Introduction

This chapter focuses on clinical gastroenterology issues of interest to pathologists, including endoscopic diagnosis and management of Barrett esophagus, management of intestinal metaplasia in the setting of chronic gastritis, and surveillance in patients with inflammatory bowel disease, colonic polyps, and colon cancer.

Surveillance in Patients with Barrett Esophagus

Most authorities recommend that patients with chronic reflux symptoms lasting 5 or more years undergo an upper endoscopy to screen for Barrett esophagus ( Table 2.1 ). The benefits of screening programs for Barrett esophagus are controversial because of a lack of sufficient evidence that such programs improve survival rates or are cost-effective. Furthermore, there is only indirect evidence to suggest that patients diagnosed with adenocarcinoma while undergoing surveillance have an increased chance of survival. Nevertheless, the current standard of care dictates that if Barrett esophagus is diagnosed, the patient should be entered into an endoscopic surveillance program for early detection of dysplasia and adenocarcinoma.

In the past, endoscopic surveillance was undertaken only in patients who were medically fit to undergo esophagectomy. However, with the advent of nonsurgical ablative endoscopic techniques (e.g., photodynamic therapy, argon plasma coagulation, cryotherapy) and endoscopic mucosal resection (EMR), the number of patients eligible for surveillance has increased. Recent experience with EMR suggests that it may be the treatment of choice in patients with high-grade dysplasia (HGD) or intra­mucosal adenocarcinoma in the setting of Barrett esophagus, given the opportunity for histologic assessment of the area.

Aggressive treatment of reflux with proton pump inhibitors is warranted before surveillance endoscopy, because active inflammation with repair can mimic dysplasia.

Currently, endoscopic surveillance is performed by obtaining four-quadrant biopsies at 2-cm intervals with the use of jumbo biopsy forceps. In addition, specific attention is paid to mucosal abnormalities such as ulcers, irregular lesions, nodules, and polyps, and these lesions should be submitted separately. In patients with known or suspected dysplasia, biopsies should be obtained at 1-cm intervals instead of the standard 2 cm. Studies have shown that endoscopy with magnification and narrow band imaging (NBI) allows for better localization of HGD and may allow more targeted and fewer biopsies.

The recommended interval of surveillance for dysplasia in patients with Barrett esophagus is determined by the presence and degree of dysplasia found ( Table 2.2 ). In the absence of dysplasia, the surveillance interval is every 3 to 5 years with four-quadrant biopsies every 2 cm. If the pathology is indeterminate, the grade of dysplasia should be clarified with an expert gastrointestinal pathologist. Antisecretory medication should be increased to reduce the presence of esophagitis, and upper endoscopy with biopsies should be repeated. The presence of low-grade dysplasia (LGD) should be confirmed with endoscopy within 6 months, followed by surveillance every 12 months.

Patients with flat HGD confirmed by an expert gastrointestinal pathologist should undergo a repeat endoscopy within 3 months with four-quadrant biopsies every 1 cm if an eradication method is not used. The prevalence of cancer in resection specimens from patients who have undergone an esophagectomy for HGD ranges from 5% to 41%, and the rate of progression to cancer in patients with HGD approaches 30% at 10 years. Options for patients with flat HGD include intensive surveillance (every 3 months), esophagectomy, and ablative therapies such as BARRX or radiofrequency ablation. Patients with HGD with mucosal irregularity should undergo endoscopic mucosal or surgical resection.

Surveillance in Patients with Chronic Gastritis and Intestinal Metaplasia or Dysplasia

The most common causes of chronic gastritis are Helicobacter pylori infection, environmental exposures including smoking, and autoimmune processes. Biopsies obtained during endoscopy from patients with chronic gastritis may reveal intestinal metaplasia (IM). A study from the United States demonstrated that 13% of patients at low risk for gastric cancer, and 50% of patients at high risk, had IM on biopsies from normal-appearing gastric mucosa. Although gastric IM (incomplete type) is considered a premalignant lesion, the overall risk of gastric cancer in patients with gastric IM is very low. However, patients with IM and dysplasia have an approximately 100-fold increased risk of gastric cancer.

In the United States, where the incidence of gastric cancer is low, endoscopic surveillance of patients with gastric IM is not recommended in patients who are at low risk for gastric cancer. Low-risk patients include those living in developed countries, whites without any family history of gastric cancer, and individuals without dysplasia on gastric biopsy. The likelihood that endoscopic surveillance of low-risk patients with IM will increase detection of curable gastric cancer is very low, and therefore it is not likely to be cost-effective. Furthermore, IM is a histologic lesion that is not visible by the endoscopist. This makes endoscopic surveillance difficult, because numerous biopsies mapping the stomach would be needed to obtain a significant yield.

Surveillance in patients with IM who are at high risk for gastric cancer is controversial. High-risk patients include those with a family history of gastric cancer, Hispanics, blacks, and immigrants from higher-risk geographic locations. No formal recommendations or data exist to support the implementation of an endoscopic surveillance program in high-risk patients with gastric IM. The American Society of Gastrointestinal Endoscopy (ASGE) concluded that patients who are at increased risk for gastric cancer on the basis of ethnic background or family history may benefit from surveillance, but there was no specific recommendation on the frequency of endoscopy. If surveillance is performed, the ASGE recommended that endoscopic surveillance with gastric biopsies should incorporate a topographic mapping of the entire stomach histologically.

The location and type of dysplasia found determine the surveillance guidelines for patients with IM. The histopathologic classification divides cases into the subtypes of incomplete and complete IM, a distinction best determined after assessment for and eradication of H. pylori infection. Studies have suggested that if the patient has incomplete or extensive IM, topographic mapping of the gastric mucosa should be performed at 1 year, followed by repeated surveillance endoscopy every 3 years if extensive metaplasia persists. There is no consensus regarding surveillance in LGD, but most studies suggest that surveillance is not warranted in average-risk patients. The ASGE recommends that patients with confirmed HGD on gastric biopsies be considered for gastrectomy or EMR. We expect that further recommendations regarding appropriate intervals for surveillance endoscopy and the use of new techniques will be formalized in the near future.

Pernicious anemia, which can occur as a result of autoimmune chronic atrophic gastritis, is another potential risk factor for gastric cancer and gastric carcinoid. A twofold to threefold increased risk of gastric cancer has been seen, depending on the location and duration of disease. Clear guidelines for surveillance in atrophic gastritis have not yet been established. Current guidelines from the ASGE advocate performance of a screening upper endoscopy at the time of diagnosis of pernicious anemia to identify lesions such a carcinoid or gastric cancer, but there are only weak data to support subsequent surveillance endoscopy if the initial test is negative.

Surveillance for Colorectal Neoplasia in Patients with Inflammatory Bowel Disease

Inflammatory bowel disease (IBD), which comprises ulcerative colitis (UC) and Crohn’s disease, is the second most common inflammatory disorder after rheumatoid arthritis. There are approximately 1.4 million patients with IBD in the United States. Each year, between 20,000 and 25,000 new cases are diagnosed. The peak incidence occurs between the ages of 15 to 35, with males and females equally affected.

The goal of colonoscopic surveillance is to minimize the morbidity and mortality from colorectal cancer (CRC) with appropriate and timely referral for colectomy. Close interaction between endoscopist and the pathologist is crucial in the management of IBD. Although no prospective randomized studies have been performed to evaluate the efficacy of surveillance colonoscopy to detect dysplasia or CRC in UC patients, case-control studies suggest a reduction in mortality in those undergoing surveillance. Surveillance colonoscopy should optimally be performed when the patient is in clinical remission, because active inflammation may hinder the histologic diagnosis of dysplasia.

Biopsies taken during surveillance colonoscopy are graded as positive for dysplasia, negative for dysplasia, or indefinite for dysplasia. Dysplasia is further classified as LGD, HGD, or carcinoma. The greatest interobserver variability among pathologists lies in the interpretation of the LGD and indefinite-for-dysplasia categories. Therefore, once dysplasia is detected, a second pathologist with expertise in interpretation of gastrointestinal biopsies should confirm the diagnosis. Dysplastic mucosa may be characterized as either flat or raised. Flat dysplasia is generally considered to be endoscopically undetectable, is identified by random biopsies, and can be further classified as either multifocal or unifocal. Raised or polypoid dysplasia is referred to by the acronym DALM : dysplasia-associated lesion or mass.

Current guidelines from the American College of Gastroenterology (ACG), the American Gastroenterology Association (AGA) ( Table 2.3 ), and the British Society of Gastroenterology(BSG) ( Table 2.4 ) recommend that colonoscopic surveillance begin 8 to 10 years after the onset of symptoms of colitis in patients with UC or with Crohn’s colitis involving at least one third of the colon. The results of the colonoscopy determine the extent of disease, and appropriate patients are then entered into a surveillance program. Repeated surveillance colonoscopy is performed every 1 to 3 years (AGA) or 1 to 5 years (BSG). Patients with coexisting primary sclerosing cholangitis should begin surveillance colonoscopy at the time of diagnosis of liver disease and continue annually thereafter regardless of the extent of disease. Other risk factors associated with an increased risk of developing colorectal neoplasia include CRC in a first-degree relative, ongoing active endoscopic or histologic inflammation, and anatomic abnormalities such as a foreshortened colon, stricture, or multiple inflammatory pseudopolyps. Several studies have correlated increased severity of colonoscopic macroscopic and histologic inflammation with a higher risk of CRC. Male gender has been identified as a risk factor for development of CRC. Patients with proctitis or distal proctosigmoiditis are not at increased risk for the development of CRC and do not need to undergo surveillance.

There is wide variability in the practice of surveillance by gastroenterologists as well as inconsistency in the management of patients with dysplasia. Current guidelines recommend the use of chromoendoscopy and directed biopsies or four-quadrant random biopsies every 10 cm for a minimum of 33 total colonic biopsies, or 6 biopsies in 6 pathology specimen bottles. The recommendation for 33 biopsies is based on a retrospective analysis that revealed a 90% positive predictive value for dysplasia with 33 biopsy specimens and a 95% positive predictive value with greater than 56 specimens. It is also recommended that in patients with UC, four-quadrant biopsies should be taken every 5 cm in the distal sigmoid and rectum, given the increased risk of carcinoma in those areas. Other endoscopists obtain six specimens from each of the following sections: cecum and ascending colon, transverse colon, descending colon, sigmoid, rectosigmoid, and rectum. Additional biopsies should be obtained from any suspicious mucosal lesions. The BSG guidelines recommend pancolonic dye spraying and targeted biopsies of abnormal mucosa. If chromoendoscopy is not used, then two to four random biopsies every 10 cm should be taken.

The AGA and BSG guidelines recommend proctocolectomy in cases of flat HGD. Most authorities also recommend proctocolectomy in patients with multifocal flat LGD or a single repetitive focus on more than one colonoscopy. Many authorities now recommend proctocolectomy in patients with even a single focus of flat LGD because this has been shown to be associated with concurrent adenocarcinoma in 20% of patients and to progress to higher grades of dysplasia in 50% of cases. A meta-analysis of 20 studies found that when raised or flat LGD is detected at surveillance, there is a ninefold increased risk for CRC and a 12-fold increased risk for any advanced lesion. Patients with LGD who elect against colectomy should undergo repeat surveillance colonoscopy on a 3- to 6-month basis. For patients with indefinite dysplasia, colonoscopy should be repeated at an interval of 3 to 6 months.

The management of a dysplastic “polyp” in patients with UC or Crohn’s colitis has similar guidelines. If a well-circumscribed dysplastic polyp is found proximal to histologically demonstrable colitis, it should be managed as a simple adenoma. DALMs were first identified by Blackstone and colleagues in 1981 and were associated with a high rate of CRC at colectomy. More recently, a raised dysplastic lesion with the appearance of sporadic adenoma has been termed an adenoma-like DALM . In contrast, poorly circumscribed lesions with indistinct borders and an irregular surface, or plaque like lesions, have been termed nonadenoma-like DALMs . Alternative terms are endoscopically resectable and endoscopically nonresectable polypoid dysplasia , respectively.

The endoscopist must make a distinction between an adenoma-like DALM and a nonadenoma-like DALM, because these lesions overlap histologically. Patients with UC who are found to have an area of endoscopically resectable dysplasia (adenoma-like DALM) may undergo polypectomy and continued endoscopic surveillance if no other areas of flat dysplasia are detected in the adjacent mucosa or elsewhere in the colon. It is recommended that additional biopsies be taken immediately adjacent to the polyp and elsewhere in the colon to exclude flat dysplasia. If no dysplasia is found, repeat surveillance colonoscopy should be performed within 6 to 12 months. In contrast, patients with an area of nonresectable polypoid dysplasia (nonadenoma-like DALM) are usually referred for colectomy because of the high rate of association of these lesions with synchronous or metachronous cancer. Recommendations for the management of flat and polypoid dysplasia are presented in Figure 2.1 .

Suggested surveillance strategy in patients with inflammatory bowel disease and dysplasia.

(From Farraye FA, Odze RD, Eaden J, Itzkowitz SH. AGA technical review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology. 2010;138:746-774.)

Studies have demonstrated that the use of chromoendoscopy can greatly increase the detection rate of dysplasia in patients with UC who have been enrolled in a surveillance program. Chromoendoscopy with targeted biopsies revealed significantly more dysplastic lesions than conventional colonoscopy with random biopsies. The overall sensitivity of chromoendoscopy for predicting neoplasia was 93% to 97%. Given these findings, consensus guidelines from several organizations have endorsed the use of chromoendoscopy in surveillance colonoscopy by trained endoscopists. As more data regarding chromoendoscopy become available and new imaging techniques are developed, guidelines for surveillance endoscopy in patients with IBD will be refined to reflect these advances. It is also likely that molecular biology techniques will play a more important role in the future as an adjunct to endoscopic biopsy.

Screening and Surveillance Guidelines for Colon Polyps

The following is a review of the management of colonic polyps in patients who do not have IBD. This summary includes screening for colon polyps, surveillance after polypectomy and resection for CRC, and the approach to the patient with a malignant polyp.

CRC is the second most common cause of cancer death in the United States. The overall mortality rate approaches 60%. Approximately 5% to 6% of U.S.-born individuals will develop colon cancer in their lifetime, and 2.5% will die of the disease. The incidence does not vary significantly between men and women. It is estimated that almost 143,000 new cases of CRC will be diagnosed and almost 51,000 deaths will occur from CRC in the United States in 2013. CRC is a suitable disease for screening because it is a common malignancy with a long, asymptomatic preclinical phase and a high survival rate if detected in its early stage. Prevention of CRC should be achievable by application of screening programs to identify asymptomatic patients with adenomatous polyps and to remove them. In The National Polyp Study, colonoscopic polypectomy decreased the expected incidence of CRC by 53%. An estimated 14.2 million colonoscopies and 2.8 million flexible sigmoidoscopies were performed in 2002 in the United States.

Management of Sessile Serrated Adenomas/Polyps

There is no evidence that small, distally located hyperplastic polyps carry an increased risk for CRC, but it is now accepted that certain variants of hyperplastic-appearing or serrated polyps are precursors to CRC. For example, serrated polyps have been linked to the development of sporadic adenocarcinomas with high-level microsatellite instability (MSI-H), which are associated with the development of “interval cancers” after colonoscopy. Hyperplastic-appearing polyps at risk for such progression are usually large (>5 mm), sessile with a layer of yellow mucus, and found proximally in the colon on colonoscopy. These have been called atypical hyperplastic polyps , sessile serrated polyps (SSP), or sessile serrated adenomas (SSA) and sessile serrated adenomas/polyps (SSA/Ps). These SSA/Ps tend to be found later in life (median age, 61 years), with a slight female predominance. Initially, SSAs are not dysplastic, but over time, due to increased microsatellite instability, they develop dysplasia and are precursors to CRC, accounting for approximately 15% to 20% of these cancers. Dysplastic serrated adenomas are classified as sessile serrated adenomas with dysplasia (SSAD) or traditional serrated adenomas (TSA), which tend histologically to appear more like traditional adenomas.

Because of their malignant potential, the most recent guidelines recommend that large, proximally located, hyperplastic-appearing serrated polyps be managed in the same way as adenomas of similar size. These guidelines recommend that serrated lesions proximal to the sigmoid colon and all lesions larger than 5 mm be completely resected. When lesions are removed piecemeal, a follow-up colonoscopy should be performed in 2 to 6 months to ensure that no residual polyp tissue has been left behind. SSAs smaller than 10 mm should have repeat surveillance in 5 years, whereas larger lesions and those containing any dysplasia should undergo surveillance in 3 years. See Table 2.5 for a summary of recommendations for the colonoscopic surveillance of serrated polyps.

Table 2.5

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