Why is depth of invasion (DOI) not the most significant prognostic factor in oesophageal cancer?

Why Lymph Node Status Supersedes Depth of Invasion as the Primary Prognostic Factor in Esophageal Cancer

Lymph node metastasis, not depth of invasion, is the most significant prognostic factor in esophageal cancer as it directly correlates with mortality and recurrence-free survival. 1, 2

Relationship Between Depth of Invasion and Lymph Node Status

While depth of invasion (DOI) is important, it primarily serves as a predictor for lymph node involvement rather than being the ultimate determinant of prognosis:

• Lymph node metastasis is the only significant independent prognostic factor in multivariate analysis of submucosal esophageal cancer 2
• DOI correlates strongly with likelihood of lymph node metastasis:
  • T1a (mucosal invasion): 0-12% risk of lymph node metastasis
  • T1b (submucosal invasion): Up to 36% risk of lymph node metastasis 3
  • T2: 43% risk of lymph node metastasis
  • T3: 77% risk of lymph node metastasis 4

Survival Outcomes by Prognostic Factors

Lymph Node Status

• Lymph node involvement significantly worsens prognosis, with long-term survival not exceeding 25% 5
• Patients with positive lymph nodes have significantly higher recurrence rates 3

Depth of Invasion

• 5-year recurrence-free survival:
  • Tumors confined to mucosa: 100%
  • Tumors invading submucosa: 60% 3
• 5-year overall survival:
  • Tumors confined to mucosa: 91%
  • Tumors invading submucosa: 58% 3

Lymphovascular Invasion

• Independent prognostic factor in multivariate analysis 3
• Associated with both tumor recurrence (p=0.001) and overall survival (p<0.001) 3
• Known poor prognostic factor in esophageal carcinomas 1

Clinical Implications for Management

The understanding that lymph node status supersedes DOI has important treatment implications:

1. For T1a (mucosal) lesions:

   • Endoscopic resection is typically curative due to low risk of lymph node metastasis 1
   • Provides excellent outcomes with similar long-term prognosis as surgery 5

2. For T1b (submucosal) lesions:

   • Risk stratification based on depth of submucosal invasion:
     • SM1 (<500μm): May be managed endoscopically in selected cases 1
     • SM2-3 (>500μm): Surgical resection with lymphadenectomy recommended 1
   • Additional risk factors for lymph node metastasis must be considered:
     • Lymphovascular invasion
     • Poor differentiation
     • Tumor size 1

3. For more advanced disease:

   • Multimodal therapy including surgery, chemotherapy, and radiation based on lymph node status 5

Pitfalls in Assessment

• Relying solely on DOI without considering lymph node status may lead to undertreatment
• Endoscopic assessment of invasion depth has limitations and final histological staging from resection specimens is crucial 6
• Duplicated muscularis mucosae in Barrett's esophagus can complicate accurate assessment of invasion depth 1
• Even intramucosal cancers with invasion into duplicated muscularis mucosae have reported 10% risk of lymph node metastasis 1

Conclusion

While depth of invasion is an important staging parameter and predictor of lymph node metastasis, it is the lymph node status itself that ultimately determines prognosis and survival in esophageal cancer. Treatment decisions should therefore prioritize assessment of lymph node involvement, with depth of invasion serving as one of several factors to consider in this evaluation.