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Editorials |
1 From the Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021. Received April 25, 2003; accepted May 5. Address correspondence to the author (e-mail: libermal@mskcc.org).
Index terms: Breast neoplasms, radionuclide studies, 08.12166 • Editorials • Lymphatic system, radionuclide studies, 997.12974 • Radionuclide imaging, in diagnosis of neoplasms
Sentinel lymph node biopsy has been used in breast cancer for approximately one decade (1,2). The sentinel node hypothesis states that the sentinel nodes are the first nodes draining a tumor and that the histologic status of the sentinel nodes predicts the status of the regional lymphatic basin. Studies correlating the results of sentinel lymph node biopsy with axillary dissection in more than 3,000 women with breast cancer have shown that sentinel lymph node biopsy has a technical success rate of 88%, sensitivity of 93%, and accuracy of 97% (3). Sentinel lymph node biopsy is currently used in many centers as an alternative to axillary dissection for women with small invasive breast cancers and lymph nodes that are clinically negative for malignancy. Axillary dissection is performed if sentinel nodes are not found or if axillary nodes are suggestive of disease at physical examination and may be performed if tumor is present in sentinel nodes.
Technical parameters for sentinel lymph node biopsy vary. Studies differ with respect to many parameters, including the labeling agent (radioisotope, blue dye, or both) used for preoperative lymphatic mapping , the volume and site (peritumoral, intradermal, periareolar, or intratumoral) of injection, and the interval between injection and surgery. Among the studies in which radioisotope methods were used, some incorporated the use of preoperative lymphoscintigraphic imaging, while others involved intraoperative use of the gamma probe without preoperative lymphoscintigraphy for identification of the "hot spots" of radioactivity. Although excellent results have been reported in the literature for a variety of methods, many researchers have suggested that the best results are obtained when blue dye and radioisotope are used in combination (3).
In this issue of Radiology, Tanis and colleagues from the Netherlands Cancer Institute present the results of a study of lymphoscintigraphic imaging in lymphatic mapping for sentinel lymph node biopsy in women with breast cancer (4). The method generally used at their center—one of the first sites in the world at which sentinel lymph node biopsy was performed in women with breast cancer—is intratumoral injection of radioisotope on the day before surgery and injection of blue dye on the day of surgery (5). This study builds on previous classic work from Tanis and colleagues (6) in defining the anatomy and physiology of lymphatic drainage of the breast from the perspective of the use of sentinel lymph node biopsy.
In the current study (4), each of 25 women were administered two injections of radioisotope, the first on the day before surgery and the second on the day of surgery, as well as an injection of blue dye immediately before surgery. Two investigators evaluated the paired lymphoscintigrams obtained on the day before surgery and on the day of surgery. In each of the 25 women, the lymphoscintigraphic images obtained on the day before surgery (after the first injection) showed the same pattern of lymphatic drainage as the lymphoscintigraphic images obtained on the day of surgery (after the second injection). The authors concluded that the results of lymphoscintigraphy for lymphatic mapping in breast cancer are highly reproducible.
This study represents the first attempt, to my knowledge, to scientifically address the reproducibility of results of lymphoscintigraphic mapping of sentinel lymph nodes by using the same technique in the same women with breast cancer. The issue is important, but the study does have some limitations. The sample size was small. The intratumoral injection technique used in this study is one of the less common techniques for sentinel node biopsy, and data regarding reproducibility with this technique do not necessarily apply to other methods. It is not clear whether the lymphoscintigrams obtained on the day before and on the day of surgery were reviewed together (introducing potential bias) or separately. The reading of lymphoscintigrams obtained on the day of surgery may have been affected by the short interval between the second injection and imaging. In spite of these issues, the data provide supportive evidence for the reproducibility of results of lymphoscintigraphic imaging in lymphatic mapping in women with breast cancer.
That the pattern of lymphatic drainage of the breast in one woman is reproducible from one day to the next is consistent with indirect evidence from previous reports. In a previous study from the Netherlands, Borgstein et al (7) found 100% concordance between delineation of the sentinel node with intradermally administered blue dye and delineation with intraparenchymally administered radioisotope. Linehan et al (8) reported that the same sentinel node was both hot and blue in 97% of women who received intraparenchymally administered radioisotope and intraparenchymally administered blue dye and in 95% of women who received intradermally administered radioisotope and intraparenchymally administered blue dye. The results of these studies suggest that although patterns of breast lymphatic drainage may differ from woman to woman, the pattern for a particular woman is quite constant.
The study of Tanis et al (4) highlights the role of lymphoscintigraphic imaging in lymphatic mapping. Although lymphoscintigraphic imaging is not universally used in the performance of sentinel lymph node biopsy, data support its utility. Visualization of sentinel lymph nodes at lymphoscintigraphy is predictive of a technically successful sentinel node biopsy procedure: Cody et al (9) found that a positive lymphoscintigram was significantly (P < .0005) associated with technical success in both univariate and multivariate models. Lymphoscintigraphic results can also alert the surgeon to the presence of multiple sentinel lymph nodes, as well as to the presence of unusual patterns of lymphatic drainage, before surgery. Surgeons at the Netherlands Cancer Institute have stated that the lymphoscintigram can act "as a road map in a strange city" (5).
Injecting the isotope on the day before surgery rather than on the day of surgery has logistic advantages. Yeung et al (10) found no significant difference between intradermal injection on the day before versus on the day of surgery with respect to the technical success rates of sentinel lymph node biopsy, the number of sentinel nodes found, or the concordance between isotope and dye presence in the sentinel nodes. These results were confirmed in an updated study by McCarter et al (11). The results of Tanis et al (4) suggest that the specific sentinel nodes identified at lymphoscintigraphy with injection the day before and the day of surgery are the same. These studies support a protocol that involves isotope injection on the day before surgery, enabling increased efficiency in scheduling (both for nuclear medicine physicians and for the operating room) without compromising lymphatic mapping results (10).
The intratumoral injection method used by Tanis et al (4) requires that the tumor remain in vivo; women who have previously undergone surgical excision of the primary tumor are not candidates for this technique. Although some investigators have suggested that previous surgical biopsy may alter lymphatic drainage pathways and interfere with sentinel lymph node biopsy, most researchers have found no significant difference in the technical success of sentinel lymph node biopsy between women who had and those who had not previously undergone surgical biopsy (3). Other methods, such as peritumoral or intradermal injection of isotope, have high technical success rates and would be applicable in women who have previously undergone percutaneous biopsy, as well as in women who have previously undergone surgical excision (12). Further study of patterns of lymphatic drainage before and after surgery, as suggested by Tanis et al (4), would be useful.
Tanis et al (4) report a high frequency of drainage to nonaxillary sentinel nodes, most of which were in the internal mammary region. In their study, lymphatic drainage after intratumoral injection of radioisotope was exclusively to axillary lymph nodes in 17 (68%) of the 25 women, to axillary and nonaxillary nodes in seven (28%) women, and to nonaxillary nodes in one (4%) woman. In previous studies, drainage to internal mammary sentinel lymph nodes was identified at lymphoscintigraphy in 0%–35% of patients; among the subset of those patients who underwent resection of internal mammary sentinel nodes, 18% had internal mammary sentinel node metastases (13). In contrast, internal mammary sentinel lymph nodes are generally not identified with methods in which only blue dye or only intradermal injection of a radioisotope is used. This raises a question: Should internal mammary sentinel lymph nodes be removed during sentinel lymph node biopsy?
Several lines of evidence argue against routine removal of internal mammary sentinel nodes (13). First, women with tumors larger than 1 cm or tumors with axillary nodes that are positive for malignancy are generally treated with chemotherapy. Internal mammary sentinel node metastasis would only affect systemic treatment in a woman with a tumor smaller than 1 cm and axillary nodes that are negative for malignancy; results of meta-analysis suggest that this scenario accounts for no more than 2.4% of women who undergo internal mammary sentinel node biopsy and for less than 1% of all women who undergo lymphatic mapping (13). Second, among women who undergo modified radical mastectomy and systemic therapy without resection of internal mammary nodes, the incidence of local recurrence in the internal mammary region as a component of first treatment failure is low (<1%) (13). Third, results of prospective randomized trials in women who have undergone extended radical mastectomy suggest that surgical resection of internal mammary lymph nodes does not reduce local-regional recurrence or improve survival (13). Existing data are limited, particularly regarding women with tumors smaller than 1 cm and axillary nodes that are negative for malignancy, and research to determine the potential utility of internal mammary node radiation therapy is ongoing. The treatment of internal mammary sentinel nodes remains controversial (14).
More than half (52%) of women in the study of Tanis et al (4) had metastases to sentinel lymph nodes. This is a high proportion, particularly in light of the small tumor size in the women in the study, and may reflect the use of immunohistochemical methods in pathologic analysis of the sentinel nodes. Use of immunohistochemical methods increases the sensitivity of the sentinel lymph node biopsy procedure (15). Results of retrospective studies suggest that micrometastases detected with immunohistochemical methods, serial sections, or both are associated with a decrease in disease-free and overall survival (15,16).
The authors report one false-negative result in a patient with a palpable lymph node. In the validation studies of sentinel lymph node biopsy, the mean false-negative rate was 7% (range, 0%–22%). The mean false-negative rate was significantly lower in validation studies in which immunohistochemical methods were used than in those in which they were not (3% vs 8%, P < .01) (15). The case reported by Tanis et al (4) illustrates one potential cause of a false-negative sentinel lymph node biopsy result: the replacement of a node by tumor. This emphasizes the importance of intraoperative palpation in sentinel lymph node biopsy. If a node is suggestive of disease at intraoperative physical examination, it should be excised, even if it does not take up dye or radioisotope.
The American Cancer Society has estimated that 212,600 women will be diagnosed with invasive breast cancer this year; of these women, over half will be free of axillary metastases (17). Sentinel lymph node biopsy may enable us to spare many of these women the morbidity of axillary lymph node dissection. Results of validation studies of sentinel lymph node biopsy in breast cancer confirm that the method is highly accurate. Data from the Netherlands Cancer Institute study support the reproducibility of results of lymphoscintigraphic imaging in lymphatic mapping for sentinel node biopsy in women with breast cancer. Results of further work, including studies of the reproducibility of the results of other sentinel lymph node biopsy methods and long-term follow-up, will allow more women to benefit from this minimally invasive approach to breast cancer treatment.
ACKNOWLEDGMENTS
The author thanks Hiram S. Cody III for critical review of the manuscript and David C. Perlman for invaluable assistance.
FOOTNOTES
See also the article by Tanis et al in this issue.
REFERENCES
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