Volume 22 • Number 1 • 2008

CANCER
Principles & Practice
of Oncology 7th Edition

Sentinel Lymph Node Biopsy in

Melanoma in 2008

Vincent T. DeVita, Jr.

J. M. Thomas, M.S., F.R.C.P., F.R.C.S., and A. J. Hayes, M.A., F.R.C.S., Ph.D.
Samuel Hellman
Introduction Steven A. Rosenberg

Sentinel lymph node biopsy (SLNB) in melanoma has been intensively investigated
and, apart from the final results of the Multicenter Selective Lymphadenectomy Trial
(MSLT-1)1 and a few other refinements, sufficient information is available to come
to an initial consensus about the value of this investigation and its consequences.
Nevertheless, it is difficult to think of a surgical procedure or a therapy that has
given rise to such a wide spectrum of opinion despite the fact that all parties are
interpreting the same data. The dominant opinion is that SLNB in melanoma should
be regarded as “standard of care,” which implies that patients not offered the pro-
cedure are being disadvantaged in some way. It has even been suggested that not
offering patients the opportunity for SLNB may have medicolegal consequences.2
Although detractors of the procedure are in a minority, some have argued that
SLNB is of no benefit and should be abandoned.3–7

The results of MSLT-1 were first presented at the meeting in Los Angeles in Decem-
ber of 2004 and were formally announced at the American Society of Clinical On-
cology (ASCO) in May of 2005,8 but were not published until September of 2006.1
Until these results were known, it was not unreasonable to regard SLNB as the latest
and best form of innovative care, especially in view of the prognostic importance of
sentinel node (SN) status. Furthermore, particularly in the United States and Austra-
lia, the SLNB procedure replaced elective lymph node dissection (ELND). Results of

Authors:
J. M. Thomas, M.S., F.R.C.P., F.R.C.S., and A. J. Hayes. M.A., F.R.C.S., Ph.D., Sarcoma and Melanoma Unit,
Department of Academic Surgery, Royal Marsden Hospital, London, England.

The opinions and/or clinical experiences outlined herein are those of the authors and do not necessarily
represent the views of the editors or publisher.
 Sentinel Lymph Node Biopsy in Melanoma Volume 22, Number 1
four randomized controlled trials of ELND were showing no over-
all survival (OS) advantage,9–12 but of greater concern was that
no deposits of melanoma were present in approximately 80% of
the ELND specimens, meaning that these patients were undergo-
ing excessive and unnecessary surgery which was associated with
significant surgical morbidity, especially chronic lymphedema. The
immediate attraction of the SLNB procedure was that it selected
patients for ELND (or completion/early/immediate lymphadenec-
tomy as it became known) based on the presence or absence of
melanoma deposits in the SN. Subsequently, the identification of
tiny deposits of melanoma within the SN by immunohistochem-
istry (IHC)13 that could not be identified by conventional staining
techniques fueled further interest and fascination in the proce-
dure. It is for these perfectly logical and intuitive reasons that the
SLNB procedure became “standard of care” before full evaluation
had been completed.
Over the past decade or so, the SLNB has dominated clinical
practice and research in melanoma. Sufficient information and
outcome data are now available to allow a more critical analysis
of the procedure with a view to refinement of clinical practice.
A re-evaluation of the procedure is justified if only because the
results of MSLT-1 do not even show a trend toward an OS advan-
tage. Our responsibility as physicians is to provide patients with
accurate information on which to base their decisions. We believe
that the arguments presented in this review are evidence-based
and deserve careful consideration.
A Framework for Assessing the Use of SLNB in
Melanoma
The theoretical basis underpinning the purported value of SLNB
and subsequent completion lymphadenectomy in SN-positive cas-
es can be summarized by the following three points.
1. Prognostic information. Knowing the status of the SN provides
prognostic information over and above that which is provided
by the histologic characteristics of the resected primary tumor.
This allows a more accurate stratification of a patient’s risk for
relapse at distant sites, for the purposes of adjuvant treatment,
or for entry into trials of adjuvant therapy. If there is no effec-
tive adjuvant treatment, then the only possible benefit of the
prognostic information is in lessening, but not eradicating, pa-
tients’ uncertainty as to whether their disease will recur.
2. Therapeutic benefit resulting from surgical resection. Comple-
tion lymphadenectomy in SN-positive patients may have an
intrinsic therapeutic benefit by removing LNs containing malig-
nant cells when they are not apparent clinically or by standard
radiologic techniques. Inevitably this will influence the pattern
of disease recurrence, but to achieve a therapeutic advantage,
early lymphadenectomy must be shown to reduce the inci-
dence of systemic spread.
3. Potential detrimental effects of surgery. The two potential ben-
efits of SLNB must be evaluated in the context of morbidities
associated with the procedure. There is a small but significant
morbidity of the procedure itself. Of greater concern (see be-
low) is that a proportion of patients will undergo unnecessary
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completion lymphadenectomy as a result of prognostic false-
positivity within the SN. There is also a lingering concern that
completion lymphadenectomy in SN-positive patients may in-
crease the risk for in-transit recurrence14,15–19 despite the fact
that, overall, the incidence of in-transit disease is similar in both
arms of MSLT-1.1
We would have no objection to the SLNB procedure if it were
known or were likely that all SN-positive patients would prog-
ress to palpable nodal recurrence. The operations of immediate
and delayed lymphadenectomy are identical, and we know from
the results of MSLT-1 that the morbidity is similar. Our main con-
cern relates to prognostic false-positivity, meaning that some tiny
deposits of melanoma in the SN are destined for destruction or
dormancy rather than progression. Furthermore, if the evidence
suggests that SLNB serves only as a prognostic tool for risk strati-
fication, then the question must be asked as to how superior that
prognostic information is over detailed histologic assessment of
the primary tumor and ultrasound of the SN basins. In the ab-
sence of adjuvant treatments, is there any benefit to the patient
in having imperfect prognostic information?
Based on these comments, this review is structured as follows: (a)
evidence for therapeutic benefit for SLNB and immediate lymph-
adenectomy; (b) the role of SLNB as a prognostic tool; (c) the
evidence for prognostic false-positivity within positive SNs, and
(d) the importance of ultrasound in screening and surveillance of
SN basins.
SLNB as a Therapeutic Tool: MSLT-1
MSLT-1 was designed to compare the survival of SN-positive pa-
tients undergoing immediate lymphadenectomy (the biopsy arm)
with that of patients treated by delayed lymphadenectomy when
metastatic regional nodes became palpable (the observation arm).
To achieve this primary end point, the trial entered and random-
ized 2001 patients,20 but the published results relating to survival
described only a subgroup of 1269 patients with tumors of inter-
mediate thickness (1.2 to 3.5 mm).1 No survival information or pri-
mary tumor-related details have been published about the 732 pa-
tients with tumors thinner than 1.2 mm or thicker than 3.5 mm.
Summary of Trial Design and Results
Forty percent of patients were randomized to the observation arm
and, according to the protocol, were treated by wide local exci-
sion (WLE) of the primary tumor and delayed lymphadenectomy
when the regional LNs became palpable. Sixty percent of patients
were randomized to the biopsy arm and after WLE were investi-
gated by SLNB. Immediate lymphadenectomy was performed if
any SNs contained metastatic melanoma (SN-positive). The results
showed no difference in OS (87.1% biopsy arm vs. 86.6% obser-
vation arm) and a 5% difference at 5 years in disease-free survival
(DFS) in favor of the biopsy arm (78.3% vs.73.1%). The abstract
conclusion confirmed the prognostic value of SN status. A post-
randomization subgroup analysis claimed a 20% survival advan-
tage when the 122 SN-positive patients in the biopsy arm, who
underwent immediate lymphadenectomy, were compared to the
78 patients in the observation arm, who were treated by delayed
lymphadenectomy1 (Fig. 1).
Volume 22, Number 1 Thomas and Hayes 
Is There a Subgroup Survival Advantage?
The claim of a 20% survival advantage for immediate lymph-
adenectomy in the abstract conclusion1 is based on a subgroup
analysis and is in stark contrast to the absence of any melanoma-
specific survival advantage at the point of randomization. Because
the subgroup analysis result is at such odds with the primary end
point, this result must be scrutinized to determine if the compari-
son is valid.
Subgroup analyses within a randomized trial are valid only if the
subgroup is identified before randomization such that the char-
acteristic that defines the subgroups is randomly allocated.21
These two subgroups were not defined before the randomiza-
tion. Rather, they are post-randomization selected subgroups and
the patients in each subgroup were identified by the procedure
under investigation. Within a randomized controlled trial, a de-
finitive survival comparison between post-randomization selected
subgroups is not valid.
The rationale for making the comparison between these two
nonrandomized subgroups is based entirely on the assumption
that all patients with positive SNs will inevitably progress to pal-
pable nodal disease and that these two subgroups are prog-
nostically equivalent. As will be shown later, multiple sources
of indirect and direct evidence now indicate that some positive
SNs are not destined to progress to palpable nodal recurrence.
Hence the two subgroups are not prognostically equivalent, and
the 20% survival difference is not the result of any therapeutic
advantage from immediate lymphadenectomy. The reporting of
an invalid subgroup analysis has served only to cloud what is a
very clear conclusion of the primary end point of this large trial,
i.e., that there is at present no evidence that SLNB offers an OS
benefit to patients.
Disease-Free Survival
The 5% advantage in DFS at 5 years means that 100 patients
must undergo SLNB for five patients in the biopsy arm to have
a DFS advantage. In the absence of any difference in OS, this
could simply mean a delay rather than a prevention of recur-
rence. In MSLT-1, the site and timing of first recurrence were
directly influenced by the SLNB procedure itself. In patients with
FIG. 1. Trial design and treatment of patients with intermediate-
thickness melanoma. Based on data from Morton et al.1
melanoma of intermediate thickness, the most likely site of first
recurrence is the regional LNs. Patients in the biopsy arm who
were SN-positive underwent a prophylactic lymphadenectomy
at the time of diagnosis, and therefore these patients will inevi-
tably have fewer regional nodal recurrences. This is confirmed
in the results relating to site of first recurrence, which show a
threefold increase in nodal recurrence in the observation arm
and a small increase in distant recurrence in the biopsy arm
(11% vs. 7%). In this cohort of patients, moreover, regional
nodal recurrences invariably appear before distant recurrences.
For these reasons, an apparent advantage in DFS in favor of the
biopsy arm is almost inevitable. To overcome bias caused by trial
design, regional nodal recurrences should be excluded from the
calculation of DFS. MSLT-1 was funded by the National Cancer
Institute, and an appeal on this matter has now been upheld
by its Clinical Investigations Branch (personal communication to
JMT). In the future, DFS in MSLT-1/2 will also be calculated on
the competing incidences of local/in-transit and distant recur-
rences alone.
Differing Practices Among MSLT-1 Centers
Another issue that makes the interpretation of MSLT-1 even more
difficult is differing follow-up practices among participating units.
In all publications relating to MSLT-1, as well as in the accom-
panying editorial,22 it has been stated or assumed that delayed
lymphadenectomy in the observation arm was performed when
metastatic nodes became palpable. That is not the case. Almost
half of the patients entered into MSLT-1 (946 of 2001) were from
the Sydney Melanoma Unit. It now transpires that the 378 or
so patients entered into the observation arm were investigated
by lymphoscintigraphy at the time of WLE of the primary tumor
when the site of the SN was marked by a “small permanent tat-
too” to facilitate regular interrogation by ultrasound.23 Delayed
lymphadenectomy was performed not when the regional nodal
metastases became palpable but when nonpalpable metastases
were identified by ultrasound and the diagnosis proven by ul-
trasound-guided cytology. In the same publication, the authors
confirmed that ultrasound could identify metastatic deposits of
melanoma in the SN at 4-mm diameter in the groin and neck and
4.5-mm diameter in the axilla. It is not known how many months
it would take for such occult deposits to become palpable, but
this practice directly affected and compromised the primary end
point of MSLT-1, i.e., OS difference from the point of randomiza-
tion. This information was not mentioned in the New England
Journal of Medicine article.1
Unanswered Questions Relating to MSLT-1
Several questions relating to MSLT-1 remain unanswered. Why
were 732 patients omitted from the first publication of the re-
sults, contrary to CONSORT guidelines? If these 732 patients had
been included, how would this have affected the DFS as calcu-
lated? If DFS was recalculated, as is now endorsed by National
Cancer Institute, would the small DFS advantage in favor of the
biopsy arm be maintained, lost, or reversed?
Have the results of MSLT-1 been invalidated by the anomalous
management at the Sydney Melanoma Unit? The core assump-
tion that all positive SNs, if not removed, will eventually progress
to palpable nodal recurrence is challenged by the hypothesis of
prognostic false-positivity. Does this prognostic difference not ex-
plain the 20% survival advantage in favor of immediate lymphad-
enectomy claimed in the subgroup analysis?
 Sentinel Lymph Node Biopsy in Melanoma Volume 22, Number 1
Sentinel Lymph Node Status as a Staging and
Prognostic Tool
Sentinel lymph node (LN) status at the time of diagnosis of the
primary tumor is the most important single prognostic factor in
melanoma.24–27 It has been shown repeatedly that the disease-
specific survival is significantly better in SN-negative patients com-
pared to SN-positive patients (approximately 95% vs. 70% at 3
years) and that SN-positivity predicts for distant spread and death.
Unfortunately, this prognostic importance does not translate into
a therapeutic benefit because no surgical procedure or systemic
therapy has been shown to improve OS in melanoma. Algorithms
of histologic factors relating to the primary tumor have been
shown to be almost as prognostically accurate as SN status.28
It is noteworthy that prognostic tools are still important in their
own right. There is still no absolute consensus worldwide that
adjuvant therapy should not be used in melanoma despite the
lack of an OS benefit. The “Kirkwood” adjuvant interferon regi-
men suggests a prolongation of DFS.29 Furthermore, almost all
new adjuvant trials will wish to include SN-positive patients. The
difficulty with this is that prognostically false-positive patients will
also be included, and in the future there may be a consensus that
only patients with metastases in the SN greater than a certain size
should be entered into trials of adjuvant therapy.
How effective is SLNB as a prognostic tool compared to informa-
tion available from the primary tumor and noninvasive imaging of
the nodal basins? SLNB was well established before it was realized
that high-resolution ultrasound with Doppler was the best meth-
od of imaging nonpalpable occult metastatic melanoma in the
regional LNs.30 It is known that ultrasound alone can detect occult
nodal metastases in up to one-third of SN-positive patients.23,31
Experienced radiologists can identify deposits of melanoma as
small as 3 mm and can confirm the diagnosis by ultrasound-guid-
ed cytology.32 Occult metastases of this diameter are also easily
identified by SLNB, but it has never been shown that SN status
maintains its staging and prognostic importance in ultrasound-
negative patients. Ultrasound is a simple noninvasive procedure
and ultrasound screening of the regional node basin(s) at the
time of diagnosis of the primary tumor may provide the greatest
challenge to SLNB. Those who are skeptical of the importance of
ultrasound may say that, like SLNB, ultrasound can only antecede
the clinical diagnosis of metastatic melanoma. However, there is
one very important difference. It is likely that all nodal metasta-
ses large enough to be visualized by ultrasound are destined to
progress to palpable nodal recurrence. On the other hand, SLNB
can detect most deposits of melanoma likely to progress but also
readily identifies some tiny deposits likely to be prognostically
false-positive and destined for dormancy or destruction.
Patterns of Melanoma Recurrence in SN-Negative Patients
Undoubtedly, many patients undergo SLNB hoping for reassur-
ance that their SNs are free of melanoma. However, being SN-
negative gives no guarantee of remaining recurrence-free and, as
always, the incidence of recurrence will increase with prolonged
follow-up. With reference to publications providing a median fol-
low-up of 2 years or more, the recurrence rate at any site is of the
order of 9.6% to 13.7%.33–37 These series agree that the site of
first recurrence in SN-negative patients is distant in approximately
half the patients, that isolated SN basin recurrence is uncommon,
and that the remaining sites of first recurrence are a combination
of synchronous in-transit and SN basin recurrences. This infor-
mation confirms that, in a small group of patients, melanoma
disseminates entirely via the bloodstream rather than via the lym-
phatic system.
Prognostic False-Positivity in the SN in Melanoma
Prognostic (or biological) false-positivity refers to tiny deposits of
melanoma within the SNs that are destined for dormancy or de-
struction and not for progression to palpable nodal recurrence.38
This hypothesis fundamentally challenges the central tenet of the
SLNB procedure, which assumes, without any evidence, that all
positive SNs (if not removed) will inevitably progress to palpable
nodal recurrence. Prognostic false-positivity results in patients
being incorrectly up-staged, being given inaccurate prognostic
information, undergoing unnecessary completion lymphadenec-
tomy, and possibly unnecessary adjuvant therapy or entry into
such trials. A simple mathematical model is presented below to
estimate the incidence of prognostic false-positivity together with
other lines of supporting evidence.
Indirect Evidence for Prognostic False-Positivity
Indirect evidence for prognostic false positivity comes from four
sources. First, many authors have reported that melanoma mi-
crometastases below a certain size have no adverse prognostic
significance.35,39–43 For example, Van Akkooi et al.35 state that pa-
tients with micrometastases less than 0.1 mm in the SN should
be judged to be SN-negative. Spanknebel et al.41 conclude that
patients whose micrometastases are detectable only by IHC have
a prognosis similar to that of patients with negative SNs. These
observations, however, depend on the SN being removed for his-
tologic examination, which could be construed as contributing to
the therapeutic benefit.
Second, there is an unexplained paradox in which younger patients
with melanoma have a significantly better prognosis than older
patients despite exhibiting a higher incidence of SN-positivity.44,45
As shown in Fig. 2, the mortality from melanoma rises steeply
with advancing age, whereas the incidence of SN-positivity re-
duces with increasing decades of age. In the absence of evidence
that melanoma spreads more commonly by the bloodstream in
FIG. 2. Incidence of SN-positivity with increasing decades of age
compared with melanoma-specific mortality.44,45
Volume 22, Number 1 Thomas and Hayes 

elderly patients, the most likely explanation is that, in younger pa-
tients, a more competent host response can eliminate tiny micro-
metastases or induce dormancy. In a study of 3076 patients, Chao
et al.44 showed that the incidence of SN-positivity was 23.1% in
patients less than 30 years of age but that the incidence declined
with increasing decades of age to 12% in patients between 61
and 70 years (P <0.001). Similarly, Statius Muller et al.45 showed a
decreasing incidence of SN-positivity from 36% in patients 18 to
30 years old to 17% in patients 71 to 84 years of age.
Before the results of MSLT-1 were known, two publications raised
expectations that immediate lymphadenectomy in SN-positive pa-
tients would lead to a survival advantage. Both studies compared
the survival of SN-positive patients who underwent early lymph-
adenectomy with patients who underwent delayed lymphadenec-
tomy for palpable nodal recurrence. Kretschmer et al.46 claimed a
12% survival advantage at 5 years, while Morton et al.,47 in the
“matched-pair” analysis, claimed a 22%, 32%, and 37% survival
advantage at 5, 10, and 15 years, respectively, in favor of immedi-
ate lymphadenectomy. In the absence of any melanoma-specific
survival advantage in MSLT-1, these claims of a large survival ben-
efit from immediate lymphadenectomy can only be explained by
prognostic false-positivity.
therefore only 119 patients in the biopsy arm would be expected
to progress in a similar fashion, 26 of whom are already identified.
Therefore, only 93 of the 122 SN-positive patients would have
been expected to progress to palpable nodal recurrence, which
yields an incidence of prognostic false-positivity of approximately
24%. In other words, 24% of SN-positive patients with interme-
diate-thickness tumors in MSLT-1 were wrongly up-staged, were
given incorrect prognostic information, and underwent unnec-
essary completion lymphadenectomy and, possibly, unnecessary
adjuvant therapy. This calculation suggests that the 20% survival
advantage claimed in the subgroup analysis is due to a prognostic
difference in the two subgroups compared and is not the result of
any therapeutic benefit from immediate lymphadenectomy. Simi-
larly, for all strata50 the incidence of prognostic false-positivity is
34% (Fig. 3B) partly because the rate of false-negativity almost
doubles, to 6.3%. These simple mathematical calculations provide
compelling evidence that prognostic false-positivity is a reality.38

Finally, there is also preclinical evidence suggesting that tumors

greater than 1 mm3 may be biologically distinct from those smaller
than 1 mm3. For a tumor to progress beyond 1 mm3, the devel-
opment of a tumor vasculature is required.48 A number of com-
plex biological steps49 are necessary for this, but if a tumor fails to
acquire the necessary angiogenic and invasive phenotype it will
then remain dormant at a submillimeter size. There is no reason to
assume that microscopic deposits have developed this necessary
angiogenic and invasive phenotype. In contrast, larger nodal me-
tastases have, by definition, developed their own microcirculation
and therefore fall into a different (and worse) prognostic category.
A
Estimating the Incidence of Prognostic False-Positivity
Direct evidence of prognostic false-positivity comes from the sub-
group analysis in MSLT-1, which claimed a 20% survival advantage
at 5 years in favor of early lymphadenectomy when the survival of
122 SN-positive patients in the biopsy arm was compared to that
of 78 patients who were treated by delayed lymphadenectomy
in the observation arm (see Fig. 1). This survival comparison is
biologically invalid because the assumption is made that all posi-
tive SNs will inevitably progress to palpable nodal recurrence. It is
also statistically invalid for the reasons discussed above.21 Because
the two arms of the trial were randomized, the proportion of
patients in each arm who were destined to progress to palpable
nodal disease should be the same. Therefore, the proportion of
patients undergoing lymphadenectomy should also be the same.
In fact, when the 26 false-negative patients in the biopsy arm
who developed palpable nodal disease during follow-up and un-
derwent delayed lymphadenectomy are taken into account, it can
be shown that a higher proportion of patients underwent lymph-
adenectomy in the biopsy arm (19.4% or {122+26}/764) com- B
pared with the observation arm (15.6% or 78/500) The excess of
patients undergoing lymphadenectomy in the biopsy arm are the FIG. 3. The method of calculation of the prognostic false-positiv-
prognostically false-positive patients. ity in patients with intermediate-thickness tumors (A) and of all
strata entered into the Multicenter Selective Lymphadenectomy
We can calculate the proportion of prognostically false-positive Trial (MSLT-1) (B). WE, wide excision, SN, sentinel node; SNB, sen-
patients as follows. As shown in Fig. 3A, 15.6% of patients in tinel node biopsy. Based on data from Morton et al.1,20 Repro-
the observation arm progress to palpable nodal recurrence, and duced with permission from Nature Clinical Practice Oncology.38
 Sentinel Lymph Node Biopsy in Melanoma Volume 22, Number 1

The incidence of prognostic false-positivity will decrease as more
patients in the observation arm develop nodal recurrence. How-
ever, because the median time to nodal recurrence in the obser-
vation arm of MSLT-1 was 16 months and the median follow-up
was 60 months,1 it is unlikely that nodal recurrence will increase
sufficiently to significantly affect the calculated incidences of
prognostic false-positivity. Nevertheless, if it is assumed that nodal
recurrences in the observation arm and among false-negative pa-
tients in the biopsy arm will increase at the same rate, then a 10%
and 20% increase in palpable nodal recurrence among patients
with intermediate-thickness tumors would reduce the incidence
of prognostic false-positivity to 13% and 8.4%, respectively. It
would take a 30% increase in nodal recurrence to reduce the inci-
dence to less than 1%. For all strata, a 10% and 20% increase in
nodal recurrence would reduce the incidence of prognostic false-
positivity to 27% and 20%, respectively, and it would take a 50%
increase in nodal recurrence to reduce prognostic false-positivity
to less than 1%.
High-resolution ultrasound identifies a resting inactive LN as being
oval in shape with an echo-poor (black) cortical rim of lymphoid
tissue surrounding an echogenic hilus (gray) that demonstrates
little or no vascularity (Fig. 4A). This appearance has been likened
to the pulp around the stone of a cherry. These appearances may
change in response to infection but are reversible. Progressively
in melanoma, the following changes occur in a metastatic LN.
The earliest sign is irregularity of the lymphoid cortex, which may
progress to a nodule (Fig. 4B). As the LN becomes increasingly
involved with melanoma, it becomes round rather than oval, the
echogenic hilus is progressively lost, the neovascularity intensifies,
and the volume of the LN expands (Fig. 4C).

Does RT-PCR Analysis for Tyrosinase Provide Additional

Prognostic Information in SN-Negative Patients?
Detection of tyrosinase mRNA by reverse transcriptase-poly-
merase chain reaction (RT-PCR) in negative SNs was intended
to identify SN-negative patients who were destined to recur
and in the expectation that the incidence of SN false-negativity
could be reduced. Unlike histology with IHC there was always
a risk that molecular staging would introduce an incidence of
false-positivity because of the effect of capsular nevus cells.
Review of the literature shows that there is no consensus
about the ability, if any, of RT-PCR to up-stage negative SNs.
Several series, including the Sunbelt Melanoma Trial with 1446 A
SN-negative patients, report that RT-PCR in SN-negative pa-
tients failed to detect a subgroup of patients with an increased
probability of recurrence.51 At the other extreme, many authors
report that RT-PCR can upstage 25% to 65% of histologically
negative SNs.52–57 Furthermore, some of these series report a
DFS difference in SN-negative/RT-PCR-negative patients com-
pared to SN-negative/RT-PCR positive patients.53,55,56 However,
there is agreement that SN-negative/RT-PCR-negative patients
have an extremely low risk for recurrence at any site. Because
patients entered into MSLT-2 can be deemed to be SN-positive
on RT-PCR criteria alone, it is useful to focus on the experience
from the John Wayne Cancer Institute from which this trial is
directed. Using a multimarker RT-PCR assay55,57 the researchers B
demonstrated that histologically negative SNs were RT-PCR-
positive in up to 40% of cases. Therefore, using RT-PCR in
SN-negative patients in MSLT-2 is likely to increase prognostic
false-positivity even further.

Ultrasound in the Assessment of SN Basin(s) in

Melanoma

Ultrasound screening of the SN basin(s) in search of occult (non-

palpable) metastases in melanoma is a neglected technique and,
in general, is poorly understood. Deposits of melanoma as small
as 3–4 mm can be identified on the basis of morphologic crite-
ria, and pathologic neovascularization can be identified on power
Doppler mode. The lesion can then be targeted for cytologic
examination, which is reported to have a specificity of 100%.
Ultrasound is operator-dependent and considerable expertise is
required.30,58,59
C
FIG. 4. High-resolution ultrasound of a normal lymph node (A),
of partial replacement of a lymph node by melanoma (B), and
of complete replacement by melanoma, with and without power
Doppler, which shows prominent neovascularization (C).
Volume 22, Number 1 Thomas and Hayes 
The American Joint Committee on Cancer (AJCC) staging system
for melanoma60 does not define the size of a micrometastasis, but
a metastatic deposit large enough to be identified by ultrasound
must be regarded as a macrometastasis or as occult clinical dis-
ease. This entire spectrum of tumor burden is bundled together
and classified as N1a or N2a. The crucial importance of tumor bur-
den to prognosis has been discussed above and, for this reason,
the next AJCC classification must differentiate between micro-
metastatic and nonpalpable, occult macrometastatic deposits of
melanoma in the SN. Similarly, in the context of prognostic false-
positivity, macrometastases identified by ultrasound will inevitably
progress to palpable nodal recurrence, which is why SN basins
should be screened by ultrasound before patients are referred for
SLNB. Ultrasound can detect occult metastatic melanoma in up
to one-third of positive SNs.23,31 In a recent ASCO presentation,
Voit et al.32 showed that, when the SN is identified by lymphos-
cintigraphy, ultrasound can detect metastatic melanoma in 50%
of patients ultimately proven to be SN-positive.32
At our Unit we do not advise SLNB for patients with primary mela-
noma. Relevant regional node basin(s) are screened by ultrasound
at the time of diagnosis. If no suspicious LNs are identified then,
after wide excision of the primary tumor, patients embark on
an ultrasound surveillance program of the regional LNs with the
intent of performing delayed lymphadenectomy when nonpal-
pable, clinically occult nodal recurrence is detected sonographi-
cally and proven by ultrasound-guided cytology. Extrapolating
from the results of MSLT-1, there is no risk that patients are being
disadvantaged by this method of management. On the contrary,
patients whose SNs are prognostically false-positive are protected
from unnecessary lymphadenectomy because such disease will
not progress to occult or palpable nodal recurrence. Ultrasound
detection of occult clinical disease presents a great challenge to
SLNB because SN status has never been shown to have prognostic
significance in ultrasound-negative patients.
Conclusions: The Status of SLNB in 2008
SLNB does not impart a survival benefit to patients with mela-
noma. It is a prognostically imperfect tool because it identifies a
cohort of prognostically false-positive patients. At present, these
patients are wrongly up-staged, are given inaccurate prognostic
information, and undergo unnecessary lymphadenectomy and
unnecessary adjuvant therapy or entry into adjuvant trials.
Historically, there has been a trans-Atlantic difference in percep-
tion of the introduction of SLNB. In Europe, ELND was rarely per-
formed and therefore SLNB constitutes an increase in the amount
of surgery at the time of diagnosis. However, in the United States
and Australia, because ELND was routinely performed, the intro-
duction of SLNB meant a reduction in the amount of surgery at
the time of diagnosis. This difference in perception is compound-
ed by differing views regarding the efficacy of adjuvant therapy in
melanoma. In some centers in the United States, SN-positive pa-
tients are advised to receive interferon, whereas in other centers
in the United States and mostly elsewhere in the world, interferon
is not advised because any advantage in DFS is not considered a
sufficient benefit to outweigh the morbidity of treatment.
Notwithstanding these differing perceptions, we argue that it is
now appropriate for management of the regional LNs in mela-
noma to be refined further with the replacement of SLNB by ul-
trasound screening and surveillance. MSLT-1 has now shown that
SLNB does not give the patient a benefit in terms of OS, and
the benefit in terms of DFS is unclear. Hence, it is essentially a
prognostic tool. Because, as we have shown, it is an imperfect
tool with prognostically false-positive patients being over-treated,
we argue that SLNB should not be recommended for routine use
outside of a randomized controlled trial.
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Some compounds discussed in this publication may be in investigative stages and not yet approved by the FDA for uses mentioned. The reader is urged
to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions.
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