The development of axillary lymph node surgery

Virchow in the mid-nineteenth century observed metastasis of subdiaphragmatic cancers [1] to supraclavicular lymph nodes (LNs). This observation established the concept that cancer cells travel through lymphatic trunks to LNs at a distance away from the primary cancer. Forty years later Halsted, seeing breast cancer (BC) with bulky axillary metastases (mets), and invasion into the pectoralis muscle developed a radical operation to remove the breast, the pectoralis muscle and all the axillary LNs. Some women undergoing this operation were cured of their cancer [2,3]. Without any other effective treatment options available and the obvious improvement in cure rates, the Halsted radical mastectomy (RM) became the gold standard for BC management at the beginning of the 20^th century.

The era of RM for the surgical management of BC continued for at least seven decades. The importance of monitoring treatment outcomes began to take shape in the early 1900s. Histological evaluation of tumors and understanding of differences in tumor biology also advanced. By the 1920s, it was evident that BC was sometimes indolent and at other times aggressive, with a range of behaviors between those extremes [4]. RM was a disfiguring operation, causing disability, and lymphedema in up to 70% of patients [5]. Surgeons questioned the necessity of the procedure. Gray in Detroit, by injection of lymphatics at autopsy [6], proved that lymphatic vessels from the breast did not traverse the pectoralis major muscle and that lymphatic drainage of the breast into axillary LNs followed a path around the lateral border of that muscle. This observation questioned the rationale for removing the pectoralis muscle in RM where BC had not invaded the muscle. Patey developed a modified operation in which he left the pectoralis muscles intact and resected less LNs than in the RM [7]. However, other surgeons, were still encouraged by the improved outcomes of RM, and promoted even more extensive operations, including the excision of internal mammary and supraclavicular LNs, expecting even better results [8].

McWhirter [9] reported a 5-year survival rate of 43.7% in BC patients treated with simple mastectomy, without removal of the ipsilateral axillary LNs, followed by radiation of the axillary, supraclavicular and internal mammary LN basins, an outcome similar to that achieved by RM. Given these results, he proposed that axillary LN dissection was unnecessary when the nodes were not involved and also hypothesized that the RM failed when disease had spread to the axilla because the operation did not treat the supraclavicular or internal mammary nodal basins. At the time when clinicians believed strongly that radical surgical resection of LNs was the most sensible option, and anything less was inadequate, the concept of using radiation to treat subclinical mets in LN basins was met with much resistance. In a randomized trial RM, compared to simple mastectomy followed by radiation therapy, showed no significant difference in survival rates [10]. Despite these findings, confusion remained over the best surgical treatment in BC and clinicians treating BC did not follow uniform guidelines.

Studies in the early 1950’s that compared radical to modified radical mastectomy (MRM) showed similar survival rates but lower post-operative debility for patients undergoing the modified operation that left the pectoralis muscle in place [10]. Concomitant skepticism around the use of radiation therapy to treat the axilla, and dissatisfaction with the morbidity associated with the RM, and the recognition that the RM did not prove better than the modified operation, increased the popularity of MRM. The MRM subsequently became the standard of surgical care.

Meanwhile a major change in thinking came from the National Surgical Adjuvant Breast and Bowel Project (NSABP), chaired by Fisher [11]. Based upon animal studies and also observations of angiogenesis in and around growing cancers [12], the new hypothesis of systemic BC mets was that cancer cells accessed the systemic circulation directly at the site of the primary tumor and that regional LN metastasis was coincidental. Clinicians began to believe that BC was a systemic disease from the outset.

Pathologists seeing BC cells in endothelium-lined spaces, and uncertain as to whether these were blood vessels or lymphatic capillaries, coined the term lymphovascular invasion (LVI). Molecular characterization of lymphatic endothelial cell markers allowed pathologists, using immunohistochemistry, to distinguish blood vessel from lymphatic capillary invasion [13] and to show that > 90% of the vessels in LVI in BC were lymphatic, not blood vessels. Survival studies later showed LVI to be a significant predictor of regional LN mets [14]. This supports the Virchow/Halsted hypothesis, which focused on the importance of the LNs as the main portal of tumor cells in an orderly pathway to systemic sites. LNs continued to be important, and surgeons felt justified in removing them all by complete axillary lymph node dissection (CALND).

Sentinel lymph node biopsy

The first use of the term ‘sentinel node’ came from an investigation into the possible relationship between ileocecal lymph flow and the development of gastric and duodenal peptic ulcers. In 1923 lymphophilic dye injected into the ileocecal area was traced to the first LNs [15]. Later the idea of a sentinel lymph node (SLN) as the first node(s) to receive drainage from malignant tumors, and therefore targeted for resection, was reported for malignant parotid gland tumors [16] and the penis [17]. Farmers in Paraguay with penile cancer were treated surgically by penectomy and bilateral inguino-femoral lymphadenectomy, resulting in devastating lower limb lymphedema in almost every case. Cabanas, an American-trained urologist, devised an operation based on the identification and evaluation of the first echelon node draining the penis. By injecting contrast material viathe dorsal lymphatics of the penis, he reliably identified the first lymph node to drain the primary tumor, the sentinel lymph node (SLN). If the SLN was negative for cancer, he hypothesized that cancer had not metastasized to the locoregional nodal basin, and the patient would not benefit from inguino-femoral and iliac dissection.

The original hypothesis that initiated the SLN era was based upon the belief that mets in the first LN draining a malignant tumor would be representative of the entire nodal basin. The theory of SLN biopsy (SLNB) is based on two principles: first, the existence of an orderly and predictable pattern of lymphatic drainage to a regional node basin, and secondly, that the first node or nodes function as an effective filter for tumor cells.

Nathanson in a mouse footpad model of melanoma showed orderly mets of tumor to the popliteal SLN, and then the femoral node and then the lungs [18]. Studies in this model incorporated methylene blue dye, which, when injected into the footpad adjacent to the growing tumor, entered the lymphatic capillaries and traveled to the ipsilateral popliteal LN [19]. Following this report Morton injected lymphophilic blue dyes intradermally in healthy cats and demonstrated [20] drainage to sentinel nodes by visualizing LNs filled with blue dye.

Morton, regarded by many as the ‘father’ of the modern SLN era, did the first SLN studies in melanoma patients [21]. In the 1970’s prophylactic complete lymphadenectomy selectively used in skin melanoma patients with clinically negative regional LNs sometimes resulted in chronic lymphedema. This complication was particularly distressing in patients with pathologically negative LNs but thought justifiable in patients whose LNs showed mets, since removing LN mets was thought to be therapeutic.

How could one identify which patients had positive LNs so that only those patients would be offered ‘therapeutic’ lymphadenectomies? The decision as to which LN basin to remove was dependent upon 19^th century anatomic lymphatic drainage studies. It was logical to selectively remove the groin or axillary LNs for lower and upper limb melanomas, respectively. But the issue was different for truncal and head and neck melanomas where purely anatomic criteria for selecting the appropriate LN basin to remove surgically was sometimes proven wrong. The lymphoscintigram, using an intradermal radioactive colloid injection followed by gamma imaging, enabled more accurate identification of lymphatic drainage patterns from truncal melanomas [22]. The images consistently revealed the direction of lymph flow from the melanoma site and also showed the collection of the tracer in the SLN. This changed the way surgeons selected the LN basin to operate in doing complete lymphadenectomies. However, the technology did not immediately change the rationale for removing all the LNs in a targeted basin. It took another decade before Morton started to investigate the possibility of removing the SLN with the idea that melanoma patients with pathologically negative SLNs could safely avoid complete lymphadenectomy.

The dilemma of how to find the SLN in patients in the operating room was a practical one. Gamma probes were initially not available for use intra-operatively to find the lymphoscintigraphically identified ‘hot’ node. Accurate intra-operative identification of a lymphoscintigraphic SLN was the primary challenge. After the important animal studies in mice and cats, Morton’s landmark clinical study accurately identified the SLN in melanoma patients [21] following peri-tumoral injection of isosulphan blue. This study initiated the SLN era, first in melanoma, then in BC, and other human cancers that tend to metastasize to LNs.

SLNB was first introduced as part of BC nodal staging by Giuliano, et al. [23] using peri-tumoral blue dye injection alone. Blue lymphatics were seen coursing through the axilla. The blue SLN was found in only 65% of patients by following these visible lymphatic vessels. Simultaneously, the use of intra-operative gamma probes with radioisotopes was developed by Krag, et al. [24], and together these studies established the role of blue dye and radioisotope in SLNB in BC. Dye injection into the subareolar plexus [25] revealed the importance of a single lymphatic trunk draining the eleven o’clock right breast and the two o’clock left breast, which led to simpler techniques of breast injection and better ways of finding the SLN. The improved surgical technique of lymphatic mapping demonstrated that it was both a feasible and accurate method of staging the axilla [26, 27]. The use of a combination of blue dye and a radioactive tracer, as well as peri areolar/subareolar injection sites for both the dye and the tracer, were subsequently noted to improve SLN identification rates [28-31].

The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 (1999-2004) randomized clinically node negative (cN0) patients to SLNB alone over SLNB followed by completion axillary lymph node dissection (CALND) [32]. This trial illustrated that SLNB alone had similar disease-free and overall survival compared to CALND in cN0 BC patients. Secondary endpoints of NSABP B-32 showed that patients who underwent a CALND had significantly more lymphedema, shoulder dysfunction and paresthesia than those who underwent SLNB alone [33]. The American College of Surgeons Oncology Group (ACOSOG) Z0010 enrolled BC patients onto a phase II trial studying the prognostic significance of bone marrow and sentinel node micro metastases [34].

The landmark ACOSOG Z0011 trial compared CALND to SLNB alone in patients with tumors 5 cm or smaller (T1, 2) cN0 and systemic mets free (M0) with 1-2 positive SLNs (pN1) undergoing lumpectomy. SLNB alone was non-inferior to complete lymphadenectomy [35]. There were no statistically significant differences in disease-free survival, overall survival or locoregional recurrence between groups. This study, plus the historical observations that suggested axillary surgery does not affect overall survival, and the knowledge that CALND has adverse effects revolutionized axillary management. SLNB has replaced CALND for most patients with early stage, pN1 BC undergoing upfront surgery.

The introduction of SLNB has revolutionized not only the surgical management of BC but has led to changes in the overall management of this disease. Instead of removal of all axillary metastatic tumor by CALND, SLNB became an important test to determine whether there was metastasis in the node, which often determined whether systemic chemotherapy was indicated. In time CALND disappeared for many patients [35,36]. Absent clinical evidence of axillary nodal disease, SLNB is the appropriate surgical approach to women with operable BC and CALND can safely be avoided in most cases undergoing breast conserving surgeries even when the SLN contains tumor.

Ongoing value of sentinel node biopsy

LN mets, tumor size, lymphovascular invasion (LVI) and histological tumor grade are the best-established traditional prognostic factors in BC [37]. Clinicians wanting to know the pathologic status of the SLN in patients with a clinically negative ipsilateral axilla (cN0) BC for prognostic purposes and to guide adjuvant therapy recommendations rely on SLNB, usually done at the same time as a mastectomy or lumpectomy. At least four questions arise regarding the need to do SLNB in the operating room: first, are radiologic scans sensitive and specific enough to avoid biopsy? Second, can needle biopsy alone reliably obtain the information? third, can we avoid biopsy of the SLN altogether? fourth, is SLNB therapeutic?

Magnetic Resonance Imaging, CT scans, PET scans and axillary ultrasound, despite showing images of LNs, are not sensitive or specific enough to always determine the presence of metastatic BC in the SLN(s) [38]. Ultrasound of the axillary LNs is quick, easy, and inexpensive and the accuracy of identifying BC mets by morphology is fairly high if combined with needle biopsy [39]. Ultrasound-guided needle biopsy of random axillary LNs based upon LN morphology may miss the true SLN [40]. Surgeons find the SLN in a plane corresponding to the lowest hair follicles in the axilla, usually the lowest node. But could a radiologist or surgeon consistently identify the true SLN by looking with an ultrasound only at those lowest nodes? We studied this question by doing a needle biopsy of the lowest axillary LN, placing a metal clip in the node, removing the SLN surgically and x-raying the node. The ‘clipped node’ was the SLN in 79% of cases [40]. Because only 95% or higher accuracy would be comparable to surgical SLNB, ultrasound guided needle biopsy was not accurate enough to replace SLNB.

Current efforts to avoid SLNB are dependent upon individual clinical circumstances. Axillary surgery is contra-indicated in some patients. This includes patients with stage IV BC where SLNB has no therapeutic or prognostic value and is unlikely to guide systemic therapy. Surgeons instinctively avoid any axillary surgery in moribund or extremely feeble patients with cN0 early-stage BC when the predicted demise from other causes is more likely than from the BC. Women older than 70 years who are biologically healthy, and with the least aggressive early BC, and with a significantly lower likelihood of SLN mets [41] may safely avoid SLN biopsy [42] because the procedure does not significantly affect the outcome. Small, low grade tubular BCs, and other low-grade lesions, rarely metastasize to LNs and SLNB is often omitted.

The likelihood of LN mets based on pathologic morphology, such as grade, size, LVI and proliferative indices is already known [43]. With increasing knowledge of the molecular mechanisms of LN mets [44-46], and the associations amongst patient demographics [47], molecular markers [48], histology [43] and LN mets, we anticipate using better selection criteria to identify patients needing SLNB.

Molecular markers in the primary BC, helpful in predicting mets, may one day replace SLNB. To get there we will need to be sure that removing a tumor laden SLN is not itself therapeutic. To determine whether SLNB is truly therapeutic would require an unlikely prospective clinical trial, one which would randomize selected BC patients to undergo SLNB or no axillary surgery and no radiation or chemotherapy that might influence the results. Although such a perfectly constructed trial is unlikely to be done, there are three ongoing clinical trials—SOUND, INSEMA, BOOG 2013-08—comparing SLNB to observation in cN0 women with no abnormal LNs seen on ultrasound. With only preliminary data reported we anticipate the findings from these studies may make pathologic evaluation of LNs in specific cohorts of women with BC outdated.

Lymph node surgery in patients with positive nodes

We have a better understanding of the importance of molecular subtypes of BC and how that relates to the prediction of chemotherapy response. Improved pre-operative systemic therapies, and a more informed understanding of BC biology have allowed less aggressive surgery of the breast and axillary LNs following pre-operative chemotherapy [49,50]. Clinical trials are looking at the option of avoiding CALND in exceptional responders [51], particularly when the pathologist finds no residual tumor in lymphadenectomy specimens – a complete pathologic response. The conversion from node positive to pathologically node negative occurred in 40% to 74% of patients receiving anti-HER2 directed preoperative therapy [52,53].

 BC management guidelines, such as those available from the National Comprehensive Cancer Network, routinely update recommendations for BC management based upon new data, such as molecular markers. The hormone receptors, Her2/neu expression and multigene signature panels such as the 21-gene Oncotype Dx Recurrence Score on BC cells, coupled with pathologic data and demographics, often informs the type of systemic therapy and when to give it. Women with Her2/neu positive tumors that present with axillary LN mets commonly receive neoadjuvant chemotherapy and anti-Her2 antibodies. Patients with positive LNs who have negative hormone receptor and Her2 expression, so-called triple negative BC (TNBC), may get neoadjuvant immunotherapy with chemotherapy [54]. A complete pathologic response to such neoadjuvant therapy might prompt a different surgical management of the axillary LNs.

Patients with cN1-3 disease at presentation are often treated with neoadjuvant systemic therapy (NST). Guidelines for the surgical management of these patients after completion of NST includes the option of CALND. However, it has been argued that these patients might benefit from an SLNB in the same way that patients with early-stage BC have benefited in being able to avoid CALND. One issue has been that SLNB has a higher false negative rate because the technique of SLNB seems to be adversely affected by chemotherapy [55,56]. Surgeons at MD Anderson Cancer Institute devised a method, targeted axillary dissection, to significantly improve the SLN find rate after NST [57,58]. A metallic marker (clip) placed during needle biopsy of the affected node before NST [40] is useful when surgery is performed. The clipped node is identified intra-operatively by radio-active, or a magnetized seed, or by wire localization techniques, removed and, if a complete pathologic response is documented, CALND may be avoided, saving the patient from uncomfortable complications, like chronic lymphedema. Patients receiving radiation to the breast or chest wall often receive a dose in the axilla. Use of the metallic marking clip has markedly improved the accuracy of SLNB [59,60].

The paucity of long-term data on patients who are pathologically LN positive after NST leaves room to question how to treat patients without a complete pathologic response to NST [61]. While failure to respond completely to systemic therapy is a poor prognostic indicator, the current recommendation to treat patients with residual SLN mets undergoing mastectomy with CALND is not based upon solid evidence. The Alliance A011202 trial which enrolled patients with persistently positive SLN after NST from 2013 to 2022 investigated the question of whether axillary radiation could replace CALND. The currently unreported results of this trial will undoubtedly offer invaluable information regarding the natural history of disease in these patients and provide much needed guidance for surgical and adjuvant therapy recommendations.

Conclusion

In the three decades since the beginning of the modern SLNB era the relatively simple technique of removing the first LN to which a BC can metastasize dominates the current surgical approach to the axilla in BC patients, replacing the mostly defunct former standard of removing all the axillary nodes in all patients undergoing mastectomy or lumpectomy for BC. However, the extent of axillary intervention for patients with BC continues to be fluid. As we keep improving our knowledge of BC biology, we will become better able to predict the likelihood of SLN mets by combining clinical, radiological, pathological, molecular, and genetic information. At a time when positive SLNs prompted a CALND, algorithms based on demographics, pathology and molecular markers helped predict which patients with positive SLNs were likely to have positive upper echelon non-SLNs [62]. That information was used initially to determine which patients should have a CALND until clinical trials cemented current guidelines where fewer patients undergo the more extensive axillary surgery. We can use evolving molecular and other information to help decide which patients can safely avoid SLNB. We expect the indications for SLNB to decrease over time. In the future SLNB may disappear into the archives of surgery as many surgical procedures have done in the past.

Declarations

Competing Interests: None

Author contributions.. S. David Nathanson critically reviewed the literature and his own experience while helping develop the sentinel node technique and edited the manuscript and approved the final manuscript.

Funding: SDN supported by the Nathanson/Rands Breast Cancer Research Chair, Detroit, MI

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