Historically, surgery is the mainstay of treatment for esophageal cancer. Czerny was the first who resected a cervical esophageal cancer in 1877. In 1913, Torek performed the first transthoracic esophageal cancer resection successfully.¹ A rubber tube was used as the esophageal substitute connecting the esophagostomy and gastrostomy for feeding in the patient, who lived for another 17 years. Reconstruction using stomach as a conduit after intrathoracic esophageal cancer resection was performed by Ohsawa, a Japanese surgeon in Kyoto, in 1933.² In 1946, Lewis described a 2-phase approach via right thoracotomy and laparotomy.³ Tanner reported the same procedure in 1947.⁴ McKeown later described the 3-phase esophagectomy via right thoracotomy, laparotomy, and cervical incision.⁵

In addition to surgical treatment, there has been a proliferation of treatment options, especially with regard to different combinations of chemotherapeutic agents and radiotherapy, in the past 2 decades. Significant divergence in the epidemiologic pattern between Western and Eastern countries has been observed, which has had a major impact on the management of this disease.

Esophageal cancer is the eighth most common cancer worldwide and the sixth most common cause of death from cancer.⁶ There is significant variation of incidence among different geographic regions and various ethnic groups. The disease is common in countries of the so-called “Asian esophageal cancer belt,” which stretches from eastern Turkey and east of Caspian Sea through northern Iran, northern Afghanistan, and southern areas of the former Soviet Union, such as Turkmenistan, Uzbekistan, and Tajikistan, to northern China and India. In high incidence areas, the occurrence of esophageal cancer is 50- to 100-fold higher than that in the rest of the world. It is the fourth most common cancer in China.⁷ The age-standardized incidence rate of esophageal cancer in China is 27.4 per 100,000, compared to 10 in Japan, 7.9 in northern Europe, 7.6 in western Europe, 5.8 in North America, and 5.5 in Australia/New Zealand.⁶ The crude age-adjusted mortality is up to 140 per 100,000, and esophageal cancer is the one of the most common causes of cancer death in China.⁸ Esophageal cancer most commonly presents in the sixth and seventh decades of life. In most countries, esophageal cancer is a male-predominant disease.

Over the past three decades, there has been an epidemiologic shift from squamous cell cancers to adenocarcinoma of the lower esophagus and cardia in the white populations in Western countries. The incidence of adenocarcinoma has surpassed that of squamous cell cancers since the 1990s. In Eastern countries, however, squamous cell cancer remains the predominant type and is mostly located in the mid esophagus.

The etiologic factors for the development of esophageal cancer vary between the different histologies (Table 26-1). Smoking and drinking are independent contributing factors, as shown by prospective studies of patient who drink but do not smoke and, conversely, of patients who smoke but do not drink.⁹

Genetic predisposition may be important in the pathogenesis of esophageal squamous cell cancer. Case-controlled studies have identified familial aggregation, suggesting that the cancer may be heritable.¹⁰ Mitochondrial studies have proved historical population migrations from central-northern to southern-eastern China, where another high-incidence area is found,¹¹ again suggesting that hereditary factors may play a part. Genetic polymorphism is important in individuals with chronic alcohol consumption.¹² Approximately 36% of East Asians show a physiologic response to drinking that includes facial flushing, nausea, and tachycardia. This facial flushing response is predominantly related to an inherited deficiency in the enzyme aldehyde dehydrogenase 2 (ALDH2). Alcohol is metabolized to acetaldehyde by alcohol dehydrogenase and the acetaldehyde is, in turn, metabolized by ALDH2 to acetate. Two main variants for ALDH2 exist, resulting from the replacement of glutamate with lysine at position 487. Only individuals homozygous for the glutamate allele have normal catalytic activity. Homozygotes with the lysine alleles have no detectable activity, whereas heterozygotes with Glu/Lys alleles have much reduced ALDH2 activity. The inability to fully metabolize acetaldehyde results in its accumulation in the body, leading to the facial flushing and unpleasant side effects. Lys/Lys homozygotes could not tolerate much alcohol because of the intensity of the side effects, and so paradoxically, they do not have increased risk because they simply do not consume a significant amount of alcohol. Individuals who are Glu/Lys heterozygotes may become habitual drinkers because they can become tolerant to the side effects of alcohol and yet have suboptimal catalytic activity, and thus the acetaldehyde accumulates. These are the individuals most susceptible to the carcinogenic effects of alcohol consumption, which are related to acetaldehyde causing DNA damage and other cancer-promoting effects.¹³ A simple questionnaire that elicits the history of a flushing response was shown to be useful in identifying at-risk individuals. They could be advised against drinking or to undergo screening endoscopy. The risk of developing cancer may be reduced or earlier diagnosis possible.¹⁴

For squamous cell cancer, in addition to drinking and smoking, dietary and environmental factors are important, especially in Asian countries. Nitrosamines and their precursors (nitrate, nitrite, and secondary amines), such as pickled vegetables, are incriminated.¹⁵ Nutritional depletion of certain micronutrients, particularly vitamins A, C, and E, niacin, riboflavin, molybdenum, manganese, zinc, magnesium selenium, as well as inadequate consumption of fresh fruits, vegetables, and protein, predispose the esophageal epithelium to neoplastic transformation.¹⁶ Changes in specific dietary habits, such as replacing traditional methods of food preservation and storage with refrigeration, together with consumption of vitamin-rich food, may have produced a drop in incidence rates in certain areas of China, especially in urban cities such as Shanghai.¹⁷ Other dietary risk factors include consumption of hot beverages, opium smoking, chewing betel nuts, and mate drinking in South American countries.

The human papillomaviruses¹⁸ and certain fungi belonging to the genera Fusarium, Alternaria, Geotrichum, Aspergillus, Cladosporium, and Penicillium are infective agents variably found to be associated with esophageal cancer.

Patients with other aerodigestive malignancies have a particularly high risk of developing squamous cell carcinoma (SCC) of the esophagus, presumably because of exposure to similar environmental carcinogens and “field cancerization.” Using esophageal cancer as the index tumor, multiple primary cancers were found in 9.5% of patients, of which 70% were in the aerodigestive tract.¹⁹ The overall incidence of synchronous or metachronous esophageal cancer in patients with primary head and neck cancer is estimated to be 3%.²⁰

Diseases that are known to predispose to esophageal cancer are few. The risk from achalasia is estimated to be 7- to 33-fold, but symptoms of achalasia are present for an average of 15 to 20 years before the emergence of cancer.²¹ Other diseases include lye corrosive strictures, Plummer-Vinson syndrome, tylosis, and celiac disease.

For adenocarcinoma, the reasons to account for the significant rising incidence can be attributed to the obesity epidemic, gastroesophageal reflux disease,²² and Barrett esophagus, which are less common in Asian populations, with the reported prevalence of Barrett esophagus ranging from 0.06% to 19.9% in Asia.²³ Gastroesophageal reflux disease affects up to 44% of the general population in the United States, and approximately 5% to 8% will develop Barrett esophagus,²⁴ with an estimated annual rate of neoplastic transformation of 0.1% to 0.3%.^25,26 The degree of dysplasia is associated with the risk of malignant transformation, with an annual rate of 0.25% for patients without dysplasia and 6% for patients with high-grade dysplasia.²⁷ Epidemiologic data suggest a protective role of Helicobacter pylori against reflux. The high prevalence of H pylori infection in Eastern populations may guard against reflux and Barrett esophagus and may account for the difference in cancer cell type.²⁸ However, this association remains controversial.

Early Neoplastic Lesions

SQUAMOUS CELL DYSPLASIA

Diagnosing esophageal cancer at an early stage is crucial in improving the prognosis. The 5-year survival rate is approaching 90%, and a 25-year survival rate of 50% can be achieved when cancer is diagnosed at an early stage.²⁹ In high-incidence countries such as China and Japan, national screening programs aim at early diagnosis.

The initial technique of screening in China was to use an inflatable balloon that was swallowed and retrieved to obtain abrasive cytology, whereas in Japan, a cytology sample was harvested using an encapsulated sponge.^30,31 This type of screening cytology has been replaced by primary endoscopic examination in high-risk areas or in populations at increased risk. Traditionally, chromoendoscopy using Lugol’s iodine is a useful adjunct (Fig. 26-1). In addition, there is significant advancement of endoscopic technology to detect early neoplastic lesions. The development of narrow-band imaging allows optical chromoendoscopic examination. A high-resolution or magnifying endoscopy allows detail examination of mucosal capillary pattern and detection of early neoplastic neovascularization. A classification system of the intraepithelial papillary capillary loop (IPCL) has been introduced to grade the severity of these early neoplastic changes (Fig. 26-2).³²

BARRETT ESOPHAGUS AND ADENOCARCINOMA

Screening and surveillance for early cancer due to Barrett esophagus are controversial. Gastroesophageal reflux is prevalent among the white populations; approximately 20% of adults have heartburn at least once per week, 5% of whom have Barrett esophagus; thus, a very substantial number of patients will require screening. However, the absolute risk of adenocarcinoma is low even in subgroups of patient with severe reflux symptoms. Moreover, 40% or more of patients with esophageal adenocarcinoma have no prior reflux symptoms and therefore would not be detected through screening programs targeted to those with such reflux symptoms.²² Current guidelines suggest that for patients with an established diagnosis of Barrett esophagus, surveillance is recommended. Systemic 4-quadrant, 2-cm biopsy protocol using jumbo biopsy forceps is recommended.³³ Dysplasia is so far the only reliable indicator of risk for development of invasive cancer. The recommendations given by the American College of Gastroenterology with regard to endoscopy interval and treatment are listed in Table 26-2.³⁴

Endoscopy and systemic biopsies remain the gold standard for diagnosis of Barrett esophagus, dysplasia, and early cancer. Other modalities such as cytology (with or without fluorescence in situ hybridization [FISH]), autofluorescence imaging, narrow-band imaging, optical coherence tomography, and confocal laser endomicroscopy are investigational techniques aimed at enhancing diagnostic capabilities.³⁵ It has been reported that acetic acid chromoendoscopy can increase diagnostic yield of Barrett esophagus by 6 times and the number of biopsies required to detect 1 neoplasia was 15 times fewer compared conventional protocol based biopsy approach.³⁶

Advanced Cancer

Evaluation of symptoms, physical signs, and demographic factors helps in the diagnosis of advanced cancer. Patients may present with different symptoms depending on the extent of disease. Elderly patients complaining of dysphagia must be assumed to have esophageal cancer until proven otherwise. Patients with chronic reflux symptoms who develop dysphagia must have tumor in the differential diagnosis in addition to reflux stricture.

In advanced disease, the most common presenting symptom is dysphagia (80%-95%) that is progressive in severity. Many patients delay seeking medical advice until severe dysphagia and weight loss have occurred. Regurgitation is common, especially when the patient lies supine at night. Fluid regurgitation can lead to coughing, aspiration, and chest infection. Food boluses passing the tumor site may cause retrosternal pain (odynophagia). Hoarseness is the result of tumor invasion of the recurrent laryngeal nerve either by the primary tumor or nodal metastases.

The demographics of patients with SCC are different from those of patients with adenocarcinoma (Table 26-3). Patients with SCC are usually blue-collar workers with recent significant weight loss. Chronic smoking and alcohol consumption are common and lead to a higher prevalence of chronic lung disease and liver cirrhosis. A proximally located tumor more easily predisposes to aspiration pneumonia from regurgitated fluid and, in advanced cancer, tracheoesophageal fistula. Supraclavicular regions should be examined for the presence of nodal spread. Patients with adenocarcinoma usually come from a higher socioeconomic class. Adenocarcinomas are associated with obesity-related diseases such as gastroesophageal reflux disease and ischemic heart disease.

Accurate staging allows stage-directed therapies and quality control for clinical trials. To achieve this, an evidence-based staging system and comprehensive modalities of investigation are crucial.

Staging System

The most commonly used staging system worldwide is the American Joint Committee on Cancer (AJCC) staging and the International Union Against Cancer (UICC) TNM (tumor-node-metastasis) system.

The definitions of TNM, tumor grade, level of tumors, and nodal stations are shown in Tables 26-4, 26-5, 26-6, 26-7, 26-8, 26-9, 26-10, 26-11 and Figures 26-3 and 26-4. The T stage advances as tumor invades from mucosa deep to muscle, adventitia, and beyond the esophagus. Regional nodes encompass areas from the neck and through the mediastinum to the upper abdomen, including the celiac nodes. The segregation of N1 to N3 is by the number of involved lymph nodes. Location is defined by the position of the epicenter of the tumor in the esophagus and classified as X: location unknown; Upper: cervical esophagus to lower border of azygos vein; Middle: lower border of azygos vein to lower border of inferior pulmonary vein; and Lower: lower border of inferior pulmonary vein to stomach, including gastroesophageal junction. Squamous cell cancers are stage-grouped differently to adenocarcinoma. Stage-groups of both tumor types are further sub-classified as clinical (cTNM); post-neoadjuvant (ypTNM) and pathological (pTNM) stage according to the latest 8th edition of AJCC staging system.

Controversy exists regarding whether adenocarcinoma of the gastroesophageal junction (GEJ) should be staged as esophageal or gastric cancer. Adenocarcinoma of the cardia was staged as esophageal cancer according to the seventh edition of the AJCC staging system. However, assigning tumors at this location as esophageal or gastric is somewhat arbitrary. Since the launch of the seventh edition of the AJCC staging system in 2010, accumulating evidence, especially from the East (eg, Japan and Korea),^37,38 has suggested that type III tumors should be staged as gastric cancer instead of esophageal cancer. The definition of esophagogastric junction is thus revised in the 8th edition of AJCC system such that cancer involving it with epicenters no more than 2 cm into the gastric cardia are staged as adenocarcinoma of the esophagus and those with more than 2cm involvement of the gastric cardia are staged as stomach cancer, even if the edges of the tumors invades the esophagogastric junction.³⁹

In daily practice, an anatomic classification system for adenocarcinoma of the GEJ that is widely adopted is the Siewert classification. This assigns tumors 5 cm proximal and distal to the GEJ into types I to III (esophageal, cardiac, and subcardiac; Fig. 26-5). The three types of cancers differ in regard to patient demographics, possible etiology, histopathologic features, treatment approach, and prognosis. Although widely recognized with much data to support the classification, there are certain drawbacks to this system. First, assigning tumors to type I to III may lack accuracy preoperatively, especially when advanced tumors may have obliterated the landmarks endoscopically; the system classifies tumors by the epicenter of the tumor. Second, treatment, especially surgical approaches, would more depend on the proximal and distal extent of the tumors rather than the epicenter; for instance, a small tumor of 2 cm centered on the GEJ is approached quite differently from a 10-cm tumor that also centers on the GEJ. This has to be kept in mind before using this system.

The modalities to achieve precise staging include barium contrast studies, bronchoscopy, upper endoscopy, computed tomography (CT) scan, percutaneous ultrasound of cervical lymph nodes with or without fine-needle aspiration (FNA) cytology, endoscopic ultrasound (EUS) with or without FNA, 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scan, and laparoscopy and/or thoracoscopy.

Barium Contrast Studies

The availability of other new staging modalities makes barium contrast studies much less essential. Features indicative of presence of malignancy include mucosal irregularity, shouldering, stenotic lumen, and dilatation of proximal esophagus (Fig. 26-6). Other signs that are suggestive of advanced-stage disease include tortuosity, angulation, axis deviation from the midline, sinus formation, and fistulation to the tracheobronchial tree.

Bronchoscopy

Bronchoscopy is performed to assess tumor invasion of the tracheobronchial tree, especially for proximally located tumors. Signs indicative of tumor involvement include widening of carina, extrinsic compression particularly from posterior tracheal wall, direct tumor infiltration, and fistulization. Histopathologic confirmation of tumor invasion of the tracheobronchial tree precludes upfront surgical resection.

Computed Tomography Scan

The main value of CT scan in the staging of esophageal cancer is its ability to detect distant metastasis, such as that in liver, lung, bone, and kidneys. The sensitivity for liver metastases larger than 2 cm is approximately 70% to 80%, but sensitivity is reduced to 50% if the lesion is <1 cm.³⁹ Lung metastasis is seldom a solitary lesion, and if it presents as a solitary mass, investigation should be directed to primary lung cancer or benign nodules.

In evaluation of the primary esophageal tumor, the precision of CT scan is inferior to EUS. In the diagnosis of T4 disease by CT scan, obliteration of the fat plane between the esophagus and the aorta, trachea and bronchi, and pericardium is suggestive of invasion, but the paucity of fat in cachectic patients makes this criterion unreliable. When the area of contact between the esophagus and the aorta extended for more than 90 degrees of the circumference, an 80% accuracy of infiltration was reported,⁴⁰ but this is by no means absolute.

The sensitivity of detecting mediastinal and abdominal nodal involvement is suboptimal with CT scans because only size alone can be used as diagnostic criterion. However, normal-sized lymph nodes may contain metastatic deposits, and enlargement of lymph nodes may be due to reactive and inflammatory hyperplasia. Studies using high-resolution helical CT scanning have demonstrated sensitivities of 11% to 77% and specificities of 71% to 95% for detection of regional nodal disease.⁴¹ CT scanning is now commonly performed together with PET scanning; a composite picture is created in the same setting to correlate more accurate anatomy with metabolic uptake (Fig. 26-7).

Endoscopic Ultrasound and Percutaneous Ultrasound

EUS is the only imaging modality able to distinguish the various layers of the esophageal wall, usually seen as 5 alternating hyper- and hypoechoic layers (Fig. 26-8). The accuracy of EUS for tumor and nodal staging averages 85% and 75%, respectively, compared to 58% and 54% for CT scanning. In about one-third of patients, a conventional EUS probe cannot pass through the esophageal lumen due to tumor stricture. Miniaturized ultrasound catheter probes can be used to pass through the working channel of a conventional endoscope, which can achieve comparable accuracy to conventional EUS. A study found that predilation is safe in this situation, but the success rate of complete examination depends on the size of dilation (36% for 11-12.8 mm and 87% for 14-16 mm).⁴²

Echo features of lymph nodes that suggest malignant involvement include echo-poor (hypoechoic) structure, sharply demarcated borders, rounded contour, and size greater than 10 mm, in increasing order of importance. A collective review showed that the overall accuracy of staging nodal disease was 77%.⁴³ The accuracy of EUS may differ for different lymph node locations and is related to the depth of penetration of EUS (about 3 cm). It is best for detecting paraesophageal nodes, and sensitivity varies inversely with the axial distance of the nodes from the esophageal axis. The ability to perform EUS-guided FNA cytology of suspicious nodes (such as celiac nodes) is another factor that makes EUS superior to CT scanning.

Percutaneous ultrasound is particularly useful for obtaining FNA biopsies of cervical lymph nodes. In one large study of 519 patients, cervical lymph node metastasis was detected in 30.8% of patients (160 of 519 patients). The sensitivity, specificity, and accuracy of US diagnosis in patients who underwent subsequent cervical lymphadenectomy were 74.5%, 94.1%, and 87.6%, respectively. In those who did not undergo neck dissection, the chance of cervical nodal recurrence was low, at less than 5%.⁴³

Information gained by combining preoperative cervical ultrasound and EUS can be highly prognostic. In one study, when the number of metastatic nodes was stratified into subgroups of 0, 1 to 3, 4 to 7, and 8 or more nodes, the number of involved lymph nodes was prognostically similar to the eventual subdivisions as determined by histologic diagnosis.⁴⁴ However, both percutaneous ultrasound and EUS are highly operator-dependent, and meticulous application is required to produce these results.

FDG-PET Scans

PET is gaining popularity in esophageal cancer staging and is commonly used in conjunction with CT scans for better anatomic definition. For detecting the primary tumor, the sensitivity of PET ranges from 78% to 95%, with most false-negative tests occurring in patients with T1 or small T2 tumors.^41,45 Adenocarcinomas of the GEJ and proximal stomach sometimes show limited or absent FDG accumulation regardless of tumor volume (FDG nonavidity). Some investigators observed this phenomenon in as many as 20% of these patients, and it seems to be related to the diffusely growing subtype and poorly differentiated tumors.⁴⁶

PET does not provide definition of the esophageal wall and thus has no value in determining T stage. For locoregional nodal metastases, its spatial resolution is also insufficient to separate the primary tumor from juxtatumoral lymph nodes because of interference from the primary tumor, and thus, most studies demonstrated poor sensitivity. This is especially true for nodes in the middle and lower mediastinum, where most primary tumors are found. In one study, the sensitivities of PET for detecting cervical, upper thoracic, and abdominal nodes were 78%, 82%, and 60%, respectively, but were only 38% and 0%, respectively, for the mid and lower mediastinum.⁴¹ Specificity of PET in detecting regional nodes is usually much better, reaching 95% to 100% in some studies.^45,47 The low rate of false-positive findings is important in preoperative staging.

A meta-analysis of 12 publications on PET scanning in esophageal cancer showed that the pooled sensitivity and specificity for the detection of locoregional metastases were 0.51 (95% confidence interval [CI], 0.34-0.69) and 0.84 (95% CI, 0.76-0.91), respectively. For distant metastases, the corresponding figures were 0.67 and 0.97. When 2 studies (out of 11) that had particularly low sensitivities for detection of distant metastases were excluded (probably because they included more early tumors), the pooled sensitivity improved to 0.72 and specificity to 0.95.⁴⁸ This study highlights that the accuracy of PET in locoregional nodes is only moderate.

Thoracoscopy and Laparoscopy

Thoracoscopy and laparoscopy have their advocates. Thoracoscopic staging usually involves a right-sided approach, with opening of the mediastinal pleura from below the subclavian vessels to the inferior pulmonary vein with lymph node sampling. Laparoscopic staging can include celiac lymph node biopsy and the use of laparoscopic ultrasound for detecting liver metastases. One multi-institutional study (CALGB 9380) reported results in 113 patients, and the strategy was feasible in 73% of patients. Thoracoscopy and laparoscopy identified nodes or metastatic disease missed by CT scan in 50% of patients, by magnetic resonance imaging (MRI) in 40%, and by EUS in 30%. Although no deaths or major complications occurred, this approach did involve general anesthesia, one-lung anesthesia, a median operating duration of 210 minutes, and a hospital stay of 3 days.⁴⁹ Laparoscopy could be used in diagnosing metastases (especially peritoneal spread) or identifying unsuspected cirrhosis, which may contraindicate resection, and it could be performed as a preliminary procedure during the time of esophagogastrectomy. Its main contribution would be in lower esophageal and cardiac adenocarcinoma, whereas its value is expected to be minimal for more proximally located tumors.⁵⁰ Given their invasiveness, thoracoscopy and laparoscopy should be reserved for patients in whom positive confirmation of metastatic disease is not otherwise obtainable and is essential in deciding on treatment.

Stage-Directed Therapy

Treatment options for esophageal cancer were limited in the past. Surgical resection, radiotherapy, and plastic stenting for palliation were the only 3 choices. With the advancement of technology, there has been a proliferation of therapeutic options. Staging has becoming increasing more important in stratifying patients for different treatment methods, either alone or in combination with others.

Early Squamous Cell Cancers

Early tumors include T1a-EP, LMP, MM and T1b-SM1, SM2, and SM3 lesions as defined in Table 26-12. The risk of nodal metastases is the most important factor to consider in choosing the therapeutic option. The reported rates of nodal involvement in T1a-EP, T1a-LMP, and T1a MM tumors are 0%, 3.3%, and 12.2%, respectively. For T1b-SM1, SM2, and SM3 lesions, the respective rates of lymph node involvement are 26.5%, 35.8%, and 45.9%, respectively.⁵¹ Five-year survival rates are 80% to 100% for mucosal cancers and 50% to 65% for submucosal cancers.

Tumors with minimal risk of nodal metastases, such as T1a-EP and LMP, are amenable to endoscopic mucosal resection (EMR). Circumferential mucosal resection may result in cicatricial stenosis. Therefore, EMR is indicated for lesions not exceeding two-thirds of the circumference of the esophagus. EMR can also be a feasible treatment for tumors of moderate risk of nodal metastases such as T1a-MM or T1b-SM1 (200 μm deep from the muscularis mucosa) but without evidence of nodal spread in pretreatment staging investigation. SM2 and SM3 lesions are associated with significant risk of nodal metastases and should be treated with the same approach as in advanced cancers. The distinction of SM2/SM3 lesions from more superficial ones, however, is difficult, even with high-frequency EUS. In practice, therefore, these tumors are often resected endoscopically based on endoscopic appearance and the experience of the endoscopist. The resected specimens are then examined histologically to assess depth of infiltration and hence curability. A decision is then made regarding whether additional treatment would be needed. The Japan Esophageal Society has published guidelines on the treatment for early cancers, especially regarding the indications for endoscopic resection.⁵² Clinical trials are also being carried out to enhance local control and cure rate of endoscopic resection, such as the addition of radiotherapy in preventing local recurrence.⁵³

Endoscopic resection techniques include EMR and endoscopic submucosal dissection (ESD). EMR is performed by injection of saline into the submucosal plane to raise the mucosal lesion. The lesion is then sucked into a cap fitted onto the tip of endoscope, looped by a snare wire, and cut by blend-current electrocautery. The limitation of this technique is that the size of the lesion should be less than the size of the cap, and the generally recommended size of the lesion should be less than 2 cm. For larger lesions, if resected by EMR, complete resection can only be achieved with piecemeal resection, which is associated with increased recurrence rate when compared to ESD.

ESD is more complex. There are several steps in ESD, as follows: (1) marking: the border of the lesion is marked by electrocautery; (2) submucosal injection: injection of solution into the submucosal tissue plane; (3) precut: cutting the mucosal edges along the line of marking; (4) submucosal dissection: dissecting the lesion from the submucosal bed; and lastly (5) hemostasis. There are various types of solutions used for submucosal injection; examples include glycerol, hyaluronic acid, hypertonic saline, and mannitol. The common feature of these solutions is that they can be retained in the tissue plane longer to delay dispersion. Methylene blue or indigo carmine can be added for better visualization and adrenaline to improve hemostasis. Different through-the-scope instruments are available for the cutting and dissection; the choice is mainly based on endoscopist preference. Comparing ESD with EMR, ESD has less chance of positive margins, more en-bloc resection, and lower recurrence rate, but it has slightly higher bleeding and perforation rates. The technique for ESD is more demanding, and the learning curve is longer.

For ablative therapy, radiofrequency ablation (RFA) has been applied for squamous esophageal dysplastic lesions.⁵⁴ The advantage is that it is technically easy to operate, but the drawback is that no surgical specimen for detailed histopathologic examination is available.

Early Adenocarcinoma and High-Grade Barrett Dysplasia

Barrett high-grade dysplasia, synonymous with intraepithelial cancer, is the last preinvasive stage in the metaplasia-dysplasia-cancer sequence. Treatment options include intensive surveillance, mucosal ablation, and esophagectomy.

INTENSIVE SURVEILLANCE

Proponents of endoscopic surveillance claim that such a strategy can diagnose invasive cancer at an early stage and treatment can be delayed until then without compromising prognosis. The assumed high morbidity and mortality rates of esophagectomy are also a deterrent to immediate surgical resection. Opponents of surveillance observe that the incidence of early adenocarcinoma or high-grade dysplasia is estimated at 1.1% to 6% annually, but some estimates are as high as 13.4% per year.^25,26,55 High-grade dysplasia is currently the only reliable marker of preinvasive cancer, but interobserver concordance is suboptimal in distinguishing invasive and noninvasive lesions. When esophagectomy is carried out in patients who have high-grade dysplasia, invasive cancer is identified in the surgical specimen in up to 42% of patients, even when patients have been recruited in surveillance programs. More recent evidence, however, suggests that this figure is an overestimate; a meta-analysis of histologic findings after esophagectomy for high-grade dysplasia revealed invasive adenocarcinoma (at least submucosal cancer) in 12.7% of patients, and most of these patients had visible lesions such as nodularity at endoscopy, a known risk for invasive caner. In the absence of visible lesions, this figure is as low as 6.7%.⁵⁶ Most would regard the finding of high-grade dysplasia as a threshold for intervention. In patients who have visible lesions, such as raised nodules, and not just a flat Barrett mucosa, endoscopic resection is recommended to ensure no invasive cancer is present, followed by ablative therapy of the remaining flat columnar mucosa. Given the high incidence of progression from high-grade dysplasia to early adenocarcinoma, current guidelines recommend intervention, preferable with endoscopic therapy (Tables 26-2 and 26-13).³⁴