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Surgical and Molecular Pathology of Barrett Esophagus Sherma Zibadi, MD, Phd, and Domenico Coppola, MD

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Surgical and Molecular Pathology of Barrett Esophagus Sherma Zibadi, MD, Phd, and Domenico Coppola, MD Grading is essential for treatment plans, follow-up visits, and therapeutic interventions. Three Layers of Paint. Photograph courtesy of Craig Damlo. www.soapboxrocket.com. Surgical and Molecular Pathology of Barrett Esophagus Sherma Zibadi, MD, PhD, and Domenico Coppola, MD Background: Patients with Barrett esophagus (BE) are predisposed to developing dysplasia and cancer. Adenocarcinoma, which is associated with BE, is the most common type of esophageal tumor and, typically, it has an aggressive clinical course and a high rate of mortality. Methods: The English-language literature relating to tumor epidemiology, etiology, and the pathogenesis of BE was reviewed and summarized. Results: The role of pathologists in the diagnosis and pitfalls associated with grading Barrett dysplasia is addressed. Current molecular testing for Barrett neoplasia, as well as testing methods currently in develop- ment, is discussed, focusing on relevant tests for diagnosing tumor types, determining prognosis, and assessing therapeutic response. Conclusions: Grading is essential for developing appropriate treatment plans, follow-up visits, and therapeutic interventions for each patient. Familiarity with current molecular testing methods will help physicians correctly diagnose the disease and select the most appropriate therapy for each of their patients. Introduction tinal metaplasia are also defined as Barrett mucosa.1 Barrett mucosa refers to a metaplastic process in- Barrett esophagus (BE) is more common in men duced by the acid-peptic content of the stomach and has a male:female ratio of 3:1 to 7:1.2 Although that then erodes the esophageal squamous mucosa. BE can present at any age, its peak incidence oc- During endoscopy, changes of any length recognized curs in the sixth decade of life and it occurs more as columnar-type mucosa in the distal esophageal ep- frequently in whites (80% of patients) than patients ithelium that, on biopsy, are confirmed to have intes- of other races.3 Patients with BE are predisposed to esophageal adenocarcinoma (EAC; 5-year survival rate of 14%–22%), which has increased in incidence From the Department of Pathology and Oncological Sciences, Uni- during the last 30 years.4,5 versity of South Florida Morsani College of Medicine (SZ), and the Guidelines for diagnosis and surveillance inter- Departments of Anatomic Pathology (DC), Chemical Biology and Molecular Medicine, and Tumor Biology, H. Lee Moffitt Cancer vals for patients diagnosed with BE have been es- Center & Research Institute, Tampa, Florida. tablished and developed by the American College of Submitted July 8, 2014; accepted September 11, 2014. Gastroenterology (Table 1).1 Address correspondence to Domenico Coppola, MD, Department of Anatomic Pathology, Moffitt Cancer Center, 12902 Magnolia Etiology and Pathogenesis Drive, Tampa, FL 33612. E-mail: [email protected] Typically, patients acquire BE as a result of gastro- No significant relationships exist between the authors and the 6,7 companies/organizations whose products or services may be esophageal reflux. The factors putting patients at referenced in this article. risk for BE are several and include duodenogastric April 2015, Vol. 22, No. 2 Cancer Control 177 Table 1. — ACG Guidelines for BE of BE varies between 14% and 40%,26 and 7% to Dysplasia Diagnosis Follow-Up 15% of patients will have EAC at the time of initial 27 None present 2 EGDs with biopsy in 1 y EGD every 3 y diagnosis of BE. Low grade Highest grade on repeat EGD 1-y interval with biopsies within 6 mo until no Pathology Expert pathology dysplasia (× 2) Grossly, the esophagogastric junction in BE is dis- confirmation placed by areas of velvety, gastric-type mucosa that 11 High grade Mucosal irregularity Continued 3-mo macroscopically appear salmon in color. These ar- Repeat EGD with biopsies surveillance or eas of gastric-type mucosa proximally extend from to rule out esophageal intervention their typical location. The area of BE may be ulcerat- carcinoma within 3 mo based on results and outcomes ed or contain islands of residual, whitish squamous Expert pathology confirmation mucosa surrounded by pink-colored, gastric-type Invasive Expert pathology confirmation Esophagectomy mucosa (Fig 2). It is possible that the health care adenocarcinoma professional may be unable to distinguish the ap- ACG = American College of Gastroenterology, BE = Barrett esophagus, EGD = esophagogastroduodenoscopy. pearance of simple BE — grossly and endoscopi- 28 Adapted from Macmillan Publishers Ltd: Wang KK, Sampliner RE; Practice Param- cally — from BE with early cancer and dysplasia. eters Committee of the American College of Gastroenterology. Updated guidelines With regard to its location, BE characteristically in- 2008 for diagnosis, surveillance and therapy of Barrett’s esophagus, Am J Gastro- enterol, 103(3):788-797, copyright 2008. volves the lower one-third of the esophagus, but it may involve the middle and upper esophagus as it reflux, which is a delay in the clearance of acid juice progresses.11 from the esophagus, a resting pressure in the sphinc- Previously, BE was histologically indicated by the ter of the lower esophagus less than the optimal rate, presence of intestinal metaplasia or the gastric, cardia, and the presence of hiatal hernia.8-11 or oxyntic type of columnar mucosa in the esopha- Other etiological factors include postgastrectomy gus.29,30 However, in the modern era of endoscopy, bile reflux12 and esophageal injury (eg, lye ingestion, the American Gastroenterological Association requires tobacco use).13,14 Alcohol intake does not promote the presence of unequivocal intestinal metaplasia for BE15 and Helicobacter pylori infection has a protec- there to be a diagnosis of BE.31,32 tive effect, particularly if Helicobacter possesses the The nonintestinalized, gastric-type mucosa was CagA gene.16 In infants, BE may arise from congen- previously thought to have no potential for malig- ital rests of gastric columnar epithelium reacting to nant transformation; however, in recent years, small gastroesophageal reflux.5,17 (presumably early) EACs arising in the absence of The way in which normal squamous epi- intestinal metaplasia have been reported.33-35 Thus, thelium transitions into specialized columnar these findings suggest that the identification of gob- epithelium is not yet clear.18 However, based let cells as a requirement for diagnosing BE should on the theory of restitution and replication pro- be challenged.26-38 For example, the requirement no posed by Jankowski et al,19 after the acid-pep- longer exists in Japan, which was the first country tic content of the stomach erodes the parabasal to propose the existence of malignant potential for and superficial layers of the squamous mucosa nonintestinalized BE.35,38 In recent years, this view (Fig 1A), the basal progenitor cells move into de- has been supported by study findings indicating that nuded areas.5 In the setting of persistent gas- goblet cell–containing epithelium has similar DNA troesophageal reflux, these multipotential stem abnormalities as metaplastic esophageal columnar cells become resistant to acid and bile, selective- epithelium without goblet cells.39,40 ly differentiating into columnar epithelium that Although goblet cell metaplasia is not always an secretes mucin (Fig 1B).5,19 By contrast, the up- obligate precursor of malignancy, it is important to ward movement of the columnar epithelium from point out that the recognition of goblet cell metapla- the stomach could cause metaplasia due to wound sia remains the most important criterion in clinical healing of the ulcerated mucosa.5 practice for the routine histological recognition and diagnosis of BE. Cancer Risk In BE, the intestinalized mucosa rarely has a vil- BE is a premalignant condition associated with EAC liform appearance and Paneth cells, absorptive cells, and dysplasia.20,21 During the last several decades, and intestinal-type endocrine cells are typically absent the incidence of EAC has risen.21-23 Approximately because of the incomplete form of metaplasia pres- 10% to 20% of patients with symptomatic gastro- ent. Uncommonly, the complete form of metaplasia esophageal reflux who undergo endoscopy have presents in conjunction with the usual incomplete BE.24 However, many patients with BE are asymp- form of metaplasia. tomatic.25 The prevalence of dysplasia in the setting Shaped like barrels, goblet cells have a distended 178 Cancer Control April 2015, Vol. 22, No. 2 Bile A Acid Superficial compartment Desquamating cells Parabasal compartment Capillaries Basal compartment Positively labeled nuclei/cells by autoradiography Submucosa Papillae region Basal region Smooth muscle B Bile Acid Superficial compartment Desquamating cells Parabasal compartment Capillaries Positively labeled nuclei/cells Basal compartment by autoradiography Submucosa Papillae region Basal region Smooth muscle C Bile Acid Rapidly dividing mucin-secreting cells Superficial compartment Desquamating cells Parabasal compartment Capillaries Positively labeled nuclei/cells Basal compartment by autoradiography Submucosa Papillae region Basal region Smooth muscle Fig 1A–C. — (A) Basal progenitor cells move into denuded areas after the gastric acid-peptic content from the stomach has eroded the squamous mucosa. (B, C) Persistent gastroesophageal reflux causes multipotential stem cells to differentiate into columnar, mucin-secreting epithelium resistant to acid and bile. Reprinted from Am J Pathol, 154(4), Jankowski JA, Wright
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