Esophageal Cancer
Squamous cell carcinoma or adenocarcinoma of the esophagus; presents late with dysphagia and weight loss.
Also known as: esophageal cancer, esophageal carcinoma, esophageal adenocarcinoma, squamous cell carcinoma esophagus
Overview
Malignant neoplasm arising from the esophageal epithelium. Two principal histologies: squamous cell carcinoma (SCC, ~30% in US, upper/mid esophagus) and adenocarcinoma (AC, ~70% in US, distal esophagus and GEJ, arising from Barrett mucosa).
Epidemiology
~21,000 new cases and ~16,000 deaths annually in the US. 5-year survival ~20% (improving with multimodal therapy in localized disease). Worldwide, SCC predominates (Asia, Africa); in Western countries, AC has overtaken SCC due to rising obesity and GERD.
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Risk factors
- Adenocarcinoma: chronic GERD, Barrett esophagus, obesity (central), male sex, white race, smoking, age >50
- Squamous cell carcinoma: smoking, heavy alcohol (synergistic), hot beverages, nitrosamine-rich diet, achalasia, caustic ingestion (lye), tylosis, HPV (some regions), Plummer-Vinson syndrome, low socioeconomic status
- Both: prior thoracic radiation, family history
Pathophysiology
Adenocarcinoma: chronic acid reflux → Barrett intestinal metaplasia → low-grade dysplasia → high-grade dysplasia → invasive AC. Squamous cell: carcinogen-driven (tobacco, alcohol, nitrosamines, HPV) progression from dysplasia to invasion. Both spread submucosally via rich esophageal lymphatics, often with skip lesions.
Clinical presentation
Symptoms
- Progressive solid-food dysphagia (initially solids, later liquids) — hallmark
- Unintentional weight loss
- Odynophagia
- Anemia or occult/overt GI bleeding
- Chest pain or retrosternal discomfort
- Hoarseness (recurrent laryngeal nerve invasion)
- Cough or aspiration (tracheoesophageal fistula — late finding)
Signs / physical exam
- Cachexia, temporal wasting
- Lymphadenopathy (supraclavicular — Virchow node)
- Hepatomegaly if metastatic
- Hoarseness from vocal cord paralysis
Classic findings
Older smoker or chronic GERD patient with progressive dysphagia for solids followed by liquids and >5% weight loss.
Differential diagnosis
- Achalasia / pseudoachalasia — Progressive dysphagia to solids and liquids; manometry — but pseudoachalasia FROM esophageal cancer can mimic primary achalasia
- Peptic stricture — Long-standing GERD, slow progression; smooth tapered narrowing on imaging; biopsy if any suspicion
- Eosinophilic esophagitis — Young, atopic; biopsy with ≥15 eos/HPF
- Schatzki ring — Intermittent solid-food dysphagia (steakhouse syndrome); thin ring at GEJ
- Extrinsic compression (lung cancer, mediastinal mass, aortic aneurysm) — Imaging shows extrinsic mass; biopsy of esophagus normal
- Esophageal motility disorder (DES, jackhammer) — Manometric abnormality; normal mucosa on EGD
Diagnostic workup
Diagnostic criteria
Histologic diagnosis on biopsy. Staging by AJCC 8th edition (TNM): T (depth: mucosa → submucosa → muscularis propria → adventitia → adjacent structures), N (regional nodes), M (distant). Stage 0-IV directs therapy.
Labs
- CBC (anemia)
- BMP, LFTs, albumin
- Nutritional assessment
Imaging
- Upper endoscopy with biopsy — establishes diagnosis; multiple biopsies of suspicious lesion
- Endoscopic ultrasound (EUS) — most accurate for T and N staging
- PET-CT (FDG) — distant metastases
- CT chest/abdomen/pelvis with contrast — local extent and metastases
- Bronchoscopy if upper/mid tumor near airway
- Barium esophagram — apple-core lesion (not required for diagnosis)
Diagnostic algorithm
| Feature | Adenocarcinoma | Squamous Cell Carcinoma |
|---|---|---|
| Location | Distal esophagus / GEJ | Upper and mid esophagus |
| Predominant region | US, Western Europe | Asia, Africa, Eastern Europe |
| Key risk factors | GERD, Barrett, obesity, smoking | Tobacco, alcohol, hot beverages, achalasia, lye injury |
| Precursor | Barrett intestinal metaplasia | Squamous dysplasia |
| Incidence trend | Rising in West | Declining in West |
| Response to chemoradiation | Good | Excellent (often more chemoradiosensitive) |
Treatment
First-line
- Multidisciplinary team (GI, surgical oncology, medical oncology, radiation oncology, nutrition)
- Smoking and alcohol cessation; nutritional optimization
- Stage-directed therapy (see by_subtype)
T1a (mucosal) — Stage 0/IA
- Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD)
- Radiofrequency ablation of residual Barrett
- 5-year survival >90%
Locally advanced (T1b-T4a, N0-N3, M0)
- Neoadjuvant chemoradiation (carboplatin + paclitaxel + 41.4 Gy — CROSS regimen) followed by esophagectomy
- Definitive chemoradiation if not surgical candidate (cisplatin/5-FU or carboplatin/paclitaxel + 50.4 Gy)
- Perioperative chemotherapy (FLOT — 5-FU/leucovorin/oxaliplatin/docetaxel) for GEJ adenocarcinoma — alternative to CROSS
Metastatic (Stage IV)
- Palliative systemic therapy: chemotherapy (fluoropyrimidine + platinum) ± trastuzumab if HER2+
- Immunotherapy — nivolumab or pembrolizumab (depending on PD-L1 CPS, histology)
- Palliative interventions: esophageal stent, brachytherapy, photodynamic therapy, gastrostomy for nutrition
- Best supportive care and palliative care referral
Complications
- Tracheoesophageal fistula (cough with swallowing, recurrent pneumonia)
- Esophagorespiratory fistula
- Aspiration pneumonia
- Malnutrition and cachexia
- Hemorrhage (rarely massive from aortic involvement)
- Metastases — liver, lung, bone, peritoneum, distant nodes
- Post-esophagectomy: anastomotic leak, chylothorax, pulmonary complications
PANCE pearls
- Any patient ≥50 with new dysphagia or alarm features deserves prompt EGD — do not assume GERD.
- Adenocarcinoma now outnumbers squamous cell in the US, mirroring the rise in GERD/obesity/Barrett.
- Endoscopic resection (EMR/ESD) is curative for mucosal (T1a) disease and avoids esophagectomy in selected patients.
- CROSS regimen (neoadjuvant chemoradiation + surgery) is standard of care for locally advanced disease (van Hagen, NEJM 2012).
- FLOT4 trial established perioperative FLOT as standard for resectable GEJ adenocarcinoma over ECF.
- PET-CT detects occult metastases in ~15% of patients deemed resectable by CT alone — essential before curative-intent therapy.
- Virchow node (left supraclavicular) and Sister Mary Joseph nodule (periumbilical) suggest M1 disease.
References
- NCCN 2024 — NCCN Guidelines Version 4.2024 — Esophageal and Esophagogastric Junction Cancers
- CROSS Trial — van Hagen P et al. Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer. NEJM 2012;366:2074-2084
- FLOT4 — Al-Batran SE et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4). Lancet 2019;393:1948-1957
- ACG 2022 Barrett — Shaheen NJ et al. Diagnosis and Management of Barrett's Esophagus: An Updated ACG Guideline. Am J Gastroenterol 2022;117:559-587
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