Esophageal Adenocarcinoma

Esophageal adenocarcinoma (EAC) is a malignant glandular tumor arising predominantly in the distal esophagus and gastroesophageal junction (GEJ), classified by Siewert types I (5+ cm above GEJ, treated as esophageal), II (1 cm above to 2 cm below — true junctional, treated as esophageal or gastric), III (2-5 cm below — treated as gastric). Pathogenesis follows the metaplasia-dysplasia-carcinoma sequence: chronic GERD with acid and bile reflux causes inflammation, leading to Barrett's esophagus (intestinal metaplasia replacing squamous epithelium), progression through low-grade dysplasia, high-grade dysplasia, intramucosal carcinoma, then invasive adenocarcinoma. Annual progression rates: nondysplastic Barrett's 0.1-0.5%, low-grade dysplasia 0.7-1.4%, high-grade dysplasia 6-19%.

Epidemiology shows striking Western increase: incidence in US has increased >500% since 1970s, now ~6.7 per 100,000 in white males, exceeding squamous cell carcinoma. Risk factors include male sex (8:1 ratio), white race, GERD (5x risk if frequent symptoms), Barrett's esophagus (40-125x risk), obesity (especially central), smoking (2x), age >50 years, family history, hiatal hernia, low fruit/vegetable intake, H. pylori actually protective (reduces acid). Genetic factors include TP53 mutations early (often in dysplastic Barrett's), CDKN2A inactivation, SMAD4 loss, ERBB2/HER2 amplification (15-25%), MET amplification, MYC amplification. Clinical presentation: dysphagia (most common, progressive solids first), weight loss, regurgitation, chest pain, GI bleeding, hoarseness from recurrent laryngeal involvement, advanced disease with malignant fistulas, lymphadenopathy.

Diagnosis is by upper endoscopy with biopsies (multiple from any nodule, ulceration, or 4-quadrant biopsies of suspicious mucosa per Seattle protocol), endoscopic ultrasound (EUS) for T and N staging (particularly important for early lesions), CT chest/abdomen/pelvis for distant staging, PET-CT for occult metastases, bronchoscopy if airway involvement suspected, laparoscopy for selected GEJ tumors. Staging uses 8th edition AJCC TNM. HER2 testing for advanced disease, PD-L1 for immunotherapy candidates, MSI/MMR testing. Treatment: T1a (intramucosal) — endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) curative if R0; T1b (submucosal) — endoscopic resection if low-risk superficial submucosal, otherwise esophagectomy; T2-T4a or N+ — neoadjuvant chemoradiotherapy (CROSS protocol with carboplatin/paclitaxel + 41.4 Gy) followed by surgery; alternatively perioperative chemotherapy (FLOT regimen — 5-FU/leucovorin/oxaliplatin/docetaxel) for GEJ tumors; definitive chemoradiation for unresectable; metastatic — palliative chemotherapy (FOLFOX, mFOLFIRI), HER2-directed therapy with trastuzumab (HER2+), immunotherapy with pembrolizumab/nivolumab (PD-L1+ or MSI-H), supportive care. Esophagectomy approaches: Ivor Lewis (right thoracotomy + laparotomy), McKeown (3-field), transhiatal, minimally invasive, robotic. Five-year survival: T1a 80-95%, T1b 65-75%, locoregional with neoadjuvant 35-50%, metastatic 5-10%.