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Role of Sentinel Node Biopsy in the Management of Malignant Melanoma

Role of Sentinel Node Biopsy in the Management of Malignant Melanoma

ABSTRACT: The use of elective lymph node dissection for intermediate-thickness melanoma has remained controversial. The technique of sentinel node biopsy (intraoperative lymphatic mapping and selective lymphadenectomy) has been developed in an attempt to identify patients who may benefit from an elective node dissection while sparing patients without occult metastases the morbidity of an elective lymphadenectomy. Current methods of performing a sentinel node biopsy include both a dye and radiolabeled technique. Although the accuracy of sentinel node biopsy for identifying nodes at risk for occult metastases has been demonstrated, a survival benefit from dissection of nodal basins that contain occult metastases remains to be determined. This article reviews the basis for, technical considerations of, and surgical results with selective lymphadenectomy in an attempt to clarify the role of this modality in the management of patients with cutaneous melanoma. [ONCOLOGY 10(8):1237-1242, 1996]

Introduction

Malignant melanoma has been increasing in incidence at a rate
of 4% to 6% per year and currently accounts for 3% of new cancer
cases in both men and women. In 1996, an estimated 38,300 new
cases of melanoma will be diagnosed in the United States, and
7,300 people will die of this disease [1]. Due to increased public
awareness, patients with melanoma present at earlier stages than
they did in the past. This may explain the steady improvement
in overall 5-year survival, which now exceeds 80% [1].

Regional lymph nodes are the most frequent sites of metastasis
of cutaneous melanoma, and the management of regional lymph nodes
remains a subject of controversy. Morton and others [2] have proposed
the technique of intraoperative lymphatic mapping and selective
lymphadenectomy, also known as the "sentinel node biopsy,"
as a means of selecting patients with occult nodal metastases
for therapeutic lymphadenectomy while avoiding the morbidity of
this procedure in patients without nodal disease. In this article,
we will review the basis for the need for selective lymphadenectomy,
as well as technical considerations of and surgical results with
this modality, in an effort to further define its role in the
management of patients with malignant melanoma.

Role of Elective Lymphadenectomy

Prior to discussing the role of elective lymphadenectomy, a review
of the staging system for melanoma is necessary. The 1993 American
Joint Committee for Cancer (AJCC) staging system for melanoma
is shown in Table 1. The presence of nodal metastases denotes
stage III disease and carries a 5-year survival rate of 28% [3].
Therapeutic dissection is advocated in patients with stage III
disease, as some of these patients may remain disease free if
distant metastasis has not yet occurred.

The role of lymph node dissection in patients with stage I or
II disease is less clear. Proponents of elective lymphadenectomy
in these groups cite data showing improved survival in patients
with occult nodal metastases when compared with patients with
palpable disease [4]. Opponents stress that the majority of patients
will be subjected to an unnecessary operation that is not without
significant morbidity. Shaw and Koea reported 67% and 36% incidences
of immediate and long-term complications, respectively, in a series
of 101 lymphatic dissections. Complications were highest following
groin dissection, with 22 of 52 patients experiencing long-term
lymphedema [5]. Therefore, elective node dissection can be justified
only if a survival advantage can be documented that offsets the
morbidity of the dissection.

The risk of elective adenectomy may also be justified if prognostic
information is gained that identifies patients who may benefit
from adjuvant therapy. However, to date randomized trials have
failed to support the routine use of adjuvant therapy for malignant
melanoma. A prospective randomized trial conducted by Kirkwood
et al [6] demonstrated a survival benefit from the use of adjuvant
interferon-alfa-2b (Intron A). However, subgroup analysis failed
to show a statistically significant survival advantage for patients
with occult nodal disease on presentation. Therefore, the argument
supporting the use of lymphadenectomy for staging purposes is
not valid unless a benefit of adjuvant therapy can be demonstrated
in patients with occult nodal disease.

Thickness of the Primary Tumor

The thickness of the primary tumor is an important prognostic
factor and has been used to stratify patients in an attempt to
determine which subgroup may benefit from an elective node dissection
[7]. There is general agreement that the risk of occult metastases
is very low in the presence of thin melanomas (thickness, less
than .76 mm). In such cases, surgical resection of the primary
tumor alone results in a cure rate more than 95%. On the other
hand, patients with thick melanomas (equal to or more than 4.0
mm) not only have a high risk of regional node micrometastases
(more than 60%) but also have a high risk (more than 70%) of occult
distant disease [8]. These patients usually succumb to distant
disease and have little to benefit from elective dissection of
regional nodes. In patients with intermediate-thickness lesions
(equal to or more than .76 to 4.0 mm), however, the risk of occult
nodal metastases (up to 60%) outweighs the risk of occult distant
metastases (up to 20%) [8]. In this group, elective node dissection
may remove occult metastases prior to distant dissemination.

Two prospective randomized trials failed to demonstrate a survival
benefit from elective node dissection in patients with malignant
melanoma [9,10]. However, based on retrospective studies of large
melanoma registries, as well as intensive review and reanalysis
of data from both the World Health Organization and the Mayo Clinic
[10] studies, advocates of elective node dissection continue to
see a role for this therapy in the management of patients with
intermediate-thickness melanoma [7,11,12].

The Intergroup Melanoma Trial, a prospective multicenter study
sponsored by the NCI, is investigating the results of elective
lymphadenectomy in patients with stage I and II disease. This
trial has completed accrual, and results are anxiously awaited.

Sentinel Node Biopsy

Due to the controversy over the role of elective lymphadenectomy,
a method was needed to identify those patients who have microscopic
nodal metastases, and thus, who would benefit from elective node
dissection. In 1992, Morton et al [2] reported on the use of intraoperative
lymphatic mapping and selective lymphadenectomy as a means to
this end. This technique, called "sentinel node biopsy,"
allows for the selective identification, removal, and evaluation
of nodes draining the cutaneous melanoma and therapeutic dissection
if microscopic metastases are detected. Thus, surgeons can rapidly
identify those patients who may benefit from nodal dissection
and spare those without metastases the morbidity of radical lymphadenectomy.

Technique

Sentinel node biopsy involves the use of cutaneous lymphoscintigraphy
to identify areas of primary lymphatic drainage for ambiguous
sites, such as the trunk or shoulders. For lesions on the extremity,
lymphoscintigraphy is unnecessary. Previous studies by Norman
et al [13], demonstrated that cutaneous drainage patterns identified
by lymphoscintigraphy are discordant from predicted drainage patterns
in 63% of patients with head and neck melanoma and 32% of those
with primary lesions on the trunk. This series has been updated
to over 500 patients with a mean follow-up of 4 years; no nodal
recurrences have occurred in a lymphatic basin that was not identified
by preoperative scanning [14]. If lymphoscintigraphy identifies
multiple drainage basins, all should be addressed (Figure 1).

Prior to surgery, patients are asked to provide informed consent
for possible radical node dissection in the event that microscopic
metastases are detected. After induction of general or local anesthesia,
a 25-gauge needle is used to inject 2 to 3 mL of isosulfan blue
or patent blue-V dye intradermally at the site of the melanoma.
If the lesion has been previously excised by excisional biopsy,
the injection is made on either side of the scar. This technique
cannot be applied following wide excision of the tumor, as the
lymphatic drainage is altered.

An incision is made over the lymphatic basin and careful dissection
is continued perpendicular to the skin until a lymphatic containing
blue dye is identified. When a blue-stained lymphatic is found,
it is followed to identify the blue-stained sentinel node (Figure
2). Exploration around this node may reveal other sentinel nodes.
The sentinel node or nodes are sent for frozen-section and rapid
immunohistochemical analysis. While these analyses are being performed,
the primary melanoma may be removed.

Pathologic handling of the specimen involves bisecting the lymph
node and using half for frozen section and permanent hematoxylin
and eosin (H & E) staining while the other half is processed
for immunohistochemical staining for S-100 protein and the melanoma-reactive
monoclonal antibody NK1/C3. If metastases are detected, radical
lymphadenectomy is performed. If no metastases are present, the
incision is closed. If permanent specimens reveal metastases not
detected on frozen section, the patient undergoes lymphadenectomy
subsequently (Figure 3).

Results

The largest experience with sentinel node biopsy was reported
by Morton et al [2]. In their series of 237 patients, intraoperative
lymphatic mapping identified the sentinel node in 194 patients
(82%). In most patients (73%), one node was identified. Two sentinel
nodes were identified in 20% of the lymphadenectomy specimens,
and three or more sentinel nodes were found in 8%. Success varied
depending on the site of the body, with the highest success reported
for the groin. The lowest success rate was reported for an arm
tumor draining to the axilla and a shoulder lesion draining to
the neck.

In a series of 88 patients at Roswell Park Cancer Institute, the
sentinel node was identified in 90% of patients overall. Success
rates for the axilla and groin were 87% and 100%, respectively
[15].

There appears to be a learning curve associated with sentinel
node biopsy. Morton et al [2] analyzed the success rate between
the first half and second half of each surgeon's cases and noted
an improvement in the more recent time period. They concluded
that substantial experience is needed to develop the skills necessary
to perform this technique.

In Morton's study, all patients underwent a lymphadenectomy to
determine the accuracy of the sentinel node biopsy technique.
As mentioned above, the sentinel node was identified in 194 of
237 lymphadenectomy specimens in this series. Metastases were
noted in 40 (21%) of these specimens. For lesions less than 1.5
mm in thickness, metastases were observed in 9.7% of the specimens.
This compared with an incidence of metastatic disease of 36.6%
for tumors more than 1.5 mm in thickness.

Routine H & E staining detected 23 of these metastases, whereas
immunohistochemical staining alone revealed metastatic tumor cells
in 17. Thus, immunohistochemical staining is more sensitive than
conventional histologic examination. In 30 patients, metastases
were detected intraoperatively, while in 10 patients metastases
did not become apparent until permanent sections were available.
In only two cases were tumor cells identified in nonsentinel nodes,
demonstrating that nodal metastases occur in a nonrandom manner.

In a cooperative study of 132 patients conducted at the University
of South Florida, Duke, and M. D. Andersen Cancer Center, only
2 patients (1.5%) have developed recurrences following a negative
sentinel node biopsy. Both H & E and immunohistochemical staining
were negative in these patients. However, both of these nodes
were submitted for reverse transcriptase-polymerase chain reaction
(RT-PCR) for tyrosine gene products and were found to be positive,
suggesting that abnormal cells were present but were missed by
the conventional staining techniques. Thus, they may not have
been true skip metastases [14].

Morton et al have also described the use of sentinel node biopsy
for head and neck melanomas [16]. In this series of 72 patients
with clinical stage I melanoma, the sentinel node was accurately
identified 90% of the time. No nonsentinel nodes were the sole
site of metastasis. Thus, the false-negative rate was 0. At a
mean follow-up of 27 months (range, 10 to 56 months), no regional
failures have been observed.

Complications associated with the lymphatic mapping technique
are infrequent and minor. These consist of passage of dye in the
urine for 24 hours and tattooing of the skin, which may persist
for a few months.

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