Management of Dysplasia in Inflammatory Bowel Disease

Abstract

Given the chronic nature of mucosal inflammation present in patients with inflammatory bowel disease (IBD), there is a high risk of dysplastic lesions progressing to cancer, in addition to a high risk of synchronous and/or metachronous cancers developing in those diagnosed with dysplasia. Due to this, consensus guidelines recommend regular surveillance. When visible dysplasia is encountered, options include endoscopic or surgical resection depending on characteristics of the lesion. Advancements in endoscopic tools increasingly allow for endoscopic removal when appropriate. Invisible dysplasia discovered on random biopsy should prompt referral to physicians who specialize in IBD. While surgical resection with proctocolectomy significantly decreases the risk of colorectal cancer, the risk must be balanced against the morbidity of surgery and quality-of-life concerns. Management of dysplasia in IBD patients requires complex decision-making that requires balance of patient values and goals of care with cancer-related risk factors.

Management of Dysplasia in IBD

Virtually, all colorectal cancers (CRCs) develop from a dysplastic precursor lesion. Dysplasia is defined as a neoplastic change in the intestinal epithelium, restricted to the basement membrane, without invasion into the lamina propria. In inflammatory bowel disease (IBD), these lesions can be localized, multifocal, flat, or polypoid. Lesions can occur sporadically but are believed to be more aggressive when occurring in a region with presently or previously active colitis. ¹

Endoscopic biopsies when evaluating for dysplasia associated with IBD can be classified as one of four categories: no dysplasia, indefinite for dysplasia, low-grade dysplasia (LGD), and high-grade dysplasia (HGD). ² Histopathology of biopsies should be assessed by a gastroenterology-trained pathologist. LGD and HGD are differentiated based on the distribution of nuclei within the cells of the mucosa. LGD is characterized by nuclei confined to the basal half of cells, whereas in HGD the nuclei are scattered throughout the cell. ³

Historically, the term “dysplasia-associated lesion or mass” was used to describe a polypoid-like, often sessile lesion, within an area of current or prior colitis. Adenoma-like mass was used to describe a more pedunculated polyp in an area of the colon not previously believed to be affected by colitis. However, these terms were found to be confusing and inconsistently applied, leading to replacement with the Paris endoscopic classification system in an attempt to more appropriately and consistently describe dysplastic lesions in the context of IBD. ⁴ This system groups polyps into polypoid (pedunculated, semi-pedunculated, or sessile) or nonpolypoid (slightly elevated, flat, slightly depressed, or excavated/ulcerated). The Paris system was modified further with the SCENIC consensus statement recommending broader categorization of dysplasia as “visible” or “invisible” depending on whether the lesion was seen on endoscopy. This classification system includes polypoid (≥2.5 mm) and nonpolypoid (<2.5 mm) under the category of “visible,” which also includes additional descriptors such as border characteristics (distinct/indistinct) and presence of ulceration. ⁵

Risk of Synchronous Cancers

There is a theoretical risk of synchronous and/or metachronous lesions being present in IBD-associated neoplasia via the concept of field cancerization where chronically inflamed mucosa may be preconditioned and thus at higher risk for multiple cell groups to undergo neoplastic change. ^{6 7 8} Numerous studies have given evidence to this theory, warning of a high development rate of CRC in IBD patients diagnosed with LGD and HGD, although results vary widely in range. Analysis of 1,375 IBD patients in a UK registry found a 10-year CRC risk in patients diagnosed with LGD and HGD to be as high as 30 and 50%, respectively. ⁹ Another nationwide cohort of approximately 4,300 IBD patients with LGD reported a cumulative incidence of advanced neoplasia of 14.4% after 10 years. ¹⁰ A recent meta-analysis reported a pooled multivariable hazard ratio (HR) of four studies of 3.67 (95% confidence interval [CI], 2.2–6.1) for the development of CRC given prior diagnosis of LGD. ¹¹ Because of this increased risk for development of CRC, most experts recommend considering total colectomy for IBD patients with HGD or multifocal LGD. However, management of a single LGD lesion removed in its entirety during endoscopic surveillance remains somewhat controversial. Risk factors for development of HGD or CRC after diagnosis of LGD include nonpolypoid lesions (RR, 14; 95% CI, 3–61), metachronous lesions (RR, 7; 95% CI, 1.5–32), and colonic strictures (RR, 3; 95% CI, 1–7). ¹² Dysplastic lesions ≥ 1 cm in size (HR, 3.8; 95% CI, 1.5–13.4), invisible dysplasia (HR, 4.1; 95% CI, 1.3–13.4), and a history of “indefinite for dysplasia” (HR, 2.8; 95% CI, 1.2–6.5) are also reported to be risk factors. ¹³

As mentioned earlier, nonpolypoid or flat lesions are known to carry a higher risk for later development of CRC compared with polypoid lesions. A recent meta-analysis of 738 UC and CD patients with flat LGD (fLGD) diagnosed on endoscopy found a 13% rate of progression from fLGD to advanced neoplasia over a median of 3.5 years. ¹⁴ Of the 236 patients (32%) who underwent immediate surgery, CRC was found in 8 patients (pooled prevalence, 8.7%; 95% CI, 3.6–19.5%) and HGD in 11 patients (pooled prevalence, 14%; 95% CI, 5.7–30.7%). Risk factors for neoplastic progression included location of fLGD in the distal colon (HR, 3.1; 95% CI, 1.6–6).

Visible Lesions

Visible dysplastic lesions in parts of the colon uninvolved by colitis should be managed with standard polypectomy techniques. ³ Lesions identified in areas of active colitis should be evaluated for endoscopic resectability, with consideration that these lesions may be technically more difficult to fully remove due to inflammation, friability, and scarring. ¹⁵ For polypoid and nonpolypoid visible lesions that are well delineated, endoscopic resection is indicated if and only if complete resection is possible. Features of underlying malignancy include ulcerated lesions, inability to lift with submucosal injection, and surrounding neoplastic change. ¹⁶ Depending on the lesion, advanced techniques such as endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) may be necessary. If the lesion is large, ESD may be considered as it can theoretically overcome one of the challenges of EMR in removing fibrotic tissue, as frequently found in IBD patients. Moreover, ESD has been found in a recent systematic review to be a suitable tool in selected UC patients, although technically demanding. ^{17 18} Long-term efficacy of these techniques in preventing surgery or malignancy is still unclear. ¹⁹ Importantly, whenever a large polyp is removed, a tattoo should be placed to aid in future surveillance. Photodocumentation should also be considered. ²⁰ Current standard of care is to obtain additional biopsies of the flat mucosa surrounding the polypectomy site to evaluate for adjacent dysplasia. ³ In cases where the lesions are not endoscopically resectable, total proctocolectomy is indicated. Features associated with unresectability include ill-defined margins, submucosal invasion, asymmetrical lift not attributable to fibrosis from colitis, ulceration, and flat neoplastic change adjacent to lesion. ²⁰

Follow-up of patients with completely resected dysplastic polypoid lesion(s) depends on a variety of factors including degree of dysplasia, size of lesion, and the surrounding colon. If there is no history of underlying colitis in the area, routine IBD-specific surveillance should be considered. In areas affected by colitis, endoscopic examination should be repeated with short-interval follow-up (1–6 months depending on guidelines). ²¹ SCENIC guidelines recommend repeat colonoscopy in 12 months for patients undergoing en bloc resection of polypoid lesions less than 1 cm in size with negative margins. Short-interval surveillance (3–6 months) is recommended for lesions removed piecemeal or with size greater than 1 cm. As discussed earlier, most guidelines recommend prophylactic proctocolectomy for HGD, multifocal, or repeat LGD. If complete resection of visible lesion with HGD is performed, consideration can be given to continuing short-interval surveillance versus colectomy on a case-by-case basis. ^{5 15 22}

Endoscopically Invisible Lesions

Endoscopically invisible dysplasia detected through random biopsies should be confirmed by a pathologist experienced in IBD due to significant interobserver variability, with most guidelines recommending confirmation by a second experienced pathologist. ^{5 20 23}

Follow-up should entail referral to an expert in IBD surveillance for chromoendoscopy with high-definition colonoscopy. ^{5 15 20} If visible lesions are present on repeat colonoscopy with chromoendoscopy, resection and further surveillance versus proctocolectomy should be recommended based on characteristics of the lesion (see the discussion earlier). If no lesions are identified, random biopsies should be repeated. If LGD is detected randomly, risks and benefits of continued short-interval surveillance versus proctocolectomy should be discussed, considering the increased risk of patients with invisible LGD later developing HGD/CRC. ¹³

Resection Considerations

While removal of the colon and rectum markedly decreases the risk of future CRC development, the risk must be balanced against the morbidity of surgery and quality-of-life concerns. Late complications following ileal pouch-anal anastomosis in UC patients include sexual dysfunction (incidence 11–33%), small bowel obstruction (2–20%), greater than six stools per day (43%), fecal incontinence (18.6%), and chronic pouchitis (23%). ²⁴ Compared with patients who require proctocolectomy for dysplasia versus medically refractory disease, patients with dysplasia may have relatively normal baseline bowel function and thus less tolerant of decreased functionality postoperatively, although there are little data available. Interestingly, although small, one study looking at quality-of-life scores found no significant differences between these two groups of UC patients. ²⁵

Cost can also be included in the consideration of management options. Unfortunately, there are limited data looking at cost effectiveness of surgery versus continued endoscopic surveillance. One study comparing immediate colectomy versus short-interval surveillance (repeat colonoscopy at 3, 6, and 12 months, and then annually) in UC patients with newly diagnosed fLGD on colonoscopy concluded that colectomy had the advantage over surveillance in terms of quality-adjusted life-years (20.1 vs 19.9 years) and lower cost ($75,900 vs $83,900). ²⁶

Overall, management of dysplasia in IBD patients requires complex decision-making that should incorporate patient values and goals of care with consideration of patient-related risk factors (family history of cancer), disease-related risk factors (duration, primary sclerosing cholangitis, prior dysplasia), dysplasia-related risk factors (grade, location), and availability of endoscopic and surgical expertise. ²⁷

Funding Statement

Funding This publication was supported by the Washington University School of Medicine Surgical Oncology Basic Science and Translational Research Training Program grant T32 CA009621, from the National Cancer Institute (NCI). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.