A concept for the clinical implementation of sentinel lymph node biopsy in patients with breast carcinoma with special regard to quality assurance

Abstract

The development of standardized and reproducible clinical pathways is an important precondition for quality assurance in medicine, especially if a new method has not yet been ultimately validated. Sentinel lymph node biopsy (SLNB) is a widely accepted new surgical procedure in the treatment of early breast carcinoma. However, numerous steps of the method and details of the technique are not standardized and, thus, hamper quality assurance for SLNB. The German Society of Senology appointed an interdisciplinary consensus committee to work out guidelines for the standardized performance and quality-assured implementation of SLNB on a nationwide, homogeneous standard. The committee consisted of surgeons, gynecologists, radiooncologists, nuclear physicians, oncologists, and pathologists. Relevant questions related to patient selection, lymphatic mapping, surgery, histopathologic work-up, further local and systemic treatment decisions, patient information, training, and follow-up were evaluated with respect to clinical evidence, objectivity, and reproducibility. Clinical pathways were developed on the basis of this analysis. Requirements to the performing institutions and surgeons were defined. Cancer 2005. © 2004 American Cancer Society.

Sentinel lymph node (SLN) biopsy (SLNB) is a new minimally invasive procedure to determine the lymph node status of patients with breast carcinoma. Its high diagnostic accuracy has led to a rapid acceptance of the method, and it is widely used now in routine clinical practice. The St. Gallen conference of 2003 agreed that the finding of a negative axillary SLN is accepted as allowing avoidance of axillary dissection.1 In addition, the sixth edition of the tumor, lymph node, metastasis (TNM) classification system for breast carcinoma incorporates important changes, with full recognition of SLNB as an adequate staging procedure of the axilla.2, 3 However, to date, no sufficiently powered, randomized trial has provided Level I evidence for the equivalence of SLNB to the existing standard of care (axillary lymph node dissection [ALND]), especially with respect to disease-free and overall survival. Because SLNB has been validated as a diagnostic procedure, the concept of lymphatic mapping currently is accepted widely and is not regarded as controversial. The conditions of its clinical implementation, however, remain to be settled.

A consensus panel meeting was held in Philadelphia in 2001 and defined the current scientific status of SLNB.4 However, the lack of standardization remains an important issue. Measures of quality control appear indispensable for the implementation of SLNB into routine clinical practice. Numerous technical details concerning lymphatic mapping, surgery, histopathologic work-up, and training are not standardized and depend on the experience of individual centers.

To achieve a quality-assured implementation of SLNB into clinical routine on a nationwide level, the German Society for Senology appointed an interdisciplinary panel to establish a consensus for the standardization of SLNB in breast carcinoma and the definition of clinical pathways related to the procedure. The interdisciplinary panel included gynecologists, surgeons, medical oncologists, nuclear medicine physicians, pathologists, and radiooncologists. Numerous questions related to SLNB were compiled in a catalog, and the participants elaborated written propositions with regard to the current state of knowledge. A consensus was elaborated for each point on the basis of scientific evidence, objectivity, and reproducibility.

A consensus meeting was held on May 11, 2003. The updated recommendations are presented in this report.

GENERAL REMARKS

Definitions

SLN

An SLN is defined as one or more lymph node (s) to which lymphatic drainage and metastases from breast carcinoma are most likely to occur. The SLN is visualized by lymphatic mapping using either a radioactive tracer, a vital dye, or a combination of both. SLNs are identified by the uptake of any tracer or by the identification of a labeled afferent lymphatic vessel.

SLNB

SLNB is defined as the selective removal of the SLN(s).

Lymphatic mapping

Lymphatic mapping is visualization of the lymphatic drainage pathways of a solid tumor.

False-negative SLNB

A false-negative SLNB is defined by a lack of lymph node involvement in the SLN(s) associated with metastatic non-SLN(s).

False-negative SLNB rate

The number of false-negative SLNBs divided by the number of patients with positive (axillary) lymph node status is the false-negative SLNB rate.

Sensitivity

Sensitivity is calculated according to the number of patients with tumor-involved SLN(s) divided by the total number of patients with positive (axillary) lymph node status.

Current Status of SLNB

Level I evidence for the equivalence of SLNB to ALND with regard to recurrence-free and overall survival has not been provided to date. However, numerous prospective, multicenter trials have compared the histopathologic findings of the SLN(s) with the lymph node status after routinely performed, back-up axillary dissection and have found that the procedure is a reliable diagnostic tool.5–9 Several single-center trials have reported short-term follow-up results (2–4 years of observation) for patients who underwent SLNB without any further regional treatment.10–13 The only available randomized trial that has compared standard ALND with SLNB alone (in patients with a negative SLN) was a single-center study that showed no difference in terms of locoregional failure after a median follow-up of 46 months. SLNB was associated with significantly less morbidity.13 To our knowledge, no data are available to date from prospective, randomized, multicenter studies. Several ongoing clinical trials are examining the outcomes of patients after exclusive SLNB compared with women who underwent ALND with negative SLNs (National Surgical Adjuvant Breast and Bowel Project trial B-32, the United Kingdom multicenter Axillary Lymphatic Mapping against Nodal Axillary Clearance trial, and the German Clinical Interdisciplinary Sentinel Study) or with positive SLNs (American College of Surgeons Oncology Group trial Z11). The panel's conclusion regarding the current status of SLNB in routine clinical practice was as follows: Given adequate patient selection, a standardized procedure, and the implementation of quality-assurance measures, SLNB is an alternative to ALND in patients with breast carcinoma, offering equivalent staging accuracy but reduced shoulder and arm morbidity.

Premises for State-of-the-Art SLNB

Principles

Close interdisciplinary cooperation is mandatory for adequate performance of SLNB. The procedure should be carried out in a standardized and reproducible way, including a defined histopathologic examination.

Techniques for SLN detection

Compared with the use of radioisotopes, the blue-dye technique may provide similar results with respect to the identification of an SLN and the false-negative rate. However, the dye technique is associated with a longer learning phase and a greater variability of results than the radiocolloid technique.14–16 Lymphoscintigraphy offers the possibility to determine the location of the SLN(s) macroscopically and provides preliminary information about the approximate number of radiolabeled lymph nodes. Furthermore, it allows the surgeon to correlate the imaging findings with the intraoperative situation. Because the failure to identify SLNs (in the patients with numerous labeled lymph nodes) may lead to false-negative results,17 this correlation can help to increase sensitivity. With regard to quality assurance and the requirement for objectivity and reproducibility, the panel recommended the use of radioisotopes and lymphoscintigraphy for routine clinical SLNB and suggested that a combination of the radiocolloid and the vital dye technique may be the method of choice. Fulfillment of the following criteria was defined as necessary for any institution performing SLNB: 1) close cooperation between the breast surgeon, the nuclear medicine physician, and the pathologist; 2) the availability of nuclear medicine facilities for the application of the radiopharmaceuticals and of a camera for lymphoscintigraphy; 3) histopathologic evaluation according to the respective protocol; 4) the availability of a ggr; probe for intraoperative SLN detection; and 5) standardized documentation and evaluation of the data.

Numerous authors have emphasized the importance of learning curves for the successful detection of SLNs.18–21 Data are contradictory with respect to training effects on the false-negative rate.7, 9 One reason is the fact that the case load per surgeon is too low to enable reliable calculation of the false-negative rate. To achieve significant results, the analysis of hundreds of patients would be required. Furthermore, studies that examine the effects of learning are heterogeneous, because the procedures compared are different (blue dye, radioguided technique with or without lymphoscintigraphy). According to the most recent literature, the learning curve for SLNB depends on the surgeon's case load. Depending on the case load, 20–60 surgeries reportedly are required for acceptable results.21

SLNB is an interdisciplinary team approach. Success rates (for detection and false-negative SLNB) are not related exclusively to the training in the surgical procedure itself. The panel concluded that SLNB preferably should be integrated into the quality-management system of a breast cancer unit.

Reflecting data from the literature on learning curves for the detection of SLNs and the false-negative rate, comparable international agreements (Philadelphia, 2001), and the requirements for a specialized breast cancer unit in Europe, the following specific recommendations were defined for surgeons performing SLNB: 1) substantial experience in conventional ALND, 2) 50 breast carcinoma surgeries per year, and 3) performance of SLNB in a standardized technique according to current consensus recommendations; for surgeons learning SLNB in a breast center where the procedure already is clinical routine: 1) 20 SLNB procedures with the assistance of an experienced surgeon and 2) 20 SLNB procedures per year; and, for surgeons introducing the procedure in their clinic: 1) participation in a specific training course and 2) 20 SLNB procedures followed by ALND (detection > 80% with ≤ 1 false-negative result).

INDICATIONS FOR SLNB

There is no evidence that any patient characteristic or disease factor is associated with significantly impaired results and, thus, restricts the application of SLNB. Most patients who are recruited for validation trials and observational studies are women with T1–T2 breast tumors that predominantly measure up to 2 cm in greatest dimension.5–9 The only published randomized trial included patients with T1 tumors.13 Thus, the greatest evidence for the accuracy of SLNB to predict the axillary status and its reliability for locoregional control is available for small breast carcinomas. Most data from the literature indicate that tumor size does not influence the sensitivity of SLNB. However, the data are too sparse to permit pertinent conclusions for larger tumors.

SLNB has been evaluated extensively for its accuracy in predicting axillary lymph node status. In a multicenter setting, it has shown a sensitivity of ≈ 90% (false-negative rate, 10%).5–9 For patients with pT1 tumors, which usually reveal axillary lymph node involvement in ≈ 30% of patients, the theoretical risk of failure (false-negative staging, risk of locoregional tumor progression) is 3%, which is equivalent to the rate of axillary recurrence after conventional ALND.22 The theoretical chance of an individual false-negative SLNB result depends on the false-negative rate and the individual risk of axillary involvement, which is determined by predictive factors such as tumor size, grade, and lymphovascular invasion.23 Although there is some evidence that undetected lymph node metastases will not necessarily become apparent clinically13, 24 and that secondary axillary tumor growth is not necessarily relevant for overall survival,25 the consensus panel recommended that the indication for SLNB as standard procedure generally should be restricted to small and low-risk breast carcinomas (≤ 2 cm), at least at this early stage of clinical implementation. For patients with larger tumors (T2), SLNB may be indicated nevertheless, provided that the individual failure risk of the patient is discussed thoroughly (including the experience of the surgeon/institution, predictive factors for axillary lymph node involvement, and insufficient evidence for the reliability of SLNB in larger tumors) (Table 1).

Table 1. Indications for Sentinel Lymph Node Biopsy in Breast Carcinoma

Standard indication for routine clinical use	Optional indication (individual (decision required)	No indication except for clinical trials	Contraindication
DCIS: ductal carcinoma in situ. a Individual decision considering the risk for axillary involvement (predictive factors) and personal experience (false-negative rate). b Ultrasound of the axilla is recommended if the architecture of the lymph node is preserved: sentinel lymph node biopsy possible.
Unifocal breast carcinoma ≤ 2 cm	Extensive DCIS (mastectomy required)	Neoadjuvant chemotherapy	Pregnancy
			Tracer incompatibility
			Multicentricity
Primary surgery	T2 tumorsa		Inflammatory disease
			Extensive previous breast surgery
Secondary surgery after previous lumpectomy	Multifocal lesions		Previous axillary surgery
			Clinically suspicious axillary lymph nodesb

Growing evidence supports the idea that the entire breast, including the skin envelope, drains to the same axillary SLN(s).26–30 Extraaxillary SLNs are found mostly after deep (intratumoral or peritumoral injection) tracer injection (close to the thoracic wall),31 suggesting that the drainage to the internal mammary chain depends on the depth rather than on the quadrant of tumor location. Although this suggests that lymphatic mapping could be performed even in multifocal or multicentric lesions, there is not sufficient evidence for this model of functional anatomy and lymphatic drainage pattern of the breast to recommend these indications for routine clinical practice.

In weighing the risks and benefits, SLNB should not be considered a standard procedure for patients with ductal carcinoma in situ (DCIS). Even in large DCIS and in microinvasive carcinoma, axillary involvement is very rare and mostly manifests as micrometastasis.32 The rationale for recommending SLNB in patients with large DCIS is restricted to those women who need mastectomy to remove their lesion completely. In these patients, SLNB cannot be performed in a second procedure if the definite histopathologic work-up reveals an invasive carcinoma. To our knowledge to date, however, there is no evidence of any benefit for patients in this subgroup.

Although preliminary data show the feasibility of SLNB for patients who have received neoadjuvant chemotherapy,33 data are not yet sufficient to define the role of lymphatic mapping after primary systemic treatment.34 Because > 50% of patients have negative lymph node status after preoperative chemotherapy,35 investigating the value of SLNB before or after neoadjuvant chemotherapy is recommended in prospective protocols.

The panel concluded that SLNB could be performed regardless of tumor location, patient age, or primary surgical technique (breast conservation, mastectomy, oncoplastic surgery). SLNB can be performed in exceptional patients without preoperative histologic verification of the tumor provided frozen section histology is assessed intraoperatively. The indications for SLNB recommended by the consensus panel are summarized in Table 1.

PATIENT INFORMATION

The patient must be informed that SLNB is a new method that has not yet been ultimately validated. ALND, as an alternative, should be offered, and its potential adverse effects should be explained. The individual risk for lymph node involvement and the consequences of a false-negative result must be pointed out. The patient has to be informed about the use of radioactivity.

THE IDENTIFICATION OF SLN(S)

Nuclear Medicine Principles

The requirements of radioprotection laws have to be met. In Germany, an authorized expert of radiation protection must be available but does not have to be present on a permanent basis. The use of radiopharmaceuticals has to be reported to the local radiation protection authorities.

Radiopharmaceuticals

Technetium-99m-labeled colloids with a particle size of 20–100 nm and an injection volume of 0.2–1.0 mL generally are used. The amount of radioactivity has to be determined according to the time between radiocolloid injection and the surgical procedure to obtain a sufficient radiocolloid uptake in the lymph node and a high target signal intensity. If surgery is planned 24 hours after the injection and a probe with a sensitivity of 10 cps/kBq is used, then activity of 150–250 megabecquerels (MBq) will be needed. With a nuclide half-life of 6 hours (Technetium-99) and an injection time 6 hours prior to SLNB, the amount of radioactivity required is reduced by 50%. In 1-day protocols, 10–50 MBq are sufficient.

Technique of Injection

There are several options with respect to the injection technique. Tracers may be injected into the peritumoral tissue, intratumorally, intradermally or subdermally above the tumor, or in the subareolar region. Currently, the evidence suggests that the site of tracer administration does not affect the false-negative rate of SLNB.26–30 Extraaxillary SLNs are detected almost exclusively after deep tracer injection.31 Because SLNB outside the axilla is not recommended as standard procedure, a subdermal or subareolar injection is considered equally effective in the identification of the SLN and can be recommended in patients who have nonpalpable lesions or tumors in close proximity to the axilla to avoid radiation interference between the peritumoral injection site and the axilla.

Lymphoscintigraphy

Although it has been shown that successful SLNB does not necessarily require lymphoscintigraphy,36 the use of preoperative imaging is recommended strongly under the aspect of quality assurance (see Techniques for SLN detection, above). Static images in two planes are mandatory.

Requirements for the γ Probes

The minimal requirements for the γ probes are detection sensitivity of at least 5 cps/kBq and lateral shielding of < 0.1% of the maximum sensitivity. Moreover, the Compton spectrum should be separable from the photo peak. Additional recommendations regarded as optional are specified in the checklist for nuclear medicine (Table 2).

Table 2. Checklist for Nuclear Medicine

SLN: sentinel lymph node; FWHM: full width at half maximum.
Data evaluation and documentation
Interval between injection and visualization	Time _________
Visualization of any lymphatic pathway	Yes ___ No ___
Anatomic relation to the tumor	Axillary ___ Extraaxillary ___
Relative uptake	Strong___ Medium___ Weak___
> 1 SLN	Yes___ No___ Number___
Requirements for the manual probes (mandatory)
Detection sensitivity > 5 cps/kBq	Yes ___ No ___
Lateral shielding < 0.1% of the maximum sensitivity	Yes ___ No ___
Compton spectrum separable from the photo peak	Yes ___ No ___
Further recommendations for the manual probes (optional)
Radial sensitivity distribution: FWHM < 40°	Yes ___ No ___
Spatial resolution FWHM: < 25 mm	Yes ___ No ___
Acoustic signal transfer: Good correlation between measured signal and sound transformation	Yes ___ No ___
Digital measurement: Continuous indication with adjustable measurement interval	Yes ___ No ___
In the case of analog measurement: Appropriate choice of the measurement range with adjustable time constant	Yes ___ No ___

SURGICAL TECHNIQUE

Sequence of Procedures

Basically, patients can undergo SLNB before or after resection of the primary tumor. The recommendation is to start with the removal of the SLN. Breast surgery (breast-conserving procedures or mastectomy) can be performed during the intraoperative histopathologic assessment of the SLN(s). In rare patients, such as women with intraoperatively determined histology of the breast tumor, the sequence can be reversed.

Handling of γ Probe

When a hand-held γ probe is used, a collimator can reduce disturbances by scattered radiation from the tumor bed and, thus, can facilitate detection of activity. The manual probe or its base station should have adjustable sensitivity for adaptation to the background radiation. Hand-held γ probes must be checked at regular intervals according to the legal requirements for quality control. Intraoperatively, they have to be covered by a sterile sheath.

The location of the SLN is identified transcutaneously by measuring the maximum signal activity in the axilla. The preparation should be performed using an atraumatic and blood-sparing technique with repeated use of the probe. Radiolabeled and/or blue-stained lymph nodes or lymph nodes that show a stained afferent lymphatic pathway are sent separately for intraoperative histopathologic assessment. The removal of additional lymph nodes should be avoided, with the exception of enlarged or suspicious lymph nodes. Ex vivo control for tracer uptake should be performed for each SLN and the results documented. If a lymph node without any tracer uptake is resected, then it should be submitted separately and labeled as a “nonsentinel lymph node.”

Intraoperative Definition of SLN(s)

According to the concept of an orderly lymphatic diffusion of tumor cells, the SLN is defined as the first lymph node to which metastasis from a primary tumor occurs. Because several lymph nodes may receive direct drainage from a primary tumor, SLNB is not restricted to a single lymph node. Intraoperatively, SLNs are identified by an afferent stained vessel or an uptake of tracer. In approximately 15% of patients, however, > 3 SLNs can be identified,34 and it is unclear whether all of these are first-echelon lymph nodes and whether their complete removal will be beneficial clinically.37, 38 Some authors have shown that SLNB may be restricted to a certain number of SLNs and that 98% of lymph node-positive patients can be identified within the first 3 SLN sites examined.39, 40 Others recommend differentiation between SLNs and non-SLNs by comparing the SLN-to-background ratio (3:1) or the ex vivo count ratio (10:1).18 However, undetected SLNs have been identified as a source of false-negative results for SLNB. Conversely, the removal of multiple SLNs may be almost as extensive as an axillary dissection. Because the clinical or intraoperative definition of an SLN remains a controversial issue, the consensus panel recommends the excision of all radioactive and/or blue-stained lymph nodes and of those lymph nodes that show an afferent stained vessel. If > 3 SLNs are detected, then it may be helpful to use the count/background ratio (3:1) and/or the (expected) ex vivo count ratio (10:1) to restrict the procedure to a reasonable extent.

All SLNs should be numbered in the order of their removal and sent separately for histopathologic work-up. The number of counts, the method used for detection (dye uptake, visualization of lymphatic vessels), and the location (Level I, Level II, or other) should be documented.

Postoperatively, the axilla must be screened thoroughly for residual radioactivity. The highest target count should be documented. The intraoperative situation (location and number of removed SLNs) should be compared with the lymphoscintigraphic findings, and the correlation should be checked and documented.

Blue-Dye Method

The dye method can be used in addition to the radioguided technique and may facilitate the localization of an SLN. This method is restricted to intraoperative use and is suitable for short-term planning. The injection volume is 2–5 mL. Based on palpation, the tracer can be injected into the peritumoral tissue, intradermally or subdermally, or into the subareolar region. Peritumoral injection is preferable, because it minimizes cosmetic alterations, such as tattooing of the skin. Between 5 minutes and 10 minutes after injection, the preparation of the lymphatic pathway can be performed. If the tumor is located in the vicinity of the axilla or if a mastectomy is planned, then an approach from the primary incision on the breast may be chosen. Otherwise, a small, separate incision (maximum, 4 cm) should be made directly over the SLN. Preparation must be performed by atraumatic spread using the surgical scissors to avoid disruption of the lymphatic vessels.

PATHOLOGIC EVALUATION OF SLNS

The SLN is examined both intraoperatively and postoperatively. Intraoperative assessment allows axillary surgery in a single session if the SLN is positive intraoperatively or truly negative on the definite histopathologic evaluation. The postoperative examination provides the final histopathologic status of the SLN for the definitive decision on further locoregional and systemic treatment.

Intraoperative Examination

Imprint cytology and the frozen-section technique have shown comparable results with respect to accuracy of the intraoperative evaluation.41 In the case of a negative intraoperative finding, the definitive histopathologic work-up still may reveal a metastasis, requiring secondary axillary surgery.

The best results from intraoperative assessment of SLNs are attained when the final histologic investigation is restricted to the same cut surface that was examined intraoperatively.42 It should be kept in mind, however, that this is a source of bias: The more detailed the definitive work-up, the more false-negative results of intraoperative evaluation will be identified. Metastases that measure > 2 mm in greatest dimension usually will be detected as suspicious findings during a careful investigation of the cut surfaces by the naked eye after slicing the lymph node. These findings can be verified microscopically with either method. If macrometastases are identified, then the examination is completed with one paraffin slide from the respective level. Stepwise intraoperative evaluation of the SLNs is not justified, particularly in view of the loss of tissue in cases of negative or inconclusive results.

Postoperative Examination

The extent and meticulousness of the histopathologic work-up of SLNs should depend on the relevance of the results for further treatment decisions. The prognostic significance of micrometastases, their predictive role for the involvement of non-SLNs, and the clinical consequences of a false-negative staging due to undetected micrometastases still are being debated. However, the clinical implications of micrometastatic involvement of SLNs do not justify a systematic search for all micrometastases.

There is no doubt that all macrometastases should be detected during the definitive pathologic examination. Prerequisites for the detection of all (macro)metastases ≥ 2 mm are the complete embedding of the lymph node and a homogeneous distribution of the levels histologically examined from the tissue blocks. This can be achieved by producing SLN slices of 3 mm thickness for the macroscopic examination and for step sectioning. In instances of negative macroscopic findings, the slices should be examined at regular, 500-μm intervals (maximum, 6 steps). This approach provides a theoretical detection rate for macrometastases of 100%.43 Inhomogeneously distributed serial sections only near the surface of the tissue block should be avoided, because macrometastases in the remaining portion of the tissue may be missed.

Macrometastasis, micrometastasis, and isolated tumor cells (ITCs) are defined by the International Union Against Cancer (UICC) TNM classification system and by the American Joint Committee on Cancer (AJCC).2, 3 For clinical use and for research, it is important to describe micrometastases by the measurement of their greatest dimension and not by the method of detection (immunohistochemistry or hematoxylin and eosin staining). Studies that have reported a prognostic significance of micrometastases generally evinced a lack of standardization of the pathology protocol and of the nomenclature. Some of the described micrometastases may have been macrometastases in which the greatest dimension was not detected. Despite numerous publications, the prognostic significance of micrometastatic lymph node involvement remains unclear.41, 44, 45

The current protocol was based strictly on a defined, reproducible description of micrometastatic disease in the SLN. The rationale for defining minimal requirements for pathologic examination of the SLN(s) is the detection of macrometastases. With the detection of all metastases measuring ≥ 2 mm in greatest dimension, the theoretical rate of histopathologically missed metastases does not exceed 2%.46

Immunohistochemistry

The use of cytokeratin immunohistochemistry may facilitate the pathologic assessment. It can be helpful in detecting small or noncohesive metastases in doubtful cases, especially in invasive lobular carcinoma. With respect to cost effectiveness, the immunohistochemical examination cannot be recommended for routine use.

Molecular Pathology

The molecular pathologic examination of SLNs remains an experimental method. Reverse transcriptase-polymerase chain reaction analysis is a highly sensitive method. However, it is difficult to find an RNA sequence that is specific for single tumors. Hence, it may be necessary to use a panel of markers, particularly because the morphology of positive cells cannot be assessed. High sensitivity, however, is associated with the risk of false-positive results.

Documentation of the Histopathologic Findings

SLNB requires standardized documentation of the histologic findings. Every SLN must be sent separately for histopathologic examination with a specific identification number. The location and sequence of removal and the method of detection (including target count) should be documented by the surgeon. The histopathologic results are reported as the pathologic lymph node (pN) category according to the UICC TNM classification system2, 3 (see Table 3).

Table 3. Documentation Standard for Histopathologic Findings in the Sentinel Lymph Node

pN category: pathologic lymph node category; IHC: immunohistochemistry; sn: sentinel lymph node; +: positive; −: negative.

Macrometastases

Lymph node metastasis with greatest maximum dimension

Perforation of the capsule (yes/no)

Reference to pN category of the axillary dissection specimen

Micrometastases

Micrometastasis with greatest maximum dimension

Reference to pN category of the axillary dissection specimen

Isolated tumor cells

Isolated tumor cells detected morphologically (i.e., by step sectioning and/or IHC): pN0 (i+) (sn)

Isolated tumor cells detected by both morphologic (see above) and nonmorphologic (molecular) methods: pN0 (i+) (mol+) (sn)

Isolated tumor cells detected morphologically (i.e. by step sectioning and/or IHC) but not by nonmorphologic (molecular) methods: pN0 (i+) (mol−) (sn)

Isolated tumor cells exclusively detected by nonmorphologic (molecular) methods: pN0 (mol+) (sn)

Negative for metastases and isolated tumor cells

SLN without metastases, without isolated tumor cells after additional morphologic examination (step sections and/or IHC): pN0(i−) (sn)

SLN without metastases and without isolated tumor cells after additional examination by both morphologic (see above) and nonmorphologic (molecular) methods: pN0 (i−) (mol−)(sn)

SLN without isolated tumor cells after examination only by nonmorphologic (molecular) methods: pN0 (mol−) (sn)

THE ROLE OF SLNB IN LOCOREGIONAL AND SYSTEMIC TREATMENT DECISIONS

In addition to standards for patient selection and the technical procedure, clear guidelines for local and systemic treatment decisions after SLNB must be defined. This is of utmost importance, because lymphatic mapping provides new and complementary information relative to standard ALND. A more detailed histopathologic work-up will lead to higher rates of macrometastases and micrometastases as well as ITCs. Furthermore, SLNs may be found outside of the axilla, raising questions of whether there is a benefit from the local treatment of these lymph nodes (resection, radiotherapy) and what may be the impact of extended staging on adjuvant therapy and patient outcome.

Under quality-assured conditions, it seems appropriate to omit ALND or radiation therapy of the axilla for patients with negative SLN(s). Systemic therapy is indicated according to the recommendations for lymph node-negative patients. Patients with a positive SLN should undergo standard axillary dissection to achieve locoregional control and to obtain adequate information on the tumor stage (N1/N2).

To our knowledge, data are inconclusive with respect to the significance of micrometastatic disease in SLNs for locoregional control and the requirement for further treatment. In 7–34% of these patients, the involvement of non-SLNs has been reported.41 Based on these data, standard Level I and II axillary dissection is recommended in patients with incidentally detected micrometastatic disease in the SLN. There is some evidence, however, that undetected lymph node (micro)metastases will not necessarily become clinically apparent13, 24 and that a small rate of secondary axillary tumor growth is not relevant to overall survival.25 By using the histopathologic protocol described in this report, the theoretical rate of undetected metastases in SLN(s) will not exceed 2%.45 According to the applied model,46 all of these missed metastases would be micrometastases. This rate of undetected lymph node involvement seems acceptable with respect to its theoretical impact on locoregional failures and overall outcome. Further evidence on the role of micrometastatic disease will be required and may give rise to amendment of these guidelines.

Adjuvant treatment decisions ideally are based on predictive factors that indicate a benefit for a specific therapy with regard to disease-free and overall survival. For breast carcinoma, only hormone receptor status has clinical significance as a predictive factor in the adjuvant setting. Prognostic factors can identify subgroups of patients with an adverse prognosis and, in terms of strong prognostic power, may serve as selection criteria for adjuvant therapy. The axillary lymph node status has proven to be such a strong prognostic factor in breast carcinoma and plays an important role in the determination of adjuvant therapy.1

Although numerous trials have examined the prognostic significance of micrometastases in axillary lymph nodes,41, 43, 44 the prognostic relevance of metastases measuring < 2 mm in greatest dimension remains unclear. The prognostic power of micrometastatic lymph node involvement, if any, appears low. The benefit of adjuvant therapy based on the axillary lymph node status seems doubtful in this subgroup of patients. Especially in the group of postmenopausal women with positive receptor status and micrometastatic lymph node involvement, a benefit from adjuvant chemotherapy, as recommended for patients with a positive axillary lymph node status,1 appears unlikely. However, because patients with micrometastatic lymph node involvement are staged as pN1mi, and data are inconclusive with respect to the prognostic significance of these metastases, the panel decided to recommend adjuvant therapy for these patients. The specific treatment (antihormone vs. combination hormone therapy), however, should be individualized and should be based on additional prognostic factors.

In accordance with the St. Gallen declaration of 20031 and the recommendation of the Philadelphia consensus committee in 2001,2 no further local treatment (ALND, radiotherapy) of the axilla is recommended for patients with ITCs (i+) detected in the SLN (pN0[i+]). Systemic therapy is recommended according to the guidelines for lymph node-negative patients.

To our knowledge, there is no evidence that surgical removal of extraaxillary lymph nodes is associated with improved locoregional control or better survival rates.47 Although, in three recent studies, a survival advantage was described for patients who received postmastectomy radiation that included the lymphatics,48–50 the separate contribution of lymph node irradiation in addition to radiotherapy of the chest wall cannot be determined.51 However, for patients who have an SLN detected in the internal mammary pathway, radiotherapy of the retrosternal lymph nodes may be considered according to the patient's individual risk profile (e.g., axillary lymph node involvement).52

It is unclear whether extended staging by removal of extraaxillary SLNs will improve systemic therapy and lead to better survival rates. Because most adjuvant treatment decisions also are based on factors other than N status, the impact of additional information regarding the extraaxillary lymph node status on the therapeutic outcome appears low. Weighing the risks, costs, and potential benefits of extraaxillary lymph node resection, the panel does not recommend SLNB outside the axilla for routine clinical use but encourages participation in clinical trials. The recommendations of the panel for local and systemic treatment decisions after SLNB are summarized in Table 4.

Table 4. The Role of Sentinel Lymph Node Biopsy in Further Locoregional and Systemic Treatment Decisions

SLN status	Local treatment	Systemic therapy
pN category: pathologic lymph node category; sn, SN: sentinel lymph node; mi: micrometastases; i+: isolated tumor cells.
pN0(sn)	None	According to guidelines for N0
pN1	Axillary dissection Levels I and II	According to guidelines for N1
pN1 (mi)	Axillary dissection Level I and II	Systematic treatment
	Alternatively (second preference), radiotherapy of the regional lymphatics	Specific therapy individualized
pN0(i+)(sn)	None	According to guidelines for N0
Detection of extraaxillary SN	None	According to guidelines for N0/N1 (axillary status)

FOLLOW UP CARE

The current guidelines for follow-up care of patients with breast carcinoma seem appropriate for women who have undergone SLNB.53 Additional measures, such as ultrasound of the axilla, are not required. It is recommended that institutions have access to follow-up data, especially with regard to long-term recurrences.

CONCLUSIONS

The main objective of the current report was the establishment of practical guidelines for the use of SLNB in clinical routine to facilitate a nationwide, homogeneous standard in the clinical implementation of the method. The recommendations are based on the Philadelphia consensus meeting, which was published in 2002,3 but they also extend to issues of quality assurance. Because the technical procedure of SLNB still is under clinical investigation, and both the spectrum of indications and the technical procedures are in the process of optimization, the current consensus recommendations will have to be adjusted continuously in light of insights from forthcoming study results. Moreover, the panel strongly encourages clinicians who perform SLNB in their institution to participate in clinical trials.

Acknowledgements

The authors thank G. Cserni, O. E. Nieweg, R. Kreienberg, and W. Jonat for their critical revision and valuable contributions to this article. They also thank D. Roseweare for revision of the English text.