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(Radiology. 1999;211:835-844.)
© RSNA, 1999

Breast Imaging

Sentinel Lymph Node Biopsy after Percutaneous Diagnosis of Nonpalpable Breast Cancer1

Laura Liberman, MD, Hiram S. Cody, III, MD, Arnold D. K. Hill, MD, Paul Peter Rosen, MD, Samuel D. J. Yeh, MD, Tim Akhurst, MD, Elizabeth A. Morris, MD, Andrea F. Abramson, MD, Patrick I. Borgen, MD and D. David Dershaw, MD

1 From the Breast Imaging Section (L.L., E.A.M., A.F.A., D.D.D.) and Nuclear Medicine Service (S.D.J.Y., T.A.), Department of Radiology; the Breast Service, Department of Surgery (H.S.C., A.D.K.H., P.I.B.); and the Department of Pathology (P.P.R.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021. From the 1998 RSNA scientific assembly. Received May 22, 1998; revision requested July 14; revision received August 12; accepted November 9. Address reprint requests to L.L.


   Abstract
TOP
 Abstract
Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To determine the technical success rate of sentinel lymph node biopsy in women with nonpalpable infiltrating breast cancer diagnosed by using percutaneous core biopsy and to determine the frequency with which sentinel lymph node biopsy obviated axillary dissection.

MATERIALS AND METHODS: Retrospective review revealed 33 women who underwent sentinel node biopsy after percutaneous core biopsy diagnosis of nonpalpable infiltrating breast cancer. Sentinel nodes were identified with radioisotope and blue dye; the procedure was technically successful if sentinel nodes were found at surgery. All sentinel nodes were excised. Axillary dissection was performed if tumor was present in sentinel nodes.

RESULTS: Sentinel nodes were found at surgery in 30 women (91%). Sentinel nodes were identified with both radioisotope and blue dye in 22 (73%) of these women, with only radioisotope in six (20%), and with only blue dye in two (7%). Sentinel nodes were found in 12 (80%) of 15 women in the first half of the study versus all 18 (100%) women in the second half (P = .08). Sentinel nodes were free of tumor in 23 (77%) of 30 women. In six (86%) of seven women with tumor in sentinel nodes, the sentinel nodes were the only nodes with tumor.

CONCLUSION: Sentinel node biopsy was successful in 30 women (91%) with nonpalpable infiltrating carcinoma diagnosed with percutaneous core biopsy and obviated axillary dissection in 23 women (70%). Using both radioisotope and blue dye may increase the success rate. A learning curve exists, and success improves with experience.

Index terms: Breast, biopsy, 00.1261, 00.1267 • Breast neoplasms, surgery, 00.1267, 00.30, 00.45 • Breast neoplasms, therapy, 00.126, 00.30 • Lymphatic system, biopsy, 997.1261 • Lymphatic system, neoplasms, 997.33


   Introduction
TOP
 Abstract
 Introduction
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The surgical treatment of infiltrating breast carcinoma has traditionally included axillary lymph node dissection (1). The information obtained from axillary lymph node dissection is the best available prognostic indicator for women with breast carcinoma and is used to guide treatment decisions (2,3). For women with tumor in axillary nodes, axillary lymph node dissection may provide regional control (4). Whether axillary lymph node dissection improves survival remains controversial (5–10). Furthermore, axillary lymph node dissection has associated morbidity, including numbness, scarring, and lymphedema (11).

Sentinel lymph node biopsy has recently been introduced in the treatment of women with breast carcinoma (12–37). The sentinel lymph node hypothesis is that the sentinel nodes are the first nodes draining a tumor and that the histologic status of the sentinel nodes is predictive of the status of the regional nodes (12). The sentinel nodes can be identified with blue dye, radioisotope, or a combination of methods; excised; and subjected to careful histopathologic analysis. If the sentinel node hypothesis is correct, then women with infiltrating breast carcinoma and sentinel nodes with negative findings may be spared the morbidity of an axillary lymph node dissection.

Early work supports the feasibility and accuracy of sentinel lymph node biopsy. There have been, to our knowledge, 18 published peer-reviewed studies correlating the results of sentinel node biopsy with those of axillary dissection in women with breast carcinoma (12-29) (Table 1). Ten of these studies used radioisotope, four used blue dye, and four used a combination of both methods. In these studies, which have included a total of over 2,000 sentinel node biopsy procedures, investigators have reported a technical success rate of 66%–100%, sensitivity of 83%–100%, specificity of 100%, positive predictive value of 100%, negative predictive value of 92%–100%, and accuracy of 95%–100%. In light of the excellent results of these studies, some surgeons experienced in the technique have begun to offer sentinel lymph node biopsy as an alternative to axillary dissection for women with small infiltrating breast carcinomas; axillary dissection is performed only if tumor is found in the sentinel nodes.


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  		TABLE 1. Published Experience with Sentinel Lymph Node Biopsy in Breast Cancer
 
In recent years, percutaneous imaging-guided biopsy has been increasingly used to diagnose carcinomas detected at screening mammography. These small, percutaneously diagnosed cancers have a low likelihood of axillary metastases and therefore are ideally suited for sentinel node biopsy. This study was undertaken to determine the technical success rate of sentinel lymph node biopsy in women with nonpalpable infiltrating breast carcinoma diagnosed by using percutaneous core biopsy and to determine the frequency with which sentinel lymph node biopsy obviated axillary dissection in these women.


   MATERIALS AND METHODS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Patient Population
From September 1996 to June 1997, 60 women underwent sentinel lymph node biopsy with correlative axillary dissection, which was in all cases in accordance with a protocol approved by our institutional review board (protocol 1). After analysis of the results in those 60 women (23) and with the approval of the institutional review board, it was our clinical practice to offer sentinel node biopsy as an alternative to axillary dissection to women with clinically negative axillary nodes who, on the basis of clinical, imaging, and histologic findings, were thought to have T1 infiltrating breast carcinoma; axillary dissection was performed only if tumor was identified in the sentinel nodes at histologic analysis (protocol 2). Informed consent was obtained for all sentinel node biopsy procedures.

Retrospective review of surgical records from June 16, 1997, to April 17, 1998, revealed 33 women who underwent sentinel lymph node biopsy at our institution after percutaneous core biopsy diagnosis of nonpalpable infiltrating breast carcinoma (as per protocol 2); these 33 women constitute the basis of this study. Women ranged in age from 42 to 82 years (median age, 60 years). All women had mammographically detected carcinomas and clinically negative axillary nodes at preoperative physical examination. Mammographic findings were mass in 27 women, calcifications in four, and both in two; the median mammographic lesion size was 1.0 cm (range, 0.5–2.2 cm).

Percutaneous Biopsy Methods
Percutaneous core biopsy was performed at our institution in 24 (73%) women and at outside facilities in nine (27%). The guidance method, known in 30 women, was ultrasonography (US) in 17 women and stereotaxis in 12; in one woman, biopsy of a mass was performed by using US guidance and biopsy of calcifications was performed by using stereotactic guidance (both were carcinomas). At our institution, stereotactic guidance (StereoGuide with Digital Spot Mammography; LoRad, Danbury, Conn) was used for all lesions evident as calcifications. Biopsy of masses was performed under the guidance of stereotaxis or US (model 128-XP, Acuson, Mountain View, Calif; or Ultramark 4 Plus, Advanced Technology Laboratories, Bothell, Wash). The choice of stereotactic versus US guidance for percutaneous biopsy of breast masses was based on several considerations, including lesion visibility and accessibility, equipment availability, and the preferences of the radiologist (L.L., E.A.M., A.F.A., D.D.D.) and the patient.

The tissue acquisition device for percutaneous biopsy, known in 30 women, was a 14-gauge automated needle in 21 women and a directional vacuum-assisted biopsy probe in nine (11 gauge in eight and 14 gauge in one). At our institution, all stereotactic biopsies were performed by using directional vacuum-assisted biopsy (Mammotome; Biopsys/Ethicon Endo-Surgery, Cincinnati, Ohio), and all US-guided biopsies were performed by using a 14-gauge needle (Automatic Cutting Needle, Manan Medical Products, Northbrook, Ill; Biopty-Cut needle, Bard Urological, Covington, Ga; or Ultra-Core biopsy needle, Medical Device Technologies, Gainesville, Fla) and a long-excursion, automated gun (Pro-Mag 2.2, Manan Medical Products; or Biopty, Bard Urological).

The median number of core biopsy specimens, known in 22 women, was five (range, three to seven) for 14-gauge automated core biopsy and 17 (range, 14–37) for directional vacuum-assisted biopsy. The number of core biopsy specimens obtained was determined by the radiologist performing the biopsy on the basis of radiographs of specimens for biopsy of calcifications, images obtained during the biopsy procedure, visual inspection of tissue specimens, and information in previous literature (38–40).

Sentinel Lymph Node Identification and Analysis
Sentinel lymph nodes were identified by using a combination of radioisotope and blue dye. Radioisotope was injected into the breast parenchyma in 28 women and intradermally in five; the latter five women were part of an ongoing study investigating the efficacy of intradermal injection for sentinel node biopsy.

Intraparenchymal radioisotope injection was accomplished by using the following technique. For women who underwent breast-conserving surgery, preoperative needle localization was performed by using a modified Kopans wire (Cook, Bloomington, Ind). After needle localization, 0.3 mCi (11.1 MBq) of unfiltered technetium 99m sulfur colloid (CIS-US, Bedford, Mass) in 4 mL of normal saline was injected by using a 25-gauge needle at four points (at the 12-, 3-, 6-, and 9-o'clock positions) around the localizing wire. The injections were into the breast parenchyma adjacent to the tumor. For women who underwent mastectomy, the radioisotope was injected into the breast parenchyma at four points (at the 12-, 3-, 6-, and 9-o'clock positions) around the prior percutaneous biopsy site, as determined by means of physical examination of the breast and correlation with imaging studies.

In those women in whom an intradermal technique was used, 0.1 mCi (3.7 MBq) of unfiltered 99mTc sulfur colloid in 0.05 mL of normal saline was injected with a 28-gauge needle superolateral to the site of the primary tumor in the breast.

Preoperative lymphoscintigraphy was performed by using a large–field of view dual-head gamma camera with a low-energy, high-resolution collimator. Transmission images in the anterior and lateral projections were obtained with a cobalt 57 flood source. The median interval between injection and acquisition of the last lymphoscintigraphic image was 50 minutes (mean, 55 minutes; range, 35–158 minutes). The time between injection and surgery varied between 2 and 4 hours.

Intraoperatively, the handheld gamma probe (C-Trak; Care-Wise Medical, Morgan, Calif) was used to obtain counts in the room background, the breast injection site, and the "hottest" spot in the axilla. An injection of 4 mL of isosulfan blue dye (Lymphazurin; Zenith Parenterals, Rosemont, Ill) was made in one to three aliquots around the tumor site, and within 5–10 minutes an incision was made in the axilla and sentinel node biopsy was performed with guidance from the combination of the gamma probe and the appearance of blue dye in lymphatic channels and nodes. Counts in the nodes were obtained both in situ and ex vivo, and counts in the axillary background were obtained after removal of the node. Technical success was defined as identification of the sentinel node or nodes at surgery. A node was considered to be a sentinel node if it exhibited blue staining at surgery, its removal resulted in a fourfold or greater reduction in axillary counts, or both.

All sentinel nodes were excised and analyzed by using frozen and paraffin sections. If the results of initial paraffin hematoxylin-eosin staining of the sentinel node were negative, three additional levels were examined by using hematoxylin-eosin staining and cytokeratin immunohistochemistry with AE1/3 and CAM 5.2 antibodies. If frozen section, paraffin section, or immunohistochemical analysis of the sentinel nodes yielded carcinoma, axillary dissection was performed. A lymph node was considered to contain metastatic carcinoma if one or more tumor cells were identified in a section stained with hematoxylin-eosin or at immunohistochemical analysis. Nonsentinel axillary lymph nodes were examined with a single hematoxylin-eosin section according to the standard procedure used for axillary dissections in this institution. If sentinel lymph nodes were free of tumor and the axillary nodes were clinically negative at intraoperative examination, no further axillary surgery was performed. Tumors were classified according to the TNM system of the American Joint Committee on Cancer (41).

Data Analysis
Medical records and histologic findings were reviewed. Results were entered into a computerized spreadsheet (Excel; Microsoft, Redmond, Wash). Statistical analyses were performed with {chi}2 and Fisher exact tests by using a computerized statistics program (EPI-INFO; Centers for Disease Control, Atlanta, Ga).


   RESULTS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Histologic findings in the 33 cancers were infiltrating ductal carcinoma in 26 (including 21 that also had findings of ductal carcinoma in situ), mixed infiltrating ductal and infiltrating lobular carcinoma in five (including three that also had findings of ductal carcinoma in situ), and infiltrating lobular carcinoma in two. Histopathologic size of infiltrating carcinoma was 0.1–1.9 cm (median, 1.1 cm).

The tumor was in the left breast in 20 women and in the right breast in 13 women. Tumors were located in the upper outer quadrant in 18 (55%) women, upper inner quadrant in seven (21%), lower inner quadrant in four (12%), and lower outer quadrant in four (12%). Surgical treatment for carcinoma was breast-conserving surgery after preoperative needle localization in 30 (91%) women and mastectomy in three (9%). The median time from percutaneous biopsy to surgery, known in 31 women, was 21 days (range, 9–220 days).

Preoperative lymphoscintigraphy revealed focal areas of radiotracer uptake separate from the injection site in 12 (36%) women. In 11 women, lymphoscintigraphy revealed uptake in one to five axillary lymph nodes (median, one; mean, 1.5). In one woman with a lower inner quadrant carcinoma, lymphoscintigraphy demonstrated uptake in one axillary and one internal mammary lymph node. In this woman, tumor was present in the axillary sentinel lymph node at surgery; the internal mammary node was not excised, and subsequent axillary dissection revealed no other nodes with metastatic cancer. This patient, who had a 1.2-cm infiltrating and in situ ductal carcinoma, was treated with chemotherapy.

Sentinel nodes were identified at surgery in 30 (91%) of the 33 women. A total of 48 sentinel nodes were found in these 30 women; the median number of sentinel nodes was one, and the mean was 1.6 (range, 1–5). The sentinel nodes were identified with both blue dye and radioisotope in 22 (73%) of these 30 women, with only radioisotope in six (20%) women, and with only blue dye in two (7%) women. In 29 women, the sentinel nodes were in level I of the axilla (41); in one woman, a single sentinel node was found in an intramammary location.

No sentinel nodes were found in three (9%) women. All three women had undergone needle localization, intraparenchymal injection of radioisotope, and subsequent injection of blue dye in accordance with the protocol. Histologic analysis revealed infiltrating ductal carcinoma in all three women, measuring 0.8 cm, 1.2 cm, and 1.5 cm, respectively. Axillary lymph node dissection in these three women showed no axillary metastases in two women and tumor in four of 16 lymph nodes in one woman. Sentinel lymph nodes were identified in 12 (80%) of 15 women who underwent sentinel lymph node biopsy in the first half of the 10-month study and in 18 (100%) of the 18 women who underwent sentinel lymph node biopsy during the second half (P = .08).

Sentinel nodes were free of tumor in 23 (77%) of 30 women. In these 23 women, sentinel node biopsy obviated axillary lymph node dissection. Axillary dissection, performed in the seven women with tumor in sentinel nodes, revealed no additional metastases in six (86%) women and one additional positive node in one woman. In six (86%) of seven women with tumor in sentinel nodes, axillary lymph node dissection was performed during the initial surgical procedure due to the identification of tumor at frozen section analysis of the sentinel nodes; the presence of tumor in sentinel nodes was confirmed at paraffin section analysis in these women. In one woman, tumor was identified in the sentinel node at immunohistochemical analysis, after frozen section and hematoxylin-eosin–stained paraffin section analysis of the sentinel node resulted in negative findings. Axillary dissection, performed at a later date, revealed no other nodes with metastatic cancer in this patient.

A total of 178 nonsentinel nodes were removed in the 30 women in whom sentinel node biopsy was technically successful. Of these 178 nonsentinel nodes, 128 were removed in seven women who underwent axillary dissection due to tumor in sentinel nodes. An additional 50 nonsentinel nodes were removed in axillary fat during surgery in nine women. Carcinoma was present in seven (15%) of 48 sentinel lymph nodes versus in one (0.6%) of 178 nonsentinel lymph nodes (P < .001). The one woman with tumor in a nonsentinel node also had tumor in a sentinel node.


   DISCUSSION
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
For sentinel lymph node biopsy to be useful in women with breast carcinoma, two conditions must be met. First, the procedure must have a high technical success rate: The labeling method must allow reliable identification of the sentinel lymph nodes. Second, the histologic status of the sentinel node must reflect the histologic status of the axilla. In particular, the procedure must have a high negative predictive value if women with negative sentinel nodes are to be spared axillary lymph node dissection.

Technical parameters for sentinel lymph node biopsy are not standardized (Tables 2, 3) (12–29). Studies differ with respect to labeling agent (radioisotope, blue dye, or both), volume and site of injection, and interval between injection and surgery. In many studies, some of these parameters are not reported.


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  		TABLE 2. Nuclear Medicine Protocols for Sentinel Lymph Node Biopsy
 

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  		TABLE 3. Blue Dye Protocols for Sentinel Lymph Node Biopsy
 
For radioisotope methods, the particle size is important: Ideally, the particles must be small enough to gain access to the lymphatic vessels but large enough to be trapped in the first draining (ie, sentinel) nodes. In a study in which they compared different radioisotopes, Krag et al (25) reported that the highest technical success rate was achieved with unfiltered 99mTc sulfur colloid, but they had limited experience with other agents: Unfiltered 99mTc sulfur colloid was used in 120 (76%) of 157 cases. Linehan et al (34) showed that the sentinel lymph nodes were identified in 65 (88%) of 74 cases by using unfiltered 99mTc sulfur colloid versus 27 (66%) of 41 cases by using filtered 99mTc sulfur colloid. The higher success rate with unfiltered 99mTc sulfur colloid is probably because the majority of the colloid is injected in the form of large particles, which are likely to be trapped in the sentinel nodes, rather than in the form of smaller particle colloids that are injected after filtering has been performed, which tend to pass through sentinel nodes and cause diffuse activity in the axilla.

Several other factors affect the technical success of sentinel node biopsy. The success rate is higher with experience. Giuliano et al (13) reported a technical success rate for the blue dye method of 66% in 1994 (59% in the first half and 72% in the last half), which rose to 93% in a subsequent study in 1997 (16). Guenther et al (18), also using blue dye, identified the sentinel node in 12 (48%) of the first 25 cases and in 48 (80%) of the last 60 cases. The volume of injection affects outcome: In a study of sentinel node biopsy by using radioisotope methods, Krag et al (25) found that an intraparenchymal injection volume of 8 mL or greater was significantly associated with a higher success rate and hypothesized that the acute expansion of the interstitial space with a high injection volume led to increased tracer uptake into the lymphatic vessels. Other factors suggested to be associated with technical failure of sentinel lymph node biopsy in one study included age of more than 50 years and medial tumor location (29).

Identification of sentinel lymph nodes is dependent on uptake of the labeling agent by the lymphatic pathways that drain the tumor. Surgical biopsy can disrupt lymphatic drainage pathways. For this reason, it has been hypothesized that prior surgical excision may lower the success rate and accuracy of sentinel lymph node biopsy (14,22), and some investigators (14,17,19,21) have excluded women who have undergone prior surgical biopsy from their sentinel node biopsy protocols. In a multiinstitutional study of sentinel lymph node biopsy by using radioisotope, Krag et al (29) reported a significantly higher frequency of failure to identify a hot spot in women who had undergone prior surgical biopsy when compared with that in women who had undergone percutaneous breast biopsy or no previous biopsy (odds ratio, 7.1; 95% CIs, 2.17, 23.3). While Borgstein et al (22) also noted a significantly lower likelihood of successful sentinel node biopsy in women who had undergone prior surgical excision, others (12,24–26,36) have found no statistically significant difference in the technical success rate of sentinel node mapping in women who did and in women who did not undergo prior surgical biopsy (Table 4). We report a high technical success rate in the women in our study in whom carcinoma was diagnosed by using percutaneous rather than surgical biopsy.


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  		TABLE 4. Effect of Prior Biopsy Technique on Success of Sentinel Lymph Node Biopsy
 
In our study, sentinel lymph node biopsy was technically successful in 30 (91%) of 33 women with nonpalpable breast cancer and obviated axillary dissection in 23 (70%). The three technical failures occurred in the first half of our 10-month study and may reflect our learning curve. It is likely that use of both blue dye and radioisotope contributed to our high technical success rate, as has been suggested by others (Table 5) (14,15,23,24). The reported technical success rates of sentinel node biopsy in the literature are 69%–99% for radioisotope alone, 66%–93% for blue dye alone, and 90%–100% for the combined method (Table 1). Radioisotope injection allows the surgeon to localize the sentinel nodes prior to making an incision, and blue dye enables the surgeon to visually identify the sentinel nodes; the combination of methods may shorten the learning curve and increase the likelihood of technical success.


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  		TABLE 5. Additive Effect of Blue Dye Plus Radioisotope in Sentinel Lymph Node Biopsy
 
In most women in this study, the radioisotope was injected into the parenchyma adjacent to the localizing wire. Other investigators have reported radioisotope injection under the guidance of palpation or imaging, along the localizing wire, through the localizing needle, and beneath the skin. Krag et al (25) found that the method of guiding radioisotope injection (palpation, mammography, or US) did not affect the technical success rate. Borgstein et al (15) reported 100% concordance in delineation of the sentinel node with intradermal blue dye and intramammary radioisotope in a series of 33 women. These studies suggest that there may be considerable latitude with respect to the site of injection of the labeling agent. Further work is necessary to clarify this issue.

In our study, preoperative lymphoscintigraphy revealed sentinel nodes in 36% of women. The low yield at lymphoscintigraphy may be due to the slow uptake of unfiltered 99mTc sulfur colloid into the lymphatic vessels, with inadequate time between injection and imaging. Other studies have reported better results with lymphoscintigraphy, with visualization of sentinel lymph nodes in 58%–99% of cases (Table 6) (15,17,19–23). Although Borgstein et al (22) state that the information from lymphoscintigraphy can be useful to the surgeon, some investigators who inject radioisotope for sentinel node biopsy do not report using lymphoscintigraphy (12,14,24–26). We identified sentinel nodes at surgery in 91% of women by using the combination of blue dye and radioisotope, in spite of the relatively poor performance of lymphoscintigraphy. The role of preoperative lymphoscintigraphy in sentinel lymph node biopsy deserves further investigation.


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  		TABLE 6. Lymphoscintigraphic Imaging of the Sentinel Lymph Node
 
Tumor was found in sentinel nodes in seven (23%) of 30 women in our study. This is consistent with the 24%–31% frequency of axillary metastases in women with T1 breast carcinoma in the published literature (Table 7) (42–46). Carcinoma was present in seven (15%) of 48 sentinel lymph nodes versus one (0.6%) of 178 nonsentinel nodes. The higher frequency of carcinoma in sentinel than in nonsentinel nodes supports the sentinel node hypothesis and confirms the findings of previous investigators (12–14,18) (Table 8). Previous study findings (12–29) show that in approximately half of women with tumor in sentinel nodes, axillary dissection reveals tumor in nonsentinel nodes (Table 1). The likelihood of finding tumor in nonsentinel nodes is greater with larger tumors (eg, T3 as opposed to T1 or T2 tumors) (25) and in women with a greater number of positive sentinel nodes (25,29). The low frequency of metastases in nonsentinel nodes observed in the women in our study is probably due to the small size of these nonpalpable, mammographically detected carcinomas.


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  		TABLE 7. Frequency of Axillary Metastases versus Tumor Size
 

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  		TABLE 8. Frequency of Carcinoma in Sentinel versus Nonsentinel Lymph Nodes
 
Although sentinel nodes were at level I in 29 (97%) of 30 women in this study, others (12–14,25) have reported sentinel lymph nodes outside of level I in 6%–37% of women (Table 9). In to our knowledge the largest existing series in which sentinel node biopsy was performed by using radioisotope with correlative axillary dissection, Krag et al (29) reported that 89% of 445 hot spots in women who underwent sentinel node biopsy were at level I; the rest were in the internal mammary region (4%), at level II (4%), or elsewhere. Published literature (47) prior to the advent of sentinel node biopsy indicates that the frequency of "skip" metastases (axillary metastases at level II or elsewhere with no evidence of metastases at level I) is 10%–12%: In fact, these skip metastases likely represent sentinel nodes outside of level I. Sentinel node mapping can be used to identify these variations of lymphatic drainage and is therefore preferable to axillary sampling or level I axillary dissection for assessment of the axilla. If radioisotope methods are used, the gamma probe (with or without lymphoscintigraphy) can alert the surgeon to the possibility of an unusual location for the sentinel node (ie, level II or internal mammary) before incision.


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  		TABLE 9. Location of Sentinel Lymph Nodes in the Published Literature
 
Few data address the issue of internal mammary lymph nodes at sentinel node biopsy. While Albertini et al (14) stated that internal mammary sentinel nodes could not be localized adequately because of interference from the activity around the site of the primary tumor, Krag et al (25) found and excised internal mammary sentinel nodes in six (5%) of 119 patients. Cody and Urban (48) reported internal mammary metastases in 20% of T1N0 lesions in a highly selected group of women (many with medial lesions) who underwent radical mastectomy and internal mammary dissection in 1965–1978; internal mammary node metastases were associated with a worsened disease-free and overall survival rate. Although internal mammary node status is a prognostic indicator, it rarely affects treatment. At our institution, chemotherapy is administered to women with tumors measuring over 1 cm and to women with tumor in axillary nodes. Therefore, a positive internal mammary node would affect the treatment decision only for women with subcentimeter carcinomas and negative axillary nodes. The assessment of internal mammary nodes at sentinel node biopsy should be addressed in future work.

In one woman in this series, carcinoma was identified in the sentinel node by using immunohistochemical analysis after routine hematoxylin-eosin staining findings were negative. Other investigators (16,22,26,35) have reported that 11%–36% of women with sentinel node metastases are identified only with immunohistochemical analysis. These micrometastases may be of prognostic importance (49–53). One advantage of sentinel node biopsy is that it can be used to identify the lymph nodes most likely to be involved with tumor, which enables application of techniques such as immunohistochemical analysis to the nodes likely to be of highest yield. Immunohistochemical analysis may add to the accuracy of the sentinel node biopsy procedure: In a study of women who had negative sentinel node findings by using hematoxylin-eosin staining and immunohistochemical analysis, Turner et al (30) found carcinoma in a nonsentinel node in only one (2%) of 60 patients and in one (0.09%) of 1,087 nonsentinel nodes.

Our study does not address the accuracy of sentinel lymph node biopsy, because the protocol was to perform axillary lymph node dissection only if tumor was present in sentinel nodes. Other studies, however, have demonstrated that sentinel node biopsy is highly accurate in women with small infiltrating carcinomas. Veronesi et al (17) reported an accuracy of 100% (45 of 45 tumors) for tumors measuring less than 1.5 cm versus 97% (111 of 115 tumors) for larger tumors. Galimberti et al (21) reported an accuracy of 100% (38 of 38 tumors) for tumors measuring less than 1.2 cm versus 97% (194 of 200 tumors) for larger lesions. O'Hea et al (23) reported an accuracy of 100% (19 of 19 tumors) for tumors measuring 1 cm or less, 98% (43 of 44 tumors) for T1 lesions, and 82% (nine of 11 tumors) for T2 or T3 lesions. The high accuracy of sentinel node biopsy in women with small tumors is in part due to the low prior probability of axillary metastases in these women.

In analyzing sentinel node biopsy, it is important to evaluate not only its accuracy but also other parameters, including sensitivity (54,55). In women with T1 breast carcinoma, approximately 75% of whom are free of axillary metastases (42–46), a sentinel lymph node biopsy procedure that resulted in the interpretation of every sentinel node as free of tumor would have 0% sensitivity but would be 75% accurate. The false-negative rate of sentinel node biopsy should be reported as the proportion of women with axillary metastases in whom the sentinel nodes are free of tumor (ie, number of women with false-negative findings/[number of women with true-positive + false-negative findings], or 1 - sensitivity). In the published literature (12–29), the sensitivity of sentinel node biopsy has averaged 94% (range 88%–100%) (Table 1); thus, the false-negative rate of sentinel node biopsy has averaged 6% (range, 0%–12%). In gaining experience with sentinel node biopsy and in reporting and analyzing the results, an adequate number of women with axillary metastases should be included to assess the procedure's sensitivity and false-negative rate. It would also be helpful if data were analyzed in subgroups based on tumor size, location, and histology, to aid in establishing patient selection guidelines for sentinel node biopsy.

Percutaneous evaluation of sentinel nodes may be possible in the future. Parker et al (31) reported on 20 women who received an injection of 0.5–1.0 mCi (18.5–37.0 MBq) 99mTc sulfur colloid adjacent to their primary breast cancer, followed 1 hour later by lymphoscintigraphy. The skin overlying the area of increased activity in the axilla was marked and the area was then examined by using a handheld gamma detector and real-time US. A needle localization wire was placed in the node, and the area was excised along with other areas of increased activity in the axillary bed at surgery. At least one sentinel node was correctly identified and needle localized in 19 (95%) of 20 women; in the one woman in whom the sentinel node was not identified preoperatively, none was found at surgery, either. These findings suggest that it is possible to identify the sentinel nodes percutaneously and establish the groundwork for potential percutaneous histologic assessment of the sentinel lymph nodes.

The American Cancer Society estimates that infiltrating breast cancer will be diagnosed in 175,000 women in 1999, of whom 62% (108,500) will be free of axillary metastases (56). Sentinel node biopsy may spare many women with small infiltrating breast carcinomas from axillary dissection. Currently, however, clinical use of sentinel node biopsy in lieu of axillary dissection may best be (a) reserved for high-volume centers with close coordination of surgery, nuclear medicine, and pathology; (b) limited to small (eg, T1) tumors; (c) implemented after a preliminary trial with correlative axillary dissection to document the performance of sentinel node biopsy in the investigator's own institution; and (d) conducted in the context of a carefully designed study, with informed consent, meticulous recording of technical parameters, and accrual of follow-up data (57,58). This approach will help to refine and standardize the method of sentinel node biopsy so that more women will benefit from this minimally invasive approach to the treatment of small infiltrating breast carcinomas.


   Acknowledgments
 
The authors thank David C. Perlman, MD, for invaluable assistance.


   Footnotes
 
Author contributions: Guarantor of integrity of entire study, L.L.; study concepts and design, L.L., H.S.C., A.D.K.H.; definition of intellectual content, L.L., H.S.C., A.D.K.H., S.D.J.Y., P.P.R., P.I.B., E.A.M., A.F.A., T.A., D.D.D.; literature research, L.L., H.S.C., A.D.K.H.; clinical studies, L.L., H.S.C., A.D.K.H., S.D.J.Y., P.P.R., P.I.B., E.A.M., A.F.A., T.A., D.D.D.; data acquisition, L.L., H.S.C., A.D.K.H., T.A.; data analysis, L.L., H.S.C., A.D.K.H.; statistical analysis, L.L.; manuscript preparation, L.L.; manuscript editing and review, L.L., H.S.C., A.D.K.H., S.D.J.Y., P.P.R., P.I.B., E.A.M., A.F.A., T.A., D.D.D.


   References
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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