The role of sentinel lymph node biopsy in breast cancer.

BACKGROUND: Lymphatic mapping and sentinel lymph node (SLN) biopsy are new techniques that accurately provide crucial staging information while inflicting far less morbidity than complete axillary dissection. As these techniques continue to gain acceptance, issues such as adequacy of training, certification, and outcomes measures become increasingly important. The purpose of this paper is to report the initial lymphatic mapping experience at the H Lee Moffitt Cancer Center and Research Institute and to provide a detailed description of the technical aspects of lymphatic mapping. STUDY DESIGN: From April 1994 to April 1998, 700 patients with newly diagnosed breast cancers underwent an IRB-approved prospective trial of lymphatic mapping using a combination of Lymphazurin (USSC, Norwalk, CT) blue dye and filtered technetium 99m-labeled sulfur-colloid. Failure of the procedure was defined as the inability to detect an SLN by either radiocolloid uptake within a lymph node by the gamma probe or the inability to visualize blue staining of a lymph node. Learning curves were then generated as the failure rate versus serial number of patients for each of the 5 surgeons involved in this study. RESULTS: The SLN was identified in 665 of 700 patients (95.0%). A total of 1,348 SLNs were successfully removed, of which 238 (17.7%) were positive for metastatic disease in 176 of 665 patients (26.5%). In patients who underwent a complete axillary dissection after SLN biopsy, SLNs were identified in 173 of 186 patients (93.0%). Of the 173 patients, 53 patients (30.6%) had positive SLNs and 120 patients (69.4%) had negative SLNs. In the 120 patients with negative SLNs, one patient was found to have disease on complete dissection, for a false-negative rate of 0.83% (95% CI: 0.02%, 4.6%). A learning curve representing the mean of the 5 surgeons' experience indicates that on average 23 patients are required by an individual surgeon to achieve a 90% +/- 4.5% success rate and 53 patients are required to achieve a 95% +/- 2.3% success rate (p = 0.05). CONCLUSIONS: These data validate lymphatic mapping and SLN biopsy as indispensable tools in the surgical treatment of breast cancer. With adequate multidisciplinary training, these techniques can be readily implemented at institutions treating breast cancer.

The effects of postinjection massage on the sensitivity of lymphatic mapping in breast cancer.

BACKGROUND: The technique of lymphatic mapping and sentinel lymph node (SLN) biopsy is rapidly becoming the preferred method of staging the axilla of the breast cancer patient. This report describes the impact of postinjection massage on the sensitivity of this surgical technique. STUDY DESIGN: Lymphatic mapping at the H Lee Moffitt Cancer Center is performed using a combination of isosulfan blue dye and Tc99m labeled sulfur colloid. Data describing the rate of SLN identification and the node characteristics from 594 consecutive patients were calculated. Patients who received a 5-minute massage after injection of blue dye and radiocolloid were compared with a control group in which the patients did not receive a postinjection massage. RESULTS: When compared with controls, the proportion of patients who had their SLN identified using blue dye after massage increased from 73.0% to 88.3%, and the proportion of patients who had their SLN identified using radiocolloid after massage increased from 81.7% to 91.3%. The overall rate of SLN identification increased from 93.5% to 97.8%. The proportion of nodes that were stained blue among those removed increased from 73.4% to 79.7% after massage. CONCLUSIONS: As experience increases with this new procedure, the surgical technique of lymphatic mapping continues to evolve. The addition of a postinjection massage significantly improves the uptake of blue dye by SLNs and may also aid in the accumulation of radioactivity in the SLNs, further increasing the sensitivity of this procedure.

Learning curves for breast cancer sentinel lymph node mapping based on surgical volume analysis.

BACKGROUND: Implementation of new procedures, including lymphatic mapping for breast cancer, must be done and overseen by the medical community in a responsible way to ensure that the procedures are performed correctly. This study addresses the issues of adequacy of training and certification of surgeons performing lymphatic mapping. Ensuring quality in surgical care requires outcomes measures that are described in this study. STUDY DESIGN: Sixteen surgeons performed lymphatic mapping in 2,255 patients with breast cancer using a combination blue dye and Tc99m-labeled sulfur colloid to identify the sentinel lymph nodes (SLNs). All participants were trained in a 2-day CME-accredited course. The Cox learning curve model (total number of mapping failures/total number of mapping cases) for a consecutive series of lymphatic mapping cases is described. The relationship of the Surgical Volume Index, the cases performed in a 30-day period, to the failure rate for each surgeon was modeled as a logistic regression curve (y = e(a+bx)/[1 + e(a+bx)]). RESULTS: Surgeons performing less than three SLN biopsies per month had an average success rate of 86.23% +/- 8.30%. Surgeons performing three to six SLN biopsies per month had a success rate of 88.73% +/- 6.36%. Surgeons performing more than six SLN biopsies per month had a success rate of 97.81% +/- 0.44%. CONCLUSIONS: This experience defines a learning curve for lymphatic mapping in breast cancer patients. Data suggest that increased volumes lead to decreased failure rates. These data provide surgeons performing SLN biopsy with a new paradigm for assessing their skill and adequacy of training and describes the relationship between volume of cases performed and success rate of SLN detection.

Sentinel lymphadenectomy: a safe answer to less axillary surgery?

UNLABELLED: Lymphatic mapping techniques have the potential of changing the standard of surgical care of breast cancer patients. This paper reports a prospective study documenting the safety and efficacy of sentinel lymph node biopsy in 167 breast cancer patients and reviews the world literature on the procedure. METHODS: One hundred sixty-seven patients with newly diagnosed breast cancers underwent a prospective trial of intra-operative lymphatic mapping using a combination of vital blue dye and filtered technetium-labeled sulfur colloid. A sentinel lymph node (SLN) was defined as a blue node and/or "hot" node with a 10/1 ex-vivo gamma-probe ratio of SLN to non-SLN. All SLN were bi-valved, step-sectioned, and examined with routine H&E stains and immunohistochemical stains for cytokeratin. Cytokeratin-positive SLN were defined as any SLN with a defined cluster of positive staining cells which could be confirmed histologically on H&E sections. Finally, a review of the worldwide data was undertaken using a uniform analytical method to compare the rates of sensitivity, diagnostic accuracy, and false negatives of SLN mapping. RESULTS: In 167 patients, 337 SLN were harvested, for an average of 2.01 SLN/patient. Fifty-two (31.1%) of the patients had metastasis in the SLN. In the 115 patients with negative SLN, 1 was found to have tumor in higher axillary nodes, for a false negative rate of 0.88%. Fifty-nine (37.8%) of the patients were diagnosed by fine-needle aspiration, 89 (53.3%) by excisional biopsy, and 19 (11.4%) by core biopsy. Positive SLN were identified in 1/17 (5.9%) patients with DCIS. Metastasis was found in 33/115 (28.7%) of the patients with infiltrating ductal tumors and in 11/19 (57.9%) of the patients with infiltrating lobular tumors. Positive SLN were identified in 7/16 (43.7%) of the patients with mixed cellularity tumors. Metastasis in the SLN was detected in 7/55 (12.7%) of the 59 patients with T1a-T1b tumors and in 21/58 (36.2%) of the patients with T1c tumors. Positive SLN were found in 17/30 (56.7%) of the patients with T2 tumors and in 6/7 (85.7%) of the patients with T3 tumors. A literature review of 731 patients (including this study) demonstrates a sensitivity rate of 95% and a diagnostic accuracy rate of 98%. The overall false negative rate is 3.1%. CONCLUSIONS: This study demonstrates that SLN biopsy is a highly sensitive and accurate method of predicting axillary nodal status. It is a reproducible technique that is easily learned. The future addition of more sensitive methods such as PCR evaluation of nodal involvement may reduce the need for widespread use of adjuvant chemotherapy with its high cost and attendant morbidity and mortality. We believe that this technique will eventually become the standard of care in the treatment of breast cancer, particularly for T1 and T2 lesions and perhaps also for high-grade DCIS tumors.

Techniques for lymphatic mapping in breast carcinoma.

Lymphatic mapping and sentinel lymph node biopsy are new surgical techniques enabling surgeons to accurately determine the status of the axillary nodal basin in breast cancer patients. This article provides a detailed description of the lymphatic mapping technique including a discussion of the most commonly used equipment.

Learning curves and certification for breast cancer lymphatic mapping.

To determine the usefulness of lymphatic mapping and SLN biopsy, two distinct aspects of the technique must be evaluated, mapping success rates and mapping accuracy. The mapping success rate simply reflects the ability to successfully map a SLN. Mapping accuracy is reflected by the false-negative rate defined as the proportion of patients with axillary metastases among those in whom the SLN is negative for disease. It is critical within each institution that these two measurements be obtained to validate the multidisciplinary collaborative effort. It seems that surgeons with appropriate training should be able to map with 85% efficiency with zero or one false-negative cases in their first 10 patients with metastatic disease. It is our recommendation that individual surgeons join together and follow an institutional (IRB approved) protocol for lymphatic mapping in which each surgeon is required to perform at least 30 procedures of SLN biopsy followed by completion axillary lymph node dissections (phase I). There are several advantages for surgeons and patients to participate in national trials as a new technique is established: 1. Patients are fully informed. 2. For those patients who have SLN biopsy followed by a CLND (phase I), there is still an added advantage in that the SLN can be scrutinized more closely resulting in more accurate staging. 3. The surgeon and the institution can be reimbursed even while the surgeon is on the learning curve. 4. It provides for good publicity for the institution. The data should be reviewed for each surgeon after completing the first 30 cases. If the aforementioned goals of 85% success with one or fewer false-negative cases is achieved, then the individual surgeon may move on to a second (phase II) mapping protocol. In phase II, a SLN biopsy is performed and a CLND is performed only if a SLN cannot be located or the SLN contains metastases. Should the aforementioned criteria not be met, then additional procedures or onsite intraoperative mentoring may be required to further evaluate the deficiencies of the mapping procedure by the surgeon or institution. Remember that failure to map may be a function of surgical skill, nuclear medicine injection methodology, or the pathologic evaluation of the SLN. Should institutional problems arise, onsite mentoring may be helpful by someone with adequate mentoring skills to troubleshoot a potential problem. The previously outlined recommendations are similar to the recently published requirements of the American Society of Breast Surgeons that recommend documentation of 30 cases or more with an 85% or higher success rate in identifying a SLN and 5% or greater false-negative rate (single false-negative SLN in the series). A national network of training centers is being established for radioguided surgery. This new technology has the potential of being applicable to 350,000 new cases of cancer diagnosed annually in the United States. Applications include breast cancer, melanoma, and other skin tumors like Merkel cell carcinoma and poorly differentiated squamous cell carcinoma, parathyroid localization, vulvar and vaginal lesions, and bone localization. This network of training centers will provide an opportunity for surgeons, nuclear medicine physicians, and pathologists to come together and learn about this new technology. Training will include didactic sessions, live surgery, and hands-on experience with animal models. The faculty will consist of leading experts from across the country. Participating centers include the H. Lee Moffitt Cancer Center and Research Institute, John Wayne Cancer Institute, and the M.D. Anderson Cancer Center. Training sites will also be available in Durham, NC; Pittsburgh, PA; Seattle, WA; Little Rock, AR; and St. Louis, MO. The network provides access to a national lymphatic mapping database (http:/(/)mapping.rad.usf.edu), participation in national trials, and web site listings (melanoma.net, or breastdoctor.com, and endocrine

Do cytokeratin-positive-only sentinel lymph nodes warrant complete axillary lymph node dissection in patients with invasive breast cancer?

The small number of nodes harvested with lymphatic mapping and sentinel lymph node (SLN) biopsy has allowed a more detailed pathologic examination of those nodes. Immunohistochemical stains for cytokeratin (CK-IHC) have been used in an attempt to minimize the false negative rate for SLN mapping. This study examines the value of CK-IHC positivity in predicting further lymph node involvement in the axillary basin. From April 1998 through May 1999, 519 lymphatic mappings and SLN biopsies were performed for invasive breast cancer. SLNs were examined by imprint cytology, hematoxylin and eosin (H&E), and CK-IHC. Patients with evidence of metastatic disease by any of the above techniques were eligible for complete axillary node dissection (CAND). The frequency with which these modalities predicted further lymph node involvement in the axillary basin was compared. Of the 519 lymphatic mappings, 39 patients (7.5%) had a CK-IHC-positive-only SLN. Five (12.8%) of these 39 patients had at least 2 SLNs positive by CK-IHC. Twenty-six of the CK-IHC-positive-only patients underwent CAND. Three of these 26 patients (11.5%) had additional metastases identified after CAND. The sensitivity levels with which each modality detected further axillary lymph node involvement were as follows: CK-IHC, 98 per cent; H&E, 94 per cent; and imprint cytology, 87 per cent. A logistic regression to compare the prognostic value of the three modalities was performed. All were significant, with odds ratios of 19.1 for CK-IHC (P = 0.015), 5.3 for H&E (P = 0.033), and 3.86 for imprint cytology (P = 0.0059). These data validate the enhanced detection of CK-IHC for the evaluation of SLNs. Detection of CK-IHC-positive SLNs appears to warrant CAND in patients with invasive breast cancer. However, the therapeutic value of CAND or adjuvant therapies based on CK-IHC-positive SLNs would be best answered by prospective randomized trials.

Lymphatic mapping with sentinel lymph node biopsy in patients with breast cancers <1 centimeter (T1A-T1B).

Because of its high cost and attendant morbidity, the necessity of axillary dissection in patients with small invasive primary tumors has been questioned. Lymphatic mapping with sentinel lymph node (SLN) biopsy is an alternative to complete axillary dissection; however, researchers have excluded patients with T1A-T1B lesions. Seven hundred patients with newly diagnosed breast cancers underwent an Institutional Review Board-approved prospective trial of intraoperative lymphatic mapping using a combination of Lymphazurin and filtered technetium-labeled sulfur colloid. An SLN was defined as a blue node and/or hot node with a 10:1 ex vivo radioactivity ratio in the SLN versus non-SLNs. All SLNs were evaluated by both hematoxylin and eosin and cytokeratin immunohistochemical stains. Of the 700 patients, 665 (95.0%) were mapped successfully. One hundred ninety-six (28.0%) had T1A-T1B tumors. Forty patients (20.4%) with T1A-T1B tumors had metastases to the SLNs. We conclude that breast cancer SLN mapping is highly accurate and sensitive when combined dye techniques (radiocolloid and vital blue dye) are utilized. This technique is particularly useful in patients with small invasive primary tumors, which, despite their size, still demonstrate a significant rate of axillary metastasis. These patients should not be excluded from lymphatic mapping protocols.

Fluconazole increases bactericidal activity of neutrophils.

BACKGROUND: Candida infections after injury are associated with significant mortality. Death often results from gram negative sepsis. Because antifungal therapy lowers mortality seen with Candida infections, this study was undertaken to determine whether fluconazole (FCZ) augments host response against bacteria, specifically, the bactericidal activity of polymorphonuclear neutrophils (PMN). METHODS: PMN from 23 volunteers were incubated with phosphate-buffered saline or FCZ (20 micrograms/mL or 40 micrograms/mL). Bactericidal activity of these PMN, as well as FCZ alone, was determined using Escherichia coli and a colony forming unit protocol. RESULTS: PMN possess potent bactericidal activity while FCZ possesses minimal inherent bactericidal activity. PMN bactericidal activity is significantly augmented by preincubation with FCZ. This enhanced bactericidal state is greater than the combined individual bactericidal properties of either FCZ concentration and PMN. CONCLUSIONS: FCZ augments PMN bactericidal activity. This augmentation may help to explain the improved survival of critically injured patients receiving FCZ.

Implementation of new surgical technology: outcome measures for lymphatic mapping of breast carcinoma.

BACKGROUND: Recent advances in technology and the subsequent development of minimally invasive surgical techniques have heralded a new era in the surgical treatment of breast cancer. The dilemma of how to train surgeons in new technologies requires teaching, certification, and outcomes reporting in a non-threatening and non-economically damaging manner. This study examines 700 cases of lymphatic mapping and sentinel lymph node (SLN) biopsy for breast cancer and documents surgeon-specific and institution-specific learning curves. METHODS: Seven hundred cases of lymphatic mapping and SLN biopsy were examined. All procedures were performed using a combination of vital blue dye and radiolabeled sulfur colloid. Learning curves were generated for each surgeon as a plot of failure rate versus number of cases. RESULTS: Examination of the learning curves in this study demonstrates similar characteristics. Following a high initial failure rate, there is a rapid decrease after the first twenty cases. The learning curve, representing the mean of the five surgeons' experience, indicates that 23 cases and 53 cases are required to achieve success rates of 90% and 95%, respectively. CONCLUSIONS: The initial reports regarding lymphatic mapping combined with this experience of 700 cases confirm the presence of a significant learning curve. Although this procedure may have an inherent failure rate, it is important to identify those factors that are under the control of the surgeon and, therefore, subject to improvement. We believe that these data provide surgeons performing lymphatic mapping and SLN biopsy with a new paradigm for assessing their skill and adequacy of training.

Lymphatic mapping and sentinel lymph node biopsy in patients with breast cancer.

The standard of care for the evaluation of axillary nodal involvement remains complete lymph node dissection. Lymphatic mapping and sentinel lymph node (SLN) biopsy are changing this long-held paradigm; indeed, several leading institutions already reserve complete axillary dissection for patients with metastasis to the SLN. In addition to reviewing the literature, this chapter describes our lymphatic mapping experience at the H Lee Moffitt Cancer Center and Research Institute with 1147 breast cancer patients. Our results, in addition to a meta-analysis of data from 12 institutions comprising an additional 1842 patients undergoing complete axillary dissection, demonstrate that SLN biopsy is an accurate method of axillary staging. Although the results from small series may exaggerate the probability of false negative results, the risk of nodal disease based on tumor size and other risk factors should be evaluated when considering the results of SLN sampling.