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Differences in Sentinel Lymph Node Pathology Protocols Lead to Differences in Surgical Strategy in Breast Cancer Patients

¹ Department of Surgery, Radboud University Nijmegen Medical Center, P.O. Box 9101, NL-6500 HB, Nijmegen, The Netherlands
² Department of Pathology, Radboud University Nijmegen Medical Center, P.O. Box 9101, NL-6500 HB, Nijmegen, The Netherlands
³ Department of Pathology, Viecuri Medical Center, Tegelseweg 210, NL-5912 BL, Venlo, The Netherlands
⁴ Department of Pathology, Rijnstate Hospital, P.O. Box 9555, NL-6800 TA, Arnhem, The Netherlands
⁵ Department of Surgery, Canisius-Wilhelmina Hospital, P.O. Box 9015, NL-6500 GS, Nijmegen, The Netherlands
⁶ Department of Surgery, Viecuri Medical Center, Tegelseweg 210, NL-5912 BL, Venlo, The Netherlands
⁷ Department of Surgery, Rijnstate Hospital, P.O. Box 9555, NL-6800 TA, Arnhem, The Netherlands
⁸ Department of Epidemiology and Biostatistics, Radboud University Nijmegen, P.O. Box 9101, NL-6500 HB, Nijmegen, The Netherlands
⁹ Department of Medical Oncology, University Hospital Maastricht, P.O. Box 5800, NL 6202 AZ, Maastricht, The Netherlands

Correspondence: Address correspondence and reprint requests to: Marieke J. Bolster, MD; E-mail: m.bolster{at}chir.umcn.nl

	ABSTRACT

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Background: Internationally, there is no consensus on the pathology protocol to be used to examine the sentinel lymph node (SN). At present, therefore, various hospitals use different SN pathology protocols of which the effect has not been fully elucidated. We hypothesized that differences between hospitals in SN pathology protocols affect subsequent surgical treatment strategies.

Methods: Patients from four hospitals (A–D) were prospectively registered when they underwent an SN biopsy. In hospitals A, B, and C, three levels of the SN were examined pathologically, whereas in hospital D, at least seven additional levels were examined. In the absence of apparent metastases with hematoxylin and eosin examination, immunohistochemical examination was performed in all four hospitals.

Results: In total, 541 eligible patients were included. In hospital D, more patients were diagnosed with a positive SN (P < .001) as compared with hospitals A, B, and C, mainly because of increased detection of isolated tumor cells. This led to more completion axillary lymph node dissections in hospital D (66.3% of patients (P < .0001), compared with 29.0% in hospitals A, B, and C combined). Positive non-SNs were detected in 13.9% of patients in hospital D, compared with 9.7% in hospitals A, B, and C (P = .70). That is, in 52.4% of patients in hospital D, a negative completion axillary lymph node dissection was performed, compared with 19.3% of patients in hospitals A, B, and C combined.

Conclusions: Differences in SN pathology protocols between hospitals do have a substantial effect on SN findings and subsequent surgical treatment strategies. Whether ultrastaging and, thus, additional surgery can offer better survival remains to be determined.

Key Words: Breast cancer • Sentinel lymph node • Pathology protocol • Micrometastasis • Surgical treatment • Nonsentinel lymph node metastasis

	INTRODUCTION

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The axillary lymph node status is still the most important prognostic factor in primary breast cancer. During recent years, the sentinel lymph node (SN) procedure was shown to be a reliable strategy to replace axillary lymph node dissection (ALND) in selected patients with primary breast cancer.¹ On the basis of figures from the pre-SN era, it was assumed that a completion ALND could be avoided in approximately 60% of patients with operable breast cancer by performing an SN biopsy.²

Obviously, a reliable examination of the SN by the pathologist is crucial, because a false-negative finding may result in undertreatment both locally and systemically. Consequently, pathologists have intensified the examination of the SN by using serial sectioning and immunohistochemistry (IHC), whereas previously, the axillary lymph nodes were examined by hematoxylin and eosin (H&E) in one or two slides only. In the past decade, a lot of research focused on this topic, and this was summarized in an excellent review. It was shown that an intensified examination of the SN results in a significantly increased detection of isolated tumor cells and micrometastases.³ Unfortunately, internationally, there is no consensus on the SN pathology protocol to be used.^4,5 At present, therefore, various hospitals use different SN pathology protocols.

So far, there are no data on whether differences in SN pathology protocols affect subsequent surgical treatment strategies. In our region, we prospectively collected clinical and pathologic data on breast cancer patients who underwent an SN procedure. In the four involved hospitals, different pathology protocols existed. Therefore, we decided to test the hypothesis that differences in SN pathology protocols between hospitals would lead to different numbers of completion ALNDs performed, of which the relevance was aimed to be determined.

	PATIENTS AND METHODS

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Patients from four hospitals (A, B, C, and D) were prospectively registered when they underwent an SN biopsy because of a cytological or histological proven invasive breast cancer with a clinical tumor size of 5 cm. Patients were excluded from an SN biopsy when there was clinical proof of axillary lymph node metastases, multifocality in the primary breast tumor, or radiotherapy of the breast or axilla in the past; when patients had received neoadjuvant systemic therapy; or when the SN was not detectable. The ethics committee approved the investigational protocol.

The prospectively collected data included the lymph node status with the number of nodes examined, the number of positive nodes, the size of metastases, classification according to the tumor-node-metastasis categories defined in the 6th edition of the TNM Classification of Malignant Tumors,⁶ and the detection method (H&E/IHC). These items were separately registered for SNs and non-SNs. Also, primary tumor characteristics (localization, tumor size, histology, histological grade, lymph and/ or blood vessel invasion, and hormone receptor status), patient characteristics (age), and information on the surgical procedure (SN biopsy with or without ALND, lumpectomy or mastectomy, and various combinations) were collected.

The surgical procedure was, in all four hospitals, in accordance to the Dutch guidelines for treatment of breast cancer.⁷ SN localization was performed by using the combined technique of blue dye and radioisotope in all patients. In the presence of isolated tumor cells, micrometastases, or macrometastases in the SN, a completion ALND was recommended.

The pathology procedure for the SN examination is also described in the Dutch guidelines for treatment of breast cancer. However, in these guidelines, only the minimal criteria are described. Pathologists are advised to examine the SN with H&E at, at least, three levels of the paraffin block, with IHC to be used in case of doubt. These minimal recommendations actually led to quite different local pathology protocols. In hospitals A, B, and C, three levels of the SN were pathologically examined. In hospital D, at least 7 additional levels were examined (at least 10 levels in total). In the absence of apparent metastases with H&E examination, IHC examination was performed in all four hospitals.

All lymph nodes in the ALND specimen were examined. In hospital B, at least three levels were examined with H&E and IHC. In hospital D, the nodes were examined at least at two levels with H&E, and in hospitals A and C they were examined at one level. In hospitals A, C, and D, IHC examination was used only when H&E examination was not conclusive.

According to the international tumor-node-metastasis classification (2002), isolated tumor cells, micrometastases, and macrometastases were classified as follows: Isolated tumor cells [pN0(i+)] were defined as solitary tumor cells or tumor cell clusters .2 mm. Micrometastases [pN1mi] were >.2 mm and maximally 2.0 mm. Macrometastases were >2.0 mm. For the SN findings, "SN" was added [pN(SN)]. In this article we added pN1⁺, which refers to pN1a and higher pN-positive stages.

The results of the four hospitals concerning SN findings, performance of completion ALND, and non-SN findings after a positive SN finding were compared by using ² tests. The differences in detecting a positive SN among the four hospitals were corrected for patient and primary tumor characteristics with a logistic regression analysis. P < .05 was considered statistically significant.

	RESULTS

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Patient Characteristics
Five hundred eighty-seven patients were prospectively included. In 28 patients, there was no invasive tumor component, in 13 patients the SN was not detectable, 4 patients received neoadjuvant systemic therapy, and 1 patient had already a proven axillary lymph node metastasis before surgery. These 46 (7.8%) patients were excluded, leaving 541 patients in our prospective database. Of the 541 eligible patients, 198 patients had surgery in hospital A, 153 patients in hospital B, 104 patients in hospital C, and 86 patients in hospital D. Patient and primary tumor characteristics per hospital are listed in Table 1.

There was a significant difference in detecting a positive SN among the four hospitals (P < .0001). In hospital D, more patients were diagnosed with a positive SN as compared with hospitals A, B, and C (P < .001).

Of note, when looking at patient and primary tumor characteristics, there were overall no large differences among the four hospitals that might have contributed to the difference in SN findings (Table 1). However, there was a remarkable difference in the documented presence of lymph and/or blood vessel invasion. Lymph and/or blood vessel invasion was seen more frequently in hospital D.

The higher incidence of a positive SN in hospital D compared with hospital A remained significant (P < .001) when corrected, with a logistic regression analysis, for patient and primary tumor characteristics. Similarly, with correction for patient and primary tumor characteristics, the higher incidence of a positive SN in hospital D compared with hospital B remained significant (P < .001), whereas the higher incidence of a positive SN in hospital D compared with hospital C could be partly explained by the presence of lymph and/or blood vessel invasion, now resulting in borderline significance for the difference in detecting a positive SN between these two hospitals (P = .06).

The higher incidence of a positive SN in hospital D was mainly the result of isolated tumor cells being far more often documented in patients in this hospital (P < .0001; Table 2). The detection rate of micrometastases and macrometastases in hospital D (32.6%) was not significantly different from the detection rate in hospitals A and C (24.2% and 39.4%, respectively) and was only slightly higher than in hospital B (20.9%; P = .05).

Non-SN Findings in the Four Hospitals
The number of patients per hospital with positive non-SNs after a positive SN result is shown in Table 3 and Fig. 1. In hospital D, positive non-SNs were detected in 13.9% of all patients who underwent an SN biopsy, compared with 9.6% in hospital A, 9.8% in hospital B, and 9.6% in hospital C (P = .70).

View larger version (13K): [in this window] [in a new window]   FIG. 1. Results of patients who underwent a sentinel lymph node (SN) biopsy and completion axillary lymph node dissection (ALND) per hospital.

The incidence of non-SN metastases was related to the size of the SN metastasis. For instance, in hospital A the SN contained isolated tumor cells in 16 patients. All 16 underwent a completion ALND, and of these 16 patients, 2 (12.5%) patients had positive non-SNs. Non-SN metastases occurred in 4 (26.7%) of the 15 patients with micrometastases in the SN. Of the 32 patients with macrometastases in the SN, non-SN metastases occurred in 13 (40.6%) patients. In hospital D, the SN contained isolated tumor cells in 30 patients. All 30 patients underwent a completion ALND, and of these 30 patients, 4 (13.3%) patients had positive non-SNs. Non-SN metastases occurred in 4 (30.8%) of the 13 patients with micrometastases in the SN. Of the 14 patients with macrometastases in the SN, 4 (28.6%) patients had positive non-SNs in hospital D. This indicates also for this hospital that the incidence of non-SN metastases was related to the size of the SN metastasis, although this was less strong related compared with hospital A (see for more detailed information per hospital Figs. 2–4).

View larger version (30K): [in this window] [in a new window]   FIG. 2. Status of nonsentinel lymph nodes (non-SNs) removed during completion axillary lymph node dissection (ALND) in cases with isolated tumor cells in the sentinel lymph node. In hospital A, 16 of 16; in B, 1 of 4; in C, 1 of 4; and in D, 30 of 30 cases with isolated tumor cells underwent a completion ALND.

View larger version (32K): [in this window] [in a new window]   FIG. 3. Status of nonsentinel lymph nodes (non-SNs) removed during completion axillary lymph node dissection (ALND) in cases with micrometastasis in the sentinel lymph node. In hospital A, 15 of 16; in B, 13 of 13; in C, 8 of 10; and in D, 13 of 14 cases with micrometastasis underwent a completion ALND.

View larger version (31K): [in this window] [in a new window]   FIG. 4. Status of nonsentinel lymph nodes (non-SNs) removed during completion axillary lymph node dissection (ALND) in cases with macrometastasis in the sentinel lymph node. In hospital A, 32 of 32; in B, 19 of 19; in C, 27 of 31; and in D, 14 of 14 cases with macrometastasis underwent a completion ALND.

	DISCUSSION

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As in agreement with the guidelines, a completion ALND was recommended in case of a tumor-positive SN. An ALND was performed in 66.3% of patients in hospital D, compared with 31.8% of patients in hospital A, 21.6% of patients in hospital B, and 34.6% of patients in hospital C (P < .0001).

The European Working Group for Breast Screening Pathology evaluated aspects of the practice of SN pathology in breast cancer via a questionnaire-based survey. The questionnaire revealed that the pathologic examination of SNs throughout Europe varies considerably and is not standardized. Some countries have set up national guidelines, but many institutions have developed their own guidelines for SN processing, which are more intensive than the national guidelines recommended as a minimum and which are frequently determined by the institution’s research strategy.^4,5 The European Working Group for Breast Screening Pathology recommended techniques that identify metastases >2 mm as a minimum standard (levels taken 1 mm apart should be sufficient for this), because macrometastases have proven prognostic relevance and all should be identified. Uniform reporting of additional findings may also be important, because micrometastases and isolated tumor cells may in the future be shown to have clinical relevance (step sections taken 200 or 250 µm apart are ideal for this purpose).¹¹ The value of more detailed examination with IHC is controversial. Klevesath et al.¹² concluded that all metastatic deposits identified by IHC were either micrometastasis or isolated tumor cells, and until the prognostic significance of these deposits has been determined, IHC may be of limited value in the histopathologic examination of the SN.

When looking at large trials, we see the same variety. For example, in the important randomized trial by Veronesi et al.,¹³ approximately 15 pairs of sections were cut at 50-µm intervals in each half of the SN, amounting to approximately 60 sections per SN to be examined, whereas in a recent study by Colleoni et al.,⁹ no details concerning the pathology protocol were mentioned. This shows that, apparently, the influence of pathology protocols on surgical strategies is underestimated. Looking at our study results, we found that differences in pathology protocols do, however, have a large effect on surgical treatment strategies.

The occurrence of SN metastases is associated with the primary tumor size and with lymphovascular invasion. These are the most powerful variables that are independently predictive of positive SN biopsy results.¹⁴ Tan et al.¹⁵ showed in their series the same results for the occurrence of SN macrometastases. Lack of progesterone receptors is inversely associated with the prevalence of SN metastases.¹⁰ All patients in our study were prospectively registered and considered eligible to undergo an SN procedure on the basis of similar criteria. Indeed, we did not observe gross differences among the four hospitals in patient and primary tumor characteristics that could have contributed otherwise to the outcome parameters. Lymph and/or blood vessel invasion was seen more frequently in hospital D, but the higher incidence of a positive SN in hospital D compared with hospitals A and B remained significant when corrected for lymphovascular invasion (P < .001). The higher incidence of a positive SN in hospital D compared with hospital C could be partly explained by the presence of lymph and/or blood vessel invasion, but this still resulted in borderline significance for the difference between these hospitals (P = .06). Therefore, although there were some differences in primary tumor characteristics, as shown in Table 1, this does not explain the differences in SN findings between hospitals. The differences in pathology protocols between hospitals A, B, and C versus hospital D do explain the differences in SN findings.

The big central issue is whether patients in hospital D are overtreated or whether patients in hospitals A, B, and C are undertreated. In agreement with the guidelines, a completion ALND was recommended in case of a tumor-positive SN. In hospital D, an ALND was performed in 66.3% of patients who underwent an SN biopsy, with positive non-SNs in 13.9% of the originally included patients. In contrast, in hospitals A, B, and C taken together, an ALND was performed in 29.0% of patients who underwent an SN biopsy, with positive non-SNs in 9.7% of the originally included patients. That is, in 52.4% of patients in hospital D, a negative completion ALND was performed, compared with in 19.3% of patients in hospitals A, B, and C combined. The question is whether the additional 4.2% increased detection of non-SN disease outweighs the 37.3% additional performance of a completion ALND. That is, the number needed to treat is nine patients to detect one patient with non-SN disease.

In breast cancer, it may require considerable time before small metastases left behind become clinically manifest as regional recurrences or the source of distant metastases. Also, the use of adjuvant systemic therapy has been demonstrated to decrease the risk of locoregional recurrence. Currently, most node-negative patients undergo either adjuvant chemotherapy or hormone therapy because of their patient and primary tumor characteristics.^16,17 This may protect against the outgrowth of regional tumor cells that may be left behind.

Smidt et al.¹⁸ found an incidence of .46% axillary recurrence after a negative SN biopsy, after a median follow-up of 26 months (one patient after 4 months and one patient after 27 months). Pathologically each half of the SN was step-sectioned at 500-µm intervals at three levels. Zavagno et al.¹⁹ found in their series of 479 patients no clinical axillary recurrence after a median follow-up of 35.8 months. For definitive SN examination, two sections were cut from a paraffin block at three levels, each 40 µm apart. Also, at Memorial Sloan-Kettering Cancer Center, a low relapse rate was found. With a median follow-up of 31 months, axillary recurrence occurred in 10 (.25%) of 4008 patients.²⁰ Final pathologic examination of a frozen section–negative SN included two sections from each of two levels 50 µm apart.

Longer follow-up is necessary to answer the question properly.²¹ The patients in the cohorts of the four hospitals will be observed with longer follow-up to get a definitive answer on axillary recurrence rates.

Large (randomized) prospective trials such as National Surgical Adjuvant Breast and Bowel Project B32 and American College of Surgeons Oncology Group Z10 may provide clinical evidence for the formulation of policies on axillary sparing after a positive SN biopsy result. The National Surgical Adjuvant Breast and Bowel Project B32 compares SN resection with conventional ALND in clinically node-negative breast cancer patients. An objective, among others, of American College of Surgeons Oncology Group Z10 is to estimate the prevalence and the prognostic significance of SN micrometastases detected by IHC.

To this end, we conclude that there are differences in SN pathology protocols between hospitals that do lead to differences in SN findings. These differences have a large effect on subsequent surgical treatment strategies. The question is whether the additional 4.2% increased detection of non-SN disease outweighs the 37.3% additional performance of a completion ALND. Longer follow-up will have to decide whether ultrastaging and, thus, additional surgery can offer better survival.

	ACKNOWLEDGMENTS

 
Supported by the Dutch Healthcare Insurance Board (research grant). The authors thank Wim Lemmens for support with statistical analysis.

Received for publication May 15, 2006. Accepted for publication May 18, 2006.

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