Histomorphologic tumor regression and lymph node metastases determine prognosis following neoadjuvant radiochemotherapy for esophageal cancer: implications for response classification

Abstract

Objective: We sought to quantitatively and objectively evaluate histomorphologic tumor regression and establish a relevant prognostic regression classification system for esophageal cancer patients receiving neoadjuvant radiochemotherapy.

Patients and methods: Eighty-five consecutive patients with localized esophageal cancers (cT2-4, Nx, M0) received standardized neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil, 36 Gy). Seventy-four (87%) patients were resected by transthoracic en bloc esophagectomy and 2-field lymphadenectomy. The entire tumor beds of the resected specimens were evaluated histomorphologically, and regression was categorized into grades I to IV based on the percentage of vital residual tumor cells (VRTCs). A major response was achieved when specimens contained either less than 10% VRTCs (grade III) or a pathologic complete remission (grade IV).

Results: Complete resections (R0) were performed in 66 of 74 (89%) patients with 3-year survival rates of 54% +/- 7.05% for R0-resected cases and 0% for patients with incomplete resections or tumor progression during neoadjuvant therapy (P < 0.01). Minor histopathologic response was present in 44 (59.5%) and major histopathologic response in 30 (40.5%) tumors. Significantly different 3-year survival rates (38.8% +/- 8.1% for minor versus 70.7 +/- 10.1% for major response) were observed. Univariate survival analysis identified histomorphologic tumor regression (P < 0.004) and lymph node category (P < 0.01) as significant prognostic factors. Pathologic T category (P < 0.08), histologic type (P = 0.15), or grading (P = 0.33) had no significant impact on survival. Cox regression analysis identified dichotomized regression grades (minor and major histomorphologic regression, P < 0.028) and lymph node status (ypN0 and ypN1, P < 0.036) as significant independent prognostic parameters. A 2-parameter regression classification system that includes histomorphologic regression (major versus minor) and nodal status (ypN0 versus ypN1) was established (P < 0.001).

Conclusions: Histomorphologic tumor regression and lymph node status (ypN) were significant prognostic parameters for patients with complete resections (R0) following neoadjuvant radiochemotherapy for esophageal cancer. A regression classification based on 2 parameters could lead to improved objective evaluation of the effectiveness of treatment protocols, accuracy of staging and restaging modalities, and molecular response prediction.

FIGURE 1. Overall survival of all 85 patients. Median survival was 23 months and the 3-year survival rate was 31% ± 7%.

FIGURE 2. Kaplan-Meier survival curves for patients with complete resections (RO), incomplete resections with microscopic involvement of a resection margin (R1), and patients without resection due to tumor progression during neoadjuvant radiochemotherapy (PR).

FIGURE 3. Distribution of the presence (ypN1) or absence (ypN0) of lymph node metastases between histomorphologic regression grades I to IV.

FIGURE 4. Kaplan-Meier survival curves for tumors with major histomorphologic regression (MaHR, grades III and IV) and minor histomorphologic regression (MiHR, grades I and II).

FIGURE 5. Kaplan-Meier curves for patients with minor histomorphologic regression with (class Ia; n = 29) and without (class Ib; n = 14) lymph node metastases compared with major histomorphologic regression with (class IIa; n = 9) and without (class IIb; n = 22) lymph node metastases.