Incidence In Europe, the crude incidence of esophageal cancer is approximately 4.5/100,000/year (43,700 cases), with significant geographic variation, ranging from a low of 3/100,000 in Greece to a high of 10/100,000 in France. The age-adjusted mortality rate was 5.4/100,000/year (20,750 deaths) for men and 1.1/100,000/year (6950 deaths) for women. The main risk factors for esophageal squamous carcinoma in Western countries are smoking and alcohol consumption, while the majority of patients with esophageal adenocarcinoma suffer from gastroesophageal reflux disease and the risk is related to their body mass index. The incidence of adenocarcinoma is rapidly increasing in Western countries and currently accounts for approximately half of all esophageal cancer cases. Diagnosis The diagnosis should rely on endoscopic biopsy and the histological classification is based on WHO criteria. Small cell carcinoma is very rare and must be differentiated from squamous and adenocarcinoma and treated accordingly. Staging should include clinical examination, complete blood count and liver, lung and kidney function tests, endoscopy (including upper aerodigestive tract endoscopy when the tumor is located in or above the tracheal bifurcation), and CT scan of the chest and upper abdomen. Ultrasound endoscopy should be added to evaluate the T- and N-stage of the tumor in patients who are ready for surgery. Esophagogram is useful for surgical planning [II, B]. If available, positron emission tomography (PET) is useful to identify potential distant metastases and to diagnose suspected recurrence [II, B]. PET/CT is preferable to PET alone. Treatment Treatment principles Initial treatment should be planned multidisciplinary. The main factors in selecting initial treatment are based on tumor stage, site, medical conditions and patient requirements. Selected patients with limited stage who are not suitable for surgery can be treated with radical combined radiotherapy. Palliative treatment is also recommended for patients who cannot be treated radically (see Treatment of metastatic disease). Surgery is considered the standard of care only in carefully selected patients with limited-stage tumors. Transthoracic two-field lymph node dissection for esophageal cancer and left cervical gastroesophageal anastomosis are recommended for patients with intrathoracic squamous carcinoma [III, B]. There is no uniform standard of care for cervical esophageal cancer. The extent of surgery for adenocarcinoma remains controversial, and a randomized study showed no significant improvement in long-term survival with expanded transthoracic resection over transdiaphragmatic resection. Preoperative radiotherapy (combined with or without postoperative radiotherapy) did not add any survival benefit over surgery alone. This treatment is not recommended [I, A]. The evidence for clinical benefit of preoperative chemotherapy is appropriate for all types of esophageal cancer, but the level of evidence is higher for adenocarcinoma. Preoperative and postoperative chemotherapy should be administered for adenocarcinoma of the lower esophagus and gastroesophageal junction [I, B]. Although a meta-analysis and a recent phase III trial showed a survival benefit with preoperative radiotherapy, it is not clear which patients (based on stage, tumor site, and histology) would benefit most from this treatment [I, B], and postoperative mortality appears to be increased. Data on adjuvant chemotherapy (radiotherapy) are limited, except for non-radical surgery (lymph node dissection of D1 or less) for low grade esophageal and gastroesophageal junction adenocarcinoma. The value of targeted therapy in limited-stage esophageal cancer has not been proven.