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Esophageal Cancer

Esophageal Cancer Diagnosis and Staging

Epidemiology

  • Incidence Increase: Significant rise in esophageal cancer cases in recent decades.
    • 17,990 new cases in the United States in 2013.
  • Histologic Subtypes:
    • Esophageal Adenocarcinoma: Fastest-growing subtype in the U.S.
      • Surpassed Squamous Cell Carcinoma (SCC) in incidence.
    • SCC: Still predominant worldwide.
  • Demographic Variations:
    • Race:
      • SCC is three times more frequent in Blacks compared to Whites.
    • Geographic Differences:
      • U.S. Whites: Up to 5 per 100,000 incidence.
      • France: Approximately 12.5 per 100,000.
      • China: Over 100 per 100,000 in certain regions.
    • Gender:
      • Male-to-female ratio is 6:1 in most countries.
  • Risk Factors:
    • Genetic Predisposition.
    • Smoking and Alcohol: Strongly associated with SCC.
    • Gastroesophageal Reflux Disease (GERD): Linked to Barrett esophagus and adenocarcinoma.
  • Survival Rates:
    • Overall 5-year survival rate less than 18%.
  • Treatment Approaches:
    • Esophagectomy: Traditional gold standard for regional invasive cancers.
    • Endoscopic Mucosal Resection (EMR): Alternative for intramucosal carcinoma.
    • Multimodality Therapy:
      • Neoadjuvant Chemotherapy/Chemoradiotherapy followed by esophagectomy.
      • Shows increased survival benefits in locally advanced cases.

Anatomy

  • Esophagus Length: Approximately 20–30 cm, located in the posterior mediastinum.
  • Critical Points of Narrowing:
    • Cricopharyngeus Muscle.
    • Bronchoaortic Constriction.
    • Esophagogastric Junction (EGJ).
      • Common sites for iatrogenic and mechanical perforation.
  • Esophageal Layers:
    • Mucosa: Stratified squamous epithelium.
    • Submucosa.
    • Muscularis Propria.
    • Adventitia: Tissue attached to the esophagus.
  • Anatomic Divisions:
    • Cervical Esophagus: From esophageal orifice to sternal notch.
      • 15–<20 cm from incisors.
    • Upper Thoracic Esophagus: Sternal notch to azygos vein arch.
      • 20–<25 cm from incisors.
    • Middle Thoracic Esophagus: Lower border of azygos vein to inferior pulmonary vein.
      • 25–<30 cm from incisors.
    • Lower Thoracic Esophagus: Below inferior pulmonary vein to GEJ.
      • 30–40 cm from incisors.
  • Lymphatic Drainage:
    • Dense network in submucosa facilitating longitudinal spread.
    • Drains into cervical, tracheobronchial, mediastinal, gastric, and celiac nodes.
  • Common Metastatic Sites:
    • Retroperitoneal/Celiac Lymph Nodes.
    • Liver.
    • Lungs.
    • Adrenals.
    • Bone: May present with bone pain or hypercalcemia.
    • Pleural Effusion and Ascites.

Nomenclature

  • Staging Classifications:
    • Clinical Stage (Pretreatment):
      • Based on exams, imaging, endoscopy, biopsies, and non-resective exploration.
      • Denoted as cT, cN, cM.
    • Pathologic Stage (Postsurgical):
      • Includes surgical resection findings and histology.
      • Denoted as pT, pN, pM.
    • Posttherapy Stage:
      • After neoadjuvant or sole systemic/radiation therapy.
      • Denoted as ycT, ycN, ycM or ypT, ypN, ypM.
    • Restaging:
      • Determines disease extent post-therapy or at recurrence.
  • Residual Tumor ("R" Status):
    • R0: No residual tumor.
    • R1: Microscopic residual tumor.
    • R2: Macroscopic residual tumor.
    • RX: Cannot assess residual tumor presence.

Histologic Type

  • Adenocarcinoma:
    • Malignant epithelial tumor with glandular differentiation.
    • Commonly arises from Barrett esophagus in the lower third.
    • May originate from heterotopic gastric mucosa or submucosal glands.
  • Squamous Cell Carcinoma (SCC):
    • Malignant tumor with squamous differentiation.
    • Features keratinocyte-like cells, intercellular bridges, keratinization.
  • Mixed Adenosquamous Carcinoma:
    • Rare with both glandular and squamous features.
    • Exhibits aggressive behavior.

Histologic Grade

  • Tumor Grades:
    • GX: Grade cannot be assessed.
    • G1: Well differentiated (Low Grade).
    • G2: Moderately differentiated (Intermediate Grade).
    • G3: Poorly differentiated (High Grade).
    • G4: Undifferentiated (High Grade).

TNM Classification and Updates

Tumor (T) Classification

  • TX: Primary tumor cannot be assessed.
  • T0: No evidence of primary tumor.
  • Tis: High-grade dysplasia (noninvasive neoplastic epithelium).
  • T1: Invades lamina propria, muscularis mucosae, or submucosa.
    • T1a: Invades lamina propria or muscularis mucosae.
    • T1b: Invades submucosa.
  • T2: Invades muscularis propria.
  • T3: Invades adventitia.
  • T4: Invades adjacent structures.
    • T4a: Resectable invasion (pleura, pericardium, diaphragm).
    • T4b: Unresectable invasion (aorta, vertebral body, trachea).

Node (N) Classification

  • N0: No regional lymph node metastasis.
  • N1: Metastasis in 1–2 nodes.
  • N2: Metastasis in 3–6 nodes.
  • N3: Metastasis in 7 or more nodes.

Metastasis (M) Classification

  • M0: No distant metastasis.
  • M1: Distant metastasis present.

Updates in the Seventh Edition

  • T Stage Revisions:
    • Tis includes all noninvasive neoplastic epithelium.
    • T4 subdivided into T4a (resectable) and T4b (unresectable).
  • N Stage Modifications:
    • Regional nodes include any paraesophageal nodes from thoracic inlet to celiac axis.
    • Elimination of M1a and M1b subclassifications.
    • Introduction of nodal burden categories (N1–N3).
  • Separate Staging Systems for SCC and Adenocarcinoma.
  • Inclusion of Tumor Grade in staging.
  • Precise Definition of GEJ Tumors based on location.

Anatomic Location and Esophagogastric Junction (EGJ) Tumors

  • Siewert Classification:
    • Type I: Adenocarcinoma of distal esophagus.
      • Epicenter 1–5 cm above the anatomic EGJ.
    • Type II: True carcinoma of the cardia.
      • Epicenter 1 cm above to 2 cm below the EGJ.
    • Type III: Subcardial carcinoma.
      • Epicenter 2–5 cm below the EGJ.
  • AJCC Seventh Edition Staging:
    • Tumors with midpoint in:
      • Lower Thoracic Esophagus, EGJ, or within 5 cm proximal of the stomach extending into EGJ/esophagus are staged as Esophageal Adenocarcinoma.
    • Tumors more than 5 cm distal to EGJ or within 5 cm but not extending into EGJ/esophagus (Siewert Type III) are staged as Gastric Cancer.

Diagnostic Tools in Esophageal Cancer

Tumor Detection

Upper Gastrointestinal (UGI) Symptoms

  • Common Presentations:
    • Dysphagia
    • Weight Loss
  • Investigation:
    • Flexible Upper Endoscopy with Biopsy
    • Surveillance Endoscopy in patients with Barrett Esophagus

Radiodiagnosis

Upper Gastrointestinal Contrast Studies (Barium Swallow)

  • Purpose:
    • Initial evaluation when endoscopy is unavailable
    • Provides a "road map" before endoscopy
  • Findings:
    • Polypoid Tumor
    • Strictures with mucosal irregularity
    • "Apple Core" Constrictions
  • Additional Information:
    • Tumor Location
    • Esophageal Axis at tumor level
    • Presence of Hiatal Hernia or Diverticulum
  • Limitations:
    • Decreased Accuracy compared to endoscopy
    • Inability to Biopsy
  • Indications:
    • When endoscopy is not readily available
    • Strictures precluding complete endoscopic evaluation

Upper Endoscopy and Biopsy

  • Standard Initial Diagnostic Modality
  • Advantages:
    • Detailed visualization of esophageal lumen morphology
    • Ability to biopsy suspicious lesions
  • Reporting Should Include:
    • Tumor Morphology
    • Distance from Incisors
    • Length of Lesion
    • Circumferential Involvement Percentage
    • Relation to Gastroesophageal Junction (GEJ)
    • Presence of Skip Lesions
    • Barrett Esophagus characteristics
  • Biopsy Protocol:
    • Multiple Biopsies increase diagnostic accuracy
      • Six or more samples approach 100% diagnostic yield
    • Avoid necrotic or fibrotic areas
  • Alternative Techniques:
    • Brush Cytology for tight malignant strictures
      • Obtain brushings before biopsy to maximize yield
  • Follow-Up:
    • If histology confirms cancer, proceed with staging studies for treatment planning

FDG-PET/CT Scans

  • Modality: 2-[18F]-fluoro-2-deoxyglucose PET/CT
  • Function:
    • Detects metabolically active tissue using a glucose analogue (FDG)
    • Identifies primary tumors, metabolically active lymph nodes, and metastatic sites
  • Advantages:
    • Combined PET/CT improves diagnostic accuracy
    • Helps distinguish between inflammatory and malignant lymph nodes
  • Sensitivity and Specificity:
    • Primary Tumor Detection Sensitivity: 78%–95%
      • Lower sensitivity in small tumors (T1 and T2)
    • Nodal Detection Sensitivity varies:
      • Higher for cervical and upper thoracic nodes
      • Lower for mid- and lower mediastinal nodes
    • Specificity for Nodal Staging: 76%–95%
  • Main Utility:
    • Identifying distant metastasis
      • Changes management from curative to palliative in some cases
    • Independent Predictor of overall survival in nonmetastatic esophageal cancer
  • Limitations:
    • Not effective for T staging
    • Poor spatial resolution for separating primary tumor from adjacent lymph nodes

CT Scan and Magnetic Resonance Imaging (MRI)

CT Scan

  • Role:
    • First radiologic test after cancer diagnosis
    • Evaluates lesion, surrounding structures, regional organ invasion, lymph node metastasis
  • Findings Suggesting Invasion:
    • Obliteration of Fat Planes between esophagus and adjacent structures (e.g., aorta, trachea)
    • Thickening or Indentation of trachea or bronchi
  • Sensitivity and Specificity:
    • For detecting T4 disease:
      • Sensitivity: 25%
      • Specificity: 94%
  • Limitations:
    • Cannot reliably distinguish between T1–T3 stages
    • Size Criteria for lymph nodes may miss metastatic nodes
      • Sensitivity for Nodal Involvement: 50%
      • Specificity: 83%
  • Main Value:
    • Detecting distant metastases (hepatic, adrenal, lung)
    • Guides surgical planning

MRI

  • Advantages:
    • Multiplanar Imaging Capabilities
    • Useful for assessing tracheobronchial, aortic, and pericardial invasion
  • Accuracy:
    • Conventional MRI: Correct T staging in 60% of patients
    • High-Resolution T2-Weighted MRI: Correct T staging in 81%
  • Limitations:
    • Similar to CT in detecting mediastinal lymph nodes

Endoscopic Ultrasound (EUS) and Fine-Needle Aspiration (FNA)

  • Purpose:
    • Assess depth of tumor invasion (T staging)
    • Evaluate lymph node involvement (N staging)
  • Technique:
    • High-frequency probes (7.5 and 12 MHz) visualize esophageal wall layers
    • Five-layered Structure identified:
      • Mucosa, Submucosa, Muscularis Propria, etc.
  • Accuracy:
    • T Staging Sensitivity: 81%–92%
      • Challenges in distinguishing T1a (mucosal) vs. T1b (submucosal)
    • N Staging with FNA:
      • Sensitivity, specificity, and accuracy over 85%
  • Challenges:
    • Overstaging due to peritumoral edema
    • Understaging when tumor penetration is below sonographic resolution
    • Stenotic Tumors may impede examination
      • May require dilation or use of small-caliber ultrasound catheters
  • FNA Indications:
    • Suspicious lymph nodes accessible without traversing the primary tumor
    • Particularly for celiac, porta hepatis, cervical, and upper thoracic nodes
  • Operator Dependency:
    • Accuracy influenced by experience and tumor stage
    • Interobserver agreement varies, especially for T2 tumors

Endoscopic Resection (ER)

  • Role in Staging and Treatment
  • Technique:
    • Endoscopic Mucosal Resection (EMR)
      • Resection of mucosa and part of submucosa
      • Provides specimen for definitive histologic diagnosis
  • Advantages:
    • Accurate assessment of:
      • Depth of Infiltration
      • Lymphovascular Invasion
      • Degree of Differentiation
    • Estimates risk of lymph node metastasis
  • Indications:
    • Early-stage tumors (T1 lesions confined to mucosa or submucosa)
    • Intramucosal Adenocarcinoma (T1aN0)
  • Limitations:
    • Histopathologic Interpretation can be challenging
      • High rate of discordance in assessing depth of invasion
  • Outcomes:
    • Comparable long-term disease control to surgery for suitable candidates
    • Lower complication rates but higher recurrence compared to esophagectomy

Bronchoscopy and Endobronchial Ultrasound (EBUS)

  • Bronchoscopy:
    • Evaluates tracheobronchial tree invasion
    • Signs of Involvement:
      • Widened Carina
      • External Compression
      • Tumor Infiltration
      • Fistulization
    • Biopsy and Brush Cytology recommended for suspicious findings
  • Endobronchial Ultrasound (EBUS):
    • Assesses tracheobronchial invasion with higher accuracy
    • Advantages over CT and Conventional Bronchoscopy:
      • Better specificity and sensitivity in detecting invasion
    • Utility:
      • Sampling peritracheal and subcarinal lymph nodes
      • Complementary to EUS/FNA
  • Impact on Management:
    • Identifies patients with airway invasion, influencing surgical decisions

Laparoscopy and Thoracoscopy

  • Purpose:
    • Detect occult intraperitoneal or intrathoracic metastases
    • Sample regional lymph nodes
  • Indications:
    • Adenocarcinoma of the lower esophagus or GEJ tumors
    • Suspicious findings on CT and PET scans
  • Procedures:
    • Laparoscopy:
      • Visual inspection of peritoneal cavity and liver
      • Laparoscopic Ultrasound of liver
      • Collection of peritoneal fluid for cytology
      • Biopsy of suspicious lesions
    • Thoracoscopy:
      • Less commonly used
      • Identifies intrathoracic metastases
  • Impact on Management:
    • Can upstage disease, altering treatment plan
    • Change in management in up to 20% of patients
  • Limitations:
    • Invasive Procedure
    • Requires general anesthesia
    • Not routinely used unless highly indicated

Therapy Monitoring

Importance of Assessing Response to Neoadjuvant Therapy

  • Neoadjuvant Chemoradiotherapy:
    • Improves long-term outcomes compared to surgery alone
  • Challenges:
    • Identifying nonresponders early to avoid ineffective treatment
    • Side effects may increase perioperative morbidity
    • Delayed surgery due to prolonged ineffective therapy

Imaging Modalities for Monitoring

CT Scan

  • Limitations:
    • Low accuracy in restaging after chemoradiotherapy
    • Difficulty distinguishing viable tumor from necrosis or fibrosis
    • Overstaging and understaging are common

Endoscopic Ultrasound (EUS)

  • Not Recommended for response assessment
  • Limitations:
    • Invasiveness
    • Poor reproducibility
    • Difficulty in cases of post-radiation esophagitis or strictures

FDG-PET Scan

  • Potentially More Accurate for early prediction of response
  • Findings:
    • Moderate sensitivity in detecting therapeutic response
    • Can predict metabolic response early in treatment
  • Studies:
    • MUNICON Study:
      • Early PET assessment after 2 weeks of therapy
      • Nonresponders proceeded directly to surgery
      • Showed feasibility of PET-guided treatment algorithm
    • Other studies demonstrated varying sensitivity and specificity
  • Limitations:
    • False Negatives: Residual microscopic disease below detection threshold
    • False Positives: Inflammatory reactions increasing FDG uptake
  • Clinical Implications:
    • May influence decisions on continuing or altering therapy
    • Ongoing Trials to establish definitive role

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