Sentinel Node Biopsy in Breast Cancer Patients with Large or Multifocal Tumors

  • Tuomo J. Meretoja
  • Marjut H. Leidenius
  • Päivi S. Heikkilä
  • Heikki Joensuu
Breast Oncology

Abstract

Background

The axillary recurrence (AR) rate after negative sentinel node biopsy (SNB) in patients with high risk of axillary metastases is largely unknown. The aim of this study was to analyze the risk factors for isolated AR after negative SNB with special interest in large or multifocal tumors.

Methods

A prospective SNB registry was analyzed for 2,408 invasive breast cancer patients operated between 2001 and 2007. No axillary clearance was performed in 1,309 cases with a negative SNB, including 1,138 small unifocal tumors, 121 small multifocal tumors, 48 large unifocal tumors, and 2 large multifocal tumors.

Results

Six (0.5%) isolated AR were observed during a median follow-up of 43 months. Four (0.4%) patients with small unifocal tumors and two (1.6%) with small multifocal tumors had isolated AR (p = 0.179). None of the patients with large unifocal or multifocal tumors had isolated AR. Instead of tumor size and multifocality, estrogen receptor negativity (p < 0.001), nuclear grade III (p < 0.001), Her-2 status (p = 0.002), no radiotherapy (p = 0.005), and mastectomy (p = 0.005) were found to be associated with AR.

Conclusions

A remarkable proportion of patients with large unifocal tumors and small multifocal tumors may avoid unnecessary AC due to tumor negative SNB, without an excessive risk of AR.

Sentinel node biopsy (SNB) has largely replaced diagnostic axillary clearance (AC) in nodal staging in breast cancer. According to a meta-analysis, the false-negative rate in SNB has been approximately 8%.1 Axillary recurrence (AR) rates after sole SNB have been lower than expected on the basis of the reported false-negative rates, ranging from 0% to 3.6% during short- or medium-term follow-up.2, 3, 4 Encouraged by this low axillary recurrence rate, many centers have extended the indications for SNB and perform it on most breast cancer patients without verified axillary metastases.5,6

However, patients included in studies evaluating AR or survival after SNB have been mainly those with unifocal, T1 or small T2 tumors. The AR rate after negative SNB in patients with high risk of axillary metastases is largely unknown. In general, the risk factors for AR after negative SNB have not been studied extensively, most probably due to the rarity of the event during a short or medium time of follow-up.

As regards false-negative SNB results, the reported risk factors in large patient series have included factors such as a high tumor grade and a single SN harvested.3,7,8 The false-negative rates have been similar in patients with small and large tumors, but varied between 0% and 31% in patients with multifocal tumors.9, 10, 11, 12, 13, 14, 15, 16, 17 The risk that nodal metastases remain undetected when using SNB increases with the increasing prevalence of nodal metastases.18 The prevalence of axillary metastases not only increases with increasing tumor size, but has been reported to be especially high in patients with multifocal tumors.19 Rather few patients with a high prevalence of axillary metastases will avoid AC, and a remarkable proportion of them may have residual disease in the axilla.19

For these reasons, our aim was to evaluate the outcome of SNB in patients with large and multifocal tumors, especially the AR rate after negative SNB.

Patients and Methods

Altogether 2,408 patients with invasive breast cancer underwent SNB between February 2001 and July 2007 at the Breast Surgery Unit of Helsinki University Central Hospital. SNB was performed in patients with clinically node-negative, radiologically unifocal tumors with tumor size not exceeding 30 mm on breast ultrasonography.

The patients were divided into four subgroups according to the histological size and focality of the tumor: (1) small (≤30 mm) unifocal tumors (n = 1,924), (2) large (>30 mm) unifocal tumors (n = 142), (3) small (≤30 mm) multifocal tumors (n = 310), and (4) large (>30 mm) multifocal tumors (n = 32). No distinction between multifocal and multicentric tumors was made. Patient and tumor characteristics in the four subgroups are presented in Table 1.
Table 1

Patient and tumor characteristics

 

Small unifocal tumor (n = 1,924)

Large unifocal tumor (= 142)

Small multifocal tumor (n = 310)

Large multifocal tumor (n = 32)

Age, mean (range), years

60 (25–95)

59 (33–87)

60 (30–89)

55 (31–95)

Mean tumor diameter (range), mm

15 (1–30)

44 (31–140)

16 (1–30)

43 (31–70)

Tumor grade

I

603 (31%)

32 (23%)

70 (23%)

7 (22%)

II

828 (43%)

65 (46%)

155 (50%)

18 (56%)

III

470 (24%)

44 (31%)

82 (26%)

7 (22%)

Unknown

22 (1%)

1 (1%)

3 (1%)

0

Type

Ductal carcinoma

1152 (60%)

46 (32%)

146 (47%)

8 (25%)

Lobular carcinoma

366 (19%)

80 (56%)

96 (31%)

22 (69%)

Other

406 (21%)

16 (11%)

68 (22%)

2 (6%)

Estrogen receptor status

Positive

1667 (87%)

121 (85%)

267 (87%)

30 (94%)

Negative

243 (13%)

21 (15%)

42 (13%)

2 (6%)

Unknown

14 (1%)

0

1 (0%)

0

Progesterone receptor status

Positive

1268 (66%)

84 (59%)

206 (66%)

21 (66%)

Negative

640 (33%)

58 (41%)

103 (33%)

11 (34%)

Unknown

14 (1%)

0

1 (0%)

0

Her-2 status

Positive

149 (8%)

12 (8%)

29 (9%)

3 (9%)

Negative

1534 (80%)

116 (82%)

241 (78%)

29 (91%)

Unknown

241 (12%)

14 (10%)

40 (13%)

0

Palpable

Yes

1318 (69%)

120 (85%)

230 (74%)

27 (84%)

No

606 (31%)

22 (15%)

80 (26%)

5 (16%)

The outcome of SNB was analyzed to evaluate the proportion of patients with tumor-positive sentinel nodes (SN) and the axillary clearance (AC) rate in these four subgroups. The AR rate as well as the risk factors for AR were then evaluated in patients with tumor-negative SNB without AC.

The project plan was approved by the Ethical Committee of Helsinki University Central Hospital. Written informed consent was obtained from all patients.

Surgery

The patients underwent either wide local excision or mastectomy. For SNB, preoperative lymphoscintigraphy and intraoperative identification with a gamma probe and blue dye were used as described in detail in our previous report.19

Level I–II axillary clearance (AC) was generally performed in all patients with tumor-positive sentinel node (SN) findings, and also in patients with micrometastases or isolated tumor cells (ITC).20, 21, 22, 23 AC was, however, omitted in four patients with SN macrometastasis due to severe comorbidity, and in 24 patients with micrometastases or ITC due to surgeon or patient preference. Furthermore, level I–II AC was performed in 79 patients with unsuccessful SN identification, as well as in 22 patients with tumor-negative SN findings due to surgeon or patient preference.

Histopathology

The histological classification and tumor staging and grading was based on the World Health Organization (WHO) classification of tumors.24 The following data was evaluated by specialized breast pathologists: histological tumor size (largest diameter), multifocality, histological type, tumor grade, hormone receptor status, Her-2 oncogene amplification status, and proliferation index MIB-1. Hormone receptor status and MIB-1 were assessed using immunohistochemistry. Her-2 status was assessed using immunohistochemistry, and when positive, using chromogen in situ hybridization.

SN were sent to the pathology laboratory as separate samples. The fresh specimens were cleaned from all extracapsular fat tissue, measured, sliced into 1–1.5-mm-thick sections perpendicular to their long axis, and arranged on pre-frozen Tissue-Tek® OCTTM compound. Touch preparations from the surface and frozen sections from two levels were made from these slices; these were then stained with toluidine blue and viewed.

From January 2003, rapid intraoperative immunohistochemistry was available and applied. From 21 January 2003 Cam 5.2 was used. From 1 July 2003 a quicker method with Cyto-nel Ultrapid IHC (Immuno Diagnostics Oy, Hämeenlinna, Finland) was introduced. Malignancy was reported to the operating room as soon as it was detected.

The remaining tissue was fixed in formalin, and embedded in paraffin. Two sections were stained with hematoxylin and eosin (H&E). When a metastasis 2 mm or larger was found in frozen-section procedure, only H&E sections were made from paraffin-embedded tissue. If no metastatic tissue was detected, or isolated tumor cells (ITC) or a micrometastasis was found only, a Cam 5.2 immunostain (Becton Dickinson Immunocytometry Systems, San Jose, CA, USA) was performed on paraffin-embedded tissue in addition to the regular H&E sections. Lymph nodes in the axillary clearance specimens were wholly embedded in paraffin. H&E sections were prepared from two levels, 200 μm apart. The tumor deposits were classified as micrometastases when not larger than 2 mm, and as isolated tumor cells (ITC) when not larger than 0.2 mm.24

Adjuvant Treatment

The patients received radiotherapy and systemic adjuvant treatment according to the guidelines of the Department of Oncology of Helsinki University Central Hospital. The local and systemic treatment of the SNB-negative patients without AC is presented in Table 2.
Table 2

Local and systemic treatment in the 1,309 tumor-negative sentinel node biopsy patients without axillary clearance

 

Small unifocal tumors (n = 1,138)

Large unifocal tumor (n = 48)

Small multifocal tumor (n = 121)

Large multifocal tumor (n = 2)

Breast surgery

Breast-conserving surgery

903 (79%)

21 (44%)

52 (43%)

1 (50%)

Mastectomy

235 (21%)

27 (56%)

69 (57%)

1 (50%)

Radiotherapy

No

261 (23%)

15 (31%)

63 (52%)

1 (50%)

Breast or thoracic wall only

855 (75%)

32 (67%)

55 (46%)

1 (50%)

Breast or thoracic wall and regional lymph nodes

22 (2%)

1 (2%)

3 (2%)

0

Systemic adjuvant therapy

No

472 (41%)

4 (8%)

36 (30%)

0

Endocrine only

456 (40%)

21 (44%)

56 (46%)

1 (50%)

Chemotherapy only

72 (6%)

2 (4%)

9 (7%)

0

Endocrine and chemotherapy

115 (10%)

21 (44%)

16 (13%)

1 (50%)

Chemotherapy and trastuzumab, with or without endocrine therapy

23 (2%)

0

4 (4%)

0

Follow-Up

Planned follow-up visits took place at 1, 3, and 5 years after breast surgery. Physical examination, blood cell counts and blood chemistry, and bilateral mammography were performed at these visits. Breast and axillary ultrasound, bone scan or computed tomography was performed, when necessary. All study participants had access for extra visits at the Department of Oncology whenever there was concern of breast cancer recurrence. After 5 years, follow-up continued at health centre or private clinic, according to patient preference.

Statistical Methods

Univariate analysis was performed first to determine factors associated with isolated axillary recurrences. Of special interest were effects of multifocality and tumor size on axillary recurrence rate. Chi-squared test and Fisher’s exact test were used for categorical variables and Mann–Whitney U-test was performed for continuous variables. SPSS 16.0 program was used to perform the analyses. Multivariate analysis was not performed due to the very small number of events.

Results

Outcome of SNB

Altogether 959 patients underwent AC due to tumor-positive SN findings. Of these patients 116 had ITC only, 244 had micrometastasis, and 599 had macrometastasis in their SN. In addition, 79 patients had AC due to unsuccessful SNB, 30 of them with and 49 without nodal metastases in the consequent AC. Moreover, 22 patients had AC due to patient or doctor preference despite negative SNB. Eleven of them had multifocal tumors and two had a tumor larger than 30 mm in diameter. Nodal metastases were not found in any of these 22 AC specimens. AC was omitted in 28 patients with tumor-positive SNB due to patient or doctor preference (Table 3).
Table 3

Outcome of sentinel node biopsy in the 2,408 breast cancer patients

Axillary surgery

Small unifocal tumor (n = 1,924)

Large unifocal tumor (n = 142)

Small multifocal tumor (n = 310)

Large multifocal tumor (n = 32)

Sentinel node biopsy only

N0i−

1145

48

122

2

N0i+

7

1

3

0

N1mic

10

1

2

0

N1

2

0

2

0

Sentinel node biopsy and axillary clearance

N1i+

86

7

21

3

N1mic

190

13

36

5

N1–N2

411

66

104

20

Sentinel node biopsy N0 but axillary clearance

N0i−

9

2

11

0

Axillary clearance due to failed sentinel node biopsy

N0a

46

0

3

0

N1–N2

18

4

6

2

Total Nodal status

N0i− or N0*

1200 (62.4%)

50 (35.2%)

136 (43.9%)

2 (6.2%)

N1i+

93 (4.8%)

8 (5.6%)

24 (7.7%)

3 (9.4%)

N1mic

200 (10.4%)

14 (9.9%)

38 (12.3%)

5 (15.6%)

N1–N2

431 (22.4%)

70 (49.3%)

112 (36.1%)

22 (68.8%)

aN0 node negative in axillary clearance after unsuccessful sentinel node biopsy

Only 6% of patients with large multifocal tumors were axillary node negative on either SNB or AC. Thirty-five percent of patients with large unifocal tumors, 44% of those with small multifocal tumors, and 62% of those with small unifocal tumors were axillary node negative on SNB or AC (Table 3).

Follow-Up of Node-Negative SNB Patients Without AC

AC was omitted in 1,317 patients with negative SNB. Seven patients were lost to follow-up. One patient died immediately after surgery. The AR rate was evaluated in the remaining 1,309 patients. Altogether, 171 of them had large or multifocal tumors. The median duration of follow-up in these 1,309 patients was 43 months (range 1–86 months).

Altogether six (0.5%) isolated AR were observed a median of 33 months (range 2–47 months) after surgery. Four additional patients had AR concomitantly with local recurrence. The events observed during the follow-up are presented in detail in Table 4.
Table 4

Events observed during the follow-up in the 1,309 patients with negative sentinel node biopsy patients without axillary clearance

Event

Small unifocal tumors (n = 1,138)

Large unifocal tumor (n = 48)

Small multifocal tumor (n = 121)

Large multifocal tumor (n = 2)

Recurrence

    Breast or thoracic wall only

7

0

1

0

    Axilla only

4

0

2

0

    Breast or thoracic wall and axilla

3

0

1

0

    Contralateral breast only

9

1

2

0

    Distant metastases

23

2

3

0

Death due breast cancer

11

0

2

0

Died from other causes

18

2

4

1

One patient with isolated AR and a small multifocal tumor developed another AR 6 months after salvation AC and later developed distant metastases and died of breast cancer. Another patient with small unifocal tumor and isolated AR developed distant metastases 4 months after AC. The remaining patients with distant metastases had their recurrence without prior or concomitant local or regional recurrences. Furthermore, the four remaining patients with isolated AR have been disease free since the salvation AC.

Factors Affecting Isolated AR After Tumor-Negative SNB Without AC

Four (0.4%) of the 1,138 patients with small unifocal tumors and 2 (1.6%) of the 121 patients with small multifocal tumors had isolated AR (p = 0.179). None of the 50 patients with large unifocal or multifocal tumors had isolated AR. There was no statistically significant difference in the isolated AR rate when comparing patients with small unifocal tumors with patients with either large or multifocal tumors (p = 0.179) or when comparing all unifocal tumors with all multifocal tumors (p = 0.102).

The statistically significant risk factors for isolated AR were Her-2 positivity (p = 0.008), estrogen receptor negativity (p = 0.044), high tumor grade (p = 0.033), no radiotherapy (p = 0.005), and mastectomy as the breast operation (p = 0.005) (Table 5).
Table 5

The risk factors for isolated axillary recurrences in the 1,309 tumor-negative sentinel node biopsy patients without axillary clearance

 

No axillary recurrence (n = 1,303)

Isolated axillary recurrence (n = 6)

p

Small unifocal tumor

Large or multifocal tumor

1,134

169

4

2

0.179 NS

Unifocal tumor

Multifocal tumor

1,182

121

4

2

0.102 NS

Her-2 negative

Her-2 positive

1,030

87

3

3

0.008

Impalpable tumor

Palpable tumor

469

833

1

5

0.429 NS

Estrogen receptor negative

Estrogen receptor positive

187

1,105

3

3

0.044

Progesterone receptor negative

Progesterone receptor positive

477

815

4

2

0.202 NS

MIB negative

MIB positive

119

677

0

4

1.00 NS

Grade I or II

Grade III

979

307

2

4

0.033

Ductal carcinoma

Lobular carcinoma

Other histological type

747

262

293

5

1

0

0.352 NS

No adjuvant therapy

Only hormonal therapy

Chemotherapy with or without other adjuvant

509

531

261

2

3

1

0.901 NS

No radiotherapy

Radiotherapy

335

967

5

1

0.005

Breast-conserving surgery

Mastectomy

976

327

1

5

0.005

Age (years)

  

0.627 NS

    Mean

60.5

62.7

 

    Range

25–92

36–83

 

    SD

11.9

17.5

 

Number of sentinel nodes

  

0.190 NS

    Mean

2.5

3.8

 

    Median

2

4

 

    Range

1–14

1–7

 

    SD

1.7

2.6

 

Follow-up time (months)

  

0.066 NS

    Mean

43

59

 

    Range

1–86

35–81

 

    SD

21.1

18.2

 

Diameter of tumor (mm)

  

0.999 NS

    Mean

15

14

 

    Range

1–130

2–22

 

    SD

8.6

7.1

 

SD standard deviation, NS not significant

Discussion

The 0.5% AR rate observed in the present study is well comparable with the existing literature. A recent meta-analysis with 48 studies reports an AR rate of 0.3% after tumor-negative SNB.25 In this meta-analysis, the AR rate varied between 0% and 3.6% in the individual studies.2,4

In the present study, neither the size nor multifocality of the tumor were associated with AR after negative SNB. No AR after negative SNB were observed even in patients with multifocal tumors with histological size of the index tumors exceeding 30 mm. However, only 2 of the 32 patients with a large multifocal tumor avoided AC due to tumor-negative SNB. Therefore SNB does not seem sensible in these patients. Furthermore, an increased AR risk in this patient group cannot be excluded by a follow-up of just two patients.

Almost one-half of our patients with small multifocal and one-third of patients with large unifocal tumors avoided AC due to tumor-negative SNB. The proportion of patients avoiding AC would have been even higher had AC been omitted in patients with ITC only. Moreover, the prevalence of axillary metastases among patients undergoing SNB can be reduced by preoperative axillary ultrasound.26 Unlike the last study years, preoperative axillary ultrasound was not routinely performed at our unit at the beginning of the study. Accordingly, the prevalence of tumor positive SN findings decreased during the study years. Especially the prevalence of macrometastases decreased, being 48% during the first two years and 38% during the last two years of the study (data not shown).

Instead of tumor size and multifocality, the significant risk factors for isolated AR included Her-2 positivity, high tumor grade, and estrogen receptor negativity. These are all features of biological aggressiveness. Furthermore, only 27 of our 90 Her-2-positive study patients with negative SNB received trastuzumab. Nevertheless, the AR risk seems emphasized in patients with biologically aggressive tumors, at least during a short or medium duration of follow-up.

In a series of 2,246 SNB negative patients and median follow-up of 37 months, Bergkvist et al. showed large tumor diameter, estrogen and progesterone receptor negativity, and high tumor grade to be significant prognostic factors for AR after negative SNB in a univariate model, but only high tumor grade on multivariate analysis.3 Bergkvist et al. did not, however, include Her-2 receptor status, radiotherapy or type of breast operation as variables in their study.3

Goyal et al. reported that the high tumor grade increases the false-negative rate of SNB, which is in agreement with the high AR rate observed by previous studies as well as the present study.3,7,27,28 The increased AR rate in patients with negative SNB and high tumor grade could be argued to derive from the increased false-negative rate together with the rapid proliferation rate of these tumors leading to earlier recurrences when compared with the lower-grade tumors. However, long-time follow-up data after negative SNB may reveal AR also in patients with less aggressive tumors.

Mastectomy instead of breast conservation and no radiotherapy were also associated with isolated AR. This finding is in agreement with a recent study by Wely et al.27 The vast majority of our study patients received full breast radiotherapy after breast-conserving surgery, while rather few patients with negative SNB received postmastectomy radiotherapy. The tangential radiation field frequently overlaps the lower part of the axilla, which may contribute to the lower AR rate in patients after breast conservation. Furthermore, patients with mastectomy had not only larger, but also biologically more aggressive, tumors than those with breast conservation (data not shown). Clustering of these high-risk factors together with the absence of radiotherapy most probably account for the increased AR rate in patients with mastectomy.

Two previous studies have shown that number of SN removed during SNB affects the false-negative rate of SNB.7,8 However, in the present study number of removed SN did not affect the risk of AR. In fact, number of SN harvested seemed higher in patients with isolated AR, although the difference from the patients without AR was not statistically significant. In some patients with AR, the actual heavily involved SN may have remained undetected due to diversion of lymphatic drainage to the uninvolved secondary echelon nodes. The occurrence of such event is reduced by careful palpation of the open axilla and removal of clinically suspicious nonsentinel nodes, which are included in our SNB protocol.

The major flaw of the present study lies in the study setting. Only patients with a large tumor size or multifocality revealed in the histopathological evaluation of the surgical specimen were included, not those with large or multifocal tumors in the preoperative diagnosis. These patients underwent AC without preceding SNB. Therefore, patients with invasive lobular cancer were overrepresented among patients with large and multifocal tumors. It is noteworthy that breast magnetic resonance imaging (MRI) was not routinely used in the preoperative staging in our study patients, not even in patients with invasive lobular cancer. Nevertheless, it remains unclear whether our results can be generalized in a patient population including all patients with large or multifocal tumors without axillary metastases in the preoperative diagnosis.

Conclusion

Estrogen receptor negativity, Her-2 positivity, and high nuclear grade, but not large tumor size or multifocality, seem to be risk factors for isolated AR. A remarkable proportion of patients with large unifocal tumors and small multifocal tumors may avoid unnecessary AC due to tumor-negative SNB, without an excessive risk of AR. On the other hand, AC without preceding SNB appears to be justified in patients with large, multifocal tumors due to the extremely high prevalence of axillary metastases. However, the findings of the present study remain to be confirmed by further studies.

References

  1. 1.
    Kim T, Giuliano AE, Lyman GH. Lymphatic mapping and sentinel lymph node biopsy in early-stage breast carcinoma: a metaanalysis. Cancer. 2006;106(1):4–16.PubMedCrossRefGoogle Scholar
  2. 2.
    Zavagno G, Carcoforo P, Franchini Z, et al. Axillary recurrence after negative sentinel lymph node biopsy without axillary dissection: a study on 479 breast cancer patients. Eur J Surg Oncol. 2005;31(7):715–20.PubMedCrossRefGoogle Scholar
  3. 3.
    Bergkvist L, de Boniface J, Jonsson PE, Ingvar C, Liljegren G, Frisell J. Axillary recurrence rate after negative sentinel node biopsy in breast cancer: three-year follow-up of the Swedish Multicenter Cohort Study. Ann Surg. 2008;247(1):150–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Imoto S, Wada N, Murakami K, Hasebe T, Ochiai A, Ebihara S. Prognosis of breast cancer patients treated with sentinel node biopsy in Japan. Jpn J Clin Oncol. 2004;34(8):452–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Cody HS, III. Sentinel lymph node biopsy for breast cancer: does anybody not need one? Ann Surg Oncol. 2003;10(10):1131–2.PubMedCrossRefGoogle Scholar
  6. 6.
    Costa A, Zurrida S, Gatti G, et al. Less aggressive surgery and radiotherapy is the way forward. Curr Opin Oncol. 2004;16(6):523–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Goyal A, Newcombe R, Chhabra A, Mansel R. Factors affecting failed localisation and false-negative rates of sentinel node biopsy in breast cancer–results of the ALMANAC validation phase. Breast Cancer Res Treat. 2006;99(2):203–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Krag D, Anderson S, Julian T, et al. Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial. Lancet Oncol. 2007;8(10):881–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Schule J, Frisell J, Ingvar C, Bergkvist L. Sentinel node biopsy for breast cancer larger than 3 cm in diameter. Br J Surg. 2007;94(8):948–51.PubMedCrossRefGoogle Scholar
  10. 10.
    Olson JJ, Fey J, Winawer J, et al. Sentinel lymphadenectomy accurately predicts nodal status in T2 breast cancer. J Am Coll Surg. 2000;191(6):593–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Bedrosian I, Reynolds C, Mick R, et al. Accuracy of sentinel lymph node biopsy in patients with large primary breast tumors. Cancer. 2000;88(11):2540–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Wong S, Chao C, Edwards M, et al. Accuracy of sentinel lymph node biopsy for patients with T2 and T3 breast cancers. Am Surg. 2001;67(6):522–6 (discussion 527–8).PubMedGoogle Scholar
  13. 13.
    Chung M, Ye W, Giuliano A. Role for sentinel lymph node dissection in the management of large (>; or =5 cm) invasive breast cancer. Ann Surg Oncol. 2001;8(9):688–92.PubMedGoogle Scholar
  14. 14.
    Kim HJ, Lee JS, Park EH, et al. Sentinel node biopsy in patients with multiple breast cancer. Breast Cancer Res Treat. 2008;109(3):503–6.PubMedCrossRefGoogle Scholar
  15. 15.
    D’Eredita G, Giardina C, Ingravallo G, Rubini G, Lattanzio V, Berardi T. Sentinel lymph node biopsy in multiple breast cancer using subareolar injection of the tracer. Breast. 2007;16(3):316–22.PubMedCrossRefGoogle Scholar
  16. 16.
    Bergkvist L, Frisell J. Multicentre validation study of sentinel node biopsy for staging in breast cancer. Br J Surg. 2005;92(10):1221–4.PubMedCrossRefGoogle Scholar
  17. 17.
    Ozmen V, Muslumanoglu M, Cabioglu N, et al. Increased false negative rates in sentinel lymph node biopsies in patients with multi-focal breast cancer. Breast Cancer Res Treat. 2002;76(3):237–44.PubMedCrossRefGoogle Scholar
  18. 18.
    Barone JE, Tucker JB, Perez JM, Odom SR, Ghevariya V. Evidence-based medicine applied to sentinel lymph node biopsy in patients with breast cancer. Am Surg. 2005;71(1):66–70.PubMedGoogle Scholar
  19. 19.
    Leidenius MH, Krogerus LA, Toivonen TS, von Smitten KA. Sentinel node biopsy is not sensible in breast cancer patients with large primary tumours. Eur J Surg Oncol. 2005;31(4):364–8.PubMedCrossRefGoogle Scholar
  20. 20.
    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(2):319–25.PubMedCrossRefGoogle Scholar
  21. 21.
    Cserni G, Gregori D, Merletti F, et al. Meta-analysis of non-sentinel node metastases associated with micrometastatic sentinel nodes in breast cancer. Br J Surg. 2004;91(10):1245–52.PubMedCrossRefGoogle Scholar
  22. 22.
    Christiansen P, Friis E, Balslev E, Jensen D, Moller S. Sentinel node biopsy in breast cancer: five years experience from Denmark. Acta Oncol. 2008;47(4):561–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Leidenius MH, Vironen JH, Riihela MS, et al. The prevalence of non-sentinel node metastases in breast cancer patients with sentinel node micrometastases. Eur J Surg Oncol. 2005;31(1):13–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Sobin LH, Wittekind Ch. TNM classification of malignant tumours, 6th ed. New-York: Wiley-Liss; 2002.Google Scholar
  25. 25.
    van der Ploeg IM, Nieweg OE, van Rijk MC, Valdes Olmos RA, Kroon BB. Axillary recurrence after a tumour-negative sentinel node biopsy in breast cancer patients: A systematic review and meta-analysis of the literature. Eur J Surg Oncol. 2008;34(12):1277–84.PubMedGoogle Scholar
  26. 26.
    Deurloo E, Tanis P, Gilhuijs K, et al. Reduction in the number of sentinel lymph node procedures by preoperative ultrasonography of the axilla in breast cancer. Eur J Cancer. 2003;39(8):1068–73.PubMedCrossRefGoogle Scholar
  27. 27.
    van Wely B, Smidt M, de Kievit I, Wauters C, Strobbe L. False-negative sentinel lymph node biopsy. Br J Surg. 2008;95(11):1352–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Takei H, Suemasu K, Kurosumi M, et al. Recurrence after sentinel lymph node biopsy with or without axillary lymph node dissection in patients with breast cancer. Breast Cancer. 2007;14(1):16–24.PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2009

Authors and Affiliations

  • Tuomo J. Meretoja
    • 1
  • Marjut H. Leidenius
    • 1
  • Päivi S. Heikkilä
    • 2
  • Heikki Joensuu
    • 3
  1. 1.Department of Gastrointestinal and General Surgery, Breast Surgery UnitHelsinki University Central HospitalHelsinkiFinland
  2. 2.Department of PathologyHelsinki University Central HospitalHelsinkiFinland
  3. 3.Department of OncologyHelsinki University Central HospitalHelsinkiFinland

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