Donald L. Weaver, M.D.,

N Engl J Med 2011; 364:412-421February 3, 2011

We randomly assigned women with breast cancer to sentinel-lymph-node biopsy plus axillary dissection or sentinel-lymph-node biopsy alone. Paraffin-embedded tissue blocks of sentinel lymph nodes obtained from patients with pathologically negative sentinel lymph nodes were centrally evaluated for occult metastases deeper in the blocks. The initial evaluation at participating sites was designed to detect all macrometastases larger than 2 mm in the greatest dimension. Participating sites were instructed to slice sentinel lymph nodes at approximately 2.0-mm intervals, embed all slices in paraffin tissue blocks, and examine one slide, routinely stained with hematoxylin and eosin, from each block.

Tissue blocks of sentinel lymph nodes obtained from all patients in whom metastases were not detected by the participating site were sent to the University of Vermont for further evaluation. Additional sections that were approximately 0.5 mm and 1.0 mm deeper in the block relative to the original surface were evaluated for occult metastases with the use of hematoxylin and eosin and immunohistochemical staining at each level.

Results

Occult metastases were detected in 15.9%  of the 3887 patients: 11.1% with isolated tumor-cell clusters, 4.4% with micrometastases, and 0.4% with macrometastases.  Five-year Kaplan-Meier estimates of overall survival among patients in whom occult metastases were detected and those without detectable metastases were 94.6% and 95.8%, respectively.

The 5-year Kaplan-Meier survival estimates for patients in whom occult metastases were detected were 94.6% for overall survival, 86.4% for disease-free survival, and 89.7% for distant-disease–free interval; the survival estimates for patients in whom occult metastases were not detected were 95.8%, 89.2%, and 92.5%, respectively

The differences observed between patients in whom occult metastases were detected and those in whom occult metastases were not detected with respect to 5-year Kaplan-Meier estimates of overall survival (between-group difference, 1.2 percentage points), disease-free survival (2.8 percentage points), and distant-disease-free interval (2.8 percentage points) were statistically significant but relatively small.

The magnitude of the difference in 5-year Kaplan-Meier estimates for death from breast cancer was small for detection of isolated tumor-cell clusters versus no detection (0.6 percentage points) and for detection of micrometastases versus no detection (2.4 percentage points).

Our findings argue against analysis of additional tissue levels or routine immunohistochemical analysis for sentinel-lymph-node evaluation. This conclusion is similar to that of the American College of Surgeons Oncology Group Z0010 investigators. Their observed difference in 5-year survival (0.7 percentage points) between patients in whom occult metastases were detected and patients in whom occult metastases were not detected by means of immunohistochemical analysis in initially negative sentinel lymph nodes was not significant (P=0.53). The prevalence of occult metastases in the Z0010 study (10.5%) was lower than the prevalence in this trial (15.9%).

Conclusions

Occult metastases were an independent prognostic variable in patients with sentinel nodes that were negative on initial examination; however, the magnitude of the difference in outcome at 5 years was small (1.2 percentage points). These data do not indicate a clinical benefit of additional evaluation, including immunohistochemical analysis, of initially negative sentinel nodes in patients with breast cancer. (Funded by the National Cancer Institute;