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Annals of Surgical Oncology 10:376-380 (2003)
© 2003 Society of Surgical Oncology

ORIGINAL ARTICLES

Patterns of Recurrence After Sentinel Lymph Node Biopsy for Breast Cancer

Brian D. Badgwell, MD, Stephen P. Povoski, MD, Shahab F. Abdessalam, MD, Donn C. Young, PhD, William B. Farrar, MD, Michael J. Walker, MD, Lisa D. Yee, MD, Emmanuel E. Zervos, MD, William E. Carson, III, MD and William E. Burak, Jr, MD

From the Division of Surgical Oncology, Department of Surgery, Arthur G. James Cancer Hospital, and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio.

Correspondence: Address correspondence and reprint requests to: William E. Burak, Jr, MD, Division of Surgical Oncology, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, N907 Doan Hall, 410 West 10th Ave., Columbus, OH 43210-1228; Fax: 614-293-3465; E-mail: burak.1{at}osu.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS AND PATIENTS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Sentinel lymph node biopsy (SLNB) is gaining acceptance as an alternative to axillary lymph node dissection. The purpose of this study was to determine the frequency and pattern of disease recurrence after SLNB.

Methods: Two-hundred twenty-two consecutive patients undergoing SLNB from April 6, 1998, to October 27, 1999, and who were >=24 months out from their procedure were identified from a prospectively maintained database. Retrospective chart review and data analysis were performed to identify variables predictive of recurrence.

Results: The median patient follow-up was 32 months (range, 24–43 months). A total of 159 patients (72%) were sentinel lymph node (SLN) negative and had no further axillary treatment. Five of these patients (3.1%) developed a recurrence (one local and four distant), with no isolated regional (axillary) recurrences. Sixty-three patients (28%) were SLN positive and underwent a subsequent axillary lymph node dissection. Six of these patients (9.5%) developed a recurrence (three local, one regional, and two distant). Pathologic tumor size (P < .001), lymphovascular invasion (P = .018), and a positive SLN (P = .048) were all statistically significantly associated with disease recurrence.

Conclusions: With a minimum follow-up of 24 months, patients with a negative SLN and no subsequent axillary treatment demonstrate a low frequency of disease recurrence. This supports the use of SLNB as the sole axillary staging procedure in SLN-negative patients.

Key Words: Sentinel lymph node • Breast cancer • Lymphatic mapping • Recurrent disease


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS AND PATIENTS
 RESULTS
 DISCUSSION
 REFERENCES
 
Axillary lymph node dissection (ALND) has traditionally been considered a critical component of breast cancer surgery in determining tumor stage and potentially providing regional control of the axilla.1,2 Sentinel lymph node biopsy (SLNB) has been offered as an alternative to ALND. Since its introduction in the early 1990s,3,4 SLNB has proven itself as an accurate technique for predicting the status of the axilla.5–19 Despite this, there remain only limited published data on the long-term effects of SLNB alone without concomitant ALND, especially in patients with >24 months of follow-up.

Since 1998, our institution has routinely performed SLNB on breast cancer patients; only those patients with a positive axillary sentinel lymph node (SLN) undergo a concomitant ALND. This reflects a developing practice pattern in breast cancer surgery. Yet the question remains: is the frequency of long-term regional control and systemic recurrence in SLN-negative patients compromised after SLNB alone? The purpose of this study was to determine the frequency and pattern of disease recurrence after SLNB.


   METHODS AND PATIENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS AND PATIENTS
RESULTS
 DISCUSSION
 REFERENCES
 
A prospectively maintained breast cancer patient database at the Arthur G. James Cancer Hospital of The Ohio State University was used to identify female patients who had undergone a successful SLNB procedure and who were >24 months out from the time of their SLNB procedure. From April 6, 1998, to October 27, 1999, 222 consecutive patients meeting these criteria were identified. Patients were excluded if a SLN was not localized or if they underwent a concomitant validation ALND at the time of the SLNB procedure. Eight surgeons contributed to this database.

Patients were injected at least 2 hours before their surgery with approximately 400 µCi of filtered (.2 µm) 99mTc-labeled sulfur colloid in equal distribution around the tumor itself or through the localization needle, if required (intraparenchymal). At the time of operation, 5 mL of isosulfan blue dye was injected in equal distribution around the tumor itself or through the localization needle (intraparenchymal). The sentinel node was localized by using a handheld gamma probe (Navigator; US Surgical, Norwalk, CT; and Neoprobe 1500 and 2000; Neoprobe Corp., Dublin, OH). Any lymph node exhibiting ex vivo radioactivity more than two times the background was defined as hot. When multiple potential SLNs were identified, all lymph nodes exhibiting a level of ex vivo radioactivity that was >=10% of the total level of ex vivo radioactivity found in the hottest SLN were defined as hot. Any lymph node that visibly stained blue, had a contiguous blue-stained afferent lymphatic, or both during intraoperative visualization was defined as a blue SLN. All SLNs were sent for routine histological analysis. When a SLN metastasis was present on frozen section, a concomitant ALND was performed. No patients in whom the SLN was negative on final histopathologic evaluation received postoperative external-beam radiation exclusively to the axillary region.

Follow-up data were obtained from the prospectively maintained breast cancer patient database, from review of clinic charts, from patient contacts, and from the tumor registry maintained by our National Cancer Institute Designated Comprehensive Cancer Center. Continuous variables were expressed as median (range), mean ± SD, or both. One-way analysis of variance was used to compare the means of all continuous variables. Pearson {chi}2 analysis was used for univariate comparison of all categorical variables. When the expected frequency of one or more cells of a given 2 x 2 contingency table for univariate comparison was <=5, Fisher’s exact test was used. A P value of <=.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS AND PATIENTS
 RESULTS
DISCUSSION
 REFERENCES
 
The patient demographics and tumor characteristics for all 222 consecutive patients are listed in Table 1. The median patient age was 57 years (range, 30–85 years). The median and mean pathologic tumor sizes were 1.6 cm (range, .1–6.7 cm) and 1.9 ± 1.2 cm, respectively, with most being T1 lesions. Two hundred five patients (92%) had invasive ductal carcinoma. One hundred eighty-eight patients (85%) underwent breast-conservation surgery. The median and mean numbers of SLNs found per patient were 2.0 (range, 1–16) and 2.3 ± 2.0, respectively. One hundred fifty-nine patients (72%) were SLN negative and had no further axillary treatment. Sixty-three patients (28%) were found to have a positive SLN and underwent a subsequent ALND. The median patient follow-up was 32 months (range, 24–43 months).


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  		TABLE 1. Patient demographics and tumor characteristics (n = 222)
 
The recurrence-free survival is shown in Fig. 1. The recurrence-free survival was 99% at 12 months, 97% at 24 months, and 97% at 36 months in SLN-negative patients, as compared with 97% at 12 months, 94% at 24 months, and 90% at 36 months in SLN-positive patients who underwent an ALND (P = .053). The median time to presentation of disease recurrence was 13 months (range, 5–21 months) in the SLN-negative group, as compared with 17 months (range, 1–25 months) in the SLN-positive group (P = .608).



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  		FIG. 1. Proportion of patients free from breast cancer recurrence. The solid line depicts patients with a negative sentinel lymph node, whereas the dashed line signifies patients with a positive sentinel lymph node.

 
The tumor characteristics for all 222 consecutive patients with and without disease recurrence are listed in Table 2. By univariate analysis, pathologic tumor size (P = .001 for T stage and P < .001 for mean pathologic tumor size), the presence of lymphovascular invasion (P = .018), and the presence of a positive SLN (P = .048) were all statistically significantly associated with disease recurrence. However, tumor grade, estrogen receptor positivity, extranodal extension, and HER-2/neu positivity were not associated with disease recurrence on univariate comparison. With regard to adjuvant therapy, neither the use of tamoxifen (P = .086) nor the use of systemic postoperative chemotherapy (P = .193) was associated with disease recurrence on univariate comparison. Breast-conservation therapy was also not found to be predictive of recurrence (P = .882).


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  		TABLE 2. Tumor characteristics for all patients (n = 222) with and without disease recurrence
 
The tumor characteristics for all SLN-negative patients (n = 159) with and without disease recurrence are listed in Table 3. By univariate analysis, pathologic tumor size (P = .021 for mean pathologic tumor size) was statistically significantly associated with disease recurrence. However, tumor grade, estrogen receptor positivity, lymphovascular invasion, and HER-2/neu positivity were not associated with disease recurrence on univariate comparison. With regard to adjuvant therapy, the use of tamoxifen (P = .047) was statistically significantly associated with the absence of disease recurrence on univariate comparison. However, the use of systemic postoperative chemotherapy (P = .459) was not associated with disease recurrence.


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  		TABLE 3. Tumor characteristics for all SLN-negative Patients (n = 159) with and without disease recurrence
 
The tumor characteristics for all SLN-positive patients (n = 63) with and without disease recurrence are listed in Table 4. By univariate analysis, pathologic tumor size (P = .054 for T stage and P < .001 for mean pathologic tumor size) was the only variable statistically significantly associated with disease recurrence. Tumor grade, estrogen receptor positivity, extranodal extension, lymphovascular invasion, HER-2/neu positivity, the number of lymph nodes removed at ALND, and the number of positive lymph nodes in the ALND were not associated with disease recurrence on univariate comparison. With regard to adjuvant therapy, neither the use of tamoxifen (P = .653) nor the use of systemic postoperative chemotherapy (P = .234) was associated with disease recurrence on univariate comparison.


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  		TABLE 4. Tumor characteristics for all SLN-positive patients (n = 63) with and without disease recurrence
 
The site and frequency of disease recurrence in SLN-positive and SLN-negative patients are listed in Table 5. Six (9.5%) of the 63 SLN-positive patients developed a recurrence. There were three local recurrences, one regional recurrence, and two distant recurrences. Five (3.1%) of the 159 SLN-negative patients developed a recurrence. There were one local recurrence and four distant recurrences. No isolated regional (axillary) recurrences were identified in the SLN-negative group.


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  		TABLE 5. Site and frequency of disease recurrence in SLN-positive and SLN-negative patients
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS AND PATIENTS
 RESULTS
 DISCUSSION
REFERENCES
 
The development and validation of SLNB for the staging and treatment of breast cancer has been a major medical advance of the last decade and has allowed this technique to become a standard of care in many specialty medical centers. SLNB has repeatedly been shown to have a high staging accuracy and a low false-negative rate.5–19 These results would suggest that disease recurrence in SLN-negative patients not undergoing a subsequent ALND would most likely occur outside of the axilla. However, the actual frequency and patterns of disease recurrence in SLN negative patients with long-term follow-up are not well documented in the literature. Therefore, the purpose of this study was to determine the frequency and pattern of disease recurrence after SLNB in patients who were >2 years out from their definitive breast cancer surgery.

In this study, we observed that 3.1% of SLN-negative patients developed disease recurrence during a median follow-up period of 32 months. Most of these disease recurrences represented distant metastatic disease, and no single case of isolated regional (axillary) recurrence was identified. For all 222 patients in our study population, pathologic tumor size, SLN positivity, and lymphovascular invasion were all determined to be statistically significant factors associated with disease recurrence on univariate analysis. However, age, tumor grade, estrogen receptor positivity, HER-2/neu positivity, nodal extension, and previous excisional biopsy were not significantly associated with recurrence.

The data in the literature with regard to the long-term outcome of SLN-negative patients without further axillary treatment are very limited. A previous prospective observational study by Giuliano et al.20 from the John Wayne Cancer Institute reported on 125 assessable patients in whom a SLN was identified by the vital blue dye technique; in this study, 67 patients were SLN negative and did not undergo a subsequent ALND. In this group of 67 SLN-negative patients, there were no local, regional (axillary), or distant recurrences at a median follow-up of 39 months (range, 12–51 months). Comparatively, our results demonstrated that 3.1% of 159 SLN-negative patients developed disease recurrence during a median follow-up of 32 months. Similarly, both studies demonstrated no isolated regional (axillary) recurrences. Conversely, our study demonstrated a low level of local and distant recurrence not seen by Giuliano et al.20 This difference may be due to our larger study population; however, it does correlate with other reports in the literature for disease recurrence in early-stage breast cancer.21 Nevertheless, our results and those of Giuliano et al.20 support the use of SLNB without subsequent ALND in SLN-negative patients.

As expected, most disease recurrences seen in the SLN-positive patients undergoing subsequent ALND occurred outside of the axilla. This supports the commonly held premise that breast cancer, once metastatic to the axilla, is subsequently a systemic disease. The finding of predominantly distant recurrences in SLN-negative patients in our study population suggests that factors other than the SLN status, such as the pathologic tumor size, should be taken into account when predicting distant recurrence. This is nicely demonstrated in Tables 3 and 4 in our study, in which pathologic tumor size was the only variable statistically significantly associated with disease recurrence in SLN-negative patients without further axillary therapy and in SLN-positive patients undergoing a subsequent ALND, respectively.

The false-negative rate for SLNB reported in both large published series5–17 and at our own institution during our validation phase18 is generally in the range of 5%. From this, one might predict that this false-negative rate would result in a combined frequency of regional (axillary) and distant recurrence of approximately 5%. Our study, as well as that of Giuliano et al.,20 found that this was not the case. One potential variable leading to this apparent discrepancy could be the somewhat limited duration of long-term follow-up of both studies. However, most breast cancer recurrences occur within 2 years after initial treatment, and this is within the duration of long-term follow-up of both studies. A second potential variable could be the incorporation of the lower axillary region into the radiation field directed at the breast. In this regard, the necessity of ALND is questioned in patients with small cancers who have undergone dedicated axillary radiotherapy.22 No patient in our study received dedicated radiation fields to the axillary region. A third potential variable leading to this apparent discrepancy could be the downstaging of a false-negative SLN negative axilla by postoperative adjuvant chemotherapy. Finally, a less well-defined potential variable could be that not all cells detected on sentinel node analysis are clinically significant and survive in the environment of the lymph node.23

In conclusion, our results demonstrate a low incidence of disease recurrence in SLN-negative patients, supporting its role as an accurate method of axillary staging. However, ultimately, long-term outcome from SLNB will be accurately and definitively determined only by prospective, randomized trials, such as the American College of Surgeons Oncology Group Z0011 trial and the National Surgical Adjuvant Breast and Bowel Project B-32 trial.24


   Acknowledgments
 
Supported by The Ohio State University General Surgery Research Fellowship.

The acknowledgments are available online at www.annalssurgicaloncology.org.


   Footnotes
 
This study evaluates the frequency and pattern of disease recurrence after sentinel lymph node biopsy and definitive breast cancer treatment. At a minimum of 24 months of follow-up, patients with a negative sentinel node had a very low frequency of disease recurrence.

Received for publication July 26, 2002. Accepted for publication December 16, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS AND PATIENTS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Newman LA, Hunt KK, Buchholz T, et al. Presentation, management and outcome of axillary recurrence from breast cancer. Am J Surg 2000; 180: 252–6.[CrossRef][Medline]
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  4. Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994; 220: 391–8.[Medline]
  5. Krag D, Weaver D, Ashikaga T, et al. The sentinel node in breast cancer: a multicenter validation study. N Engl J Med 1998; 339: 941–6.[Abstract/Free Full Text]
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  8. Veronesi U, Paganelli G, Viale G, et al. Sentinel lymph node biopsy and axillary dissection in breast cancer: results in a large series. J Natl Cancer Inst 1999; 91: 368–78.[Abstract/Free Full Text]
  9. Veronesi U, Paganelli G, Galimberti V, et al. Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph nodes. Lancet 1997; 349: 1864–7.[CrossRef][Medline]
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  11. Reynolds C, Mick R, Donohue JH, et al. Sentinel lymph node biopsy with metastasis: can axillary dissection be avoided in some patients with breast cancer? J Clin Oncol 1999; 17: 1720–6.[Abstract/Free Full Text]
  12. Cox CE, Bass SS, McCann CR, et al. Lymphatic mapping and sentinel lymph node biopsy in patients with breast cancer. Annu Rev Med 2000; 51: 525–42.[CrossRef][Medline]
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  15. Kollias J, Gill PG, Chatterton BE, et al. Reliability of sentinel node status in predicting axillary lymph node involvement in breast cancer. Med J Aust 1999; 171: 461–5.[Medline]
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  20. Giuliano AE, Haigh PI, Brennan MB, et al. Prospective observational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel node-negative breast cancer. J Clin Oncol 2000; 18: 2553–9.[Abstract/Free Full Text]
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