or wash water may be contaminated. For example, a microvesicular form of pneumatosis intestinalis can be caused by the accumulation of gas bubbles after inadvertent exposure to hydrogen peroxide (Fig. 142-60A) or by insufflation of gas into microtears in the mucosa during endoscopy.152 Less dramatic are the changes produced by various methods of cleaning the colon in preparation for colonoscopy. Many cleansing enemas can cause active surface inflammation and edema.153 A bisacodyl enema may produce a confusing picture that can easily be considered
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colitic (see Fig. 142-60B, Fig. 142-60C).154 Gastrografin used as an enema instead of barium is hypertonic and highly irritating.
FIGURE 142-60. Pseudolipomatosis and other artifacts. A: Pseudolipomatosis of the lamina propria after inadvertent exposure to hydrogen peroxide left after cleaning the wash channel of the colonoscope. The bubbles in the lamina propria represent gas bubbles caused by the release of nascent oxygen when hydrogen peroxide contacted the mucosa. These bubbles can be differentiated from fat cells because they lack a cell membrane and vary markedly in size. B: The mucosa in a patient who has received a bisacodyl enema. The surface epithelium is flattened and contains focal infiltrates of neutrophils (arrow). C: Focal neutrophilic infiltration of the abnormal surface epithelium at higher power (arrow).
A variety of chemotherapeutic agents can cause extensive mucosal injury. This is especially well documented with 5-fluorouracil.155 Colitis associated with bone marrow transplantation is complex;93 the early lesion is caused by the preparatory irradiation and chemotherapy and the later lesions represent graft-versus-host reaction or opportunistic infections.
Focal active inflammation is not uncommonly identified in colonic biopsies. Surface apoptosis may also be prominent. The clinical significance of these findings is hard to assess and should probably not be referred to as colitis. These changes may very well be related to bowel preparation.
Solitary Rectal Ulcer Syndrome
Solitary rectal ulcer syndrome156 (SRUS) is also known by other, perhaps better, terms such as mucosal prolapse and localized colitis cystica profunda. It is a distinct clinical entity and has a characteristic but nonspecific histological appearance (Fig. 142-61). The term is a misnomer because the lesions may be multiple, they may involve the sigmoid as well as the rectum, and usually have erosions rather than ulcers or may lack both. This entity may be confused clinically with the ulcers of Crohn’s disease or with ulcerative carcinoma because of the hard lumpy tissue palpable around the ulcer. The thickened tissue may be filled with diffuse collagenous granulation tissue,157
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excess muscle bundles, and lengthened crypts with epithelial hyperplasia.
FIGURE 142-61. Solitary rectal ulcer syndrome. A: The biopsy specimen shows erosion of the surface epithelium, obliteration of the lamina propria by fibrosis, granulation tissue and smooth muscle, and gross distortion of the glandular architecture. Hyperplasia of the glandular epithelium also is seen. B: At higher power the eroded surface epithelium and obliteration of the lamina propria by collagenous granulation tissue and fibroblasts is better seen. Observe the epithelial hyperplasia that occasionally results in the misinterpretation of these lesions as adenomas or even cancer.
In 10% to 15% of patients, cystic glands penetrate into the submucosa to form so-called colitis cystica profunda;156 these ectopic glands are benign and have no desmoplastic stromal reaction surrounding them to suggest invasive malignancy.158 Histologically, there may be gross distortion of crypt architecture and erosion of the surface epithelium with adherent exudate producing a “pseudomembrane.” The muscularis mucosae is markedly hypertrophic and disorganized and bundles of smooth muscle and collagen extend high into the lamina propria around the crypts. The epithelium may appear quite hyperplastic and atypical, but it matures as it approaches the surface where the cytologic features of neoplasia are not present.
Other Diagnoses
Other diagnoses by biopsy include melanosis coli, a benign collection of lipofuscin-containing macrophages caused by laxatives, and pneumatosis cystoides intestinalis, marked by gross polyps on colonoscopy that contain gas-filled spaces in the submucosa lined by giant and epithelioid cells.152