This cohort analysis within a randomized, prospective trial examined the effect of occult metastases in sentinel lymph nodes on disease-free survival and overall survival. Clinical treatment was based on a standard evaluation of sentinel lymph nodes without routine immunohistochemical analysis or analysis of deeper tissue levels. This initial analysis was followed by a blinded analysis of the sentinel nodes for residual occult metastases. Our findings are consistent with the hypothesis that nodal tumor burden is a continuous variable and indicate that occult metastases are an independent prognostic factor, with unadjusted and adjusted hazard ratios greater than 1.00 for death, any outcome event, and distant disease in patients in whom occult metastases in sentinel lymph nodes were detected as compared with patients in whom no occult metastases were detected. Furthermore, the subgroup analysis of the size of occult metastases indicates that the risk associated with isolated tumor-cell clusters is lower than the risk associated with micrometastases; this finding provides support for the current prognostic segregation of these two categories.
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. Additional follow-up, particularly for hormone-receptor–positive tumors, will be required to determine whether these estimates will converge or continue to diverge. Occult metastases were not discriminatory predictors of cancer recurrence. A total of 138 of 3884 patients (3.6%) had regional or distant recurrences as first events and only 30 of these events (21.7%) (in 0.8% of all the patients) occurred in patients with occult metastases. Conversely, 496 of 616 patients with occult metastases (80.5%) were alive and free of disease. Identification of occult metastases does not appear to be clinically useful for patients with newly diagnosed disease in whom systemic therapy can be recommended on the basis of the characteristics of the primary tumor.
Among women who underwent sentinel-lymph-node biopsy alone, the outcome differences between women with and those without occult metastases were also small (between-group difference, 0.5 percentage points for event-free outcome and 1.3 percentage points for combined rates of regional and distant recurrence). These minimal differences do not justify changes in clinical management. The outcomes in this group of women are highly relevant; sentinel-lymph-node biopsy alone has been widely adopted and endorsed as an alternative to axillary dissection,15
and the overall outcome in this trial shows no significant disadvantage for women who underwent sentinel-lymph-node biopsy alone as compared with women who underwent sentinel-lymph-node biopsy plus axillary dissection ().14
In general, the overall rate of regional or distant recurrence (3.5%) was low.
The 15.9% prevalence of occult metastases in the current study is within the range reported for axillary nodes (9 to 33%) and is similar to the prevalence in our preliminary study leading to this trial (11.5%).2,6
The unfavorable outcome associated with occult metastases in our sentinel-lymph-node study is similar to the results of recent pooled analyses examining the effect of occult metastases in axillary nodes, although our hazard ratios were generally lower.3
In the pooled analyses, “conclusions could not be drawn from sentinel-lymph-node biopsy studies because studies were limited by small patient groups and short follow-up.”3
Our analysis, which involved 3884 patients (616 in whom occult metastases were detected) followed for a median of more than 95 months, is limited neither by small size nor short follow-up.
The prevalence of occult metastases was significantly associated with an age of less than 50 years, a clinical tumor size of more than 2.0 cm in the greatest dimension, and planned mastectomy. The higher prevalence in these subgroups is not surprising: planned mastectomy is an indicator of larger tumor size; younger women are more likely than older women to have large, poorly differentiated tumors; and tumor size is highly correlated with the presence or absence of lymph-node metastases.16
Occult metastases may be more important in the case of larger tumors (combined hazard ratio, 1.32 × 1.40 = 1.85) (). This observation was also noted in an analysis of the National Cancer Institute’s Surveillance, Epidemiology, and End Results data with respect to the clinical significance of microme-tastases.17
Occult metastases were more likely to be present in patients receiving adjuvant therapy; however, therapy was not based on the presence of occult metastases because their presence was not known to the treating physicians. Thus, other factors known at the initiation of therapy most likely correlate with the presence of occult metastases. Perhaps the most interesting interaction was with endocrine therapy, indicating that occult metastases are associated with estrogen-receptor-positive tumors, a favorable prognostic factor, and that endocrine therapy markedly reduces the risk of a poor outcome; for example, the overall hazard ratio for death among patients with occult metastases was reduced to 0.74 when endocrine therapy was administered (combined hazard ratio, 1.40 × 0.53 = 0.74) (). Thus, occult metastases were observed in tumors with favorable prognostic features as well as in tumors with unfavorable prognostic features, underscoring the complex and unpredictable relationship among prevalence, treatment, and outcome.
The protocol for sentinel-lymph-node examination at participating sites was designed to identify all macrometastases (deposits >2.0 mm in the greatest dimension). Less than 0.4% of patients had detectable occult macrometastases; this indicates that slicing sentinel lymph nodes at approximately 2.0-mm intervals and examining a single section stained with hematoxylin and eosin from each slice is an effective method for identifying macrometastases. Furthermore, the analysis of occult metastases in this trial can be considered a study of residual isolated tumor-cell clusters and micrometastases. Isolated tumor-cell clusters had a smaller effect on outcome than micrometastases for every outcome evaluated, including overall survival, disease-free survival, distant-disease–free interval, and death from breast cancer, regardless of whether occult macrometastases were included or excluded. 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). A subgroup analysis according to metastasis size was not part of our original planned survival analysis because there is generally less statistical power in smaller samples. Despite this limitation, this trial will probably remain the largest controlled cohort study within a randomized trial to examine this issue. 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.18
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%).
An important limitation of our analysis is not unique to our study: no examination detects all occult metastases present. In fact, our quality-assurance studies show that both micrometastases and isolated tumor-cell clusters are present in unexamined tissue between the levels examined and in the tissue remaining in the paraffin blocks.7
Although isolated tumor-cell clusters may indicate micrometastases deeper in the sentinel-lymph-node blocks, this misclassification error occurs in a minority of cases (22%).7
With extrapolation from our data, it is reasonable to conclude that, regardless of whether they are detected in initial sections or in additional deeper levels, isolated tumor-cell clusters and micrometastases have less prognostic significance than macrometastases and should be classified separately. The strength of our study is that it was specifically designed to exclude macrometastases from the study population and to include virtually all residual metastases larger than 1.0 mm in the greatest dimension, and a significant proportion of occult metastases smaller than 1.0 mm by statistical chance, providing a robust outcome analysis linked to a specific standardized sentinel-lymph-node evaluation. Any analysis following our standardized approach would be expected to have similar results with respect to prevalence and outcome.
In summary, we found that small occult metastases in sentinel nodes are an independent predictor of overall survival, disease-free survival, and distant-disease–free interval. Multivariate analysis suggests that multiple factors (e.g., age and tumor size) influence the prevalence of occult metastases and the outcome and that local radiation therapy and adjuvant systemic therapy, particularly endocrine therapy, attenuate the unfavorable effect of occult metastases. The magnitude of the differences in outcome between patients with and those without occult metastases was small (1 to 3 percentage points) at 5 years but warrants continued follow-up and analysis.