Annals of Surgical Oncology Cite Track
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
10.1245/ASO.2006.08.037
Annals of Surgical Oncology 13:985-989 (2006)
© 2006 Society of Surgical Oncology
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Motomura, K.
Right arrow Articles by Inaji, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Motomura, K.
Right arrow Articles by Inaji, H.

Original Article

Three–Axillary Lymph Node Sampling for the Prediction of Nonsentinel Node Metastases in Breast Cancer Patients With Sentinel Node Metastases

Kazuyoshi Motomura, MD1, Chiyomi Egawa, MD1, Yoshifumi Komoike, MD1, Sachiko Nagumo, CT2, Hiroki Koyama, MD1 and Hideo Inaji, MD1

1 Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan
2 Department of Cytology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan

Correspondence: Address correspondence and reprint requests to: Kazuyoshi Motomura, MD; E-mail: motomurak{at}hotmail.com.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: In half of breast cancer patients with positive sentinel nodes, the sentinel nodes are the only metastatic nodes. Such patients have no more metastatic nonsentinel nodes and do not need to undergo axillary lymph node dissection. The purpose of this study was to investigate whether three–axillary lymph node sampling after sentinel node biopsy predicts the status of nonsentinel nodes in patients with sentinel node metastases.

Methods: Sentinel node biopsy was performed with dye and radioisotope. When the sentinel nodes were diagnosed as metastasis positive by using intraoperative imprint cytology, three–axillary lymph node sampling was performed, followed by axillary lymph node dissection.

Results: Of 47 cases with positive imprint cytology, 43 (91%) were diagnosed as metastasis positive on their final histological examination and were analyzed. The status of the sampled nodes was significantly associated with the status of nonsentinel nodes (P <.0001). Six (43%) of 14 patients with positive sampled nodes had at least 1 positive remaining node. Only 2 (7%) of 29 patients whose sampled nodes were negative were found to have additional nodal metastases. The sensitivity, specificity, and accuracy of the sampled nodes for the prediction of nonsentinel node metastases were 87.5%, 100%, and 95.3%, respectively.

Conclusions: We demonstrated that three-node sampling may be useful for predicting the status of nonsentinel nodes and avoiding axillary lymph node dissection in patients with only sentinel node metastases.

Key Words: Sentinel node • Breast cancer • Sentinel node biopsy • Node sampling


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A sentinel node is defined as a node on a direct drainage pathway from a primary tumor.1 Sentinel node biopsy has recently been applied as a less invasive, highly accurate alternative to axillary lymph node dissection for axillary staging in patients with breast cancer.2–7 Hence, if the sentinel nodes do not contain tumor cells, it is not necessary to perform axillary lymph node dissection for such patients.

Moreover, many breast cancer patients with sentinel node metastases do not have further metastatic spread to nonsentinel nodes on axillary lymph node dissection.2,3,5,6 If a subset of patients with metastatic disease limited to the sentinel nodes can be reliably identified, axillary lymph node dissection may not be required in this group. Several efforts have been made to identify such patient subgroups in whom nonsentinel nodes have no metastatic foci and further axillary surgery can be avoided.8–10 Predictive factors for nonsentinel node metastases have been evaluated in meta-analyses, and the size of the sentinel node metastases, extranodal extension, tumor size, number of positive sentinel nodes, and lymphovascular invasion are the candidates most likely to be associated with nonsentinel node metastases.11 Such clinicopathologic features may be able to reliably predict nonsentinel node metastases for safely avoiding axillary lymph node dissection in patients with sentinel node metastases only.

Removal of a few nodes of the lower axillary contents for axillary node staging has been attempted in patients with breast cancer. The Edinburgh group developed a four-node sampling procedure.12,13 In this procedure, at least four nodes were sought by inspection and palpation of the axillary tail and contiguous fat and selected. Four hundred seventeen patients with breast cancer who underwent mastectomy were randomized to axillary sampling or axillary lymph node dissection. The node-positivity rate was the same in the two groups. Distant relapse and survival rates were also similar in the two groups, but there was a minor difference in axillary relapse in favor of axillary lymph node dissection. The role of axillary lymph node sampling as an alternative to sentinel node biopsy remains controversial. However, it may apply to the identification of the patient subgroup in which sentinel nodes are positive but nonsentinel node are negative, and axillary lymph node dissection can be avoided.

This study evaluated the usefulness of axillary lymph node sampling after sentinel node biopsy to predict nonsentinel node metastases in breast cancer patients with sentinel node metastases. The Edinburgh group removed four nodes for axillary lymph node sampling. Because at least one sentinel node had already been removed before sampling, we chose three additional lymph nodes for sampling in this study.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Of 293 consecutive patients with T1 or T2 breast cancers and clinically negative nodes who underwent sentinel node biopsy at Osaka Medical Center for Cancer and Cardiovascular Diseases between May 2001 and May 2004, the patients whose sentinel nodes were diagnosed as positive by intraoperative imprint cytology were enrolled in this study. Patients with multiple primary tumors, nonpalpable breast cancer, prior axillary surgery, or pregnancy were excluded. Written consent was obtained from all patients. The Institutional Review Board of Osaka Medical Center for Cancer and Cardiovascular Diseases approved the study.

Sentinel node biopsy was performed by a single surgeon (K.M.), as described previously.14,15 In brief, intradermal injection of.3 mL of 37 MBq (1 mCi) of 99mTc tin colloid on the day before surgery and peritumoral injection of 5 mL of indocyanine green (Diagnogreen.5%; Daiichi Pharmaceutical Co. Ltd., Nihonbashi, Tokyo) 10 minutes before surgery were performed, and then the injection site was massaged manually. Isosulfan blue dye and patent blue dye, which are used by many investigators in Western countries, are difficult to obtain in Japan.1,2 We showed that the success rate and the accuracy of the sentinel node were 95% and 100%, respectively, by using 99mTc tin colloid and indocyanine green dye in the previous series.14 Lymphoscintigraphy was performed 1 to 2 hours after the radioisotope injection. Breast surgery with wide resection was performed before axillary surgery in all patients to minimize the influence of radioactivity from the injection site. Sentinel nodes were identified by using a gamma probe, Neo2000 (Neoprobe Corporation, Dublin, OH). Any green node and/or any node with an in vivo radioisotope count of at least 10 counts per second was removed. A sentinel node was defined as a green-stained node and/or a node with an ex vivo radioisotope count of ≥2-fold the axillary background.

Imprint cytological samples and pathologic specimens were made as previously described.14–16 Sentinel nodes were serially sectioned at 2-mm intervals. Imprint cytological samples were made from all the cut surfaces by touching them to a glass slide and were immediately fixed in 95% ethanol. Slides were subjected to a Papanicolaou stain. The diagnostic categories routinely used for cytology were negative, suspicious, and malignant, but suspicious results were regarded as negative to help prevent false-positive results in this study.16 When sentinel nodes were diagnosed as metastasis positive by using intraoperative imprint cytology, the skin incision was extended between the latissimus dorsi and pectoralis muscles, and three–axillary lymph node sampling was performed, followed by axillary lymph node dissection. Three sampled nodes were identified by inspection and palpation and removed. Ex vivo counts of the sampled nodes were also measured to make sure that they were not sentinel nodes. Sampled nodes were serially sectioned at 2-mm intervals. Imprint cytological evaluation was also performed for the three sampled nodes and was compared with the final histological results.

Sentinel nodes, sampled nodes, and axillary lymph node dissection specimens were submitted separately to pathologic examination. Hematoxylin and eosin (H&E) sections of sentinel nodes and sampled nodes were prepared from each 2-mm slice. One level of remaining nodes obtained from axillary lymph node dissection was examined by using H&E staining. When these nodes were tumor negative in paraffin sections, an additional 4 µm of the section was cut and stained with immunohistochemical (IHC) stain by using the avidin-biotinylated peroxidase complex technique with mouse monoclonal antibody against cytokeratin (NCL-CK19; Novocastra Laboratories Ltd., Newcastle, UK). Nodes with isolated tumor cells alone identified by IHC were considered to be metastasis negative in this study, according to the tumor node metastasis categories defined in the 6th edition of the International Union Against Cancer tumor-node-metastasis categories.17

The association between the status of the three sampled nodes or the clinicopathologic features, including patient age, tumor size, number of sentinel nodes, size of sentinel node metastases, number of positive sentinel nodes, presence of lymphovascular invasion, and the histological grade of the tumor,18 and nonsentinel node metastases was investigated.

Fisher’s exact test was used for the statistical analysis. Differences were considered to be significant when P <.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Of 47 patients with positive imprint cytology, 43 (91%) were classified as being metastasis positive on the final histological examination by using H&E and were analyzed in this study. Twenty-seven (62.8%) of the patients had involvement only of the sentinel node. The mean age of the 43 patients was 52 years (range, 30–75 years), and the mean tumor size was 18 mm (range, 8–28 mm). The mean number of sentinel nodes was 2.4 (range, 1–7), and the mean number of nonsentinel nodes, including sampled nodes, was 13.7 (range, 5–30). The mean size of the sentinel nodes was 10.5 mm (range, 4–40 mm), and the mean size of the sampled nodes was 8.5 mm (range, 5–24 mm). The mean number of slices of sentinel nodes was 6.9 (range, 1–20), and the mean number of slices of sampled nodes was 4.9 (range, 1–14).

The status of the sampled nodes was significantly associated with the status of the nonsentinel nodes (P <.0001; Table 1Go). Thirteen patients had at least one positive sampled node by using H&E stain, and an additional patient had positive sampled nodes with micrometastases by using IHC. Six of these patients had at least one positive remaining node, and seven patients had a negative remaining node with H&E. One additional patient had a positive sampled node with micrometastases and negative remaining nodes with IHC. Twenty-nine patients had no meta-static sampled nodes. Two had metastatic foci in the remaining nodes. Both the sentinel node and the remaining node metastases were micrometastases, as identified by H&E in one of the two patients and macrometastases in another patient. There was no patient with an H&E-negative and IHC-positive remaining node. The sensitivity, specificity, and accuracy of the sampled nodes for the prediction of nonsentinel node metastases were 87.5%, 100%, and 95.3%, respectively. The negative predictive value and positive predictive value for predicting the status of remaining nodes were 93.1% and 42.9%, respectively.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Comparison of the status of sampled nodes and remaining nodes
 
Of 14 patients with positive sampled nodes, nonsentinel node metastases were diagnosed by the first removed sampled nodes in 6 patients, by the second removed node in 3 patients, and by the third removed node in 5 patients. The patient age, tumor size, number of sentinel nodes, size of sentinel node metastases, number of positive sentinel nodes, presence of lymphovascular invasion, and histological grade of the tumor were not related to the nonsentinel node metastases (Table 2Go).


View this table:
[in this window]
[in a new window]
  		TABLE 2. Clinicopathologic features and nonsentinel node metastases
 
When the cytological data were evaluated, 14 patients had at least 1 positive sampled node in the paraffin sections. In 12 of these patients, imprint cytology of at least 1 sampled node was positive. In 1 of 29 patients with tumor-negative sampled nodes in paraffin sections, the imprint cytology of at least 1 sampled node was positive. The sensitivity, specificity, and accuracy of imprint cytology for sampled nodes were 85.7%, 96.5%, and 93.0%, respectively (Table 3Go).


View this table:
[in this window]
[in a new window]
  		TABLE 3. Comparison of the results of imprint cytology of sampled nodes with the final histopathologic diagnosis
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Attempts have been made to identify factors that can predict non–sentinel node metastases in patients with positive sentinel nodes. Chu et al.8 demonstrated that no patient with a T1a lesion and sentinel node metastases and only 6% of patients with T1/2 tumors and sentinel node micrometastasis had non–sentinel node metastasis. Reynolds et al.9 showed that none of the 18 patients with T1 tumors and micrometastasis to the sentinel node had remaining axillary lymph node involvement. Viale et al.10 showed that the size of the sentinel node metastasis was correlated with the frequency of nonsentinel node metastases and that only the subset of patients with a micrometastasis ≤1 mm might be able to avoid axillary lymph node dissection. Recent meta-analyses reported the five characteristics—the size of the sentinel node metastasis, extranodal extension in the sentinel node, tumor size, number of positive sentinel nodes, and lymphovascular invasion—that are strongly associated with non–sentinel node metastases.11 Other meta-analyses demonstrated that an estimated 20% of patients with sentinel node micrometastases had nonsentinel node metastases; whereas if the estimated proportion of nonsentinel node metastasis is approximately 9% sentinel node metastasis is detected by IHC alone.19

In this study, the status of three sampled nodes was significantly associated with the status of the nonsentinel nodes (P <.0001). In particular, the negative predictive value of three-node sampling for the status of the remaining nodes was high (93.1%). We also demonstrated that intraoperative imprint cytology can accurately identify the sampled node metastases. We previously showed that imprint cytology is a useful method for evaluating the status of the sentinel node and, thus, for making a decision regarding axillary lymph node dissection during surgery.16 Imprint cytology of the sentinel node was falsely positive in 4 (8.5%) of 47 patients in this study. However, positive imprint cytology with negative results on paraffin sections may be valid because we demonstrated that imprint cytology could detect micrometastases more precisely than final paraffin sections evaluated by H&E staining in the previous study. 16 Although the above-mentioned researchers demonstrated that the size of sentinel node metastases was a good predictor of nonsentinel node metastases, the results were mainly identified after surgery. Three-node sampling enables the identification of nonsentinel node metastases during surgery and the avoidance of a second operation. Moreover, if the sentinel node contains macrometastatic foci, even if the remaining nodes contain no metastases, axillary lymph node dissection will be performed because the clinicopathologic features cannot identify such a subgroup. Three-node sampling can identify this subgroup and avoid blind axillary lymph node dissection. In this study, 33 of 43 patients with positive sentinel nodes had sentinel node macrometastases, and 10 had micrometastases only. Of the 33 patients with sentinel node macrometastases, 21 had no sampled node metastases and nonsentinel node metastases and may have been able to avoid axillary lymph node dissection by 3-node sampling. Of 10 patients with sentinel node micrometastases, 4 had non–sentinel node metastases, and all of the metastases were macrometastases. Several articles have pointed out that large nonsentinel node metastases have been found in patients with sentinel node micrometastases only and that the incidence of non–sentinel node metastases may have been underestimated when examination was performed without serial sectioning and IHC.10,20 Three-node sampling can identify non–sentinel node macrometastases that the clinicopathologic features cannot identify in patients with sentinel node micrometastases. Most studies have found that the size of the sentinel node metastases is an independent predictor of non–sentinel node metastases.8–11,19 However, there is disagreement as to the effect of tumor size, extranodal extension of the sentinel node, and lymphovascular invasion.21–24

In our study, the tumor size, number of sentinel nodes, size of sentinel node metastases, number of positive sentinel nodes, presence of lymphovascular invasion, and histological grade of the tumor were all not related to the non–sentinel node metastases. These conflicting data could be likely due to the small sample population in these studies. Moreover, sampled nodes were serially sectioned at 2-mm intervals and examined in this study. Non–sentinel node metastases were found only in the sampled nodes of nonsentinel nodes in three of four patients with sentinel node micrometastases and nonsentinel node metastases. They could be in part a result of the different methods used for identifying non–sentinel node metastases.

The excision of 3 lymph nodes seems to be adequate because non–sentinel node metastases were diagnosed in 8 (57%) of 14 patients with sampled nodes by the second or third removed node. Whether further removal of the axillary lymph node is required is unknown. Moreover, it will be necessary to evaluate whether three-node sampling has a higher or lower incidence of complications and morbidities associated with surgery compared with sentinel node biopsy alone or axillary lymph node dissection in a future prospective clinical trial.

In summary, the status of the sampled nodes was significantly associated with the status of the nonsentinel nodes; therefore, three-node sampling may be useful for predicting nonsentinel node metastases in breast cancer patients with sentinel node metastases. Intraoperative imprint cytological examination may accurately detect metastases in the sampled nodes and avoid a second operation.

Received for publication August 30, 2005. Accepted for publication January 24, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Nieweg OE, Tanis PJ, Kroon BB. The definition of a sentinel node. Ann Surg Oncol 2001; 8:538–41.[Free Full Text]
  2. Giuliano AE, Kirgan DM, Guenther JM, et al. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994; 220:391–401.[Medline]
  3. Giuliano AE, Jones RC, Brennan M, et al. Sentinel lymphadenectomy in breast cancer. J Clin Oncol 1997; 15:2345–50.[Abstract/Free Full Text]
  4. Krag DN, Weaver DL, Alex JC, et al. Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surg Oncol 1993; 2:335–9.[CrossRef][Medline]
  5. 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]
  6. Albertini JJ, Lyman GH, Cox CE, et al. Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 1996; 276:1818–22.[Abstract]
  7. Cox CE, Pendas S, Cox JM, et al. Guidelines for sentinel node biopsy and lymphatic mapping of patients with breast cancer. Ann Surg 1998; 227:645–53.[CrossRef][Medline]
  8. Chu KU, Turner RR, Hansen NM, et al. Do all patients with sentinel node metastasis from breast carcinoma need complete axillary node dissection? Ann Surg 1999; 229:536–41.[CrossRef][Medline]
  9. 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]
  10. Viale G, Maiorano E, Mazzarol G, et al. Histologic detection and clinical implications of micrometastases in axillary sentinel lymph nodes for patients with breast carcinoma. Cancer 2001; 92:1378–84.[CrossRef][Medline]
  11. Degnim AC, Griffith KA, Sabel MS, et al. Clinicopathologic features of metastasis in nonsentinel lymph nodes of breast carcinoma patients. Cancer 2003; 98:2307–15.[CrossRef][Medline]
  12. Steele RJ, Forrest AP, Gibson T, et al. The efficacy of lower axillary sampling in obtaining lymph node status in breast cancer: a controlled randomized trial. Br J Surg 1985; 72:368–9.[Medline]
  13. Forrest AP, Everington D, McDonald CC, et al. The Edinburgh randomized trial of axillary sampling or clearance after mastectomy. Br J Surg 1995; 82:1504–8.[Medline]
  14. Motomura K, Inaji H, Komoike Y, et al. Combination technique is superior to dye alone in identification of the sentinel node in breast cancer patients. J Surg Oncol 2001; 76:95–9.[CrossRef][Medline]
  15. Motomura K, Komoike Y, Hasegawa Y, et al. Intradermal radioisotope injection is superior to subdermal injection for the identification of the sentinel node in breast cancer patients. J Surg Oncol 2003; 82:91–6.[CrossRef][Medline]
  16. Motomura K, Inaji H, Komoike Y, et al. Intraoperative sentinel lymph node examination by imprint cytology and frozen sectioning during breast surgery. Br J Surg 2000; 87:597–601.[CrossRef][Medline]
  17. American Joint Committee on Cancer. Breast. In: Greene FL, Page DL, Fleming ID, et al., (eds). AJCC Cancer Staging Handbook. 6th ed. New York: Springer, 2002:155–81.
  18. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 1991; 19:403–10.[Medline]
  19. Cserni G, Gregori D, Merletti F, et al. Meta-analysis of nonsentinel node metastases associated with micrometastatic sentinel nodes in breast cancer. Br J Surg 2004; 91:1245–52.[CrossRef][Medline]
  20. den Bakker MA, van Weeszenberg A, de Kanter AY, et al. Non-sentinel lymph node involvement in patients with breast cancer and sentinel node micrometastasis; too early to abandon axillary clearance. J Clin Pathol 2002; 55:932–5.[Abstract/Free Full Text]
  21. Rahusen FD, Torrenga H, van Diest PJ, et al. Predictive factors for metastatic involvement of nonsentinel nodes in patients with breast cancer. Arch Surg 2001; 136:1059–63.[Abstract/Free Full Text]
  22. Hwang RF, Krishnamurthy S, Hunt KK, et al. Clinicopathologic factors predicting involvement of nonsentinel axillary nodes in women with breast cancer. Ann Surg Oncol 2003; 10:248–54.[Abstract/Free Full Text]
  23. Morrow M. Is axillary dissection necessary after positive sentinel node biopsy? Yes! Ann Surg Oncol 2001; 8:74S–76S.
  24. Viale G, Maiorano E, Pruneri G, et al. Predicting the risk for additional axillary metastases in patients with breast carcinoma and positive sentinel lymph node biopsy. Ann Surg 2005; 241:319–25.[CrossRef][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Motomura, K.
Right arrow Articles by Inaji, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Motomura, K.
Right arrow Articles by Inaji, H.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS