Role of Histologic Inflammation in the Natural History of Ulcerative Colitis




The goals of therapy for ulcerative colitis have moved from symptom improvement to mucosal healing, and finally histologic resolution. The natural history of histologic inflammation in ulcerative colitis progresses from initial cellular infiltration to architectural disruption and recovery on medical therapy. Many studies have linked histologic changes to clinical outcomes, providing prognostic value to histologic abnormalities. This review covers all these components.


Key points








  • Several histologic grading systems exist to document the severity of ulcerative colitis (UC).



  • These systems have not been validated for universal use in evaluating changes in histologic findings in response to therapy.



  • Histologic features have been associated with clinical outcomes in patients with UC.






Introduction


Ulcerative colitis (UC) is a chronic, episodic inflammatory disorder of the colon that classically affects the rectum, with variable, but continuous, involvement of the proximal colon. The clinical management of UC primarily includes aminosalicylates, corticosteroids, purine antimetabolites, and tumor necrosis factor antagonists, either used sequentially or in combination. The goal of medical therapy is to achieve clinical remission. In current clinical practice, disease activity is monitored by assessing patients’ clinical symptoms and severity of colonic inflammation by colonoscopy. Consensus guidelines for clinical practice and trial end points recommend striving beyond resolution of clinical symptoms to achieve endoscopic mucosal healing. Endoscopic mucosal healing in inflammatory bowel disease (IBD) is defined by resolution of visible mucosal inflammation and ulceration. Several studies have shown that mucosal healing, as assessed by endoscopic examination, is associated with better long-term clinical outcomes compared with evaluation of clinical symptoms alone. However, there is evidence to suggest that endoscopic findings do not necessarily correlate with histologic disease, especially after treatment. Numerous scoring systems have been developed to measure the histologic features of UC and predict clinical outcome. The goal of this article is to (1) review the general pathologic features of UC, (2) review effects of medications on histology of UC, (3) discuss the pattern of histology in patients in clinical remission, and (4) address key histologic features predictive of relapse of disease or development of neoplasia.




Introduction


Ulcerative colitis (UC) is a chronic, episodic inflammatory disorder of the colon that classically affects the rectum, with variable, but continuous, involvement of the proximal colon. The clinical management of UC primarily includes aminosalicylates, corticosteroids, purine antimetabolites, and tumor necrosis factor antagonists, either used sequentially or in combination. The goal of medical therapy is to achieve clinical remission. In current clinical practice, disease activity is monitored by assessing patients’ clinical symptoms and severity of colonic inflammation by colonoscopy. Consensus guidelines for clinical practice and trial end points recommend striving beyond resolution of clinical symptoms to achieve endoscopic mucosal healing. Endoscopic mucosal healing in inflammatory bowel disease (IBD) is defined by resolution of visible mucosal inflammation and ulceration. Several studies have shown that mucosal healing, as assessed by endoscopic examination, is associated with better long-term clinical outcomes compared with evaluation of clinical symptoms alone. However, there is evidence to suggest that endoscopic findings do not necessarily correlate with histologic disease, especially after treatment. Numerous scoring systems have been developed to measure the histologic features of UC and predict clinical outcome. The goal of this article is to (1) review the general pathologic features of UC, (2) review effects of medications on histology of UC, (3) discuss the pattern of histology in patients in clinical remission, and (4) address key histologic features predictive of relapse of disease or development of neoplasia.




Pathologic features of ulcerative colitis


Depending on the phase of disease and the degree of inflammatory activity, UC is categorized as normal (no histologic abnormalities) ( Fig. 1 ), chronic inactive ( Fig. 2 ), or chronic active ( Figs. 3 and 4 ). Some patients may show activity but without features of chronicity ( Box 1 ). Chronic colitis (regardless of presence or absence of activity) is defined by the presence of histologic features indicating chronic repeated tissue injury, such as crypt architectural distortion, crypt atrophy, diffuse mixed lamina propria inflammation, basal plasmacytosis, basal lymphoid aggregates, lamina propria fibrosis, pyloric gland metaplasia, and Paneth cell metaplasia, among others. Histologically, untreated UC involves the colon in a diffuse and continuous manner. It always involves the distal most portion of rectum (except in children in rare cases). UC characteristically involves the mucosa and occasionally the superficial submucosa in severe cases. The inflammatory infiltrate is typically composed of lymphocytes, plasma cells, and a variable amount of eosinophils and neutrophils depending on the severity of activity. The density of plasma cells is usually greatest in the basal region of the lamina propria (termed basal plasmacytosis ). Basal lymphoid aggregates are also commonly present. A characteristic morphologic feature of UC is crypt architectural distortion. When distorted, crypts usually appear irregular, distended, branched, dilated, and/or foreshortened. It is considered a histologic hallmark of chronic injury. However, this feature is much more common in pretreatment, whereas in posttreatment the mucosa often normalizes completely without any evidence of crypt distortion. In a study that evaluated histologic changes following 5-aminosalicyclic acid (5-ASA) treatment, crypt distortion was observed in 43% of cases.




Fig. 1


Normal colon. The biopsy shows crypts that are arranged in a regular, test tube–like configuration. The lamina propria is composed of lymphocytes, plasma cells, and rare eosinophils. Hematoxylin-eosin, original magnification ×200.



Fig. 2


Chronic inactive colitis. The biopsy obtained from the left colon shows crypt architectural distortion (irregular size and shape of the crypts) along with Paneth cell metaplasia ( arrow ). The lamina propria is slightly expanded by lymphocytes and plasma cells. There is no evidence of activity (neutrophils or eosinophils within the epithelium). Hematoxylin-eosin, original magnification ×100.



Fig. 3


Chronic active colitis with mild to moderate activity. The biopsy shows crypt architectural distortion along with expansion of the lamina propria by lymphoplasmacytic inflammatory cell infiltrate. Basal lymphoid aggregate is also present ( black arrow ). A large crypt abscess is also identified ( yellow arrow ). Hematoxylin-eosin, original magnification ×100.



Fig. 4


Chronic active colitis with severe activity. The biopsy shows foci of neutrophilic epithelial injury along with erosion. In addition, there is prominent basal lymphoplasmacytosis ( arrows ) as well as crypt architectural distortion, all indicating chronic colitis with severe activity. Hematoxylin-eosin, original magnification ×40.


Box 1





  • Common features of activity



  • Increased eosinophils and neutrophils within the lamina propria



  • Eosinophilic or neutrophilic infiltration within the crypt epithelium (cryptitis) with or without abscess formation (crypt abscesses)



  • Surface erosion and/or ulceration



  • Hemorrhage and edema within lamina propria



  • Expansion of lamina propria by a mixed inflammatory cell infiltrate



  • Regenerative epithelial changes, including mucin depletion




  • Common features of chronicity



  • Crypt architectural distortion/atrophy



  • Basal plasmacytosis



  • Basal lymphoid aggregates



  • Paneth cell metaplasia in left colon, Paneth cell hyperplasia in right colon



  • Pyloric gland metaplasia



  • Fibrosis



  • Diffuse mixed lamina propria inflammation



Histologic features of activity and chronicity in ulcerative colitis


The histologic features of active colitis vary depending on the severity of disease. In most active cases, a neutrophilic inflammatory cell infiltrate (either with or without eosinophils) may be present within the lamina propria and in the crypt epithelium (cryptitis). When neutrophils penetrate into the lumen of crypts and are associated with necrotic debris, it is termed crypt abscess . These abscesses are common in moderate to severe disease. Crypt abscesses may be focal or diffuse, depending on the severity of disease. Rupture of inflamed crypts can lead to the development of a granulomatous response to extravasated mucin. These crypt rupture–associated granulomas should be distinguished from granulomas in Crohn’s disease.




Histologic scoring systems to assess disease activity in ulcerative colitis


Truelove and Richards were the first to introduce a histologic scoring system that was applied to biopsy specimens from patients with UC. Since then, there have been at least 18 histologic indices that have been proposed to measure to degree of inflammation in UC. Some of these include evaluating the degree of acute or chronic inflammation, inflammatory cell infiltrate within lamina propria and epithelium, architectural distortion, and integrity of colonic epithelium. However, there is no universally accepted method of assessing activity in biopsies of patients with IBD. One commonly used method scores activity as inactive if there is no evidence of activity (defined as epithelial infiltration by neutrophils), mild if less than 50% of the mucosa shows evidence of activity, moderate if more than 50% shows these features, and severe if surface erosion or ulceration is present. This method is the most commonly used method in clinical practice.


Review of the scoring systems used in clinical studies indicates that some systems use a stepwise method whereby the disease activity is divided into subjectively assessed grades, whereas others use a quantitative method by generating numerical scores that correspond to specific histologic features. Summarizing the strengths and limitations of all the 18 histologic scoring systems is beyond the scope of this review. The authors briefly discuss systems that have been commonly used in clinical studies and trials.


The Riley scoring system uses a 4-point score (none, mild, moderate, and severe) to assess 6 histologic features: presence of an acute inflammatory cell infiltrate (neutrophils in the lamina propria), crypt abscesses, mucin depletion, surface epithelial integrity, chronic inflammatory cell infiltrate (round cells in the lamina propria), and crypt architectural irregularities. This scoring system was applied in a prospective study that was aimed at predicting recurrence in 82 outpatients with asymptomatic UC in endoscopic remission. This scoring system was later modified (Modified Riley Score) to rank the degree of inflammation hierarchically and to exclude crypt architectural changes, which according to the investigators are not responsive to clinically relevant changes in inflammation. This system has never been validated but has been used in multiple randomized control trials.


Geboes and colleagues developed a scoring system that categorizes histologic changes as grade 0 (structural change only), grade 1 (chronic inflammation), grade 2 (a, lamina propria neutrophils; b, lamina propria eosinophils), grade 3 (neutrophils in the epithelium), grade 4 (crypt destruction), and grade 5 (erosions or ulcers) and generates a score from 0 to 5.4 that increases with disease severity or activity. The Geboes index has been applied to a few prospective clinical studies. Although the Riley study did not address the interobserver and intraobserver variability among pathologists in scoring the histologic variables, the Geboes scoring system has been shown to be reproducible to some degree, whereby the investigators found moderate to good interobserver agreement among 3 pathologists (kappa 0.59–0.70).


Gramlich and colleagues referred to activity as infiltration of neutrophils into the crypt epithelium. They classified activity as mild if there are rare neutrophils infiltrating the crypt epithelium, moderate if there are crypt abscesses, and severe if there are ulcers. In contrast to other systems, it does not incorporate neutrophils within the lamina propria as an indicator of activity and does not provide any clarity about scoring erosions.


Another index that was specifically developed to assess risk of neoplastic progression in UC is the Gupta index. This system is the same that is used by pathologists in clinical practice, described earlier.


The Gramlich and Gupta indices grade activity by assessing neutrophil-mediated epithelial injury; the Geboes and Riley index also include crypt architectural changes, chronic inflammatory infiltrate within lamina propria, and eosinophils, providing a much more comprehensive assessment of histologic changes. More importantly, none of these scoring systems specifically assess basal plasmacytosis or provide thresholds for normal lamina propria inflammatory cells, especially mononuclear cells and eosinophils, the density of which is known to vary with anatomic location of the biopsy as well as geographic location of patients. Individuals who live in the southern United States and closer to the equator have more numbers of lamina propria eosinophils compared with the northern states.


More recently, Mosli and colleagues assessed the intraobserver and interobserver variability in applying the Geboes and Modified Riley Score using digital images. Crypt architectural distortion, chronic inflammatory cell infiltrate, neutrophil-mediated epithelial injury, and erosions/ulcers had the highest intraclass correlation coefficient scores, whereas there was poor interobserver agreement in assessing lamina propria eosinophils and basal plasmacytosis.

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Sep 7, 2017 | Posted by in GASTOINESTINAL SURGERY | Comments Off on Role of Histologic Inflammation in the Natural History of Ulcerative Colitis

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