Role of immunohistochemical detection of lymph-node metastases in management of breast cancer. International Breast Cancer Study Group

Lancet. 1999 Sep 11;354(9182):896-900. doi: 10.1016/s0140-6736(98)11104-2.


Background: This study was designed to ascertain whether immunohistochemical methods could improve the detection of metastases in primary breast-cancer patients whose axillary lymph nodes were classified, by conventional methods, as disease free.

Methods: Ipsilateral lymph nodes (negative for metastases by routine histology) from 736 patients (participants in Trial V of the International [Ludwig] Breast Cancer Study) were examined by serial sectioning and staining with haematoxylin and eosin (two sections from each of six levels) and by immunohistochemistry of a single section (with two anticytokeratins AE-1 and CAM 5.2). After median follow-up of 12 years, disease-free and overall survival were estimated by Kaplan-Meier methods.

Findings: Occult nodal metastases were detected by serial sectioning and haematoxylin and eosin in 52 (7%) of 736 patients and by immunohistochemistry in 148 (20%). Only two (3%) of 64 invasive lobular or mixed invasive lobular and ductal cancers had node micrometastases, detected by haematoxylin and eosin, compared with 25 (39%) by immunohistochemistry. Occult metastases, detected by either method, were associated with significantly poor disease-free and overall survival in postmenopausal but not in premenopausal patients. Immunohistochemically detected occult lymph-node metastases remained an independent and highly significant predictor of recurrence even after control for tumour grade, tumour size, oestrogen-receptor status, vascular invasion, and treatment assignment (hazard ratio 1.79 [95% CI 1.17-2.74], p=0.007).

Interpretation: The immunohistochemical examination of ipsilateral axillary lymph nodes is a reliable, prognostically valuable, and simple method for the detection of occult nodal metastases. Immunohistochemistry is recommended as a standard method of node examination in postmenopausal patients.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor / analysis*
  • Breast / pathology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology*
  • Breast Neoplasms / surgery
  • Carcinoma, Ductal, Breast / drug therapy
  • Carcinoma, Ductal, Breast / mortality
  • Carcinoma, Ductal, Breast / pathology*
  • Carcinoma, Ductal, Breast / surgery
  • Carcinoma, Lobular / drug therapy
  • Carcinoma, Lobular / mortality
  • Carcinoma, Lobular / pathology*
  • Carcinoma, Lobular / surgery
  • Chemotherapy, Adjuvant
  • Combined Modality Therapy
  • Disease-Free Survival
  • Female
  • Follow-Up Studies
  • Humans
  • Immunohistochemistry
  • Keratins / analysis*
  • Lymph Nodes / pathology*
  • Lymphatic Metastasis
  • Middle Aged
  • Survival Rate


  • Biomarkers, Tumor
  • Keratins