Esophageal Cancer

What is Esophageal Cancer?

Esophageal cancer begins in the cells lining the esophagus, a 10-inch (25 cm) muscular tube connecting the throat to the stomach. The esophagus has three parts:

• Upper (cervical) esophagus: Near the throat
• Middle (thoracic) esophagus: In the chest
• Lower (distal) esophagus: Near the stomach, including gastroesophageal (GE) junction

Shifting Epidemiology

In Western countries, particularly the US, esophageal cancer has undergone a dramatic shift:

• Adenocarcinoma now dominant (60%): Increased from 10% in 1975 to 60% today - one of the fastest-rising cancers in incidence
• Squamous cell declining (35%): Decreased due to reduced smoking rates
• Geographic variation: Squamous cell still dominates in Asia, Africa, and the "esophageal cancer belt" (Iran, Northern China, Southern Russia)

Types of Esophageal Cancer

Adenocarcinoma (60%)

Develops from glandular cells, almost always in the lower esophagus and GE junction:

Characteristics

• Location: Distal esophagus and gastroesophageal junction (Siewert type I-III)
• Precursor: Barrett's esophagus in 90% of cases
• Risk factors: GERD, Barrett's esophagus, obesity, white race
• Demographics: More common in white males, Western countries
• Rising incidence: Increased 6-fold since 1975 in the US

Barrett's Esophagus Connection

• Definition: Chronic GERD causes normal squamous cells to transform into intestinal-type columnar cells (metaplasia)
• Progression: Normal → Barrett's → low-grade dysplasia → high-grade dysplasia → adenocarcinoma
• Cancer risk with Barrett's: 0.1-0.5% per year (1 in 200-1000 per year)
• Surveillance important: Regular endoscopy with biopsies can detect early changes
• High-grade dysplasia: 5-7% annual progression to cancer; often treated endoscopically before invasive cancer develops

Squamous Cell Carcinoma (35%)

Arises from squamous cells lining the esophagus:

Characteristics

• Location: Can occur anywhere in esophagus; most commonly middle third
• Risk factors: Smoking, heavy alcohol use, hot beverages, achalasia
• Demographics: More common in African Americans, Asian populations
• Geographic "hotspots": Very high rates in esophageal cancer belt (Iran, Northern China, Central Asia)
• Declining in West: Due to reduced smoking rates

Environmental and Dietary Factors

In high-incidence areas:

• Very hot tea consumption (thermal injury)
• Low fruit and vegetable intake
• Nutritional deficiencies (vitamins A, C, E, selenium, zinc)
• Pickled vegetables and moldy foods
• Opium use (in Iran)

Rare Esophageal Tumors (<5%)

• Small cell carcinoma: Very aggressive, similar to lung small cell cancer
• Lymphoma: Usually secondary involvement
• Melanoma: Rare primary esophageal melanoma
• Sarcoma: Gastrointestinal stromal tumors (GIST), leiomyosarcoma

Siewert Classification (GE Junction Tumors)

For tumors at the gastroesophageal junction:

• Type I: 1-5 cm above GE junction - treated as esophageal cancer
• Type II: 1 cm above to 2 cm below junction - true cardia tumors
• Type III: 2-5 cm below junction - treated as gastric cancer

Symptoms and Warning Signs

Early esophageal cancer often causes no symptoms. When symptoms appear, cancer is usually advanced.

Cardinal Symptom: Dysphagia

Difficulty swallowing (dysphagia) is present in 90% of patients at diagnosis:

• Progressive pattern: Starts with solid foods (meat, bread), progresses to soft foods, then liquids
• Late symptom: Indicates 50-75% esophageal obstruction
• Patients often adapt: May not report until severe because they modify diet gradually
• Red flag: New or worsening dysphagia warrants prompt evaluation, especially in those over 50

Common Symptoms

• Unintentional weight loss (50-70%): Often significant (10-15% body weight), due to difficulty eating and cancer metabolism
• Chest pain or discomfort (30-40%): Behind breastbone, especially when swallowing
• Heartburn or indigestion (30%): Worsening GERD symptoms
• Regurgitation (20%): Food coming back up
• Chronic cough (15%): From aspiration or tracheoesophageal fistula
• Hoarseness (10%): If tumor affects recurrent laryngeal nerve

Advanced Disease Symptoms

• Complete inability to swallow: Even liquids or saliva
• Coughing with eating/drinking: Suggests tracheoesophageal fistula (connection between esophagus and airway)
• Vomiting blood (hematemesis): From tumor erosion
• Black, tarry stools: Upper GI bleeding
• Bone pain: If metastases to bones
• Jaundice: If liver metastases
• Shortness of breath: Lung metastases or pleural effusion

When to See a Doctor

Seek medical attention promptly if you experience:

• New or worsening difficulty swallowing
• Unintentional weight loss >5% body weight
• Persistent chest pain
• Worsening heartburn not responding to medications
• Vomiting blood or black stools
• Chronic cough or hoarseness lasting >3 weeks

Causes and Risk Factors

Risk factors differ between adenocarcinoma and squamous cell carcinoma:

Adenocarcinoma Risk Factors

Barrett's Esophagus (Strongest Risk Factor)

• 30-60× increased risk compared to general population
• Present in ~90% of adenocarcinoma patients
• Annual cancer risk: 0.1-0.5% per year
• With high-grade dysplasia: 5-7% per year
• Surveillance recommended: Regular endoscopy for early detection

Chronic GERD (Gastroesophageal Reflux Disease)

• 5-10× increased risk with chronic, severe GERD
• Duration matters: >5 years of weekly symptoms increases risk
• Mechanism: Chronic acid exposure → Barrett's → dysplasia → cancer
• PPIs may reduce risk but evidence mixed

Obesity

• 2-3× increased risk (strongest association of any cancer with obesity)
• Mechanism: Increased abdominal pressure → GERD; hormonal changes; inflammation
• Dose-dependent: Higher BMI = higher risk
• Central obesity (abdominal fat) particularly risky

Smoking

• 2× increased risk for adenocarcinoma (less than squamous cell)
• Risk decreases 10-30 years after quitting

Demographics

• White males: 5-10× higher rates than other groups
• Age: Increases with age, peak 60-70s

Squamous Cell Carcinoma Risk Factors

Tobacco Use (Strongest Modifiable Risk Factor)

• 5-10× increased risk
• All forms: Cigarettes, cigars, pipes, chewing tobacco
• Dose-dependent: More tobacco = higher risk
• Synergistic with alcohol: Combined use multiplies risk

Heavy Alcohol Consumption

• 5-7× increased risk with heavy use (>3 drinks/day)
• Type doesn't matter: Beer, wine, spirits all associated
• Synergistic with tobacco: Together increase risk 25-100×
• Mechanism: Direct mucosal damage, acetaldehyde carcinogen, nutritional deficiencies

Hot Beverages

• Chronic thermal injury from very hot tea, coffee, mate
• Common in high-incidence areas: Iran, South America (mate)
• Temperature >65°C (149°F): Probably carcinogenic (IARC classification)

Diet and Nutrition

• Low fruits and vegetables: Deficiency in protective vitamins/antioxidants
• Pickled vegetables: In high-incidence areas
• Micronutrient deficiencies: Vitamins A, C, E, riboflavin, selenium, zinc
• Nitrosamines: From certain preserved foods

Medical Conditions

• Achalasia: Swallowing disorder; 10-15× increased risk
• Tylosis (genetic): Rare hereditary condition with 40% lifetime risk
• Caustic injury: Lye ingestion; risk increases 20-40 years later
• Head and neck cancer history: Shared risk factors (field cancerization)
• HPV infection: Possible association in some populations

Demographics

• African Americans: 2-3× higher rates than whites in US
• Male predominance: 3-4:1
• Lower socioeconomic status: Associated with higher risk

Protective Factors

• Aspirin/NSAIDs: May reduce risk of progression from Barrett's to cancer
• Statins: Possible protective effect (being studied)
• High fruit and vegetable intake: Protective antioxidants
• H. pylori infection: Paradoxically protective for adenocarcinoma (may reduce acid)

Diagnosis and Staging

Diagnostic Tests

Upper Endoscopy (EGD) with Biopsy - Gold Standard

• Procedure: Flexible scope passed through mouth to visualize esophagus, stomach, duodenum
• Biopsy: Multiple tissue samples taken from suspicious areas
• Advantages: Direct visualization, biopsy for definitive diagnosis, assess tumor location and extent
• Pathology confirms: Cancer type (adenocarcinoma vs squamous), grade, presence of dysplasia
• Sedation: Moderate sedation; takes 15-30 minutes

Barium Swallow

• Less commonly used now but can show:
  • Narrowing or irregularity of esophagus
  • Tumor location and length
  • Fistulas
• Cannot obtain tissue - endoscopy still needed

Staging Workup (Once Cancer Diagnosed)

Critical for treatment planning:

CT Scan (Chest, Abdomen, Pelvis with Contrast)

• Assesses: Tumor size, local invasion, lymph nodes, distant metastases (liver, lung, bones)
• Limitations: Cannot assess depth of tumor invasion into esophageal wall

PET-CT Scan

• Combines: Metabolic activity (PET) with anatomy (CT)
• Excellent for: Detecting distant metastases, evaluating lymph nodes
• Standard in staging workup
• Also used: To assess treatment response mid-therapy

Endoscopic Ultrasound (EUS)

• Most accurate for T-stage (depth of invasion) and N-stage (lymph nodes)
• Procedure: Ultrasound probe on endoscope visualizes esophageal wall layers
• Fine needle aspiration (FNA): Can biopsy suspicious lymph nodes
• Essential for determining if tumor is resectable and planning surgery

Bronchoscopy

• For mid-esophageal tumors to rule out tracheal/bronchial invasion
• Important: Tracheal invasion makes tumor unresectable

Laparoscopy (Staging Laparoscopy)

• For GE junction tumors
• Detects: Peritoneal metastases not visible on imaging (10-15% of cases)
• Spares: Unnecessary major surgery if metastases found

TNM Staging

Laboratory Tests

• CBC: Anemia from chronic bleeding
• Comprehensive metabolic panel: Liver and kidney function, nutritional status
• Albumin: Marker of nutritional status

Treatment Options

Treatment depends on stage, location, histology, and patient fitness. Most require multimodal therapy.

Early-Stage Disease (Stage 0-I)

Endoscopic Therapy

For high-grade dysplasia and T1a tumors (limited to mucosa):

Endoscopic Mucosal Resection (EMR)

• Technique: Lifting and removing abnormal tissue through endoscope
• Indications: Early cancers limited to mucosa, focal high-grade dysplasia
• Advantages: Avoids major surgery, preserves esophagus
• Curative for appropriate early lesions

Endoscopic Submucosal Dissection (ESD)

• Advanced technique: En bloc (one-piece) resection
• Better pathology assessment than EMR
• Higher risk of perforation but more complete removal

Ablation (After EMR/ESD)

• Radiofrequency ablation (RFA): Destroys remaining Barrett's tissue
• Cryotherapy: Freezing abnormal tissue
• Goal: Eradicate all Barrett's to prevent recurrence

Locally Advanced Resectable Disease (Stage II-III)

Standard approach: Trimodal therapy (chemotherapy + radiation + surgery)

Neoadjuvant Chemoradiation (Preferred)

Treatment BEFORE surgery:

CROSS Regimen (Most Common)

• Chemotherapy: Carboplatin + paclitaxel weekly × 5 weeks
• Radiation: 41.4 Gy over 5 weeks
• Followed by: Surgery 6-8 weeks later
• Benefits:
  • Downstages tumor (makes it smaller and less advanced)
  • Increases R0 resection rate (complete removal with negative margins)
  • Improves survival: Median survival 49 months vs 24 months with surgery alone
  • 25-30% achieve pathologic complete response (no viable cancer in surgical specimen)

Alternative Regimens

• FLOT: 5-FU, leucovorin, oxaliplatin, docetaxel (perioperative chemotherapy without radiation)
• Cisplatin + 5-FU: Older standard, more toxic

Surgery: Esophagectomy

Major operation with significant morbidity:

Types of Esophagectomy

• Ivor Lewis (transthoracic):
  • Abdominal and right chest incisions
  • Removes distal esophagus
  • Anastomosis (connection) in chest
  • Most common for distal/GE junction tumors
• Transhiatal:
  • Abdominal and neck incisions (no chest incision)
  • Esophagus removed through diaphragm
  • Anastomosis in neck
  • Lower morbidity but less lymph node removal
• McKeown (three-incision):
  • Abdomen, right chest, and neck incisions
  • For mid-esophageal tumors
  • Anastomosis in neck

Reconstruction

• Gastric pull-up (most common): Stomach is pulled up and connected to remaining esophagus
• Colonic interposition: Segment of colon used if stomach not available
• Jejunal interposition: Rare, uses small intestine

Approach

• Open surgery: Traditional
• Minimally invasive (MIE): Laparoscopic/thoracoscopic or robotic
  • Reduced blood loss, shorter hospital stay
  • Similar oncologic outcomes to open
  • Requires experienced surgeon

Morbidity and Mortality

• 30-day mortality: 2-5% at high-volume centers (>10% at low-volume centers)
• Major complications (30-50%):
  • Anastomotic leak (10-20%) - connection breaks down
  • Pneumonia (15-30%)
  • Recurrent laryngeal nerve injury (hoarseness)
  • Chylothorax (lymphatic leak)
  • Atrial fibrillation
• Hospital stay: 7-14 days typically
• Volume matters: Outcomes significantly better at high-volume centers (>20 cases/year)

Definitive Chemoradiation (No Surgery)

• For patients: Medically unfit for surgery, refuse surgery, cervical esophageal cancer
• Higher radiation dose: 50-50.4 Gy (vs 41.4 Gy preop)
• Chemotherapy: Cisplatin + 5-FU or carboplatin + paclitaxel
• Results: 20-30% cure rate for squamous cell; lower for adenocarcinoma
• Surveillance: PET-CT at 3 months to assess response

Metastatic Disease (Stage IV)

Goals: Prolong survival, maintain quality of life, palliate symptoms

Systemic Therapy

First-Line Chemotherapy + Immunotherapy (New Standard)

• For PD-L1 positive tumors (CPS ≥10):
  • Nivolumab (Opdivo) + Chemotherapy: CheckMate-649 trial showed superior survival
  • Pembrolizumab (Keytruda) + Chemotherapy: KEYNOTE-590 trial
• Chemotherapy backbone:
  • FOLFOX (5-FU, leucovorin, oxaliplatin)
  • Or cisplatin + 5-FU/capecitabine
• Median survival: 13-15 months with immunotherapy combinations vs 9-11 months with chemo alone

HER2-Targeted Therapy (Adenocarcinoma Only)

• For HER2-positive tumors (15-20% of adenocarcinomas):
  • Trastuzumab (Herceptin) + Chemotherapy: Improves survival (ToGA trial)
  • Newer agents: Trastuzumab deruxtecan (Enhertu) for second-line
• HER2 testing recommended for all metastatic adenocarcinomas

Second-Line and Beyond

• Immunotherapy monotherapy: Nivolumab, pembrolizumab (if not given first-line)
• Ramucirumab (Cyramza) + paclitaxel: VEGF inhibitor
• Irinotecan: Alternative chemotherapy
• Clinical trials strongly encouraged

Palliative Interventions

For Dysphagia Relief

• Esophageal stent:
  • Expandable metal mesh tube placed endoscopically
  • Immediate relief of obstruction
  • Allows eating
  • Complications: migration, perforation, pain
• Dilation: Stretching narrow area (temporary relief)
• Radiation therapy: External beam or brachytherapy (radioactive source placed in esophagus)
• Laser therapy or argon plasma coagulation: Destroy tumor tissue blocking lumen
• Feeding tube (gastrostomy or jejunostomy): If unable to swallow despite interventions

Radiation Therapy

• Never used alone for curative intent (except rare cases)
• Combined with chemotherapy: Concurrent chemoradiation
• Doses: 41.4-50.4 Gy depending on intent (preoperative vs definitive)
• Side effects: Esophagitis, fatigue, skin changes, stricture (late)

Prognosis and Survival

Overall Survival

• All stages combined: 21% 5-year survival
• Localized (Stage I-II): 47% 5-year survival
• Regional (Stage III): 26% 5-year survival
• Distant metastases: 6% 5-year survival

Factors Affecting Prognosis

Favorable Factors

• Early stage (0-I)
• No lymph node involvement
• Complete (R0) resection
• Pathologic complete response to neoadjuvant therapy
• Good performance status
• Squamous cell histology (for localized disease)
• Well to moderately differentiated
• Treatment at high-volume center

Unfavorable Factors

• Advanced stage (III-IV)
• Lymph node metastases (single strongest prognostic factor)
• Poor differentiation
• Positive resection margins
• Weight loss >10%
• Poor performance status
• Signet ring cell histology
• Elevated CEA or CA 19-9

Outcomes After Trimodal Therapy

• Pathologic complete response: 25-30% (no viable cancer in surgical specimen) - excellent prognosis with 50-60% 5-year survival
• Median overall survival: 49 months with neoadjuvant chemoradiation + surgery vs 24 months with surgery alone
• 5-year survival: 40-50% for resectable Stage II-III with trimodal therapy

Surveillance After Treatment

After Curative-Intent Therapy

• History and physical: Every 3-6 months for 2 years, then every 6-12 months to year 5, then annually
• Upper endoscopy: At 3-6 months post-surgery, then as clinically indicated
• CT chest/abdomen: Every 6-12 months for first 2-3 years
• Nutritional monitoring: Weight, vitamin B12, iron (if total gastrectomy component)

Recurrence

• Overall recurrence rate: 40-60% after curative treatment
• Timing: Most within 2 years; 80% within 3 years
• Sites: Locoregional (30%), distant (liver, lung, bone, brain) (50%), both (20%)
• Treatment: Usually systemic therapy; radiation for symptomatic metastases; rarely surgery for isolated recurrence

Prevention

Primary Prevention

Lifestyle Modifications

• Don't smoke: Most important for squamous cell carcinoma prevention
• Limit alcohol: Especially important to avoid heavy use; synergistic with tobacco
• Maintain healthy weight: Crucial for adenocarcinoma prevention
• Treat GERD: Lifestyle changes + medications (PPIs) for chronic reflux
• Diet:
  • High fruits and vegetables
  • Avoid very hot beverages
  • Limit processed and pickled foods

Secondary Prevention (Early Detection)

Barrett's Esophagus Screening

Consider screening endoscopy if:

• Chronic GERD (>5 years) PLUS multiple risk factors:
  • Age >50
  • Male
  • White race
  • Central obesity
  • Current or past smoking
  • First-degree relative with Barrett's or esophageal adenocarcinoma

Barrett's Esophagus Surveillance

If Barrett's esophagus diagnosed:

• No dysplasia: Endoscopy every 3-5 years
• Low-grade dysplasia: Confirm with expert pathologist, then endoscopy every 6-12 months OR endoscopic ablation
• High-grade dysplasia: Endoscopic resection (EMR/ESD) + ablation recommended
• PPI therapy: Continue to control acid

Chemoprevention (Under Investigation)

• Aspirin: Observational studies suggest 30-40% risk reduction for progression from Barrett's; clinical trials ongoing
• PPIs: May reduce progression from Barrett's but evidence mixed
• Not yet standard recommendations

Living with Esophageal Cancer

After Esophagectomy

Eating Challenges

• Small, frequent meals: 6-8 small meals instead of 3 large (stomach is smaller)
• Eat slowly: Chew thoroughly
• Stay upright: Remain upright 1-2 hours after eating
• Avoid lying flat: Elevate head of bed 30-45 degrees
• Dense calories: High-calorie, high-protein foods in small portions

Dumping Syndrome

• Occurs: When food moves too quickly from stomach to intestine
• Symptoms: Nausea, cramping, diarrhea, dizziness, sweating after eating
• Management:
  • Avoid simple sugars
  • Separate solids and liquids (drink 30 min after eating)
  • Increase protein and complex carbs
  • May need octreotide in severe cases

Reflux

• Common after esophagectomy (no lower esophageal sphincter)
• Management: PPI daily, elevate head of bed, avoid eating before bed

Nutritional Support

• Feeding jejunostomy tube: Often placed during surgery for supplemental nutrition
• Registered dietitian: Essential for managing nutrition
• Vitamin supplementation: B12, calcium, iron, vitamin D often needed
• Weight monitoring: 10-20% weight loss common initially; goal is to stabilize

Managing Treatment Side Effects

• Radiation esophagitis: See mucositis page for management
• Fatigue: Very common during chemoradiation
• Nausea: From chemotherapy
• Diarrhea: Especially with 5-FU

Emotional Support

• Anxiety and depression very common
• Support groups (Esophageal Cancer Action Network)
• Counseling or therapy
• Peer mentoring programs

Support Resources

• Esophageal Cancer Action Network (ECAN): ecan.org
• Esophageal Cancer Education Foundation (ECEF): fightec.org
• American Cancer Society: cancer.org

Frequently Asked Questions