Adenocarcinoma of the esophagus and esophagogastric junction : studies on pathogenesis, prognosis, staging and surgical treatment

Adenocarcinoma (AC) of the esophagus and esophagogastric junction (EGJ) is a disease with poor prognosis and increasing incidence in western countries. Its pathogenesis is associated with oxidative stress (OS) in the esophageal epithelium. Long-term survival is associated with successful radical surgery, early stage of the disease, and successful downstaging with neoadjuvant therapy. As surgery is accompanied with a large number of possible complications, it is essential to identify patients who might not benefit from surgery and on the other hand, could be treated with less invasive options. The aims of this study were 1) to assess the role of OS below EGJ in the pathogenesis of Barrett s esophagus (BE) and AC, 2) to assess the prognoses and causes of death in early esophageal AC, 3) to determine the value of 18F-fluorodeoxy-D-glucose positron emission tomography with computed tomography (FDG-PET-CT) in quantifying the response to neoadjuvant therapy and 4) to compare the novel mini-invasive technique (MIE) to traditional open esophagectomy (OE) in radical surgery. To quantify OS, we measured 8-isoprostane (8-IP), glutathione content (GSH), and 8-OH- deoxyglucose (8-OHdG) values from mucosa below EGJ, BE-mucosa, and AC-tumors from 43 patients with BE and/or AC and compared them to samples from corresponding sites of 15 healthy control patients. To determine the long-term prognosis of patients with early esophageal AC, we studied patient records and causes of deaths for 85 patients, treated with radical esophagectomy over a 27-year time span. To evaluate pre-treatment response to neoadjuvant therapy in locally advanced AC, we recorded FDG-PET-CT results before and after induction therapy in sixty-six consecutive patients who were to be operated on for locally advanced AC. Decrement in radioactive glucose uptake values was associated with survival and histological treatment response. We compared MIE to OE, to see, if minimal invasiveness reduces the rate of complications and if they are comparable in terms of oncologic radicality and survival. Proximal gastric GSH content was lower and 8-IP and 8-OHdG levels higher with statistical significance in the study patients (BE and AC) as compared to healthy controls. In patients with early esophageal AC, overall and long-term (>5 year) survival rates were mostly affected by diseases related to aging. During the first five years after the operations, disease recurrence was the most common cause of death. However, recurrence-free survival was 80% at five years and no new recurrences were detected after that. Microscopic eradication of locally advanced AC was optimally predicted by a 67% decrease in uptake values before and after induction chemotherapy, with a sensitivity of 79% and specificity of 75%. However, this association was not linear and complete eradication of radioactive glucose uptake, was not always associated with a complete histologic response. However, a decrease in glucose uptake was associated with improved overall and recurrence free survival. MIE and OE were equivalent in terms of 90-day mortality, pneumonia-, leak-, and overall complication rates. Also a minimally invasive technique was associated with significantly shorter overall hospital stay and significantly less blood loss during the operations. OS levels are also elevated below the EGJ, as lipid peroxidation can be detected (8-IP) and antioxidant defense (GSH) is reduced. Also the levels of 8-OHdG adducts were higher showing that DNA is being damaged by free radicals. This suggests that inflammation of the proximal gastric mucosa induced by gastroduodenal content, has a role in the pathogenesis of BE and esophageal AC. As the prognoses for patients with early esophageal AC were good, recurrence was still the most important cause of death. The risk was highest for patients with lymph node metastases and deep submucosal infiltration. Therefore radical surgery should be preferred with patients with a low risk of surgical complications and submucosal infiltration. In patients with intramucosal AC, endoscopic ablation should be considered. Evaluation of the patients responses to induction chemotherapy with FDG-PET-CT was not accurate enough to give indications better than the exclusion of metastatic disease. However, a significant decrease in radioactive glucose uptake was associated with improved survival, independently of histopathologic response. This information can be useful when balancing the risks of surgery against expected benefits. The perioperative and oncological results for MIE were comparable to those of the open approach and MIE seems to shorten hospital stay. However, the MIE technique is demanding and its mastery requires a sufficient number of cases and skilled practitioners.