title: 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.
  
  
  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.
authors.affiliation: Department of Visceral and Vascular Surgery, University of Cologne, Cologne, Germany. paul.schneider@uk-koeln.de
authors.forename: Paul M
authors.initials: PM
authors.lastname: Schneider
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Baldus
authors.forename: Ralf
authors.initials: R
authors.lastname: Metzger
authors.forename: Martin
authors.initials: M
authors.lastname: Kocher
authors.forename: Rudolf
authors.initials: R
authors.lastname: Bongartz
authors.forename: Elfriede
authors.initials: E
authors.lastname: Bollschweiler
authors.forename: Hartmut
authors.initials: H
authors.lastname: Schaefer
authors.forename: Juergen
authors.initials: J
authors.lastname: Thiele
authors.forename: Hans P
authors.initials: HP
authors.lastname: Dienes
authors.forename: Rolf P
authors.initials: RP
authors.lastname: Mueller
authors.forename: Arnulf H
authors.initials: AH
authors.lastname: Hoelscher
mesh_terms: D000230:Adenocarcinoma / Q000401:mortality / Q000473:pathology / Q000556:secondary* / Q000628:therapy; D000328:Adult; D000367:Age Factors; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000401:mortality / Q000473:pathology / Q000556:secondary* / Q000628:therapy; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D004938:Esophageal Neoplasms / Q000401:mortality / Q000473:pathology* / Q000628:therapy*; D016629:Esophagectomy / Q000379:methods; D005260:Female; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011336:Probability; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018714:Radiotherapy, Adjuvant; D018570:Risk Assessment; D012737:Sex Factors; D016019:Survival Analysis