Sentinel Node Biopsy and Axillary Dissection

Hiram S. Cody III

Introduction

For patients with breast cancer, the most important prognostic factor is axillary node status. The principal goal of axillary surgery is staging/prognostication; secondary goals include local control and (arguably) a small survival benefit. For most of the 20th century, these goals have been addressed by the historic gold standard, axillary lymph node dissection (ALND). Recently, ALND has given way to a new standard, sentinel lymph node (SLN) biopsy. This chapter will review the current status of SLN biopsy and ALND in the management of operable breast cancer.

Historical Background

Jean Louis Petit (1674–1750), director of the French Surgical Academy, was probably the first surgeon to articulate a unified concept for breast cancer surgery (1). He emphasized the importance of an en bloc resection of the breast and axillary nodes, but his insight came too early: Even by the mid-19th century, breast cancer was widely regarded as incurable by surgery. Halsted’s landmark 1894 (2) and 1907 (3) reports of his meticulous technique for “radical mastectomy” (RM) (which included removal of the breast and pectoral muscles, with a complete ALND) suggested that reducing local recurrence would increase survival, and this intuitive concept made RM/ALND the standard operation for the next 70 years despite later reports of techniques that were either more radical (extended radical mastectomy) (4) or less radical (modified radical mastectomy) (5,6). In the “Halstedian” era, the goal was to maximize cure by minimizing local failure.

In the 1970s, Fisher (7) proposed that breast cancer was a systemic disease from the outset and that survival was largely a function of tumor biology, not surgical technique. The “Fisher hypothesis” was tested in National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 randomized trial (1971–1974) (8,9,10); at 25 years’ follow-up, variations in local treatment for patients with clinically node-positive breast cancer (RM vs. total mastectomy/radiotherapy [RT]) or clinically node-negative disease (RM vs. total mastectomy/RT vs. total mastectomy alone) yielded no differences in any category of survival. B-04 did confirm the overwhelming prognostic significance of axillary node metastasis, and ALND was incorporated into all subsequent NSABP trials for invasive breast cancer. In the “Fisher” era, the primary objective of ALND was prognostication to guide systemic therapy, a secondary objective was local control, and a survival benefit was unproved.

We now know that both Halsted and Fisher were right. A remarkable series of meta-analyses from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) confirms that breast cancer is a family of diseases with a wide spectrum of behavior (11), ranging from predominantly local (Halsted) to predominantly systemic (Fisher) phenotypes. First, the EBCTCG showed that local control and survival are related (42,000 women in 78 randomized trials) (12) and estimated that for every 4 local recurrences prevented, 1 life would be saved. Second, they confirmed that there is no survival advantage for more radical versus less radical versions of mastectomy (3,400 women in nine trials) or for mastectomy versus breast conservation (3,100 women in seven trials) (13). Finally, they demonstrated an incremental survival benefit from the addition of systemic adjuvant therapy, chemotherapy, or hormonal therapy to local treatment (8,000 to 33,000 women in six separate meta-analyses comprising 194 trials) (14). These results highlight the multidisciplinary nature of contemporary breast cancer treatment and the importance of collaboration among the disciplines of surgery, medical oncology, and radiotherapy.

The SLN concepts that (a) the first, or first few, regional lymph nodes draining a tumor site could predict the status of that regional node basin, (b) these nodes could be reliably mapped by injections of radiotracer or dye, and (c) SLN-negative patients might thereby avoid the added morbidity of regional node dissection were first articulated by Cabanas (15) in 1977 for penile cancer and independently by Morton et al. (16) in 1992 for melanoma. Krag et al. (17) in 1993 (using isotope mapping) and Giuliano et al. (18) in 1994 (using blue dye) were the first to report SLN biopsy for breast cancer. Since then, 69 observational series (19) of SLN biopsy (validated by a planned “backup” ALND) and the early results of seven randomized trials (20,21,22,23,24,25,26) comparing SLN biopsy with ALND have confirmed that the morbidity of SLN biopsy is less than that of ALND, that staging accuracy is at least equivalent, and, in the single randomized trial reporting long-term results (27), that survival and other disease-related adverse events are comparable at 7 years’ follow-up. The SLN hypothesis has been validated by two elegant studies, one showing that a negative SLN is highly predictive of a negative axilla (28) and the other showing the SLN is the node likeliest to be positive (29). At present, virtually all node-negative breast cancer patients are staged by SLN biopsy alone, and the principal goal of ALND is to maximize local control in patients already proven by SLN biopsy to be node-positive.

Case Selection for Sentinel Lymph Node Biopsy

As for any new surgical procedure, most institutions began to do SLN biopsy with caution, validating their early experience with a planned backup ALND to confirm an acceptably low false-negative rate (the proportion of node-positive patients in which the SLN was negative), limiting SLN biopsy to those patients with the lowest probability of axillary node metastasis, and avoiding SLN biopsy for a variety of putative but unproven “contraindications.” Among others, these included nonpalpable breast lesions, clinically suspicious axillary nodes, any prior breast or axillary surgery, large excisional biopsy, large tumor, multicentric tumor, prior RT, prior chemotherapy, male breast cancer, and pregnancy.

Table 9.1 Indications for Sentinel Lymph Node (SLN) Biopsy and Axillary Lymph Node Dissection (ALND)

Indications for SLN Biopsy	Indications for ALND
Clinically node-negative T1–3 invasive (or microinvasive) breast cancer	Axillary node metastasis on FNA or core biopsy
Clinically node-positive with negative preoperative fine-needle aspiration or core biopsy	Prior inadequate ALND
Following neoadjuvant chemotherapy for T2–3 disease	Positive SLN on intraoperative exam
Ductal carcinoma in situ requiring mastectomy or presenting as a mass	Validation trials with planned backup ALND
Ipsilateral breast recurrence and prior SLN biopsy/ALND	Palpably suspicious nodes during SLN biopsy
Prophylactic mastectomy	Neoadjuvant chemotherapy for locally advanced (T4) disease
	Failed SLN biopsy
	Unavailability of SLN biopsy
	Axillary local recurrence (ipsilateral or contralateral)

Based on an extensive literature (30), it is now clear that SLN biopsy is suitable for (a) virtually all operable invasive breast cancers with a clinically negative axilla, (b) ductal carcinoma in situ (DCIS) that requires mastectomy (or in which invasion is suspected based on the presence of a mass), and (c) breast cancer with clinically suspicious nodes when an ultrasound-guided fine-needle aspiration or core biopsy is nondiagnostic (Table 9.1). SLN biopsy is also reasonable in the setting of prophylactic mastectomy, where invasive cancer will be found in a small proportion of cases. SLN biopsy is feasible in patients previously operated for breast cancer (31,32), especially if fewer that ten nodes were removed in a prior SLN biopsy or ALND. Finally, SLN biopsy appears to work well after aesthetic breast surgery; two studies (33,34) have used lymphoscintigraphy to document preservation of the axillary lymphatic drainage following transaxillary breast augmentation, and in a series of 70 SLN biopsy procedures (50 patients with prior breast augmentation and 20 with prior breast reduction) (35), SLNs were identified at surgery in 100% of patients.

Technique of Sentinel Lymph Node Biopsy

For those institutions wishing to start a SLN biopsy program, there are several guiding principles. First, SLN biopsy requires close collaboration among the disciplines of nuclear medicine, surgery, and pathology. Second, SLN biopsy should be done according to a well-defined and consistently applied protocol (36). Third, SLN biopsy is best learned in a formalized course, with experienced mentorship for one’s first procedures. Early on, SLN biopsy should be validated by a backup ALND to allow an audit of both the success rate (which should exceed 90%) and the false-negative rate (which should not exceed 5% to 10%). There is a learning curve for SLN biopsy, but it remains unclear how many backup ALNDs are required before one can perform SLN biopsy on one’s own. Convincing data from the Axillary Lymphatic Mapping Against Nodal Axillary Clearance (ALMANAC) trial show that for experienced surgeons working within a well-defined protocol, most failed and/or false-negative procedures occur within a surgeon’s first few cases (37).

Nuclear Medicine

The success of SLN biopsy is maximized, and the false-negative rate is minimized, by the combination of radioisotope and blue dye (22,38,39), but radioisotope accounts for the greatest proportion of this success, and with experience the marginal benefit of blue dye diminishes (40). The isotope of choice is technetium (Tc^99m) bound to a variety of carrier particles, most commonly sulfur colloid (United States), colloidal albumin (Europe), and antimony (Australia).

There is no standardization of isotope dose, particle size, volume of injectate, timing of injection, or site of injection, and many methods appear to work well. Our preference is to inject 0.1 mCi (3.7 MBq) of unfiltered Tc^99m-sulfur colloid on the morning of surgery or 0.5 mCi (18.5 MBq) the day before. With this protocol, which allows for radioactive decay (the half-life of Tc^99m is 6 hours) we have observed equivalent results with same-day or day-before isotope (41). It appears that the performance of unfiltered and filtered isotope preparations is similar.

We inject the isotope in a volume of 0.05 cc; this has the advantage of leaving a very small “hot spot” on the breast, so as not to overshadow the axilla in patients with upper outer quadrant tumors. We inject intradermally at a single site over the tumor, and have found that this technique is superior to parenchymal or peritumoral injection (42), a result that has been independently confirmed in a randomized trial by Povoski et al. (43). In the large multicenter Louisville Sentinel Node Trial (44), superficial injections (intradermal, subdermal, or subareolar) were also more successful than parenchymal (peritumoral) injection or dye-only techniques, and the false-negative rate of all methods was similar, suggesting that the lymphatics of the entire breast usually drain to the same few SLN.

Preoperative lymphoscintigraphy (LSG) is essential in SLN biopsy for melanoma, but its role in breast cancer is uncertain. Our practice is to take a single LSG image 30 to 120 minutes after isotope injection. LSG does not improve the identification of axillary SLN (45), other than to alert the surgeon that more than one axillary SLN is present. Even when the LSG is negative, the much more sensitive hand-held gamma probe will identify “hot” SLN at surgery in most patients (38). LSG demonstrates nonaxillary lymphatic drainage (primarily to the internal mammary nodes) in about 25% of patients (46,47), but the
impact of this information on treatment is minimal and its effect on local control or survival is unproved.

Surgery

SLN biopsy is a deceptively simple operation. The following reflect my experience (and that of my colleagues) at Memorial Sloan-Kettering Cancer Center (MSKCC) with more than 13,000 procedures. We perform SLN biopsy under general anesthesia for patients having mastectomy and under local anesthetic with intravenous (IV) sedation for breast conservation. Several minutes before starting surgery, we inject 1 to 5 cc of isosulfan blue dye subdermally in the breast, typically at a single site over the tumor, just superolateral to a biopsy scar or just adjacent to a localizing wire. Care is taken not to inject into a prior biopsy cavity, into the retromammary fascial plane, or into the dermis (to avoid tattooing) and to inject a smaller volume of dye for tumors in the axillary tail (to avoid direct spillage into the axilla). Giuliano et al. (18) recommended massage of the injection site to improve lymphatic uptake, but there are no data to support this practice.

Using a handheld gamma probe, we identify the isotope injection site in the breast, any focal hot spots in the axilla, and any intervening hot spots that might suggest the presence of intramammary SLN. The axilla is usually explored for SLN through a separate transverse skin line incision prior to the planned mastectomy or breast conservation procedure. When the probability of SLN metastasis is very low (i.e., in mastectomy for DCIS or prophylaxis), SLN biopsy is easily done through the mastectomy incision once the breast has been reflected off the chest wall. For mastectomy done through a single oblique incision, SLN biopsy is best done through the axillary end of the incision prior to proceeding with the mastectomy.

We prefer to perform SLN biopsy under direct vision and with adequate exposure; the inadvertent division of sensory nerves that accounts for much of the reported morbidity of SLN biopsy can usually be avoided. As dissection is deepened through the axillary fascia, any blue lymphatics are left intact and traced proximally into the axilla, blue nodes are identified, and the gamma probe is used to identify any “hot” nodes. SLN are usually found low in level I, but in about 25% of cases they are found at other locations: posteriorly along the latissimus muscle, higher in the axilla near the axillary vein, beneath the pectoralis minor in levels II to III, and (much less often) as interpectoral (Rotter’s) or intramammary SLN. The gamma probe is very useful throughout this dissection and is indispensable in patients with a very large or fatty axilla when blue lymphatics or nodes are not found.

All blue SLN and hot SLN are removed, noting for each SLN whether it is blue and/or hot, and taking 10-second isotope counts ex vivo. Most SLN are both blue and hot, but about 10% are found only by dye or by isotope. We submit a median of two to three SLN per patient. When multiple hot SLN (or a diffusely hot axilla) are found, we make every effort to remove the SLN with the highest counts, having found that the hottest SLN is the positive SLN in 80% of cases (48), and we do not in general submit large numbers of SLN, having found that 98% of positive SLN are identified within the first three SLN and 99% within the first four SLN submitted (49). Another useful guideline is the “10% rule” (50), in which all nodes with counts ≥10% of the hottest node are submitted as SLN. Nodes that after excision are neither blue nor hot are submitted routinely as “nonsentinel” nodes.

A final and critical element in SLN biopsy is careful palpation of the axilla and the submission for examination of any palpably suspicious nodes. In our initial experience with SLN biopsy, we found that a false-negative rate of 14% defining the SLN as blue and/or hot was reduced to 4.6% by defining the SLN as blue and/or hot and/or palpable (48).

We usually perform SLN frozen section (FS) during surgery. If positive, FS allows an immediate ALND, and we have found that the yield (FS positive/FS done) and sensitivity (FS positive/SLN positive) of FS are 21% and 61%, respectively (51). We also perform ALND for, 2% of patients in whom SLN mapping is attempted and fails [failure is more likely with increasing age and body mass index (52)] or when the axilla remains suspicious to palpation despite a negative FS of SLN and/or non-SLN.

The axillary incision after SLN biopsy is closed routinely, without drainage. The morbidity of SLN biopsy is less than that of ALND but is not zero; patients may experience pain, seroma, hematoma, or infection. Blue dye may cause transient bluish-green discoloration of the skin and urine, blue urticaria in, 1% of patients, and anaphylactic reactions in, 0.5% of patients (53). A faint blue stain may persist at the breast injection site(s) as long as 1 year postoperatively.

Pathology

SLN biopsy is a targeted examination of those few axillary nodes most likely to be positive. While this allows additional pathologic study by serial sectioning and/or immunohistochemical (IHC) stains for cytokeratins, there is no standardized protocol for the pathologic examination of SLN. Recommendations range from routine examination by a single hematoxylin and eosin (H&E)–stained section to an exhaustive intraoperative examination of the entire node entailing 30 to 40 sections (54). Our protocol aims to go beyond routine examination but in a way that would be logistically feasible in our high-volume practice. After a negative intraoperative FS, the frozen tissue is thawed, fixed, and examined with H&E as a “frozen section control”; the remainder of the SLN is fixed, and two adjacent 5-μm sections (one stained with H&E and one with IHC) are taken from each of two levels 50 μm apart, generating a total of five slides per SLN. We have applied this protocol to archival specimens from 368 “node-negative” patients treated at MSKCC (1976 to 1978) and found occult nodal metastases in 23%. At 20 years’ follow-up these micrometastases had prognostic significance whether they were detected by IHC or H&E and whether they were categorized as pN0i+ (≤0.2 mm in size) or pN1mi (0.2 to 2 mm in size) by the current American Joint Committee on Cancer staging system (55).

Case Selection for Axillary Lymph Node Dissection

In the simplest sense, ALND would seem to be indicated for any patient with a “contraindication” to SLN biopsy. In fact, as noted above, most of the “contraindications” to SLN biopsy have been disproved, and SLN biopsy is suitable for virtually all patients with clinical stage T1–3 N0 invasive cancers (56). While the role of ALND has diminished in the era of SLN biopsy, there are at least nine clear indications for performing it (Table 9.1).

A Positive Axilla

Patients with proven axillary node metastases require ALND. Axillary ultrasound (US) and US-guided fine needle aspiration
(FNA) play a growing role in the diagnosis of axillary node metastasis prior to surgery, and these patients can proceed directly to ALND without SLN biopsy. The results of US-guided FNA vary widely, but even among patients with unselected clinically node-negative (cN0) breast cancers US-guided FNA identified node metastases in 8% of all patients and 21% of node-positive patients (57,58,59,60,61,62,63,64,65). The clinically positive (cN1) axilla is not an indication for ALND; in the era of ALND, clinical axillary examination was equally subject to false-negative and false-positive results (66), and this is confirmed by our experience with SLN biopsy, in which 25% of patients with cN1 axillae proved to be benign (67).

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