Endoscopic Management of High-Grade Dysplasia and Superficial Esophageal Carcinoma

Screening and Surveillance

Screening for squamous cell carcinoma (SCC) of the esophagus should be considered for patient populations with known risk factors, such as tobacco and alcohol use, Plummer-Vinson syndrome, tylosis palmaris et plantaris, history of head and neck cancer, caustic injury, and achalasia. Increased body mass index (BMI), hiatal hernia, and gastroesophageal reflux disease (GERD) are all considered to be contributors to the formation of intestinal metaplasia (Barrett esophagus [BE]), a precursor lesion to EAC. On the other hand, many patients presenting with a new diagnosis of EAC do not have BE and have never had symptoms of reflux. Perhaps that is because “silent” reflux is present in this subgroup of patients or there are other variables driving the progression to neoplasia that are not fully understood. We have a little better understanding about disease progression when BE is present. Through an accumulation of incompletely understood genetic alterations, disease can progress from nondysplastic intestinal metaplasia to low-grade dysplasia (LGD), HGD, and invasive EAC. However, an orderly progression through the metaplasia-dysplasia-cancer sequence may not be recognized or even present in every patient with a Barrett-associated cancer. It is possible that episodic observation of the esophagus misses those events in real time, if they have occurred. Another explanation may be that the disease has the ability to skip intermediate stages of progression once a critical genetic mutation or mutational load is reached. Nonetheless, screening endoscopies are one of the most important elements in discovering early, curable disease that can be treated without removal of the esophagus. Unfortunately, it is the rare patient with early disease who manifests observable symptoms that would set into motion the need for an endoscopy. It is far more common that symptoms are the harbinger of locally advanced or advanced disease. Therefore devising a cost-effective screening strategy that will detect early disease is challenging. Given the low yield of endoscopy/cancer diagnoses, current recommendations by expert consensus panels indicate that there is a lack of sufficient evidence to support routine screening for Barrett-related disease. According to the American Gastroenterological Association report “well-established risk factors for Barrett's esophagus include advanced age, male sex, white ethnicity, GERD, hiatal hernia, elevated body mass index, and a predominantly intraabdominal distribution of body fat. [However], despite the considerable published data available on risk factors for Barrett's esophagus, few attempts have been made to apply this information systematically in the design of guidelines on who to screen for the condition.” The vexing issue is that we are unable to focus screening efforts upon a sufficiently high-risk population to justify the expense.

Notwithstanding the lack of concrete guidelines, most experts would recommend that any patient who has had long-standing reflux, has a family history of esophageal neoplasia, continues to be symptomatic with GERD despite therapy, or has unexplained anemia should consider endoscopic screening of the esophagus. Likewise, longitudinal studies have shown that initial presentation with erosive esophagitis (Los Angeles [LA] Classification of GERD grade C/D) and regular proton pump inhibitor (PPI) use were independently associated with progression to BE, warranting screening in these populations. After BE has been discovered, endoscopic efforts convert from screening to surveillance, the purpose of which is to detect the presence of esophageal lesions that are at high risk of progressing to EAC. Although the benefit of surveillance has also not been conclusively proved, several studies have shown that patients who contracted EAC while under surveillance presented at a lower stage of disease and had improved survival when compared with those not undergoing surveillance. In fact, surveillance guidelines have been developed under the assumption that the practice will reduce deaths.

Surveillance guidelines vary according to the degree of dysplasia detected in the esophageal biopsies ( Table 37.1 ). Mucosal irregularities identified on endoscopy need particular attention and should be biopsied with multiple bites taken to increase accuracy. An expert pathologist should confirm the detection of dysplasia or cancer.

Although older literature advocated for surveillance, patients with confirmed HGD should now be referred for treatment. As discussed in the introduction, bridging a technology gap that enables efficient and safe therapy has changed the recommendations for treatment of HGD. Without intervention, the progression risk from flat HGD to EAC is high, ranging from 6% to 19% per year. Patients with visible lesions, such as a nodular esophagus, have a much higher risk of progression (40% to 70%). There is also a risk of concomitant adenocarcinoma in patients diagnosed with HGD. Historical data have given us somewhat of a perspective on this risk. In one study, patients who underwent esophagectomy for HGD actually harbored invasive cancer in approximately 50% of the resected specimens. But to be equitable, other more recent studies using better endoscopy techniques and superior equipment suggest that the rate of undiagnosed cancer may be as low 11% in patients without visible lesions.

Surveillance as a treatment strategy for HGD should be reserved for those who are unable or unwilling to undergo therapy. In these cases endoscopy should be scheduled every 3 months, with random four-quadrant biopsies every 1 cm with focused biopsies on any mucosal irregularity.

Endoscopic Diagnosis and Staging

A detailed inspection of the Barrett segment with high-definition white light endoscopy with or without magnification is essential for the detection of mucosal abnormalities, nodularity, and cancer. Studies reveal that the longer the time spent inspecting the Barrett segment, the higher the likelihood of detecting suspicious lesions. In a study of 112 patients undergoing surveillance, the authors reported that endoscopists who averaged greater than 1 minute of inspection time per centimeter of Barrett detected more suspicious lesions than those who spent less time.

Topographic detection of suspicious lesions is probably also aided by various techniques for mucosal enhancement. A number of visual aids such as chromoendoscopy, narrow band imaging (NBI; Olympus, Center Valley, Pennsylvania), autofluorescence imaging, confocal laser endomicroscopy, and volumetric laser endomicroscopy have become available for detailed visualization and characterization of mucosal and cellular architecture. Although the literature has not clearly defined the benefit of these advanced imaging techniques, we advocate using mucosal enhancements that are either electronic or vital staining as a routine practice to facilitate the detection of HGD and early neoplasia. These modalities can be very helpful in targeting biopsies.

Upper endoscopy with ultrasound plays an important role in the diagnosis and staging of esophageal cancer. In cases of intermediate to locally advanced EAC, endoscopic ultrasound (EUS) is the principal method used to estimate the depth and regional nodal status of the disease. In contrast, EUS maintains a limited role for the evaluation of patients with HGD and early EAC. The accuracy of EUS staging in these disease categories is modest at best. In a study describing the accuracy of endoscopy compared with EUS, the sensitivity of EUS staging for mucosal tumors was 90%, whereas for submucosal tumors it was 46%, which was not significantly different from the sensitivity of high-resolution endoscopy in experienced hands. A systematic review compared EUS with endoscopic mucosal resection (EMR) or surgical pathology for early (T1-T2) tumors. In that study EUS predicted the depth of the target lesion with 67% accuracy (12 studies, n = 132). Because some patients had multiple lesions, analysis on an individual patient basis reduced the accuracy to only 56%. Given the available data, most experts would not recommend EUS in patients with a flat Barrett segment and HGD detected by biopsy. There are several factors that may contribute to the suboptimal accuracy of EUS in early EAC, including wall thickening due to chronic inflammation, presence of a duplicated muscularis mucosa often seen around the junction, anatomic changes at the level of the gastroesophageal junction (GEJ)/cardia, and endoscopist's experience. Despite these drawbacks, we continue to advocate for EUS in select cases in which there is a possibility of detecting malignant lymphadenopathy. Fine-needle aspiration (FNA) is especially important to verify the presence of disease in any suspicious lymph nodes. In a study of 25 patients undergoing EUS evaluation (13 with intramucosal adenocarcinoma), 7 patients were found to have suspicious lymphadenopathy. FNA confirmed malignancy in five of these seven patients. EUS identified five patients (20%) who were unsuitable candidates for endoscopic therapy. Studies like this one highlight the importance of a careful, individual approach to patients with early esophageal cancer.

EMR is the preferred diagnostic and therapeutic tool for patients with nodular Barrett or early adenocarcinoma. EMR is capable of removing small- to moderate-sized mucosal and superficial submucosal lesions. It is superior to EUS for the assessment of depth of invasion by the simple fact that depth is determined by histologic examination under the microscope. In practice, studies that compared EMR with esophagogastroduodenoscopy [EGD]-EUS report that the pathologic assessment was changed by EMR in 30% to 48% of cases. A prospective study of 75 patients with biopsy-proven HGD or early cancer reports that the pathology from an EMR changed the tumor grading or staging in 48% of patients (downgrading in 28% and upgrading in 20%). Another study of 293 EMR procedures performed on focal lesions indicated that 30% of patients changed therapy as a result of ER compared with clinical assessment. These are very significant findings; imagine redirecting the recommended therapy of an individual patient from combined multimodality therapy consisting of chemoradiation followed by esophagectomy to an organ-sparing, curative EMR.

In summary, optimal evaluation is fundamental to the management of dysplastic and early-stage mucosal and selected submucosal lesions. ER is an important diagnostic and potentially therapeutic tool for patients with early neoplastic disease.

Endoscopic Treatment of High-Grade Dysplasia/Intramucosal Cancer