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Lymphatic Mapping in the Treatment of Breast Cancer

Lymphatic Mapping in the Treatment of Breast Cancer

ABSTRACT: Developed initially for the treatment of malignant melanoma, lymphatic mapping and sentinel lymph node biopsy have recently been introduced into the treatment of early breast cancer. In breast cancer patients, harvested sentinel lymph nodes are evaluated more thoroughly by detailed pathologic examination using serial sectioning, immunohistochemistry, and reverse transcriptase-polymerase chain reaction (RT-PCR) techniques. This allows for the detection of smaller tumor volumes and leads to more accurate staging. Lymphatic mapping has a 68% to 98% success rate in identifying the sentinel lymph node. The false-negative rate (defined as a negative sentinel lymph node while a higher node or nodes in the axilla are positive) is between 0% and 2%. The morbidity associated with this procedure is minimal. We believe that lymphatic mapping and sentinel lymph node biopsy will ultimately lead to more conservative treatment of patients with breast cancer. This article describes the historical background and technical aspects of the procedure. This is followed by updated, prospectively collected outcomes data from 466 consecutive breast cancer patients who underwent lymphatic mapping at the H. Lee Moffitt Cancer Center, as well as an up-to-date review of the literature. [ONCOLOGY 12(9):1283-1292, 1998]

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 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]

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