Clinical Significance Of Occult Metastases

Although the clinical significance of micrometastases in lymph nodes has not been validated in a prospective study, there have been several retrospective studies which have addressed this important question. It is well known that lymph node status is the most important prognostic factor for patients with breast cancer. Despite this observation, 15-20% of node-negative women develop a recurrence within 10 years. It is not clear whether or not the presence of occult dissemination may be a predictor of relapse. To date, the natural history of micrometastases is unknown and the published literature is contradictory. Earlier studies using serial sectioning and H&E staining reported no significant difference in survival between patients with uninvolved nodes and those with occult metastases. However, axillary micrometastases were associated with decreased survival in certain subgroups, including those with T1 tumors or tumors larger than 1.3 mm in diameter.

The Ludwig Breast Cancer Study group reevaluated 921 breast cancer patients whose original pathological workup did not identify axillary metastases [48]. The axillary nodes were sectioned at six different levels and examined with H&E stains. The incidence of nodal metastases increased by 9%. Patients with micrometastases had lower rates of 5-year disease-free survival (58%) and overall survival (74%) compared to those with truly negative nodes (79% and 88%, respectively). These differences were found to be statistically significant.

De Mascarel et al. used immunohistochemistry to identify micrometastases in 23% of their study population [49]. In patients with invasive ductal cancer, immunohistochemistry-detected dissemination was the most significant factor associated with recurrence and had a significant impact on overall survival. Trojani demonstrated a 14% increase in micrometastases with the addition of immunohis-tochemistry which correlated with a lower survival [50]. Hainsworth et al. in a similar study concluded that the presence of occult metastases increased the 5-year recurrence rate from 16% to 32% [51].

Other investigators have reported conflicting results [52-55]. Pickren et al. evaluated 199 breast cancer patients and found a 22% increase in micrometastases with the addition of serial sectioning, but this increase did not have an impact on overall survival [52]. Friedman et al. evaluated 1153 patients, and although there was an increase in the number of micrometastases, the relative risk of distant metastases was identical in the two groups [56].

The addition of immunohistochemistry to the entire axillary specimen is impractical due to both time and financial constraints. However, the addition of immunohistochemistry to the sentinel node alone may improve the detection of tumor spread and the natural history of micrometastases may eventually be elucidated. The American College of Surgeons' Oncology Group will be conducting a prospective study to evaluate the clinical significance of immunohistochemistry-detected dissemination.

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