A generally accepted tenet of management of solid tumor malignancies—including adenocarcinoma of the breast—is that most bulky/clinically evident sites of disease are best managed by surgical resection, with radiation treatment reserved for microscopic, clinically occult foci of soft tissue disease. The goal of systemic therapy is to eradicate distant organ disease. Clearly, however, there will be overlap in the results achieved by these modalities of cancer care, and these effects can influence the extent of necessary surgery as well as the sequence of delivering these components of cancer care. For example, a patient that initially presents with bulky axillary lymph nodes will likely require an anatomically defined level I/II axillary lymph node dissection, and this surgery may be performed as initial primary treatment as long as there is no evidence of unresectable disease that would place the axillary neurovascular structures at risk for intraoperative damage. However, these patients will routinely require chemotherapy because the axillary disease reflects an increased likelihood of harboring distant organ micrometastatic disease, even in the presence of negative body imaging. These cases, therefore, become very strong candidates for receiving preoperative/neoadjuvant chemotherapy, which can also downstage the extent of the axillary disease. Whether or not axillary downstaging by neoadjuvant chemotherapy can diminish the extent of axillary surgery, and make the patient a candidate for axillary sentinel lymph node biopsy alone is an ongoing subject of debate in the oncology literature. At the other end of the spectrum, patients with low-volume disease in the axilla that is detected by a staging procedure (such as sentinel lymph node biopsy or axillary ultrasound and sono-guided needle biopsy) will typically receive adjuvant chemotherapy therapy, and the locoregional effects of systemic therapy coupled with radiation may be adequate in replacing the need for a completion axillary lymph node dissection in selected cases.

In light of the various multimodality treatment options that are available, it can therefore be useful to discuss management of breast cancer patients with pathologically proven axillary metastatic disease by categorizing their status and treatment plan as follows:

1. 
   

   Cases of axillary metastases presenting as palpable, clinically suspicious disease

   
   
   
   
   1. 
      

      Associated with a locally advanced primary breast cancer

      
      
   2. 
      

      Associated with an early-stage breast cancer

      
      
   3. 
      

      Associated with an occult primary tumor in the breast

   
   
2. 
   

   Cases of axillary metastases identified by sentinel lymph node biopsy

   
   
   
   
   1. 
      

      In patients undergoing primary surgery for early-stage breast cancer

      
      
   2. 
      

      In patients undergoing axillary staging prior to receiving neoadjuvant chemotherapy

   
   
3. 
   

   Cases of axillary metastases identified by axillary ultrasound and sono-guided fine needle aspiration (FNA) or core needle biopsy of morphologically abnormal-appearing but nonpalpable lymph nodes

   
   
   
   
   1. 
      

      In patients undergoing primary surgery for early-stage/resectable breast cancer

      
      
   2. 
      

      In patients undergoing axillary staging prior to receiving neoadjuvant chemotherapy

In distinguishing which of the three umbrella categories is appropriate for an individual patient, confirmation of nodal metastatic involvement is generally necessary. As demonstrated by the landmark NSABP B-04 trial,¹ clinical examination is notoriously inaccurate in assessing axillary nodal status. This trial accrued patients with resectable breast cancer diagnosed between 1971 and 1974, an era that predated the widespread availability of effective systemic therapy for breast cancer. Patients with node-negative disease (by clinical examination) were randomized to undergo radical mastectomy (the standard of care for breast cancer management at that time), total mastectomy plus postmastectomy radiation, or total mastectomy alone. Patients with clinically determined node positive disease were randomized to either radical mastectomy or total mastectomy followed by postmastectomy radiation, to insure some treatment of the clinically evident axillary disease. The overall survival equivalence between randomization arms within the two different trials formed the basis for transitioning from radical mastectomy to modified radical mastectomy as the standard of locoregional care for operable breast cancer. These trials failed to demonstrate any overall survival advantage associated with the axillary lymph node dissection, but the axillary surgery as a staging procedure remained a critical component of breast cancer management following completion of this trial because of the advent of systemic therapy into the breast cancer treatment portfolio. In the desire to minimize exposure to chemotherapy and endocrine agent toxicity in these early years of adjuvant systemic therapy treatment planning, it was important to limit use of these medications to those cases where the risk of distant organ micrometastatic disease was greatest. Axillary nodal metastasis was clearly the most powerful predictor available for identifying these cases. Unfortunately, however, the NSABP B-04 trials also documented the fact that clinical assessment of the axillary nodal status is inaccurate. Of the patients with clinically node-negative disease randomized to the radical mastectomy arm, 40% were actually found to be pathologically node positive. Similarly, of the clinically node-positive patients randomized to undergo radical mastectomy, 25% were found to be pathologically node negative. The B-04 trials, therefore, confirmed the need for histopathologic documentation of the axillary nodal status.

This chapter will review the available retrospective and prospective randomized clinical trials data on management options for breast cancer patients with pathologically documented axillary metastases. It will not address cases of inflammatory breast cancer (IBC). The inherently elevated risk of both locoregional and distant organ relapse in IBC has resulted in these cases typically requiring the full spectrum of our most aggressive multimodality treatments—neoadjuvant chemotherapy, modified radical mastectomy, and postmastectomy locoregional radiation (with adjuvant endocrine and/or anti-HER2/neu therapy as indicated based upon molecular marker status).² At the other end of the spectrum, this chapter will not discuss patients with isolated tumor cells in sentinel nodes either, as these cases are considered node negative by the current American Joint Committee on Cancer (AJCC) tumor/node/metastasis (TNM) staging system.

Confirmation of metastatic disease can usually be accomplished in this setting via FNA biopsy or core needle biopsy. Cytology from an FNA biopsy revealing adenocarcinoma in an axillary lymph node is adequate for diagnostic purposes, as this finding by definition confirms an invasive cancer that has metastasized to the axilla, and molecular information will usually be obtained from the primary breast cancer. In cases where the primary breast tumor is not available (e.g., with an occult breast primary) then it is preferable to biopsy the axillary disease via cores or excisional sampling, to insure adequate tissue for immunohistochemistry, as cytologic samples can be unreliable in yield for immunohistochemistry analyses.

Patients with Palpable, Bulky, Clinically Suspicious Axillary Disease in Conjunction with a Locally Advanced Breast Cancer

These patients require initial biopsy proof of the primary site of disease. This is preferably and most efficiently accomplished via percutaneous core needle biopsy, with confirmation of histopathology as well as molecular marker expression—estrogen receptor (ER), progesterone receptor (PR), and HER2/neu. Immunohistochemical evaluation of molecular markers from the breast primary tumor is preferentially obtained on cores as opposed to fine needle aspirates/cytology, to insure that the markers represent the invasive disease rather than any in situ component. If a needle biopsy of the primary breast tumor is inadequate or nondiagnostic, then an incisional biopsy or skin punch biopsy (if cutaneous extension is present) of the primary breast disease are alternative approaches. Pathologic confirmation of the axillary metastatic disease is preferable, as this documentation will then streamline management planning for the axilla as requiring a definitive axillary lymph node dissection. If histopathology and molecular marker pattern cannot be achieved from primary breast tissue sampling, then immunohistochemistry evaluation of either a cytology specimen from a fine needle aspirate or a pathology specimen from a core may be utilized as well. As noted earlier, immunohistochemistry studies of the cytologic yield from a fine needle aspirate can be more challenging and feasibility should be discussed with the institutional pathology department.

Patients with a locally advanced breast primary in conjunction with bulky palpable axillary disease should be preferentially triaged toward neoadjuvant systemic therapy, however, if the disease is technically resectable with low risk of surgical morbidity then modified radical mastectomy may be considered as the initial treatment in selected scenarios: medical suitability for tolerating chemotherapy is questionable; specific tumor features such as lobular histology or strong ER-positivity suggest that response rate to neoadjuvant chemotherapy may be sluggish^3–5; and cases where additional molecular marker information from breast tissue prior to chemotherapy is necessary. Patients with inoperable disease (tumors that are directly invading the chest wall/rib cage or nodal disease that is jeopardizing the axillary neurovascular structures) should be routinely triaged toward neoadjuvant systemic therapy as the standard of care. Performing the breast and axillary surgery after delivery of the neoadjuvant chemotherapy improves the technical ease of the surgery and strengthens the likelihood of achieving a margin-negative resection. This approach may even improve eligibility for successful breast conservation. Patients presenting with these bulky cancers are at increased risk for locoregional recurrence and will generally benefit from either postmastectomy radiation or breast plus regional nodal irradiation, depending on the breast surgery selected. A few studies have suggested that the risk of locoregional recurrence may be lower in patients that have a complete pathologic response and favorable primary tumor features, but for the majority of cases aggressive locoregional radiation following surgery will be warranted.^6–8 Anti-HER2/neu and/or endocrine therapy will of course be dictated by the individual molecular marker profile.

Patients with Palpable, Bulky, Clinically Suspicious Axillary Disease in Conjunction with an Otherwise Early-Stage and Resectable Primary Breast Tumor

Management of these cases is similar to the approach described above for patients presenting with bulky but resectable axillary and locally advanced breast disease, but the potential benefits of neoadjuvant chemotherapy are diminished in this scenario. The first priority is to pathologically confirm the breast and axillary disease via percutaneous needle biopsy. This biopsy confirmation should be accompanied by molecular marker profiling of the cancer. If the primary breast tumor is small, then histopathologic confirmation of axillary metastatic disease (versus benign inflammatory adenopathy) is particularly important, as the risk of definitive regional nodal extension is inversely related to primary breast tumor size. Many patients have palpable axillary nodes as consequence of reactive hyperplasia (which can be exacerbated by the breast biopsy procedure) and incorrectly assuming that this benign adenopathy represents metastatic disease can lead to overtreatment.

Once the axillary disease has been documented, the patient has the option of either proceeding onto definitive surgery or receiving neoadjuvant systemic therapy. Lobular histology tumors and hormone receptor-positive breast cancers tend to have a more sluggish and difficult-to-monitor response to neoadjuvant chemotherapy, and will often proceed directly to surgery.^9,10 If surgery is performed first, then an axillary lymph node dissection is necessary for durable regional control of disease. Considerations that would motivate a preference for neoadjuvant chemotherapy include:

1. 
   

   Patient requires downstaging of the breast tumor to improve lumpectomy eligibility or downstaging of the axillary disease to facilitate safe dissection;

   
   
2. 
   

   Patient is ambivalent about choice of breast surgery (mastectomy vs. lumpectomy) and wants more time to decide;

   
   
3. 
   

   Patient wishes to await genetic counseling/testing results before committing to choice of breast surgery;

   
   
4. 
   

   Patient is a candidate to receive a promising new systemic therapy agent that is only available for delivery in the neoadjuvant setting.

Management of the axilla in node-positive patients receiving neoadjuvant chemotherapy is discussed in a subsequent section.

Patients with Palpable, Bulky, Clinically Suspicious Axillary Disease and an Unknown Breast Primary

Breast cancer presenting as axillary metastases with unknown primary was first described by Halsted in 1907,¹¹ as three cases of “cancerous axillary glands with nondemonstrable cancer of the mamma.” Undoubtedly, many of the early cases of occult breast cancer were actually cases of node-positive disease associated with small or subtle breast lesions camouflaged by dense breast tissue. Fortunately, breast imaging has evolved substantially over the past several decades, and microscopic foci of disease can be detected with high sensitivity. Yet despite this improved ability to identify nonpalpable breast tumors, approximately 0.1% to 5% of breast cancer patients continue to present with clinically overt metastatic adenopathy in the axilla and an occult breast primary.^12–14 Despite the relative infrequency for this pattern of disease, it is an important topic for review because of the diagnostic and therapeutic implications. Effective (and potentially curative) locoregional and systemic treatments for node-positive breast cancer are available, and it is therefore essential that these patients be evaluated and managed appropriately.

DIFFERENTIAL DIAGNOSIS

Benign, reactive hyperplasia is the most common cause of axillary adenopathy. The mammographic appearance of central lucency and/or an ultrasound image of fatty hilum will favor benignity, however it is reasonable to pursue tissue diagnosis (with at least a portion of the tissue sent fresh to the laboratory to facilitate evaluation of a possible lymphoma diagnosis) via percutaneous needle biopsy or open excisional biopsy if there is any doubt regarding the nature of the adenopathy. Once a histopathologic diagnosis of malignancy is established, confirmation of the primary organ site is indicated. While breast cancer is the most likely cause of axillary metastases, other possibilities include neoplasms originating from lymphoma, melanoma, thyroid, lung, renal, ovarian, pancreatic, gastrointestinal, and colorectal tissue; histopathologic evaluation of the lymph node biopsy material will usually suffice in establishing a definitive diagnosis. Occasionally it will be difficult to distinguish a primary breast tumor located in the axillary tail from a true axillary lymph node. Nodes that are completely replaced by metastatic disease, and primary tumors that are adjacent to axillary lymph nodes may contribute to this dilemma. The patient with a prior history of contralateral breast cancer presents yet another diagnostic challenge, as the possibility of axillary cross-metastases also exists.

DIAGNOSTIC STUDIES

A careful history and physical exam (with particular attention to other nodal basins, the breasts, skin lesions, and scars from previously resected skin lesions) is important, and standard diagnostic workup should include a chest x-ray, mammogram, and breast ultrasound. Routine histology will usually be adequate in characterizing lymphoma, melanoma, or adenocarcinoma as the primary pattern of disease. If adenocarcinoma is confirmed as the histopathologic pattern in the axillary disease, over 90% of cases will be confirmed as having a breast primary, and extensive imaging and/or endoscopic workup to rule out a gastrointestinal or pulmonary primary is generally unnecessary. Estrogen and progesterone receptor studies as well as HER2/neu evaluation should always be performed; expression of these markers can support the diagnosis of an occult breast primary and will influence selection of adjuvant systemic therapy. Unfortunately, however these studies may be negative in one-third to one-half of breast cancers, and primary tumors of the abdominopelvic organs as well as melanoma may display hormone receptor positivity. Other stains that may facilitate characterization of the pathology include CEA, mucicarmine, and lactalbumin; the presence of these markers will confirm metastatic adenocarcinoma and mammaglobin expression has been reported as increasing likelihood of a breast primary.^15,16

While an extensive workup to look for nonbreast primaries in the setting of an adenocarcinomatous lymph node metastasis is usually a low-yield endeavor, a meticulous breast evaluation to localize an intramammary tumor is essential. Initial efforts include meticulous scrutiny of diagnostic mammogram images and bilateral breast ultrasound scanning is necessary. Magnetic resonance imaging (MRI) has become widely accepted as another essential modality, and MRI can identify the breast primary in 70% to 86% of cases.^17–19 When the MRI findings are suggestive of the breast primary, either an MRI-guided biopsy can be performed or the patient can have a second-look ultrasound with possible sono-guided core needle biopsy.

TREATMENT

Traditionally, mastectomy with axillary lymph node dissection, followed by adjuvant systemic therapy and postmastectomy radiation therapy, has been the standard management approach for patients with axillary metastases and an occult primary. However, several recent and historic reports^12,20–24 have confirmed the safety of breast-conserving approaches in this patient population. If the breast is conserved, then axillary lymph node dissection followed by breast/chest wall radiation is necessary for optimal control of locoregional disease, and baseline mammogram as well as breast MRI should be negative for any evidence of the breast primary tumor. Expanded applications of induction chemotherapy have led to variation in treatment sequence for the multimodality management of these patients. Following a percutaneous core needle biopsy establishing a diagnosis of metastatic breast cancer, it is not unreasonable to proceed with chemotherapy as the next step (as long as pretreatment molecular marker studies have been documented from the axillary biopsy procedure), followed by axillary lymph node dissection and consolidation of treatment with breast and usually regional radiation. This approach offers the benefits of in vivo tumor response monitoring, with the opportunity to cross the patient over to an alternative chemotherapy regimen in patients found to have resistant disease.

PROGNOSIS

The low incidence of this disease pattern makes it difficult to definitively assess prognosis. Interestingly, several studies have suggested that patients with occult breast cancer and axillary metastases had improved survival compared to the majority of node-positive breast cancer patients where the primary breast tumor is documented.^25–29 However other investigators^{20,22,30–32} have disputed this contention, finding similar outcome compared to other patients with axillary metastases. Extent of nodal involvement retains its prognostic impact^12,20,30 in patients with an occult breast primary, as is seen among other stage II/node-positive breast cancer patients with a clinically evident breast primary.

An initial important step in evaluating management options for patients with sentinel node metastatic disease is to document the extent of nodal involvement. Gross extracapsular extension and three or more nodes with nodes with macrometastases (greater than 2 mm) are signs of high-risk disease and these patients will benefit from completion axillary lymph node dissection as well as locoregional radiation (breast plus regional nodes in lumpectomy cases and postmastectomy radiation for mastectomy cases) to residual sterilize microscopic disease in the soft tissues beyond the surgical fields. Patients with micrometastases (0.2 to 2 mm in size) or low-volume macrometastatic disease limited to one or two nodes have more options in terms of possibly avoiding completion axillary lymph node dissection. Prospective, randomized clinical trials data and evidence-based clinical practice guidelines^33–36 (discussed below and summarized in Table 79-1) support the safety of avoiding the completion axillary lymph node dissection in patients with micrometastatic or low-volume macrometastatic sentinel node disease in the setting of lumpectomy and whole-breast radiation therapy. Patients undergoing mastectomy will usually require completion axillary lymph node dissection so that the total axillary metastatic burden can be used in order to guide recommendations regarding postmastectomy radiation. Lumpectomy patients that are not receiving whole-breast radiation also require completion ALND if sentinel node metastases are identified.