esophageal squamous cell carcinoma

**Epidemiology** - Most common esophageal cancer worldwide, especially in the "Asian esophageal cancer belt" (Iran to northern China), parts of Africa, and South America. - In the US, adenocarcinoma has overtaken SCC in incidence. SCC is more common in Black patients and in men. - Location: upper and middle third of the esophagus. Adenocarcinoma is usually in the lower third.

**Risk factors (high-yield mnemonic: "ABCDEF" of esophageal SCC)** - Alcohol - Achalasia - Hot liquids (thermal injury), such as hot tea - Tobacco and smoking - Nitrosamines (diet, such as pickled or smoked foods) and nutritional deficiencies - Caustic injury (lye ingestion) - Plummer-Vinson syndrome (iron deficiency anemia, esophageal webs, glossitis) - Tylosis (palmoplantar keratoderma) - Prior head and neck SCC - HPV is implicated in some regions - Prior thoracic radiation

**Pathophysiology** - Chronic mucosal irritation leads to squamous dysplasia, then carcinoma in situ, then invasive carcinoma. - Molecular changes include TP53 mutation, CDKN2A (p16) loss, and cyclin D1 amplification. EGFR overexpression is common. - Contrast with adenocarcinoma: Barrett metaplasia (columnar epithelium with goblet cells) from chronic GERD, obesity, and smoking.

**Clinical features** - Progressive dysphagia (solids first, then liquids), odynophagia, and weight loss. Dysphagia usually appears late, so patients often present with advanced disease. - Hoarseness (recurrent laryngeal nerve involvement), cough or aspiration (tracheoesophageal fistula), and hematemesis. - Hypercalcemia from PTHrP secretion (a paraneoplastic effect). - Metastasis: upper-third tumors spread to cervical nodes, middle-third tumors to mediastinal and tracheobronchial nodes, and lower-third tumors to celiac nodes. Common distant sites are the liver and lung.

**Diagnosis** - Upper endoscopy with biopsy is the gold standard. Histology shows keratin pearls and intercellular bridges. - Barium swallow may show an "apple core" lesion or irregular stricture. - Staging: endoscopic ultrasound (depth and nodes), CT chest/abdomen, and PET-CT for distant disease.

**Treatment** - Early disease (T1): endoscopic resection. - Locally advanced resectable disease: neoadjuvant chemoradiation followed by esophagectomy (CROSS regimen: carboplatin/paclitaxel plus radiation). For ESCC, definitive chemoradiation is an alternative to surgery because it is radiosensitive. - Metastatic disease: palliative chemotherapy, with immune checkpoint inhibitors (PD-1 inhibitors such as nivolumab and pembrolizumab) now used in first-line or adjuvant settings. Stenting and radiation provide palliation for dysphagia. - Prognosis is poor overall (5-year survival is about 20%) because of late presentation and the rich lymphatic drainage of the esophagus.

**Board pearls** - A patient with a long history of alcohol and tobacco use and dysphagia to solids, plus weight loss, points to SCC. - A patient with long-standing GERD and Barrett esophagus points to adenocarcinoma. - Long-standing achalasia raises the risk of SCC (not adenocarcinoma). - The esophagus has no serosa, so tumors spread early to adjacent structures (trachea, aorta, pericardium).