Axillary lymph node nanometastases are prognostic factors for metastatic relapse in breast cancer patients

Reviewer: John P. Plastaras, MD, PhD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: December 16, 2006

Presenter: S. Alberti
Affiliation: University of Chieti, Chieti, Italy


  • There is a wide range of outcomes after diagnosis and treatment for early stage breast cancer. The unexplained heterogeneity of outcomes may be a result of inaccurately under staged axillary lymph node metastases
  • Routine pathologic analysis of axillary lymph nodes may miss very small tumor deposits. Undetected, microscopic lymph node tumor deposits may account for a fraction the observed prognostic diversity.


  • 702 single institution, consecutive patients with 8 years of median follow-up were carefully evaluated for "nanometastases"
    • whole-axilla dissections from 1989-1993 were examined
    • pathologic N0 cases were reexamined systematically using step sectioning and cytokeratin immunohistochemistry to reveal pN0(i+) cases
  • 6676 lymph nodes from 377 pN0 whole axillary dissections
    • 250 sections per LN, resulting in 90,000 data points
  • Endpoints:
    • risk of first adverse events, distant relapse
    • compare "bona fide" pN0 with pN0(i+), pN1mi, and pN1
  • Cox regression analysis was used to determine prognostic significance of various factors, including pathologic lymph node status


  • Sensitivity should be ~90% using 50-150 micron interval with at least 10 lymph nodes dissected
  • They found 24 patients with previously undetected of nanometastases (pN0(i+))
  • There was a disproportionate number of lobular carcinoma with nanometastases compared to ductal carcinomas. Lobular carcinoma was associated with isolated tumor cells.
    • total population: 70% ductal, 16% lobular
    • nanometastases: 67% ductal, 24% lobular
  • pN0(i+) status was a strong risk factor for event free survival (p<0.0005) and metastatic relapse using univariate and multivariate analysis
  • Adverse events were rare in the first 36 months, however, after this point, events started occurring in the pN0(i+) patients, suggesting that the small size of these deposits took time to become clinically evident

Author's Conclusions

  • Nanometastasis in early stage breast cancer as detected by systematic sectioning and immunohistochemical analysis is a significant negative prognostic factor
  • The lack of a size threshold for an impact on prognosis indicates that even tiny lymph node deposits are bona fide metastases
  • Late relapse in patients with nanometastases indicates that long follow-up is required to really assess impact on relapse
  • These results support inclusion of procedures for nanometastasis detection in TNM pathological staging.

Clinical/Scientific Implications

  • Some have argued that the use of ultra sensitive methods of detection of tumors only reveals clinically insignificant tumor burdens. This paper suggests that any size of metastatic tumor deposit is an indicator of worse prognosis, and that pN0(i+) can not be ignored.
  • The serial sectioning and immunohistochemical processing of these specimens was painstaking. If this method became standard for all axillary lymph node dissections, there would be a significant impact on the cost of pathologic evaluation for breast cancer treatment
  • With the rise of sentinel lymph node sampling, the impact of this study is unclear. It supports the thorough systematic sectioning and immunohistochemical analysis of sentinel lymph nodes.