Esophageal Cancer: Adenocarcinoma and Squamous Cell

Esophageal Adenocarcinoma and Squamous Cell Carcinoma: Overview

• Esophageal adenocarcinoma and squamous cell carcinoma are compared regarding clinical and pathologic findings, and pathogenesis.
• Esophageal adenocarcinoma and squamous cell carcinoma cases are now about equal, with adenocarcinoma surpassing squamous cell carcinoma in certain regions.

Barrett Esophagus: Precursor to Adenocarcinoma

• Barrett esophagus is a complication of gastroesophageal reflux disease (GERD); stomach acid enters the esophagus.
• About 10% of symptomatic GERD patients have intestinal metaplasia, which is defined as intestinal metaplasia of the esophagus.
• Acid exposure causes squamous cells to be replaced by intestinal columnar cells through transcommitment.
• Metaplasia increases the risk of progression to dysplasia and then to adenocarcinoma.
• 0.2 to 1% of individuals with intestinal metaplasia progress to epithelial dysplasia annually.
• Adenocarcinoma risk is 30-fold higher in patients with Barrett esophagus compared to those without it.
• Increased risk occurs with increased duration of symptoms and patient age.
• Endoscopically, Barrett esophagus appears as salmon pink tongues of glandular mucosa extending from the gastroesophageal junction, interspersed with light pink squamous mucosa.
• Microscopically, goblet cells are present (intestinal metaplasia); these cells contain mucin above the nucleus.

Progression to Dysplasia and Adenocarcinoma

• Dysplastic glands with cytologic atypia, variation in cell size/shape, large dark nuclei, and loss of polarity indicate progression.
• Surveillance is essential for patients with Barrett esophagus because of the risk of progression.
• Invasive adenocarcinoma is identified by angulated glands invading the surrounding tissue, which causes a desmoplastic reaction.
• A single specimen can show Barrett esophagus, high-grade dysplasia, and invasive adenocarcinoma.

Esophageal Adenocarcinoma: Key Aspects

• Almost all esophageal adenocarcinoma cases arise in a Barrett esophagus background.
• Adenocarcinoma incidence is rising worldwide.
• Risk factors include obesity, smoking, radiation, and diets low in fresh fruits and vegetables.
• Some Helicobacter pylori serotypes are protective because they decrease gastric acid production.
• Patients present with pain and difficulty swallowing, which progresses to a liquid-only diet, and weight loss.
• Other presentations include hematemesis, chest pain, and vomiting.
• Early metastases to lymph nodes occur due to the location of lymphatics in the lamina propria.
• Tumors are typically advanced at diagnosis; overall five-year survival is less than 25%.
• Early detection through surveillance endoscopy allows for intramucosal resection and improved patient outcomes.

Pathogenesis of Adenocarcinoma

• Early TP53 and CDKN2A loss of function occurs (allelic loss, mutation, or epigenetic silencing via hypermethylation).
• CDKN2A encodes p16 and ARF proteins.
  • P16 inhibits cyclin-dependent kinase 4 and 6, which blocks the RB tumor suppressor protein from entering the G1 phase.
  • ARF inhibits MDM2, preventing it from binding to and degrading P53.
• Later mutations occur with disease progression, increasing risk with longer symptom duration, older age, and longer Barrett mucosa.
• Morphologically, lesions are often found in the distal third of the esophagus.
  • Early lesions can be flat or raised in a Barrett esophagus background.
  • Later lesions can be exophytic or ulcerated masses, showing diffuse infiltration or deep invasion.
• Most adenocarcinomas produce mucin and form glands.
• Metastasis typically occurs to gastric and celiac lymph nodes.

Squamous Cell Carcinoma: Key Aspects

• More common in men (4:1 ratio).
• Presentation is similar to adenocarcinoma.
• Risk factors:
  • Alcohol and tobacco use (synergistic effect).
  • Poverty and diets low in fresh fruits and vegetables.
  • Caustic esophageal injury (e.g., lye ingestion).
  • Plummer-Vinson syndrome: triad of dysphagia, iron deficiency anemia, and esophageal web; more common in middle-aged women.
  • Achalasia: motility disorder causing loss of peristalsis and inability to relax the lower esophageal sphincter, which leads to upstream dilation.
  • Frequent consumption of very hot beverages.
  • Radiation exposure.

Pathogenesis and Morphology of Squamous Cell Carcinoma

• Pathogenesis is less clear than adenocarcinoma.
• SOX2 amplification, cyclin D1 overexpression, and loss of function of TP53, CDH1, and NOTCH1 are implicated.
• Tobacco and alcohol have a synergistic effect on risk.
• About 50% occur in the middle third of the esophagus.
• Squamous dysplasia appears as gray-white plaques; invasive carcinoma can be polypoid, ulcerated, or fungating.
• Most tumors are moderately to well-differentiated.
• Early metastasis to lymph nodes occurs, depending on the location in the esophagus:
  • Upper third: cervical lymph nodes.
  • Middle third: mediastinal, peritracheal, and tracheobronchial lymph nodes.
  • Lower third: gastric and celiac nodes.
• Histologically, lesions invade the surrounding soft tissue with a desmoplastic response, forming necrotic cystic structures lacking mucin.

Comparison of Adenocarcinoma and Squamous Cell Carcinoma

• Similarities:
  • Both malignancies can metastasize early to lymph nodes.
• Differences:
  • Site.
  • Main risk factors.
  • Precursor lesions.