Detecting Occult Nodal Metastases in Early Breast Cancer
November 1, 1999 5 minutes read
Detecting Occult Nodal Metastases in Early Breast Cancer
Abstract & commentary
Synopsis: The presence of axillary lymph node metastatic disease confers a greater likelihood of disease recurrence and shorter survival in breast cancer patients. In the International (Ludwig) Breast Cancer Study Group, lymph node samples were stained with anticytokeratin antibodies and approximately 20% of the patients were found to have micrometastases on this basis. These patients were shown to have a higher recurrence rate and shorter survival than those who were immunostain negative.
Source: Cote RJ, et al. Lancet 1999;354:896-900.
The presence of metastatic foci of breast cancer cells in regional lymph nodes has long been known to confer valuable prognostic information and clinicians make treatment decisions based upon this information. However, there remain a substantial number of women with node negative breast cancer who develop recurrent disease. The International (Ludwig) Breast Cancer Study Group has been interested in the detection of metastatic cells in lymph node samples that by routine histology are considered negative. In an earlier report, this group analyzed samples from 921 patients with breast cancer and histologically negative ipsilateral axillary nodes by scrutinizing multiple sections of the same tissue.1 They found 83 cases (9%) in which the more careful analysis demonstrated disease involvement. Furthermore, they reported that these patients had earlier relapse and shorter survival than those without detectable occult metastases. However, the comprehensive histological analysis was cumbersome, involving an average of 144 slides per patient, and this approach is clearly impractical for routine clinical laboratories.
The purpose of the current study was to examine whether immunohistochemical staining of selected nodes would be another sensitive method to detect occult metastases and to determine if patients with such occult metastases were more likely to develop recurrent disease.
Data and patient material from Trial V of the International Breast Cancer Study were used for this analysis. In this study, node-negative patients were randomly assigned to receive either one cycle of intraoperative chemotherapy (cyclophosphamide, methotrexate, and fluorouracil) or not. These same patients were the subjects of the prior study using the extensive histological evaluation to detect occult malignancy. Unstained slides from 736 patients were collected and a single section of the lowest (first) level lymph node was immunostained with anticytokeratin antibodies. Cells were considered to be occult node metastases if they were immunoreactive and had the appearance of cancer cells.
Occult nodal metastases were detected by serial histological analysis in 52 (7%) of these patients and the immunohistochemical staining increased the yield to 148 (20%). Occult disease, detected by either method, was associated with significantly poorer disease-free and overall survival than seen in the group as a whole, but particularly for the postmenopausal patients. In fact, the detection of occult metastatic disease in premenopausal patients did not confer a worse prognosis. Nonetheless, immunohistochemically detected lymph node metastases remained an independent and highly significant predictor of recurrence even after control for tumor grade, tumor size, estrogen-receptor status, vascular invasion and treatment assignment (hazard ratio 1.79; [95% CI 1.17-2.74] P = 0.007).
Cote and colleagues conclude that routine immunohistochemical staining of axillary lymph nodes will increase the detection of microscopic metastases and provide useful prognostic information. Accordingly, they suggest that such staining should become standard practice, particularly for postmenopausal women.
COMMENTARY
This study clearly indicates that immunohistochemistry will detect microscopic, metastatic disease in ipsilateral axillary nodes in a significant fraction (20%) of patients for whom routine analysis was negative. This could be of great importance for the individual patient, for it indicates a higher risk of recurrence (also demonstrated in this study) and a worse overall prognosis. The analysis would allow such a patient to be shifted from the incorrect designation of "node-negative" to the more accurate assignment of "node-positive," and adjuvant treatment strategies developed accordingly. Indeed, it will be of interest to correlate results of adjuvant therapy studies in node-negative women with the immunohistochemical analysis. It is conceivable that all the benefit associated with adjuvant therapy is derived by these occult node-positive patients. It is also possible that true immunohistologic negative nodes identify patients who do not need any adjuvant therapy.
It is noteworthy that, in this series, the overall recurrence rate for node-negative patients was high, approximating one third of the entire group. Thus, the high yield of occult metastases might, in part, reflect some characteristic of this particular population sample. However, this does not detract from the importance of these findings nor the rationale for adopting this technique in the routine analysis of surgical specimens from breast cancer patients.
Earlier studies have resulted in mixed conclusions regarding the prognostic importance of detection of occult metastases in this population.2-4 However, none of these have had as large a sample size or as extensive a length of follow-up as the current study. In fact, this larger study allows the observation that certain histological patterns of breast cancer are more likely to have occult metastases (e.g., invasive, lobular or mixed invasive, lobular, and ductal), and the detection of occult metastases has a more meaningful effect on prognosis in post-menopausal patients.
Thus, the detection of occult metastases was demonstrated to be of prognostic importance. Of course, immunostaining did not detect all patients who were to develop recurrence, nor did it predict, with absolute certainty, that a positive patient would develop recurrence. Nonetheless, it is a rapid and inexpensive examination, and the findings proved to be of prognostic value. In this study, immunostaining was applied to only one slide from one (proximal) node. It is unclear whether examination of additional nodal material would improve the positive predictive value of the test or actually dilute it.
References
1. International (Ludwig) Breast Cancer Study Group. Lancet 1990;335:1565-1568.
2. Hainsworth PJ, et al. Br J Surg 1993;80:459-463.
3. Sedmak DD, et al. Mod Pathol 1989;2:516-520.
4. Nasser IA, et al. Hum Pathol 1993;24:950-957.
Which of the following statements about immunostaining of ipsilateral lymph nodes from breast cancer patients is true?
a. It will detect micrometastases in approximately 70% of patients who are otherwise considered node negative, but the technique is expensive and unreliable.
b. It will detect micrometastases in approximately 70% of patients who are otherwise considered node negative and the technique is inexpensive and provides useful prognostic information.
c. It will detect micrometastases in approximately 20% of patients who are otherwise considered node negative, but the technique is expensive and unreliable.
d. It will detect micrometastases in approximately 20% of patients who are otherwise considered node negative and the technique is inexpensive and provides useful prognostic information.
e It will detect micrometastases in approximately 20% of patients who are otherwise considered node negative, but those who are positive are not at increased risk of relapse.
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