Lymphoscintigraphy is a valuable tool for accurate and rapid localization of sentinel nodes, used for staging cutaneous malignant melanoma. In contrast to blue dye studies, it is able to detect these nodes in unsuspected locations and in multiple nodal beds. This article explores the advantages of and technical details needed for performing lymphoscintigraphy.
The incidence of malignant melanoma is steadily increasing in
the UnitedStates. Although treatment options have been limited and
are primarilysurgical, there have been some promising responses to
immunotherapies, such asinterferon alfa-2b. As treatment options
increase, so does the need foraccurate nodal staging of disease.
The recent use of minimally invasivesurgical biopsy of the first
node draining the tumor site has reduced the needfor extensive
radical nodal dissection, with an associated morbidity.
Althoughblue dye studies are an effective technique for identifying
this"sentinel," or first draining node, lymphoscintigraphy has
severaladvantages. In this article we will explore such advantages,
as well as thetechnical details needed for the performance of
lymphoscintigraphy. Inaddition, we will discuss the use of the
intraoperative gamma probe.
Pathology, grading, and staging-The four major types of
malignantmelanoma, in order of prevalence, are superficial
spreading, nodular, lentigomaligna, and acral lentiginous.
Melanomas are graded by tumor thickness(Breslow grades) and/or the
level of dermal invasion (Clark levels). Tumorspread is lymphatic
and hematogeneous, with lymphatic spread predominating inearly
metastatic disease. Additionally, the likelihood of nodal
metastasis isproportional to tumor thickness. Balch and coworkers
reported a 0% incidence ofregional metastases in patients with
lesions less than 0.75 mm thick, a 25%incidence in patients with
lesions between 0.76 to 1.50 mm thick, 51% forlesions 1.5 to 3.99
mm thick, and 62% for those with lesions greater than 4.0mm thick,
based on a 3-year actuarial rate of recurrence.1 Staging of
disease,as defined by the Joint Commission on Cancer, is summarized
in table 1.
In the absence of metastatic spread, treatment of malignant
melanomaconsists of wide local resection of the primary lesion.
Resection margins aredetermined by lesion thickness; 1 cm margin
for lesions of less than 1 mm indepth and 2 to 4 cm for lesions
that are 1 to 4 mm thick. Resection does notimprove survival for
patients with lesions that are greater than 4 mm thick, asthese
lesions have a high incidence of metastasis.
In cases of clinically palpable nodal disease, radical nodal
dissection isindicated. For those cases in which the lesion is 1 to
4 mm thick and there isno evident palpable adenopathy, the use of
radical node dissection to eliminatemicrometastatic disease has
been controversial, and this procedure, therefore,has been referred
to as "elective lymph node dissection"or ELND.2,3Recently, however,
there is some evidence that ELND can prolong survival incertain
groups of patients.4
The status of nodal involvement is an important prognostic
indicator. Forexample, Balch and coworkers report a 48% 10-year
survival rate in patientswith clinical stage I and II disease with
occult nodal metastases versus a 65%10-year survival for those
patients without occult nodal disease.5 Staging ofnodal involvement
has become even more important with the discovery that somepatients
with nodal disease have benefited from interferon therapy.6
Blue dye and the sentinel node
Lymphatic drainage, using a variety of blue dyes such as
isofulfan blue andmethylene blue, has been studied for decades. The
concept of identification andbiopsy of the sentinel node as a means
for staging an entire nodal bed wasdeveloped in 1992 by Morton et
al7 using blue dye. The sentinel node pathologyaccurately
represents the pathology of the nodal bed.8 To locate the
sentinelnode, the dye is injected intradermally around the tumor or
biopsy site 15minutes prior to surgical exploration of the nodal
basin. Timing is important,as nodal retention of the dye is
Limitations of blue dye studies
The use of blue dye to locate the sentinel node is limited by
the cliniciansability to predict the nodal basin that will drain
lymph and cells from theprimary tumor site. Unfortunately, pathways
of cutaneous lymphatic drainage arevariable. In their study of a
large series of patients with melanoma, Slingluffand coworkers
reported that nodal metastases were identified clinically
incontralateral nodes for primary lesions outside of watershed
regions in 10% ofcases.9 These watershed regions, from which
lymphatic drainage is quitevariable, are found in areas such as the
waist and the vertical midline of thetrunk and head (figure 1).
Studies by O'Brien et al and Wells et al have shown discordance
of 34%and 84%, respectively, between the clinically suspected basin
and that whichwas mapped by lymphoscintigraphy in lesions of the
head and neck.10,11 A markedvariability in drainage patterns in
truncal melanoma has been reported by Urenand coworkers:12 59% of
their patients had drainage to two or more nodalbasins.
Sentinel node lymphoscintigraphy
In 1992, Alex and Krag adapted lymphoscintigraphy to locate the
sentinelnode.13 This technique has been quite successful, as it
permits preoperativeidentification of the nodal basin(s) containing
sentinel node(s) (it is notuncommon to see simultaneous, or near
simultaneous, drainage to more than onenodal basin). In addition,
these researchers demonstrated the use of alightweight
intraoperative gamma probe to locate the radioactive node withinthe
wound. Using this method, timing of surgical exploration is less
crucial,as most radiopharmaceuticals used for lymphoscintigraphy
have a relatively longresidence time in nodal tissue (at least
Blue dye and lymphoscintigraphic techniques are not mutually
exclusive. Infact, concomitant use of both these agents has been
found to yield a greatersentinel node detection rate.14
The endothelial walls of the lymph capillaries are permeable to
much largerparticles than blood capillaries, and
radiopharmaceuticals that are smallenough to enter the lymphatics
but too large to diffuse into the capillariesare preferred for
lymphoscintigraphy.15 The most commonly usedradiopharmaceuticals
are 99mTc-antimony sulphide colloid, 99mT-human serumalbumin,
99mTc-sulfur colloid, and 99mTc ultrafiltered sulfur colloid.
Sulfurcolloid, ultrafiltered sulfur colloid, and human serum
albumin (HSA)preparations are available for use in the United
States. 99mTc-HSA is anon-particulate agent which demonstrates good
lymph channel visualization andrapid clearance from the injection
site. It appears to have a shorter residencetime in lymph nodes
than ultrafiltered sulfur colloid, which may restricttiming of
surgery post injection.16
Sulfur colloid is particulate and has a diameter between 100 and
1000 nm.17As particulate matter less than 100 nm is most readily
mobilized from theinjection site,16 ultrafiltered sulfur colloid,
prepared by slowly pushingsulfur colloid through 0.1 or 0.22 um
(100 or 220 nm) filters, is the mostcommonly used
radiopharmaceutical for lymphoscintigraphy. As with HSA,
themigration of the ultrafiltered colloid is more rapid than the
migration ofunfiltered sulfur colloid and, therefore, these smaller
agents permit bettervisualization of the lymph channels.
Visualization of the lymphatic channelsleading to the sentinel node
improves the diagnostic certainty of thestudy.17,18 The following
studies were performed with 99m-Tc-ultrafilteredsulfur colloid
prepared with a 0.22 um filter.
It is recommended that sentinel node lymphoscintigraphy be used
only onpatients with either intact primary lesions or those on whom
only excisionalbiopsies have been performed, as it is generally
felt that the extent ofsurgery required for wide local excision may
significantly alter lymphaticdrainage in the tissue surrounding the
Performance of the study
Two to four individual doses of 3.7 to 7.4 MBq (100 to 200
microCuries)ultrafiltered 99mTc-sulfur colloid in a volume of 0.1
to 0.2 cc each are drawninto 1 cc syringes. Small gauge needles
(preferably size 25 or smaller) areattached to each syringe.
The patient is placed in a supine or prone position on the
imaging table.The lesion or biopsy site is prepped with betadine
and an alcohol pad. A drapewith a central hole is placed to expose
an area of skin a few centimeters indiameter surrounding the lesion
or local biopsy site. Draping the site isimportant to prevent
contamination, as leakage from the site of injection iscommon.
Occasionally the backpressure following injection is great enough
tocause vertical spray; therefore, the person injecting the
material shouldconsider covering the injection site with gauze
prior to removing the needle.
To prepare the injectate, a small amount of air should be drawn
into eachsyringe to "follow" the fluid administration. Small gauge
needles maybe bent (using partially removed caps) at their middle
at an approximately 30to 45 degree angle, bevel up. Injections are
intradermal, and as such should besuperficial, as most of the
epidermis is only 0.1 to 0.2 mm thick (though solescan be up to 0.7
mm thick). Two to four intradermal injections are placedaround the
lesion, each approximately 1 to 2 cm from the lesion. In
somepostoperative scars a more distant injection may be needed to
avoid fibrotictissue. A successful intradermal injection is
characterized by a painful, tightblanched wheal with accentuation
of the hair follicles. A deeper injection intothe subcutaneous
tissues will result in undesirable large, flat tissue swellingand
poor lymphatic migration.
Imaging should commence immediately after the injection because
migrationwith ultrafiltered sulfur colloid (as well as 99mTc-HSA)
is often rapid. Theinjection site should be imaged first to
ascertain successful focal injectionsand to assess local
contamination. Some of the skin contamination can beremoved with
alcohol wipes; contaminated clothing and sheets should be
removedfrom the field of view. Prior to imaging, the injection site
can be shielded toimprove visualization of lymph channels, which
can be faint. Rapid imaging isrequired to follow channels to nodal
beds; at our institution, we obtainsequential 30 to 60 second
static images. Nodes should be imaged and recordedin order of
appearance. Channels should be followed quickly, as they are
seenonly transiently. The sentinel node is generally visualized
within the firstseveral minutes of imaging, and it is not uncommon
to visualize the node within1 to 2 minutes post injection.
Nodes should be marked on the skin with indelible markers while
the patientis posed, if possible, in the surgical position. For
example, axillary nodesare marked with the arm extended
perpendicularly from the patients side or, ifthe surgeon desires,
above the head. When possible, lateral, oblique, ortomographic
views should be used to estimate nodal depth. These views also
willhelp differentiate nodal groups that may be superimposed on
anterior orposterior views, such as subscapular and anterior
axillary nodes andsupraclavicular and posterior cervical nodes. Two
such cases are illustrated infigures 2 and 3.
Intraoperative gamma probes
Intraoperative probes are used to locate radioactive lymph nodes
forremoval. These probes are lightweight hand held instruments
containing ashielded detector attached to a charge sensitive
pre-amplifier. The probe isconnected to a rechargeable control unit
with visual and audio signal output.
Although some probes are designed with Nal crystals, the
majority usesemiconductors (figure 4). Semiconductor detectors can
be thought of as thesolid equivalent of a gas detector, with all
the advantages of a solidmaterial. In gas detectors, ion pairs (a
positively charged gas ion and anegatively charged electron) are
created by ionizing radiation. Insemiconductors, electrons also are
dislodged by ionizing radiation, but insteadof positively charged
gas molecules, positive "holes" are createdwithin the crystalline
structure (figure 5).
The primary advantage of these materials over their gaseous
counterparts istheir relative density. Therefore, a gamma photon is
more likely to interactwith a molecule in the semiconductor than in
an equivalent volume of gas. Inaddition, a greater yield of charges
will result from an interaction in asemiconductor because the
electrons in the semiconductor are less tightly boundthan those in
gas; approximately 3 keV of energy is needed to dislodged
anelectron in a semiconductor material, compared to approximately
35 keV in agas.18
Semiconductor materials are less conductive than the metals
which are usedfor carrying electric current (such as copper), hence
the name"SEMIconductor". A few of the semiconductor compounds that
are areavailable for use include cadmium telluride (CdTe), cadmium
zinc telluride(CdZnTe), and zinc telluride (ZnTe).
The semiconductor (or crystal) detector is shielded and
collimated with asleeve of tungsten so that only emissions directly
in front of the probe arecounted. The tungsten shielding blocks 99
to 99.9% of 99mTc photons (figure 4).
The energy window for the semiconductor probe is set from above
80 keV (theenergy of tungsten fluorescence) up to approximately 200
keV (or higher). Theoverall sensitivity of the probe is
approximately 60 to 70% for 99mTc.
Control units for the probes are often designed with audible
output, inaddition to numerical count displays. Some manufacturers
have modified theauditory output so that the user can differentiate
count rates up to a fewthousand cts/sec. These modifications
generally involve conversion of countrates into oscillating
frequencies, or warbles, in which the pitch frequency
isproportional to the number of counts.
When using the probe, remember to exclude photons arising from
the injectionsites from the field of view when searching for or
examining a suspectedradioactive node. Once located (figures 6 and
7), the sentinel node is excised,and its counts are measured while
the probe is directed away from the patient.It may be helpful to
compare counts in the node with those from a small sampleof
non-nodal tissue excised from the site. The node should be at least
two tothree times as radioactive as the background tissue, and is
generally 10 to 100times as radioactive. Following excision of the
node, it is wise to check thewound for residual radioactivity.
Radiation exposure from nodal tissue is minimal, and even that
from theprimary injection site is not excessive. In a preliminary
study, Edmiston andcoworkers reported an average dose of 0.4 ± 0.9
mR/hr at the surface ofthe sentinel node and 17.7 ± 3.6 mR/hr at
the surface of the injectionsite.19 Miner et al recorded the level
of exposure to a surgeon's hands as9.4 ± 3.6 mRem/case.20
A controversy exists concerning the need for a delay prior to
processingradioactive tissue in pathology. In addition to personnel
exposure, somelaboratories prefer not to contaminate their
cryotomes with radioactive tissue.Both Edmiston's study and Miner's
recommend waiting 48 to 72 hours toprocess tissue containing the
primary injection site.19,20
Lymphoscintigraphy is a valuable tool for accurate and rapid
localization ofsentinel nodes, used for staging cutaneous malignant
melanoma. In contrast toblue dye studies, lymphoscintigraphy is
able to detect sentinel nodes inunsuspected locations and in
multiple nodal beds. Successful use of thistechnique requires
correct injection of the agent, rapid early imaging, lateraland
oblique imaging for accurate localization of nodes, careful skin
markingwith the patient in the surgical position, and correct use
of theintraoperative probe. AR
Dr. Powsner is Assistant Professor of Radiology at Boston
University Schoolof Medicine, Boston Medical Center, Boston,
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