Non-neoplastic Disorders of the Colon

Radiologic Features

Endoscopy with biopsy has replaced radiology in the initial diagnosis of IBD. Features that may be seen radiographically in patients with ulcerative colitis include continuous involvement of the colon with ulcers or polyps and the occasional finding of megacolon. Strictures, fistulas, “thumbprinting,” and skip areas are not seen.

Endoscopic Features

The gross endoscopic appearance of ulcerative colitis varies with the degree of activity, duration of disease, and response to therapy. It is characterized by diffuse disease, with rectal involvement extending proximally. In the more active phases, the mucosa is typically erythematous and friable, with a granular appearance ( Fig. 10.2 ). Erosions and ulcers are common. Quiescent disease may appear normal or granular with areas of punctuate erythema ( Fig. 10.3 ). Pseudopolyps that represent mucosal remnants and inflammatory polyps may be seen in active or quiescent disease ( Fig. 10.4 ). In most cases, the normal submucosal vascular pattern is lost and is an important clue to the endoscopist in favor of a chronic colitis. In patients who have had repeated bouts of colitis, the normal haustral folds may be lost, giving the lumen a tubelike appearance. The transition between normal and abnormal mucosa is generally gradual but may be abrupt. Variations to this classic appearance may occur in some patients and are discussed next.

Pathologic Features

Gross Findings

The colonic wall is usually of normal thickness with an unremarkable serosa, and strictures are rare in patients with ulcerative colitis. The mucosa may be flattened, hemorrhagic, and friable ( Fig. 10.5 ) with numerous inflammatory polyps. Disease involvement grossly extends in a continuous manner from the rectum proximally and may involve the entire colon and appendix and even the terminal ileum (“backwash ileitis”). Skip areas are not a feature of ulcerative colitis outside of well recognized exceptions to the rule, discussed in greater detail later.

Microscopic Findings

Biopsy Findings

Morphologically, diagnostic features of a chronic colitis can be broadly divided into architectural, inflammatory, and metaplastic. Architectural features include crypt disarray and branching and result from cycles of recurrent mucosal injury and inadequate repair. Most patients with suspected IBD undergo colonoscopy much earlier in their disease course than in the past. As a result, architectural features of chronicity are seldom pronounced in mucosal biopsies at initial presentation, and pathologists often rely merely on inflammatory and metaplastic features to make a diagnosis of a chronic colitis. Inflammatory features of a chronic colitis include basal lymphoplasmacytosis, which results from a marked increase in lamina propria inflammatory cells involving the entire thickness of the mucosa and creates a distinct band of lymphoplasmacytic inflammation between the base of the crypts and the muscularis mucosa ( Fig. 10.6 ). The lamina propria infiltrate is heterogeneous with a variable number of lymphocytes, plasma cells, and eosinophils. Eosinophils and lymphoid aggregates at the mucosal–submucosal interface can be quite prominent in some cases. Neutrophils are the hallmark of disease activity and may be present within the lamina propria, crypt epithelium (cryptitis), or crypt lumens (crypt abscesses) ( Fig. 10.7 ). Disease activity in chronic colitis is subjectively graded in mucosal biopsies as mild (cryptitis only), moderate (crypt abscesses), and severe (ulcerated mucosa). A loose collection of histiocytes may be present around ruptured crypts and is variously referred to as mucin granulomas or crypt rupture reaction ( Fig. 10.8 ) and should not be confused with compact sarcoid-like granulomas of Crohn’s disease. The injured colonic epithelium is mucin depleted and attenuated, but these findings are not helpful in distinguishing an acute from a chronic colitis. Metaplastic features of chronicity include pyloric gland metaplasia, which is more common in terminal ileum biopsies, and Paneth cell metaplasia, which is helpful in left colon and rectal biopsies. Paneth cells are normal in the proximal colon but are an indicator of chronic mucosal injury and repair in the distal colon. It is important to emphasize that low-grade ischemic injury, radiation, GVHD, and medications can also result in architectural and metaplastic features similar to IBD, and an initial diagnosis of untreated ulcerative colitis or Crohn’s disease should not be rendered in the absence of diagnostic inflammatory features of a chronic colitis.

Posttreatment biopsies in patients with IBD may show complete normalization of the mucosa, continued disease activity similar to the initial biopsies, or partial resolution with some evidence of residual injury. The latter group may show a chronic inactive colitis with increased lymphoplasmacytic infiltrate but without neutrophilic infiltration in the epithelium or a chronic quiescent colitis with only mild architectural disarray and/or Paneth cell metaplasia but without any increase in lamina propria inflammation ( Fig. 10.9 ).

Flares of ulcerative colitis occur quite commonly. Endoscopic evaluation with biopsy is done to confirm active ulcerative colitis and to exclude other causes such as Clostridium difficile colitis and cytomegalovirus (CMV) infection. CMV infection is quite common in patients with ulcerative colitis, and the presence of numerous CMV inclusions in a patient with active colitis warrants treatment with antiviral medications ( Fig. 10.10 ). The significance of only rare CMV inclusions in an otherwise typical active ulcerative colitis biopsy is less clear, although these patients are often treated with both immunosuppression and antiviral medications. Corticosteroids are often used to induce remission of the underlying IBD.

Variants of Ulcerative Colitis

There are defined variants of ulcerative colitis that deviate from the typical appearance already described and deserve mention. Up to 30% of patients with left-sided colitis may have patches of active disease in the right colon, particularly in the cecum near the appendiceal orifice. This finding, often referred to as the cecal patch , should not be confused with Crohn’s disease. Similarly, patchy disease involvement may be seen in patients with severe fulminant ulcerative colitis who present acutely and undergo a total colectomy to prevent perforation or in patients who have undergone treatment. Ulcerative colitis in the pediatric population may show relative or complete rectal sparing. In adults, rare cases may show relative rectal sparing with decreased disease activity compared with the more proximal colon, but complete rectal sparing is not seen. Ileal involvement by ulcerative colitis (“backwash ileitis”) may occur in patients who have severe pancolitis, and this should not be confused with Crohn’s disease ( Fig. 10.11 ). Inflammation in the ileum in this setting is often mild, limited to the distal few centimeters, and characterized by mild inflammation in the lamina propria and active neutrophilic infiltration in the crypt or villous epithelium. Chronic changes such as pyloric gland metaplasia, reminiscent of Crohn’s disease, may also be seen but are rare. Finally, biopsies from the upper GI tract may show histologic abnormalities in a subset of patients with ulcerative colitis, the most common being a focal active gastritis. A diffuse duodenitis and even a pan-enteritis have been described in rare patients with ulcerative colitis after total colectomy and ileal pouch anal anastomosis. The cause of this diffuse enteritis is unclear.

Resection Findings

The inflammatory process is confined to the mucosa in most cases ( Fig. 10.12 ) and shows a cellular inflamed lamina propria on low power, often with crypt architectural disarray and crypt loss. Lymphoid aggregates at the mucosal–submucosal interface may be present and can be numerous in some cases. Disease activity can be variable, ranging from mild cryptitis to mucosal ulcers with associated granulation tissue. Mounds of residual mucosal remnants surrounded by ulcer may stand out as pseudopolyps. ( Fig. 10.13 ). Most patients receive some form of medical therapy before a colectomy, so it is not unusual to see patchy disease involvement in resection specimens. The submucosa may be edematous and congested but is typically without significant inflammation or fibrosis. Lymphoid aggregates may be prominent underneath areas of mucosal ulceration and should not be mistaken for Crohn’s disease.

Occasionally, resection specimens for presumed ulcerative colitis show atypical histologic features that preclude a definitive diagnosis of ulcerative colitis and raise the possibility of Crohn’s disease. The presence of strictures, fistulas, perianal disease, transmural lymphoid aggregates, granulomas away from injured crypts or deeper in the intestinal wall, and segmental disease in an untreated setting are diagnostic features in favor of Crohn’s disease. A diagnosis of Crohn’s disease in a total colectomy for presumed ulcerative colitis has significant clinical consequences because these patients are not considered candidates for ileal pouch anal anastomosis at most centers. Conversely, defined histologic variants of ulcerative colitis described in the previous section should not be mistaken for Crohn’s disease. Despite meticulous work-up and systematic review, rare cases are difficult to classify, and such resection specimens may be diagnosed as IBD, unclassified type. The use of the term indeterminate colitis is discouraged. At most centers, these patients are followed closely for definitive signs of Crohn’s disease, and an ileal pouch anal anastomosis is eventually performed if no signs of Crohn’s disease are seen on follow-up.

Differential Diagnosis

In the early phase of the disease, features of chronicity may not be well established in mucosal biopsies obtained from patients with ulcerative colitis. In this scenario, the main differential diagnosis is with acute self-limited colitis and drug-induced colitis. Acute self-limited colitis is a clinical term often used for diarrheal disorders of short duration related to an infectious cause. The biopsy findings in acute self-limited colitis are those of a focal or diffuse active colitis of varying severity. The increased lymphoplasmacytic infiltrate in the lamina propria is typically described as being confined to the upper half of the mucosa but may be full thickness in severe cases. However, the characteristic basal lymphoplasmacytosis of a chronic colitis is absent, and normal colonic crypt architecture is preserved. Similarly, a variety of medications may cause a similar pattern of injury. The most recent addition to this group are immune checkpoint receptor inhibitors that are being used with increasing frequency in the management of a variety of solid tumors.

In the chronic phase of the disease, the differential diagnosis is limited to a chronic infectious colitis or a handful of well-recognized IBD mimics. Infections that can have a chronic relapsing course, such as C. difficile , may induce mucosal changes that mimic IBD. Similarly, architectural changes of IBD may be seen in radiation or low-grade ischemic injury, but these can be easily distinguished based on the lack of a prominent inflammatory component. The distinction from diverticular disease associated colitis and diversion colitis can be challenging and is discussed in detail under these entities later.

Ancillary Studies

No specific tests for ulcerative colitis are available. Initially, patients should be tested for infectious causes that are known to be associated with long-standing colitis, particularly to exclude Shigella spp., Salmonella spp., Escherichia coli O157:H7, Campylobacter jejuni , and C. difficile . Stool studies for ova and parasites as well as exclusion of Giardia spp. may be warranted in patients with specific risk factors or relevant travel history. Patients who have a flare of ulcerative colitis while being treated with immunosuppressive therapy may also benefit from testing for CMV and C. difficile infection, which can present with deep ulcers in the background of ulcerative colitis. C. difficile infections in the setting of ulcerative colitis seldom show the typical pseudomembranous colitis pattern, and microbiologic work-up is necessary for diagnosis. Results of serologic tests for perinuclear antineutrophil cytoplasmic antibody are often positive in patients with ulcerative colitis but have limited utility in differentiating ulcerative colitis from Crohn’s disease in difficult cases.

Pathologic Features

Microscopic Findings

Dysplasia in ulcerative colitis may show cytologic and architectural changes that vary with grade of dysplasia. Architecturally, the crypts may be normal or show crypt budding, crowding, or prominent serration, the latter in the case of serrated dysplasia. Nuclear hyperchromasia, enlargement, and irregularity are often present, and the cytoplasmic features are variable and range from complete mucin depletion to abundant eosinophilic, hypermucinous, or clear cytoplasm reminiscent of foveolar type dysplasia seen in the upper GI tract. Low-grade dysplasia is similar to sporadic tubular adenomas and is characterized by elongated penicillate, hyperchromatic nuclei perpendicular to the basement membrane with variable degree of pseudostratification. An abrupt change from adjacent normal mucosa is helpful in diagnosis of dysplasia ( Fig. 10.14 ). High-grade dysplasia is characterized by more pronounced nuclear changes, including round nuclei no longer perpendicular to the basement membrane (loss of polarity), nuclear pleomorphism, marked hyperchromasia, and nucleolar prominence ( Fig. 10.15 ). In many instances, high-grade dysplasia in the setting of IBD, particularly flat invisible dysplasia, may not show architectural features of crypt crowding and budding. Diagnostic cytologic features described earlier are sufficient to classify such biopsies as high-grade dysplasia. Surveillance biopsies in ulcerative colitis, particularly those obtained during chromoendoscopy, may show serrated lesions with morphological appearance similar to sporadic hyperplastic polyps, sessile serrated adenoma or polyp (SSP), or a traditional serrated adenoma (TSA). The presence of hyperplastic polyp-like change in flat mucosal biopsies in IBD has been referred to as serrated epithelial change and does not lead to increased surveillance. SSP and TSA morphology in IBD is almost always seen in biopsies obtained from endoscopically visible lesions. The significance of hyperplastic polyp or SSP in patients with IBD with respect to recommended surveillance intervals is unclear, but the overall risk of cancer appears to be low as long as complete excision of visible lesions is performed.

The presence of a visible dysplastic lesion in the background of ulcerative colitis may either represent a sporadic adenoma or colitis-associated dysplasia. Although some molecular differences exist between these two forms of visible dysplasia, it is impossible to separate these lesions based on morphology alone. Fortunately, making this distinction is of little practical importance because management of visible lesions in the setting of ulcerative colitis depends mostly on the endoscopic appearance. Patients with well-circumscribed lesions ( Fig. 10.16 ) that can be removed endoscopically can be safely followed with surveillance after complete polypectomy. Irregular lesions with indistinct borders often require surgical intervention, although advanced endoscopic techniques such as endoscopic mucosal resection and endoscopic submucosal dissection ( Fig. 10.17 ) are increasingly used at tertiary academic centers.

Invisible dysplasia is becoming increasingly less common with the advent of chromoendoscopy. A single focus of invisible low-grade dysplasia may be followed by increased surveillance. Persistent or multifocal flat low-grade dysplasia and invisible high-grade dysplasia usually warrant a colectomy because of the high risk of concurrent adenocarcinoma.

Differential Diagnosis

Ulcerative colitis must be distinguished from a large number of mimics, including infectious colitis, medication-induced colitis, ischemic colitis, Crohn’s disease, diversion colitis, and diverticular disease associated colitis, among others. Long-standing infectious colitis may have many of the features of ulcerative colitis, including increased chronic inflammation, neutrophils, and diffuse colonic involvement. The clinical setting, lack of significant basal lymphoplasmacytosis, and microbiologic work-up are all key to avoiding a misdiagnosis of IBD at initial presentation. Medications, particularly nonsteroidal antiinflammatory drugs (NSAIDs), may present with focal active colitis, chronic active colitis, or one or many ulcers throughout the colon. Histologically, NSAID ulcers are small and discrete and lack the confluent mucosal involvement typically seen in ulcerative colitis on endoscopy. Recently, chronic colitis has also been described in patients on immune checkpoint receptor inhibitor–associated chemotherapy. The presence of a concomitant increase in intraepithelial lymphocytes and prominent apoptosis along with features of a chronic colitis are helpful features in favor of an immunotherapy-associated colitis. Like with other drug-induced colitides, correlation with timeline of disease course and resolution of symptoms after cessation of drug or immunosuppression is needed to establish the diagnosis. Chronic ischemic or radiation colitis can also be mistaken for ulcerative colitis, particularly because ischemia resulting from low vascular flow often affects the left colon, and repeated injury and repair may lead to architectural changes of a chronic colitis. However, these cases lack the typically inflammatory component of ulcerative colitis, and an initial diagnosis of IBD should never be made only on architectural features in an untreated patient. The patchy distribution of the disease is only helpful in distinguishing Crohn’s disease from ulcerative colitis at initial presentation. After institution of medical therapy, the mucosa of patients with ulcerative colitis often heals in a patchy distribution. Diverticular disease–associated colitis can have features identical to ulcerative colitis. The distribution of the colitis involving the interdiverticular mucosa in a colonic segment involved with diverticular disease and sparing of the rectum and remaining colon are helpful in making this distinction. Segments of colon that are excluded from the fecal stream develop a diversion colitis characterized by marked lymphoid hyperplasia, cryptitis, and crypt architectural distortion, which mimics ulcerative colitis. Knowledge of the clinical setting is important to avoid misdiagnosis.

Prognosis and Therapy

The goals of medical treatment in ulcerative colitis include inducing and maintaining remission, minimizing side effects, and improving the quality of life. Standard therapy includes antiinflammatory drugs, specifically, the 5-aminosalicylic acid (5-ASA) compounds (sulfasalazine and other salicylates), which are effective in preventing exacerbations in patients in remission. Steroids, either topical (enemas) or systemic, are effective in treating acute flares of disease. Biologic therapy is becoming increasingly common, particularly antibodies against tumor necrosis factor-α (TNF-α) and antibodies against adhesion molecules that affect lymphocyte trafficking. Patients with acute fulminant colitis, refractory disease, or persistent invisible dysplasia or endoscopically unresectable visible dysplasia are all treated with total colectomy. Resection with subsequent ileal pouch anal pouch anastomosis allows the patient to have relatively normal bowel function by maintaining the anal sphincter after colectomy.

Patients who are detected to have adenocarcinoma on surveillance have a significantly better prognosis than those in whom carcinoma is detected after the development of clinical symptoms. Additional long-term complications and associated conditions of ulcerative colitis include chronic anemia, hypoalbuminemia, sclerosing cholangitis, ankylosing spondylitis, arthritis, uveal disease, arthritis, vasculitis, and drug-associated complications.

Radiologic Features

As with ulcerative colitis, endoscopy has replaced radiology in the diagnosis of Crohn’s disease; however, visualization of small bowel lesions often requires radiologic imaging, particularly with magnetic resonance imaging or computed tomography (CT) enterography. Radiographic features typical of Crohn’s disease include asymmetric ileal involvement, longitudinal ulcers, cobblestone appearance, mural thickening and fat stranding, segmental stenosis and fistulas.

Endoscopic Features

The gross endoscopic appearance of Crohn’s disease is most consistently characterized as a multifocal process. Aphthous erosions ( Fig. 10.18 ), longitudinal ulcers (train track or rake ulcers) ( Fig. 10.19 ), and adjacent areas of erythematous or unremarkable mucosa are characteristic of Crohn’s disease. Additional endoscopic findings include cobblestoning resulting from alternating ulcers and edematous mucosa, strictures, fissures, and fistula. The rectum is often spared, unlike in ulcerative colitis. A variable number of inflammatory polyps may be present and are at times large and numerous, a phenomenon described as giant filiform polyposis in the literature. In both Crohn’s disease and ulcerative colitis, the normal submucosal vascular network is lost in the involved areas, assisting the endoscopist in the diagnosis of chronic colitis.

Pathologic Features

Gross Findings

Resection is typically performed only in patients who have severe complications such as obstruction resulting from strictures, abscess, fistulas, or perforation. Because the milder forms of the disease are not resected, the gross pathologic findings in resection specimens are usually prominent. The subserosal fat is often firm and contracted over stenotic areas of involvement, so-called creeping fat . Longitudinal opening of the bowel may reveal areas with normal bowel wall thickness and other areas of the bowel that are firm, thick, and pipelike ( Fig. 10.20 ). Interloop adhesions may occur. The mucosa may show a variety of changes, including aphthous erosions, longitudinal ulcers, cobblestoning, polyps, fissures, and fistulas. The process is usually multifocal, often with rectal sparing, but may become confluent. When confluent, the firm, pipelike nature of the bowel may help to distinguish Crohn’s disease from ulcerative colitis, in which fibrosis is unusual.

Microscopic Findings

Biopsy Findings

It is hard to distinguish Crohn’s disease from ulcerative colitis based on microscopic findings in mucosal biopsies since the characteristic features are present deeper in the bowel wall. The presence of granulomas away from inflamed crypts or in superficial submucosa is helpful but is seen only in a minority of patients. In most instances, knowledge of clinical and endoscopic findings is critical for diagnosing Crohn’s disease. Aphthous erosions or ulcers, characterized by focal surface epithelial injury associated with a mixed inflammatory infiltrate and sometimes associated with underlying lymphoid aggregates, are typical early lesions. Variability of inflammation within a single biopsy sample and among several biopsy fragments from the same anatomic location is often seen but not diagnostic because acute fulminant or early ulcerative colitis and posttreatment biopsies in ulcerative colitis may show the same pattern of injury. The areas of inflammation show architectural changes of chronic crypt destructive colitis, but adjacent crypts may appear totally normal ( Fig. 10.21 ). Granulomas tend to occur more frequently in pediatric patients, usually present away from inflamed crypts and in the submucosa, and are non-necrotizing ( Fig. 10.22 ).

Crohn’s disease involving the terminal ileum may show a focal active ileitis or a chronic active ileitis pattern of injury. Aphthous erosions, increased lamina propria infiltrate leading to villous blunting, and cryptitis are often seen at initial presentation. Crypt disarray is often difficult to assess in the small intestine in the presence of marked inflammation, but metaplastic features are very helpful in this setting. Pyloric gland metaplasia consisting of simple mucus glands reminiscent of the antral or pyloric mucosa are the most reproducible features of chronicity in ileal biopsies. Peyer’s patches are a normal component of the terminal ileum, particularly in young individuals, and should not be mistaken for increased lymphoplasmacytic inflammation of Crohn’s disease. The mucosa over Peyer’s patches may be distorted with flattened villi resulting from underlying expansion of lymphoid nodules in nonspecific reactive hyperplasia or from infections such as Yersinia spp.

Resection Findings

The inflammatory process is typically multifocal with a chronic enteritis or colitis, superficial and deep fissures, fistulas, and prominent transmural lymphoid aggregates ( Figs. 10.23 to 10.25 ). Ulcers are typically longitudinally oriented, separated by histologically normal edematous mucosa. Granulomas, when present, may be located at any level of the bowel wall. Lymphoid aggregates are often around dilated lymphatics or nerves. Neural hyperplasia is common in the submucosa and muscularis propria.

Ancillary Studies

No specific tests for Crohn’s colitis are available. However, as with ulcerative colitis, exclusion of infectious causes is important, particularly Yersinia infection. Antibodies to Saccharomyces cerevisiae are present in approximately 70% of patients with Crohn’s disease and are usually absent in patients with ulcerative colitis. In contrast, p-ANCA test results are positive in approximately 70% of patients with ulcerative colitis and in 10% to 30% of patients with Crohn’s disease. There is overlap of results between Crohn’s disease and ulcerative colitis, and although these tests may be helpful in rare instances, they are seldom performed to distinguish ulcerative colitis from Crohn’s disease.

Differential Diagnosis

Crohn’s disease must be distinguished from infections, ulcerative colitis, ischemic colitis, medication-associated injury, diverticular disease–associated colitis, and isolated asymptomatic ileitis. The endoscopic finding of focal aphthous erosions of early Crohn’s disease may be similar to erosions caused by medications and infections. Histologically, the erosions of Crohn’s colitis and ileitis are associated with a dense lymphoplasmacytic infiltrate. Focal active ileitis is most commonly caused by medications, particularly NSAIDs, but a small subset may be associated with Crohn’s disease, which is why correlation with clinical and endoscopic findings is essential. Isolated chronic active ileitis in an asymptomatic patient may be seen in patients undergoing routine screening colonoscopy and is associated with chronic NSAID use or low-grade ischemia and is not a manifestation of Crohn’s disease ( Fig. 10.26 ). Biopsies from other sites of the GI tract, including upper tract biopsies, are often helpful in establishing a diagnosis of Crohn’s disease.

Nonsteroidal antiinflammatory drug ulcers may be multiple and deep, and chronic blood loss may lead to a curative resection. These ulcers tend to be found on the top of mucosal folds and are circumferential rather than longitudinal. There is usually minimal inflammation away from the ulcers. Strictures may form in these cases and when circumferential, they appear like “diaphragms.” Yersinia infection causes a granulomatous ileocolitis with preferential involvement of the right colon. Granulomas with central neutrophil-rich suppuration, marked mesenteric lymph node enlargement with a necrotizing lymphadenitis should favor Yersinia infection over Crohn’s disease. Necrotizing granulomas predominate in tuberculosis and should be worked up with acid-fast bacilli stains or with more sensitive polymerase chain reaction techniques in cases in which clinical suspicion is high. Diverticular disease–associated colitis usually only involves the sigmoid colon, and the inflammation is confined to the area involved with diverticulosis.

Fulminant Crohn’s colitis can be difficult or impossible to distinguish from ulcerative colitis in a mucosal biopsy specimen because many of the distinguishing features are deep to the mucosa. Furthermore, in fulminant ulcerative colitis, inflammation may be transmural but is composed of dispersed acute and chronic inflammatory cells without the characteristic lymphoid aggregates of Crohn’s disease.

Prognosis and Therapy

Standard therapy includes antiinflammatory drugs, specifically the 5-ASA compounds (sulfasalazine and other salicylates), and steroids. Budesonide, a topical steroid that is taken orally, is effective in treating patients with ileal Crohn’s disease. It is locally absorbed and metabolized in the liver minimizing the systemic side effects seen with other steroids. Infliximab, a monoclonal antibody against TNF-α, has been found to be helpful in treating acute episodes of Crohn’s colitis, particularly fistulas and other complications. Vedolizumab, a monoclonal antibody against α4β7 integrin, is also approved for treatment of patients with Crohn’s disease. Surgery is reserved for patients with refractory disease and those with obstruction, nonresponsive fistulas, sepsis, or carcinoma. Patients who have undergone surgical intervention are at increased risk for requiring additional surgery resulting from anastomotic complications such as strictures, anastomotic leaks, and fistulas.

There is a 4 to 20 times increased risk for adenocarcinoma in patients with Crohn’s disease compared with the general population. Dysplasia occurs in patients with Crohn’s disease similar to those with ulcerative colitis. Surveillance of patients with Crohn’s colitis follows those with ulcerative colitis and depends on the extent and duration of disease. Adenocarcinomas may arise in a morphologically normal bowel, in areas of stricture, or within fistula tracts, making diagnosis difficult. Synchronous or metachronous adenocarcinomas may occur and involve the large or small intestine. Well-differentiated adenocarcinomas may arise in mucosa that has subtle low-grade dysplasia and infiltrate as deceptively bland glandular structures ( Fig. 10.27 ). Well-differentiated mucinous adenocarcinomas that arise in chronic anal fistulas can be difficult to distinguish from non-neoplastic fistula lining.

Clinical Features

After total proctocolectomy, construction of an ileal pouch anal anastomosis (J-pouch) is often performed to restore continence and improve quality of life. This is often performed in the setting of ulcerative colitis, but a J-pouch may also be created in patients with other colonic disease, particularly hereditary colorectal cancer syndromes such as familial adenomatous polyposis. Inflammation of the pouch (“pouchitis”) is a common complication that is diagnosed clinically based on symptoms of diarrhea, bleeding, urgency, low-grade fever, and occasionally abdominal pain. Although more than half of patients with a J-pouch experience at least one episode of pouchitis, pouch failure and excision are extremely rare. Pouchitis also decreases dramatically after the first 6 months of surgery and is likely related to an alteration in the small intestinal microbiome. Pouchitis is a clinical term that translates to histologic patterns of acute and/or chronic mucosal injury. First-line therapy for pouchitis is with antibiotics. Patients with chronic symptoms and refractory disease who do not respond to antibiotics are often treated with immunosuppression.

Pathologic Features

The pouch is constructed from the ileum, and even healthy pouches demonstrate some abnormal histologic features in the ileal mucosa such as villous blunting, mild expansion of the lamina propria, increased eosinophils, and increased intraepithelial lymphocytes. These are part of the “adaptive response” as the small intestine transitions to functioning as a neorectum. Patients with clinically diagnosed pouchitis demonstrate neutrophilic inflammation in both the crypt and surface epithelium. Ulcers and erosions may be seen. Chronic pouchitis often demonstrates villous architectural distortion and pyloric gland metaplasia, but this should not be taken as evidence of Crohn’s disease ( Fig. 10.28 ).

Pathologic Features

At low power, biopsy specimens of CC often show a variably thick and irregular eosinophilic subepithelial “stripe” with an intact crypt architecture and an increase in lamina propria mononuclear cells ( Fig. 10.29 ). At higher magnification, the lamina propria shows increased lymphocytes, plasma cells, and eosinophils, which may involve the full thickness of the mucosa, mimicking IBD, or may be confined to the upper half similar to the appearance in acute self-limited colitis. The surface epithelium has a patchy increase in intraepithelial lymphocytes with areas of surface damage. The surface epithelium is often stripped off from the thickened collagen table. The subepithelial collagen is irregular and usually blends imperceptibly with the basement membrane and often entraps small capillaries and inflammatory cells, which can be better visualized on a trichrome stain ( Fig. 10.30 ). The thickness of the collagen often varies from site to site in individual patients and should be evaluated only in well-oriented sections. Whereas the normal basement membrane of the colon measures 2 to 5 μm, in CC, the collagen typically has a thickness of 10 to 30 μm. Biopsies from the rectum and sigmoid colon may show less thickening and may be within a normal range. When in doubt, a trichrome stain can be used to highlight the thick and irregular collagenous band. The irregular character of the subepithelial collagen rather than the absolute thickness is helpful in making a diagnosis of CC. Care should be taken not to overinterpret a thickened basement membrane as CC because this may be a normal finding in the left colon. Surface epithelial damage with increased intraepithelial lymphocytes are always present in cases of CC. Intraepithelial neutrophils may be seen but are less prominent than the intraepithelial lymphocytes. Large numbers of crypt abscesses are probably indicative of either superimposed infection or another colitis. Paneth cell or pyloric gland metaplasia and mild crypt architectural distortion may also be present in a minority of cases because CC is a chronic colitis. The collagen layer abnormalities normalize in a significant proportion of patients on therapy, and recurrence of symptoms should not always be taken as a manifestation of relapsed CC. The terminal ileum may also be involved in a minor subset of cases with CC, and rare cases show a giant cell histiocytic response with multinucleated giant cells beneath the abnormal collagen layer.

Differential Diagnosis

Lymphocytic colitis is identical to CC except for the absence of abnormal subepithelial collagen. Eosinophils are typically less prominent in the lamina propria in LC. Chronic IBD typically shows more architectural distortion, and the clinical presentation is very different from that of CC. IBD patients present with bloody diarrhea and show mucosal abnormalities on colonoscopy. In extremely rare cases, features of both IBD and CC may be present in different part of the colon at the same procedure, and most such patients are clinically diagnosed and treated as having IBD. Mucosal prolapse shows fibromuscular proliferation in the lamina propria and architectural distortion, but the distinctive subepithelial band is not present in these cases. Enema effect may strip off the surface epithelium and make it difficult to evaluate the surface epithelium, but the lamina propria and collagen layer are both normal. Ischemia often has fibrosis and hyalinization of the lamina propria that may be misdiagnosed as CC but does not show the increased intraepithelial lymphocytosis seen in CC or the characteristic abnormal subepithelial abnormal collagen layer. Radiation colitis also shows hyalinization of the lamina propria, usually with telangiectatic blood vessels and atypical endothelial cells and fibroblasts. The hyaline material does not stain as intensely on the trichrome stain as the thick and irregular collagen layer in CC.

Prognosis and Therapy

Some patients with CC have a spontaneous remission, but others respond to simple over-the-counter antidiarrheal agents. Most patients, however, require some form of antiinflammatory therapy (steroids, 5-ASA compounds, or both). Rarely, patients with refractory disease may require a diverting ileostomy. The overall course of the disease tends to wax and wane, but it is generally not as severe as ulcerative colitis or Crohn’s disease.

Clinical Features

There is considerable overlap of clinical and pathologic features between LC and CC. Patients have chronic watery diarrhea with normal or near-normal endoscopic findings. There tends to be less of a female predominance in LC than in CC, but the age range is quite similar.

Many medications known to cause CC, including ranitidine, sertraline, ticlopidine, NSAIDs, aspirin, immune checkpoint receptors, and proton pump inhibitors, have also been reported to cause LC. The association between LC and celiac disease is even stronger than the association between CC and celiac disease. These findings again support the notion that luminal antigens somehow induce this colitis. In addition, human leukocyte antigen (HLA) studies have shown an increased incidence of HLA A1, DQ2, DQ1, and DQ3 in patients with LC, as well as other autoimmune processes.

Pathologic Features

In general, LC is similar to CC but lacks the thick and irregular abnormal subepithelial collagen layer. Eosinophils are usually less prominent in the lamina propria than in CC, and when increased, a careful look for subepithelial collagen irregularities is warranted because diagnostic changes can be mild and patchy. Special stains for collagen are also useful in this scenario to unmask subtle changes. The surface epithelial damage with increased intraepithelial lymphocytes is often more prominent in LC. Just as in CC, there is generally a superficial plasmacytosis without significant crypt distortion ( Figs. 10.31 and 10.32 ). The pathologist must avoid evaluating the number of intraepithelial lymphocytes overlying a lymphoid follicle because numerous intraepithelial lymphocytes are normal in this location. One should also recognize that normally, there are more intraepithelial lymphocytes in the right colon than the left colon. A few foci of cryptitis or a rare crypt abscess may be seen in LC, but striking neutrophilic inflammation is usually suggestive of another diagnosis, such as infection or medication-induced colitis. Recently, it was recognized that some cases of LC have less surface damage and more intraepithelial lymphocytes in the deeper crypt epithelium. Another variation of LC has been described with collections of histiocytes and poorly formed granulomas underneath the surface epithelium.

Prognosis and Therapy

Therapy for patients with LC is variable and is largely identical to that used for those with CC. Some patients’ symptoms resolve spontaneously, but others may require over-the-counter antidiarrheal medications, bismuth subsalicylate, 5-ASA compounds, or immunosuppressants. Overall, the prognosis is good because most patients eventually respond to some form of therapy. However, there is a small subset of patients who have LC and spruelike changes in their small bowel biopsies that seem refractory to all therapy. These patients have been classified as having lymphocytic enterocolitis. Some patients with this finding may have autoimmune enteropathy, common variable immunodeficiency, or in rare instances a lymphoproliferative disorder.