Lymphatic Mapping in the Treatment of Breast Cancer

Introduction

 In 1998, approximately 10 million women will reach the age of 50 years, at a rate of 5,000 women per day.[1] Based on the age incidence data for breast cancer, this means that, within the next 10 years, 296,000 women will be afflicted annually with breast cancer.[2] In the ensuing 10 years, this number is projected to climb to approximately 420,000 women per year.

These projections represent a significant increase in breast cancer prevalence without a change in incidence (Figure 1). New strategies in the care and treatment of women with breast cancer will be required to accommodate this explosion in cases caused by the aging of the "baby boomer"population.

Debate Over Axillary Lymph Node Dissection

The surgical management of breast cancer has evolved dramatically over the 20th century. In the early 1900s, Halsted,[3] Haagensen, and Urban proved the feasibility and utility of radical and ultraradical surgery in the treatment of invasive breast cancer. Studies by Patey and Dyson,[4] Meyer, Veronesi et al,[5] and subsequently Fisher et al[6] in the middle to late 1900s caused the pendulum to swing toward less invasive surgical procedures. The continued interest in less extensive surgery, the need for faster recovery, and the increasing trend toward outpatient vs inpatient treatment have brought the value of axillary lymph node dissection into scrutiny.

Axillary node dissection not only has the potential for producing a wide spectrum of complications, such as paresthesia due to costobrachial nerve injury,[7] wound infection, seroma, drain complications, and acute and chronic lymphedema, but also may result in acute treatment delays. Historically, approximately 40% of patients treated with complete axillary lymph node dissection (defined as a dissection of all nodes in levels I, II, and III) developed acute lymphedema and approximately 5% to 10% of patients experienced chronic lymphedema.

New data suggest that, although the gradual reduction in the extent of axillary dissection to levels I and II only has not changed the 40% incidence of acute lymphedema, the incidence of chronic lymphedema has decreased to 5%.[7-9] The increased scrutiny given to axillary dissection is due, in part, to the lack of an effective treatment for lymphedema. In addition, the most significant complaint by patients following breast cancer surgery is the morbidity associated with axillarydissection.

Controversy rages over the current role of axillary lymph node dissection in the management of operable breast cancer.[10-16] Indeed, trials are underway to eliminate axillary lymph node dissection in patients with small (< 1 cm) invasive primary breast cancers who are at < 10% risk for axillary nodal metastases.

Advocates of axillary dissection stress that the status of the regional nodal basin remains the single most important independent variable for predicting prognosis. They contend that the procedure benefits patients by producing

regional control of axillary disease. Proponents also argue that surgical removal of microscopic nodal metastases is curative without adjuvant chemotherapy in certain patient populations.[17]

Critics of axillary dissection maintain that overall survival depends on the development of distant metastases and is not influenced by axillary dissection in most patients.[10,12] They contend that patients with microscopic axillary metastases may be cured by adjuvant chemotherapy, with or without nodal irradiation, in the absence of axillary dissection. Many have even advocated the abandonment of axillary dissection in patients with early breast cancer.[10,12]

Adding fuel to the debate is the fact that the compromise procedure of axillary sampling has been notoriously unreliable. Compared with complete axillary dissection, sampling is associated with a higher rate of false-negative results and "skip metastases" (metastases to level II or III without evidence of disease in a lower level, ie, level I).

These controversies notwithstanding, the status of the regional nodal basin remains the most important independent prognostic factor for survival in breast cancer patients. Therefore, eliminating axillary dissection poses some major concerns for the staging, diagnosis, and treatment planning of breast cancer.

First, cancer stage defines outcomes. Abandonment of the statistically most defining criterion of outcome (ie, nodal metastasis) defies historical logic. This disregard of surgical staging, combined with the use of adjuvant therapies in all patients, may result in greater longterm morbidity (eg, leukemia, heart failure) in the entire population of patients.[17-19]

Second, the argument that micrometastatic disease has no therapeutic significance is a flawed. Lymphatic mapping and sentinel node evaluation now provide effective tools for more efficiently defining that subset of patients with micrometastatic disease.

Finally, outcomes are not rapidly known in breast cancer management. Therefore, proposed radical alterations in treatment, such as the elimination of axillary dissection, should be eschewed in favor of more prudent changes, such as the substitution of a less morbid procedure (eg, sentinel lymph node mapping).

This review will demonstrate that, through the use of lymphatic mapping, surgical staging can be performed with limited morbidity and that individual tumor behavior can be predicted with greater accuracy and sensitivity. Evidence supporting this statement comes from the authors’ experience with sentinel lymph node mapping in 700 consecutively accrued breast cancer patients. Updated, prospectively collected outcomes data from these patients will be presented, along with a description of the techniques employed to achieve these results.

This article will also review the current literature and examine the state of lymphatic mapping being practiced in the United States and the rest of the world. Series from Israel and Europe are now available for review. Finally, based on all of these data, guidelines for the incorporation of lymphatic mapping into breast cancer management are proposed.

Current Methods of Breast Lymphatic Mapping

Several methods of breast lymphatic mapping are used currently in the United States. One method involves the intraparenchymal injection of technetium-labeled sulfur(Drug information on sulfur) colloid at the periphery of the biopsy site or tumor.[28] Approximately 1 mCi of the radiocolloid is injected within 1 to 6 hours prior to surgery. Mapping is carried out with the C-Track device.
In a second mapping method, approximately 5 mL of isosulfan blue dye (Lymphazurin) is injected intraparenchymally at the periphery of the biopsy site or tumor just prior to preparation of the patient’s skin for surgery.[15,25,26] The massaging action of skin preparation and subsequent massaging of the skin and breast help distribute the blue dye. Following lumpectomy, additional dye may be injected into the surrounding breast tissue. Careful dissection is performed to visualize the blue dye in the afferent lymphatic channel.

A third method utilizes the combination of isosulfan blue dye and tech-netium-labeled sulfur colloid.[29] Approximately, 450 µCi of technetium-labeled sulfur colloid is injected 1 to 6 hours preoperatively, followed by injections of 5 mL of isosulfan blue dye at the same or nearby sites. The Neoprobe device is used to identify the area of greatest radioactivity in the axilla.

Yet another technique used by Veronesi et al in Italy involves subdermal injections of radiolabeled microcolloidal human serum albumin 8 to 12 hours prior to operative removal of sentinel lymph nodes. Injections are administered in the skin overlying the tumor or biopsy site. Approximately 1 mCi of radioactivity is administered at this site. Mapping is carried out with the C-Track device.[13]

With all of these sentinel lymph node mapping techniques, lumpectomy or mastectomy is usually performed prior to the search for the sentinel node, thus decreasing the "shine through" effect. (Of interest, only 1% to 5% of the injected technetium-labeled sulfur colloid migrates to the sentinel lymph node.) Biopsy of the sentinel lymph node is then carried out. Meticulous dissection is performed to avoid staining the surgical field with blood or prematurely disrupting the afferent lymphatic channel and staining the surgical field with blue dye.

The "shine through effect" occurs when the handheld gamma radiation detection probe senses counts originating from the primary injection site in the breast rather than the site in the axilla. This occurs when the probe is pointed in the direction of the primary injection site, which has not been excised. The shine through effect can be particularly problematic in cases where the primary injection site is close to the axilla, ie, upper outer quadrant lesions. This effect can be minimized by removing the primary tumor prior to exploring the axilla.

A blue-stained afferent lymphatic vessel is identified and followed to the sentinel lymph node, which also stains blue. The gamma detection probe is used to confirm the location of the sentinel node and to guide dissection in cases where the dye-laden lymphatic tract is difficult to identify. In vivo, sentinel lymph node radioactivity is measured with the node fully exposed. An estimated basin background count is obtained by measuring counts in the four quadrants of the axilla. A node is considered to be a sentinel node if it stains blue or has an in vivo radioactive count at least three times that of the background count or an ex vivo radioactive count 10 times greater than a neighboring nonsentinel lymph node.[29]

We have incorporated some basic tools into our practice that have made a dramatic difference in the ability to provide rapid and efficient breast cancer care. These include the application of touch preparation cytology for the evaluation of diagnostic biopsies,[30] intraoperative imprint cytologic margin analysis,[31] and intraoperative cytologic lymph node assessment for metastatic disease.[27]

Also, we utilize the combination of technetium-labeled sulfur colloid and isosulfan blue dye for lymphatic mapping of the axillary nodes.[29] Lymphatic mapping for breast cancer

has independently been reported by Giuliano et al[15,25] and Krag et al[28] with the use of isosulfan blue dye and technetium-labeled sulfur colloid, respectively. We have demonstrated the improved sensitivity of the combination of these two agents for detecting sentinel lymph nodes.[29]

Lastly, we use immunohistochemical staining of lymph nodes to identify metastatic disease.[17,26,3-36]