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10.1245/s10434-006-9022-z
Annals of Surgical Oncology 13:1412-1421 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Prospective Randomized Clinical Trial Comparing Intradermal, Intraparenchymal, and Subareolar Injection Routes for Sentinel Lymph Node Mapping and Biopsy in Breast Cancer

Stephen P. Povoski, MD1, Johannes O. Olsen, MD2, Donn C. Young, PhD3, Johannah Clarke, CNP, MS1, William E. Burak, MD1, Michael J. Walker, MD1, William E. Carson, MD1, Lisa D. Yee, MD1, Doreen M. Agnese, MD1, Rodney V. Pozderac, MD2, Nathan C. Hall, MD, PhD2 and William B. Farrar, MD1

1 Section of Surgical Oncology, Department of Surgery, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
2 Section of Nuclear Medicine, Department of Radiology, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
3 Center for Biostatistics, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA

Correspondence: Address correspondence and reprint requests to: Stephen P. Povoski, MD, N-924 Doan Hall, 410 West 10th Avenue, Columbus, OH 43210, USA; E-mail: stephen.povoski{at}osumc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Multiple injection routes, including intradermal (ID), intraparenchymal (IP), and subareolar (SA), are used for 99mTc-sulfur colloid administration for sentinel lymph node (SLN) mapping and biopsy in breast cancer. The aim of this study was to compare localization by ID, IP, and SA injection routes based on preoperative lymphoscintigraphy and intraoperative identification.

Methods: Four hundred prospectively randomized breast cancers underwent SLN mapping and biopsy.

Results: Preoperative lymphoscintigraphy demonstrated localization to the axilla in 126/133 (95%) ID, 82/132 (62%) IP, and 96/133 (72%) SA (P < 0.001 ID vs. IP and ID vs. SA; P = 0.081 IP vs. SA), with a mean duration of preoperative lymphoscintigraphy of 139 ± 18 minutes. Mean time to first localization when localization was demonstrated on preoperative lymphoscintigraphy was 8 ± 14 minutes for ID, 53 ± 49 for IP, and 22 ± 29 for SA (P < 0.001 ID vs. IP and ID vs. SA; P = 0.003 IP vs. SA). Intraoperative identification of a SLN at the time of SLN biopsy was successful in 133/133 (100%) ID, 121/134 (90%) IP, and 126/133 (95%) SA (P < 0.001 ID vs IP; P = 0.014 ID vs. SA; P = 0.168 IP vs. SA), with a mean time from injection of 99mTc-sulfur colloid to start of SLN biopsy of 288 ± 71 minutes. Mean intraoperative time to harvest the first SLN was 9 ± 4 minutes for ID, 13 ± 6 for IP, and 12 ± 6 for SA (P < 0.001 ID vs. IP and ID vs. SA; P = 0.410 IP vs. SA).

Conclusions: The ID injection route demonstrated a significantly greater frequency of localization, decreased time to first localization on preoperative lymphoscintigraphy, and decreased time to harvest the first SLN. This represents the first prospective randomized clinical trial to confirm superiority of the ID route for administration of 99mTc-sulfur colloid during SLN mapping and biopsy in breast cancer.

Key Words: Sentinel lymph node • Breast cancer • Intradermal • Intraparenchymal • Subareolar • Lymphoscintigraphy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Sentinel lymph node (SLN) mapping and biopsy technology has become a highly utilized and widely accepted method for surgical staging of axillary lymph nodes in breast cancer surgery. Since its first descriptions for breast cancer by Krag1 in 1993 and Giuliano2 in 1994, there has been considerable ongoing debate as to which route of injection provides the greatest frequency of success for localization of a SLN. Worldwide, multiple injection routes have been utilized, including intraparenchymal (IP), intradermal (ID), subdermal, subareolar (SA), and intratumoral.3 Within the United States, the IP, ID, and SA injection routes appear to be most frequently employed.3 However, to date, no prospective randomized clinical trial has been reported in the literature that compares ID, IP, and SA injection routes for SLN mapping and biopsy in breast cancer surgery. Therefore, the current prospective randomized clinical trial was designed to assess the frequency and sites of radiocolloid localization for ID, IP, and SA injection route techniques and determine if an optimal injection route for 99mTc-sulfur colloid administration could be elucidated.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Eligibility
Female patients (18 years of age or older) with a histological tissue diagnosis of breast cancer (invasive or noninvasive) by core or surgical biopsy or with a cytological diagnosis of malignant cells by fine needle aspiration (FNA) were eligible to participate. A preoperative clinical stage of Tis (non-invasive breast cancer), T1 N0 M0, or T2 N0 M0 was required. Patients with Tis disease had to have biopsy-proven ductal carcinoma in situ (DCIS) that warranted SLN mapping and biopsy. This included patients with DCIS who were to undergo a planned mastectomy for multifocal (but not multicentric) disease and patients with DCIS on a core biopsy with histological or clinical suspicion of an invasive component. Patients were not eligible to participate if they were pregnant or breast feeding, had a histological or clinical diagnosis of inflammatory breast cancer, clinically suspicious ipsilateral axillary adenopathy, received preoperative neoadjuvant chemotherapy, a history of a previously treated ipsilateral breast cancer, a history of ipsilateral axillary surgery, a history of radiation therapy to the ipsilateral breast or axillary region, or a previously placed ipsilateral sub-pectoralis or pre-pectoralis implant.

Study Design
The study protocol was first approved by the Institutional Review Board at The Ohio State University. Eligible patients were informed of the investigational nature of the study protocol and were required to read, agree to, and sign a statement of informed consent prior to participation. Patients were randomized in a 1:1:1 manner to one of three injection routes for 99mTc-sulfur colloid: ID, IP, or SA. Prior to the scheduled date of surgery, randomization was performed by the Center for Biostatistics at The Ohio State University. Randomization was stratified by the participating surgeon solely to insure injection route group equality. The primary end point of the study was to compare the proportion of patients in the ID, IP, and SA injection route groups demonstrating SLN localization of 99mTc-sulfur colloid by preoperative lymphoscintigraphy and intra-operative localization methods.

Radiocolloid Injection
On the day of surgery, each patient was injected with 99mTc-sulfur colloid (filtered to 0.20 or 0.22 microns/micrometers) by way of the predetermined and randomized injection route.

For the ID-injection-route patient, a total of approximately 400 µ Ci of 99mTc-sulfur colloid in a total volume of 0.4 ml of normal saline solution was used. For each ID injection, an attempt was made to create a visible, raised, dermal skin wheal. The ID injection was done (using a tuberculin syringe with a 27-gauge needle) in the skin overlying a palpable breast cancer or around the skin incision of a previous surgical breast biopsy site. For a nonpalpable breast cancer that was previously biopsied by ultrasound-guided core biopsy or stereotactic biopsy, the ID injection was generally done within the nonpigmented breast skin in a location adjacent to but not involving the pigmented areolar skin in the same radial "o’clock" position at which the residual breast lesion was previously determined to be located on mammogram and/or ultrasound.

For the IP-injection-route patient, a total of approximately 400 µ Ci of 99mTc-sulfur colloid in a total volume of 4 mL of normal saline solution was used. The IP injection was done (using a 25-gauge needle) peritumorally for a palpable breast cancer or around the residual palpable cavity of a previous surgical breast biopsy site. For a nonpalpable breast cancer that was previously biopsied by ultrasound guided core biopsy or stereotactic biopsy, the IP injection was generally done with ultrasound guidance or mammographic guidance around the area of the residual breast lesion.

For the SA-injection-route patient, a total of approximately 400 µ Ci of 99mTc-sulfur colloid in a total volume of 4 ml of normal saline solution was used. The SA injection process was done (using a 25-gauge needle) in accordance with the method previously described by Kern.4 Regardless of breast cancer location or site of previous breast biopsy, the SA injection was placed into the upper, outer edge of the areolar complex (at 10 o’clock for the right breast and at 2 o’clock for the left breast) and was directed medially toward the nipple and deep to (approximately 5 mm below) the central portion the areolar complex, specifically within the subdermal tissue plane. We defined the subdermal tissue plane as the superficial subcutaneous tissue layer located between the overlying dermis and the underlying breast parenchyma. All SA-injected patients received 3 ml of 1% plain lidocaine injected prior to the injection the 99mTc-sulfur colloid. First, the edge of the areolar skin was injected intradermally with 1 ml of 1% plain lidocaine using a tuberculin syringe with a 27-gauge needle. Second, 2 ml of 1% plain lidocaine was then injected subdermally and directed toward the nipple in the central portion underneath the areolar complex using a 25-gauge needle. Finally, 4 ml of 99mTc-sulfur colloid was injected subdermally and directed medially toward the nipple in a location underneath the central portion of areolar complex using a 25-gauge needle, as described above.

The injection of 99mTc-sulfur colloid was generally performed by one of the seven participating surgeons. However, in selected cases, the injection was performed by a nuclear medicine physician or a physician performing the preoperative localization procedure of a nonpalpable breast cancer with ultrasound or mammographic guidance in the Radiology Department. At the time of injection of 99mTc-sulfur colloid, each patient was asked to assess their level of injection discomfort using the Wong-Baker FACES pain rating scale,5 which ranges from a minimum score of zero to a maximum score of ten.

Preoperative Lymphoscintigraphy
After injection of the 99mTc-sulfur colloid, preoperative lymphoscintigraphy was performed in the Nuclear Medicine Department using a single-headed gamma camera imaging system (low-energy, high-resolution, parallel-hole collimator, 20% photopeak window). For those patients who did not need a preoperative localization procedure for a nonpalpable breast cancer with ultrasound or mammographic guidance in the Radiology Department and who could remain in the Nuclear Medicine Department until the scheduled time of their surgical procedure, both continuous dynamic imaging and final static imaging were generally performed. Continuous dynamic imaging was started immediately after the radiocolloid injection and continued for a total duration of approximately 90 minutes. For continuous dynamic imaging, the patient was positioned in an anterior oblique manner in order to maximize the distance between the primary injection site of the breast and the axilla and to optimize visualization of any axillary localization. Continuous dynamic imaging was performed without lead shielding of the primary injection site of the breast. After completion of the continuous dynamic imaging, final static imaging was generally performed, taking three separate 10-minute image sequences. These image sequences were taken with the patient in the anterior-posterior orientation without lead shielding to the primary breast injection site, in the anterior-posterior orientation with lead shielding to the primary breast injection site, and in the lateral orientation without lead shielding to the primary breast injection site. For those patients who required preoperative localization of a nonpalpable breast cancer with ultrasound or mammographic guidance in the Radiology Department after their initial radiocolloid injection and who could not remain solely in the Nuclear Medicine Department until the scheduled time of their surgical procedure, only final static imaging was performed and was generally started approximately 90 minutes after the radiocolloid injection.

After completion of all preoperative lymphoscintigraphy imaging, a nuclear medicine physician reviewed all images and documented all sites of localization, including axillary and extraaxillary locations.

Intraoperative SLN Mapping and Biopsy Procedure
In the operating room, the surgeon utilized a hand-held gamma probe detection unit consisting of either the Navigator GPS unit (Tyco Healthcare, Mansfield, MA, USA) or the Neoprobe neo2000 unit (Dublin, OH, USA) for intraoperative mapping. Transcutaneous localization was determined prior to making any surgical incision. Initially blinded to the results of localization from preoperative lymphoscintigraphy, the surgeon first performed an initial intraoperative transcutaneous survey of the patient with the hand-held gamma probe to determine the site(s) of localization. Once the surgeon documented the site(s) of localization by the initial survey, results of the localization by preoperative lymphoscintigraphy were disclosed, and a secondary intraoperative transcutaneous survey was performed by the surgeon with the hand-held gamma probe to again determine the site(s) of localization.

After the transcutaneous survey and prior to the surgical incision, all patients were injected intraparenchymally with blue dye. Generally, 1% isosulfan blue dye was used. However, during times when 1% isosulfan blue dye was not available, 1% methylene blue dye was used. Intraoperative ultrasound was used at the discretion of the surgeon to guide the IP blue dye injection.

The patient then underwent an axillary SLN biopsy procedure using the hand-held gamma probe detection unit to detect radiocolloid ("hot") uptake and using visual inspection to detect blue dye ("blue") uptake. A SLN was defined as any lymph node that was either "hot" and "blue", "hot" only, or "blue" only. A "hot" SLN was defined as any lymph node that contained a level of radioactivity 10% or greater of the total level of radioactivity found in the "hottest" SLN. Maximum sustainable counts (counts per second) recorded by the hand-held gamma probe detection unit were used to determine the counts over the primary injection site of the breast and the ex vivo counts for each SLN candidate. Ten-second cumulative counts were not recorded. A "blue" SLN was defined as any lymph node that visibly stained blue, had a contiguous blue-stained afferent lymphatic channel, or both. Intraoperatively, no attempts were made by the operating surgeon to surgically biopsy any radiocolloid uptake to the internal mammary region.

At the time of surgery, frozen-section analysis with hematoxylin and eosin (H&E) staining in the Surgical Pathology Department was generally performed on all submitted SLNs. Complete axillary lymph node dissection was performed at the time of axillary SLN biopsy if the SLN was found to contain malignant cells on frozen section analysis. Postoperatively, all submitted SLNs were serially sectioned and stained with H&E, and immunohistochemical staining for cytokeratins (AE1:AE3) was also performed.

Statistical Analysis
Based on previously published retrospective data on localization rates for 99mTc-sulfur colloid by IP, ID, and SA injection routes,6–10 the sample size for this study protocol was calculated under the assumption that approximately a 10% clinically important difference in the frequency of localization would be needed. Since pairwise analyses (ID vs. IP, ID vs. SA, and IP vs. SA) were planned to determine the best injection route, adjustment in the overall alpha level for multiple pairwise comparisons was made using the Bonferroni correction (0.05/3 = 0.017). At this adjusted two-sided alpha level of 0.017 and with a statistical power of 0.8, the required total sample size was calculated to be 396, with 132 in each injection route group. The software program nQuery Advisor 4.0 (Saugus, MA, USA) was used to calculate sample size.

One interim analysis was performed after 198 randomized breast cancers underwent SLN mapping and biopsy using an O’Brien-Fleming adjusted level of significance of 0.0018. Since the O’Brien-Fleming stopping boundary had not been exceeded in that interim analysis, the study protocol was continued.

Final analyses of all data were based on all eligible patients who were randomized in an intention-to-treat manner and who were ultimately taken to the operating room for attempted axillary SLN mapping and biopsy procedure. For overall and pairwise binomial variable comparisons, either Pearson chi-square test or Fisher exact test was utilized. Continuous variables were expressed as means (± standard deviation) and/or median (range). For overall continuous variable comparisons, the Kruskal–Wallis test (a nonparametric equivalent to one-way AVOVA) was first utilized. For all subsequent pairwise continuous variable comparisons, the Mann–Whitney U test (two-tailed) was utilized. All reported P values were two-sided. If an overall P value was determined to be 0.05 or less, then pairwise comparisons were made. All pairwise comparisons were determined to be significant at a P value of 0.017 or less. The software program SPSS 13.0 for Windows (Chicago, IL, USA) was used for all statistical analyses.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Between August 13, 2002 and November 16, 2005, 414 newly diagnosed breast cancers (including 404 patients with unilateral breast cancer and five with synchronous bilateral breast cancers) underwent randomization to one of three 99mTc-sulfur colloid injection routes, with 137 (33%) ID, 141 (34%) IP, and 136 (33%) SA. At some time after completion of the randomization process but prior to the time of anticipated surgery, 14 breast cancers ultimately did not participate in the clinical trial. The reasons for nonparticipation included six who simply stated that they had changed their mind about participation, six who had insurance that would not cover the cost of surgery if done through The Ohio State University system, one who was found to have metastatic disease to the lungs, and one who was determined not to have a diagnosis of breast cancer on reevaluation of outside biopsy slides through the Department of Pathology at The Ohio State University. These 14 nonparticipants were excluded from all subsequent analyses.

Between August 29, 2002 and December 12, 2005, 400 randomized breast cancers (including 392 patients with unilateral breast cancer and four with synchronous bilateral breast cancers) were ultimately taken to the operating room for their axillary SLN mapping and biopsy procedure, including 133 (33%) ID, 134 (34%) IP, and 133 (33%) SA. Patient demographics and tumor characteristics for the three 99mTc-sulfur colloid injection route groups were well balanced and are shown in Table 1Go.


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  		TABLE 1. Breast cancer patient demographics and tumor characteristics
 
The mean amount of 99mTc-sulfur colloid administered was essentially the same for all three injection route groups, with 418 ± 12 µ Ci for ID, 419 ± 13 µ Ci for IP, and 418 ± 11 µ Ci for SA (overall P = 0.665). Using the Wong-Baker FACES pain rating scale, there was no significant difference in patient subjective assessment of the level of injection discomfort, with a mean score of 2.7 ± 1.9 for ID, 3.0 ± 2.0 for IP, and 2.7 ± 1.9 for SA (overall P = 0.188). No allergic reactions to 99mTc-sulfur colloid were noted in any of the three injection route groups.

Preoperative lymphoscintigraphy was performed on 398 breast cancers and was inadvertently not performed on two breast cancers from the IP 99mTc-sulfur colloid injection route group. Mean duration of preoperative lymphoscintigraphy imaging was fairly uniform for the three injection route groups, with 141 ± 20 minutes for ID, 138 ± 18 for IP, and 138 ± 17 for SA (overall P = 0.580). Preoperative lymphoscintigraphy localization to the axilla occurred in 126/133 (95%) ID, 82/132 (62%) IP, and 96/133 (72%) SA (P < 0.001 for ID vs. IP; P < 0.001 for ID vs. SA; P = 0.081 for IP vs. SA) by a mean duration of preoperative lymphoscintigraphy imaging of 139 ± 18 minutes. Continuous dynamic imaging was able to be performed on 160 breast cancers (n = 69 for ID, n = 43 for IP, and n = 48 for SA). Mean time to first localization to the axillary region on continuous dynamic imaging when localization was demonstrated on preoperative lymphoscintigraphy was 8 ± 14 minutes for ID, 53 ± 49 for IP, and 22 ± 29 for SA (P < 0.001 for ID vs. IP; P < 0.001 for ID vs. SA; P = 0.003 for IP vs. SA). Preoperative lymphoscintigraphy localization to the internal mammary region occurred in 1/133 (1%) ID, 14/132 (11%) IP, and 2/133 (2%) SA (P < 0.001 for ID vs. IP; P = 0.624 for ID vs. SA; P = 0.002 for IP vs. SA). Preoperative lymphoscintigraphy localization to the supraclavicular region occurred in 2/133 (2%) ID, 1/132 (1%) IP, and 0/133 (0%) SA (overall P = 0.366).

Mean duration from injection of 99mTc-sulfur colloid to the start of the intraoperative transcutaneous survey was consistent amongst the three injection route groups, with 269 ± 70 minutes for ID, 264 ± 70 for IP, and 266 ± 67 for SA (overall P = 0.789). The initial and secondary intraoperative transcutaneous surveys demonstrated identical results for localization to the axilla and was recognized in 130/133 (98%) ID, 86/134 (64%) IP, and 106/133 (80%) SA (P < 0.001 for ID vs. IP; P < 0.001 for ID vs. SA; P = 0.005 for IP vs. SA) by a mean duration from the injection of 99mTc-sulfur colloid to the start of the intraoperative transcutaneous survey of 266 ± 69 minutes. Intraoperative transcutaneous localization to the internal mammary region on the initial transcutaneous survey was recognized in 1/133 (1%) ID, 3/134 (2%) IP, and 1/133 (1%) SA (overall P = 0.450). Intraoperative transcutaneous localization to the internal mammary region on the secondary transcutaneous survey was recognized in 1/133 (1%) ID, 7/134 (5%) IP, and 1/133 (1%) SA (P = 0.066 for ID vs. IP; P = 1.000 for ID vs. SA; P = 0.066 for IP vs. SA). Intraoperative transcutaneous localization to the supraclavicular region was not appreciated on the initial transcutaneous survey for any of the three injection route groups but was recognized on secondary transcutaneous survey in 0/133 (0%) ID, 1/134 (1%) IP, and 0/133 (0%) SA (overall P = 0.370). Overall, findings on preoperative lymphoscintigraphy changed findings on intraoperative transcutaneous localization from that of the initial survey to that of the secondary survey in only seven of 398 (1.8%) breast cancers undergoing both preoperative lymphoscintigraphy and intraoperative transcutaneous survey, with such a change demonstrated in 2/133 (2%) ID, 5/132 (4%) IP, and 0/133 (0%) SA (overall P = 0.062).

IP blue dye was used in all but one breast cancer case from the ID 99mTc-sulfur colloid injection route group, with 1% isosulfan blue dye used in 388/399 (97%) of cases and 1% methylene blue dye used in 11/399 (3%) of cases. The amount of IP blue dye injected was identical in all three injection route groups, with a mean of 4.6 ± 0.6 ml and a median of 5.0 (range, 2.5–5.0) ml (overall P = 0.825). An intraoperative allergic reaction was noted in four of 388 (1.03%) cases injected with IP 1% isosulfan blue dye. Three of 388 (0.77%) developed cutaneous blue hives intra-operatively, and one of 388 (0.26%) developed intraoperative hypotension at the end of the surgical procedure (approximately 120 minutes after the injection of IP 1% isosulfan blue dye). No intraoperative allergic reactions were noted in any of the 11 cases injected with IP 1% methylene blue dye.

Mean duration from the injection of 99mTc-sulfur colloid to the start of the axillary SLN biopsy procedure was fairly similar for the three injection route groups, with 290 ± 69 minutes for ID, 287 ± 75 for IP, and 286 ± 68 for SA (overall P = 0.759). Intraoperative identification of a "hot" SLN within the axilla with the hand-held gamma probe at the time of axillary SLN biopsy occurred in 133/133 (100%) ID, 121/134 (90%) IP, and 126/133 (95%) SA (P < 0.001 for ID vs. IP; P = 0.014 for ID vs. SA; P = 0.168 for IP vs. SA) by a mean duration from the injection of 99mTc-sulfur colloid to the axillary SLN biopsy of 288 ± 71 minutes.

Mean duration from the injection of IP blue dye to the start of the axillary SLN biopsy procedure was also fairly similar for the three 99mTc-sulfur colloid injection route groups, with 21 ± 10 minutes for ID, 23 ± 26 for IP, and 20 ± 11 for SA (overall P = 0.693). Intraoperative identification of a "blue" SLN within the axilla at the time of SLN biopsy occurred in 93/132 (71%) ID, 83/134 (62%) IP, and 91/133 (68%) SA (overall P = 0.304) by a mean duration from the injection of IP blue dye to the axillary SLN biopsy of 21 ± 17 minutes. Of the 20 breast cancer cases in which there was no identification of a "hot" SLN, only one patient, from the SA 99mTc-sulfur colloid injection route group, had a SLN identified solely as "blue." Axillary concordance—defined as the proportion of cases in which both 99mTc-sulfur colloid and IP blue dye localized to the axilla and at least one SLN was both "hot" and "blue"—was strikingly similar for the three injection route groups, occurring in 90/93 (97%) ID, 82/83 (99%) IP, and 87/91 (96%) SA (overall P = 0.462).

Mean intraoperative time needed to harvest the first SLN at the time of the axillary SLN biopsy was significantly shorter for the ID injection route group, consisting of 9 ± 4 minutes for ID, 13 ± 6 for IP, and 12 ± 6 for SA (P < 0.001 for ID vs. IP; P < 0.001 for ID vs. SA; P = 0.410 for IP vs. SA).

Maximum sustainable counts over the primary injection site of the breast were 14,840 ± 15,355 for ID, 4,978 ± 8,027 for IP, and 7,136 ± 8,697 for SA (P < 0.001 for ID vs. IP; P < 0.001 for ID vs. SA; P < 0.001 for IP vs. SA). Maximum sustainable ex vivo counts within the "hottest" axillary SLN were 1,970 ± 6,465 for ID, 359 ± 555 for IP, and 969 ± 1,460 for SA (P < 0.001 for ID vs. IP; P = 0.027 for ID vs. SA; P < 0.001 for IP vs. SA).

There was no statistically significant difference in the mean number of SLNs identified at the time of axillary SLN biopsy for the three injection route groups, with 2.5 ± 1.4 for ID, 2.2 ± 1.2 for IP, and 2.6 ± 1.6 for SA (overall P = 0.234). Of those breast cancers in which a SLN was identified (n = 381), metastatic disease was ultimately identified on final histological analysis within a SLN in 44/133 (33%) ID, 28/121 (23%) IP, and 32/127 (25%) SA (overall P = 0.167). This metastatic disease was classified as macrometastatic (> 2 mm) in 29/44 (66%) ID, 18/28 (64%) IP, and 22/32 (69%) SA (overall P = 0.932), micrometastatic (≤ 2 mm, but > 0.2 mm) in 11/44 (25%) ID, 6/28 (22%) IP, and 7/32 (22%) SA (overall P = 0.923), and submicrometastatic (≤ 0.2 mm) in 4/44 (9%) ID, 4/28 (14%) IP, and 3/32 (9%) SA (overall P = 0.756). Lastly, of all 400 breast cancers evaluated (including those 19 breast cancers in which a SLN was not identified), metastatic disease was ultimately identified on final histological analysis within a lymph node in 44/133 (33%) ID, 31/134 (23%) IP, and 37/133 (28%) SA (overall P = 0.194).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Now, well into the second decade in the evolution of SLN mapping and biopsy for breast cancer staging and surgical management, significant controversy remains with regards to standardization of the methodology. Central to this controversy is the ongoing debate as to which route of injection of radiocolloid provides the greatest frequency of successful localization of a SLN. In this regard, a great deal of support remains firmly in place for the IP injection route that was originally described by Krag1 for radioisotope and by Giuliano2 for blue dye. However, numerous retrospective reports have been subsequently published in support of both the ID6–23 and SA24–31 injection routes. To date, despite the vast number of publications in the literature on SLN technology for breast cancer (which currently numbered more than 2,400 publications at the time of the writing of this report), not a single prospective randomized clinical trial comparing ID, IP, and SA injection routes has been published.

The current study, representing the first reported prospective randomized clinical trial comparing ID, IP, and SA injection routes for administration of 99mTc-sulfur colloid during SLN mapping and biopsy for breast cancer, confirms the superiority of the ID injection route to that of both IP and SA injection routes for identifying axillary SLNs. By preoperative lymphoscintigraphy, the ID injection route demonstrated a significantly greater frequency of localization to the axilla, as well as a significantly shorter duration of time to detection of initial localization within the axilla. Intraoperatively, the ID injection route demonstrated a significantly greater frequency of identification of a "hot" SLN within the axilla with the hand-held gamma probe at the time of the initial and secondary transcutaneous survey and at the time of the axillary SLN biopsy. In addition, the ID injection route resulted in significantly higher maximum sustainable ex vivo counts within the "hottest" SLN and a significantly shorter time needed to harvest the first SLN at the time of the axillary SLN biopsy. The findings of our current prospective randomized clinical trial clearly validate the well-respected retrospective findings that have previously been reported from the Memorial Sloan-Kettering Cancer Center SLN database9,13,15,16 and from the Louisville Breast Cancer Multiinstitutional Study Group SLN database.8

A major point of contention among supporters of the IP injection route for radiocolloid administration and for routine utilization of preoperative lymphoscintigraphy imaging is the concept of radiocolloid localization to the internal mammary lymph node chain. This is readily identifiable on preoperative lymphoscintigraphy with the IP radiocolloid injection route but is generally absent or nearly absent with the ID or SA radiocolloid injection routes. Reports in the literature have demonstrated localization to the internal mammary lymph node chain on preoperative lymphoscintigraphy with IP radiocolloid to be as high as 15%–45%, with the highest levels of internal mammary localization reported from techniques involving subtumoral IP radiocolloid injection, high-dose IP radiocolloid injection, and prolonged time interval from IP radiocolloid injection to performance of preoperative lymphoscintigraphy.32–36 Our current study nicely confirms that the IP radiocolloid injection route is associated with a significantly greater frequency of localization to the internal mammary lymph node chain on preoperative lymphoscintigraphy, with such localization seen in 11% of IP cases but only 1% of ID cases and 2% of SA cases. However, the difference seen in the frequency of localization to the internal mammary lymph node chain on the subsequent intraoperative transcutaneous survey by the three radiocolloid injection route groups lacked any statistical power. In addition, findings of preoperative lymphoscintigraphy ultimately failed to significantly change findings from those of the initial to the secondary intraoperative transcutaneous survey (i.e., thus affecting the results of only 1.8% of all the breast cancer in our study undergoing both preoperative lymphoscintigraphy and intraoperative transcutaneous survey). Similarly, preoperative lymphoscintigraphy demonstrated much lower frequencies of axillary localization by all three radiocolloid injection routes (95% for ID, 62% for IP, and 72% for SA) than was ultimately seen by final intraoperative identification of a SLN at the time of axillary SLN biopsy (100% for ID, 90% for IP, and 95% for SA). While the shorter total duration from injection of 99mTc-sulfur colloid to completion of preoperative lymphoscintigraphy (139 ± 18 minutes) versus the longer total duration from injection of 99mTc-sulfur colloid to the start of the axillary SLN biopsy procedure (288 ± 71 minutes) likely accounted for a large portion of the difference in the frequency of localization, the lesser degree of localization seen by preoperative lymphoscintigraphy for all three injection routes speaks against advocating its routine use. So while our IP radiocolloid injection route results for preoperative lymphoscintigraphy are academically satisfying by confirming the higher frequency of localization to internal mammary lymph node chain, its ultimate clinical impact was negligible on the axillary SLN biopsy procedure. Therefore, as has been previously reported in several retrospective studies,10,37–40 we do not believe that the routine use of preoperative lymphoscintigraphy is necessary for identification of SLNs in most breast cancer patients.

Obviously, the staunchest supporters of the IP radiocolloid injection route will find this above statement unacceptable since they have long contended that isolated metastatic nodal involvement of the internal mammary lymph node chain in axillary lymph node negative patients has potential important implications in designing postoperative adjuvant therapy. However, data supporting this contention was chronologically generated in a time well before the current era of standard utilization of adjuvant systemic chemotherapy. Likewise, such a scenario would today impact adversely only a fraction of a single percentage of patients since the vast majority of those affected would already be candidates for systemic adjuvant chemotherapy based upon factors independent of their internal mammary lymph node status.

Supporters of the ID injection route have long proposed that the skin of the breast and the underlying glandular breast tissue share common lymphatic pathways that ultimately drain into the same axillary lymph nodes. In 1997, Borgstein et al.11 first hypothesized this concept and demonstrated a 100% axillary concordance of ID blue dye and IP radiocolloid. Similarly, in 1999, Linehan et al.13 demonstrated 95% axillary concordance of IP blue dye and ID radiocolloid. Since that time, multiple other reports have confirmed this finding. In the current study, there was a high level and strikingly similar degree of axillary concordance of 99mTc-sulfur colloid and IP blue dye that was shared by all three 99mTc-sulfur colloid injection routes groups (97% for ID, 99% for IP, and 96% for SA). This finding suggests that the same group of axillary lymph nodes are ultimately targeted regardless of which one of the three injection routes for 99mTc-sulfur colloid administration was utilized and further supports the concept of common lymphatic pathways that ultimately drain into the same axillary lymph nodes.

One may propose that the level of injection discomfort is a potentially important variable in the selection of the most ideal injection route for 99mTc-sulfur colloid administration. Several authors have previously suggested that there may be differences in the level of discomfort experienced by patients with injection of 99mTc-sulfur colloid by way of ID, IP, and SA injection routes.15,26,41 However, the results of the current study, using the Wong-Baker FACES pain rating scale to assess the level of discomfort experienced by injection of 99mTc-sulfur colloid, failed to show any significant difference in the level of discomfort reported by patients within the three radiocolloid injection route groups.

In summary, the findings of this prospective randomized clinical trial clearly illustrate the major advantages of the ID injection route for administration of 99mTc-sulfur colloid for SLN mapping and biopsy during breast cancer surgery. First and foremost, it allows for the greatest success of identification of a SLN within the axilla. Second, it allows for minimization of the time from injection of 99mTc-sulfur colloid to the time when a SLN can be successfully identified within the axilla. Third, it results in the generation of the hottest axillary SLN and shortest intraoperative time to harvest the axillary SLN. All of these variables lead to maximization of axillary SLN identification and minimization in time spent to successful axillary SLN identification. In conclusion, this represents the first prospective randomized clinical trial to confirm the superiority of the ID injection route for 99mTc-sulfur colloid administration. Resultantly, this clearly validates the ID injection route as the route of choice for 99mTc-sulfur colloid administration for SLN mapping and biopsy of the axilla during breast cancer surgery.


   ACKNOWLEDGMENTS
 
The authors would like to thank Suzanne Knott, Cheri Balser, Janine Cobar, and the nursing staff at JamesCare in the Dublin Breast Care Center for their assistance in patient randomization and registration process, the Nuclear Medicine Department staff for their assistance with the preparation and injection of 99mTc-sulfur colloid and performance of preoperative lymphoscintigraphy, and The Author G. James Hospital operating room staff for their assistance with intraoperative data collection.

Received for publication March 31, 2006. Accepted for publication May 23, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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