A Govindarajan

CR Scoggins

CR Scroggins

DL Morton

JM Hilari

KM McMasters

MS Sabel

SL Wong

Vernon K. Sondak

WC Conway

English

PubMed

Crossref

Nonsentinel Node Metastases in Melanoma: Do They Reflect the Biology of the Tumor, the Lymph Node or the Surgeon?

Springer - Publisher Connector

EDITORIAL
Nonsentinel Node Metastases in Melanoma: Do They Reflect
the Biology of the Tumor, the Lymph Node or the Surgeon?
Editorial to Accompany Ghaferi et al., ASO-2009-03-0312.R1
Vernon K. Sondak, MD1,2
1Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, Tampa, FL; 2Departments of Oncologic Sciences and
Surgery, University of South Florida College of Medicine, Tampa, FL
Two decades ago, elective lymph node dissection was
essentially abandoned as a surgical strategy for melanoma
patients for clinically negative (cN0) regional lymph nodes,
based on three key facts: (1) less than 20% of patients with
cN0 intermediate-thickness melanomas have histopatho-
logic evidence of nodal involvement (pN1), (2) an effective
salvage strategy—therapeutic lymph node dissection at the
time of nodal relapse—was felt to exist for pN1 patients
upon nodal relapse, and (3) there was no compelling evi-
dence that elective node dissection conveyed outcome
advantages for pN1 patients (in particular, improved sur-
vival, better regional disease control or decreased surgical
morbidity) of sufficient magnitude to offset the inescapable
drawback that 80% or more of the patients subjected to the
procedure were incurring morbidity without any expecta-
tion of oncologic benefit. Elective node dissection has now
been replaced by sentinel node biopsy, and we find our-
selves today in an eerily parallel situation regarding
completion node dissection for our sentinel node-positive
patients. Specifically, (1) less than 20% of patients with a
positive sentinel node have histopathologic evidence of
involvement of nonsentinel nodes (usually arbitrarily
defined as those regional nodes not removed at sentinel
node biopsy for whatever reason), (2) an effective salvage
strategy—therapeutic lymph node dissection at the time of
nodal relapse—may exist for sentinel node-positive
patients upon nodal relapse, and (3) there is as yet no
compelling evidence that completion node dissection
conveys outcome advantages for sentinel node-positive
patients (in particular, improved survival) of sufficient
magnitude to offset the drawback that all sentinel node
positive patients are incurring morbidity including some as
yet undefined percentage who would never relapse in the
remaining regional nodes.1–3
However, it is well to introduce the caution that these
two situations—elective node dissection in the absence of
any clinical evidence of nodal involvement, and comple-
tion node dissection in the presence of histopathologic
proof of sentinel node involvement—are not entirely
analogous. The sentinel node biopsy experience has taught
us that some regional lymph node metastases undetected on
routine histologic evaluation of a bisected lymph node
submitted as part of a node dissection are readily appar-
ent—and unequivocally clinically significant—when the
node is serially sectioned and evaluated with immunohis-
tochemical stains for melanocyte antigens. Since
‘‘nonsentinel nodes’’ are almost never examined using
serial sectioning and immunohistochemistry, we must
assume that the frequency of involvement of nonsentinel
nodes is greater than currently recognized—and the yield
(if not necessarily the benefit) of completion node dissec-
tion is almost surely underestimated. Nonetheless,
understanding the clinicopathologic factors that predict
nonsentinel node involvement would surely inform the
decision of whether or not to pursue completion dissection
in all cases of positive sentinel nodes. So what have we
learned about the biology of melanoma metastasis as it
relates to the nonsentinel node?
TWO NODES ARE WORSE THAN ONE
While the majority of sentinel node-positive patients
have only one positive sentinel node and no other sentinel
 Society of Surgical Oncology 2009
Published Online: 11 August 2009
V. K. Sondak, MD
e-mail: vernon.sondak@moffitt.org
Ann Surg Oncol (2009) 16:2965–2967
DOI 10.1245/s10434-009-0667-2
or nonsentinel nodal involvement identified, patients with
pathologically involved nonsentinel nodes, by definition,
have at least two positive nodes. Since the number of
pathologically involved nodes is a recognized prognostic
factor, it is evident that positive nonsentinel nodes will
convey a poor prognosis, which would be statistically
significant in any series with adequate power to detect a
nonrandom difference. In this issue of the Annals of Sur-
gical Oncology, Ghaferi et al. attempt to evaluate the
biologic implications of nonsentinel node involvement by
comparing 90 patients with two or three positive sentinel
nodes and no nonsentinel node involvement with 41
patients with the same number of positive nodes in whom
at least one involved node was a nonsentinel node.3 Distant
disease-free and overall survival were both statistically
significantly worse for the nonsentinel node-positive
cohort, although the authors do not present a multivariate
analysis to evaluate whether other factors may account for
this difference. Even if a multivariate analysis did indicate
a difference, we still would need to account for the dif-
ference in tumor burden between patients with two nodal
micrometastases seen only on immunohistochemistry and
those with at least one nodal metastasis large enough to be
seen on routine evaluation of a bisected node. To date, we
simply do not know enough about how to make this
adjustment to accept on face value the conjecture that
nonsentinel node metastasis indicates an inherent biologic
ability of a melanoma to spread systemically, simply
because it could spread within a nodal basin.
NOT ALL NODES ARE THE SAME
Ghaferi et al. found that older patients were more likely
to have positive nonsentinel nodes, and even more signif-
icantly, that older age and the presence of a nonsentinel
node metastasis were the only factors statistically signifi-
cantly correlated with worse distant disease-free and
overall survival in their multivariate model.3 While it is
possible that melanomas arising in older patients have an
inherently different biology with more frequent hematog-
enous spread, it is also plausible that older nodes are
different from younger nodes in terms of their filtration
efficiency and/or immunologic functionality. A recent
observation that sentinel nodes in older patients demon-
strated lower levels of radioactivity than those from
younger patients supports the concept that lymphatic flow
and/or nodal filtration efficiency may decrease as we age,
with potential oncologic consequences.4 Furthermore,
emerging evidence suggests older patients are more likely
to have false-negative sentinel nodes, which adds some
credence to the idea that tumor cells may more readily pass
through the ‘‘inefficient’’ sentinel node in older patients
and gain access to second-echelon nodes and the systemic
circulation.5
NOT ALL SURGEONS ARE THE SAME
Before we ascribe too much biologic significance to
nonsentinel node metastases, we need to recognize the
potential confounding role of the surgeon. Not all sur-
geons—even in a single center with established protocols
for defining the sentinel node—are equally aggressive in
pursuing every lymph node with radioactivity above
baseline. It stands to reason that any ‘‘hot’’ node, even one
containing just a fraction of the radioactivity of the hottest
node, is more likely to harbor metastatic melanoma than a
completely cold node; so the diligence with which sentinel
nodes are cleared by the surgeon will directly influence the
likelihood with which ‘‘nonsentinel node’’ metastases are
found—since sentinel nodes left behind become nonsenti-
nel nodes when the completion node dissection is
performed. It is also predictable that surgeons may be less
likely to pursue every sentinel node in a basin when they
suspect that the initial sentinel node has a very high like-
lihood of harboring metastases (to avoid extensive
operative manipulation of a basin that will require com-
pletion dissection). Future series reviewing nonsentinel
node metastasis frequency should include the surgeon as a
potential predictive variable, and should also include
evaluating the lymphoscintigram to determine how many
radioactive nodes were visualized compared with how
many sentinel nodes were removed.
However, all of this discussion centering around the
frequency of positive nonsentinel nodes addresses only one
of the factors that will determine whether completion node
dissection can safely be omitted in some sentinel node-
positive patients.6,7 We must also understand the safety and
efficacy of salvage node dissection at the time of nodal
relapse. Available data suggest that lymphadenectomy
performed for clinically evident nodal disease is associated
with more complications and poorer regional control rates
than when the same procedure is done for microscopic
disease.8 We all look forward to the results of the second
Multicenter Selective Lymphadenectomy Trial (MSLT-2),
a prospective randomized evaluation of nodal observation
as an alternative to completion dissection after a positive
sentinel node biopsy, which will shed considerable light on
this issue. However, we also have to be aware of some
potential pitfalls regarding the MSLT-2 trial.
This trial includes patients whose sentinel node is
positive only by reverse-transcriptase polymerase chain
reaction (RT-PCR), a technique that has not been validated
as predictive of worse survival or of increased risk of
nonsentinel node metastasis. In fact, the results of RT-PCR
2966 V. K. Sondak
analysis of the sentinel node in the Sunbelt Melanoma Trial
indicated that the outcome for histologically negative
sentinel nodes was identical regardless of RT-PCR status.9
While MSLT-2 uses different primers and paraffin-
embedded rather than fresh nodal tissue, concerns remain
about the validity of including these patients in any anal-
ysis of the impact of completion lymph node dissection.10
MSLT-2 is also likely to be impacted by selection bias, as
patients who are known or suspected to be at high risk of
having nonsentinel node involvement (e.g., older patients,
those with thick, ulcerated or high mitotic rate primaries,
and those with multiple positive sentinel nodes) may be
less likely to be recruited to the trial and less likely to
consent to randomization if they are approached. If the
group of patients most likely to benefit from completion
lymph node dissection is underrepresented in the MSLT-2
trial, the results may not be generalizable; patients and
physicians may use them indiscriminately to make deci-
sions nonetheless. Finally, the primary endpoint of MSLT-
2 is survival, yet regional failure and morbidity rates may
be equally compelling reasons to recommend completion
lymphadenectomy even in the absence of a survival benefit.
The data generated from MSLT-2 will be highly informa-
tive, but experience has shown that patients and even
physicians do not always see eye to eye when interpreting
the results of randomized trials.
A final, completely anecdotal word of caution, based on
a recent case. A woman in her mid-30 s with a 1.1-mm
melanoma on the thigh was found to have a solitary
micrometastasis (\0.1 mm in greatest dimension and
apparent only after immunohistochemical staining) in an
inguinal sentinel node. Her lymphoscintigraphy indicated
only a single inguinal hot spot, with no through transit into
the pelvis, which corresponded well to the counts observed
in the solitary blue lymph node removed at surgery.
Clearly, this was a woman who would be considered to be
at very low risk for finding nonsentinel node metastases on
completion node dissection. She was offered participation
in the MSLT-2 trial, but for professional and personal
reasons refused to even consider inguinal node dissection
and declined surgery. Eighteen months later, she developed
palpable disease in the same groin and a superficial and
deep inguinal node dissection indicated more than a dozen
involved nodes, including pelvic nodal metastases. Was
she just an ‘‘outlier’’ and would all of these nodes have
been discovered had the same surgery been performed a
year and a half earlier? Perhaps, but that seems unlikely.
Conversely, it is easy to imaging that the very morbidities
this patient sought to avoid are now more likely—and more
likely to be severe and/or permanent—than they would
have been if a completion lymphadenectomy had been
done soon after the sentinel node biopsy. While this is just
a single case, it is by no means a unique case in our
experience and it also recapitulates the findings of MSLT-1
wherein more positive nodes were found at therapeutic
lymphadenectomy upon nodal relapse than at completion
lymphadenectomy following sentinel node biopsy.11 Cases
such as these have strengthened our resolve to urge patients
not to forego completion node dissection outside the setting
of a prospective clinical trial, and to continue to pursue
strategies to minimize the morbidity of completion
lymphadenectomy.12
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3. Ghaferi AA, Wong SL, Johnson TM, et al. Prognostic signifi-
cance of a positive non-sentinel lymph node in cutaneous
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Nonsentinel Node Metastases in Melanoma 2967


Age-related lymphatic dysfunction in melanoma patients. Ann Surg Oncol.

Can completion lymph node dissection be avoided for a positive sentinel node in melanoma? Ann Surg Oncol.

Factors associated with false negative sentinel lymph node biopsy in melanoma patients: Results from a prospective randomized trial. Ann Surg Oncol.

Frequency of nonsentinel lymph node metastasis in melanoma. Ann Surg Oncol.

Histological features of melanoma sentinel lymph node metastases associated with status of the completion lymphadenectomy and rate of subsequent relapse. Ann Surg Oncol.

Inguinal node dissection for melanoma in the era of sentinel lymph node biopsy.

Limiting the morbidity of inguinal lymphadenectomy for metastatic melanoma.

Melanoma patients with positive sentinel nodes who did not undergo completion lymphadenectomy: a multi-institutional study. Ann Surg Oncol.

Molecular staging of pathologically negative sentinel lymph nodes from melanoma patients using multimarker, quantitative real-time RT-PCR. Ann Surg Oncol.

Prognostic signiﬁ-cance of a positive non-sentinel lymph node in cutaneous melanoma. Ann Surg Oncol.

Prospective multiinstitutional study of reverse transcriptase polymerase chain reaction for molecular staging of melanoma.

Sentinel-node biopsy or nodal observation in melanoma.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2766452

Nonsentinel Node Metastases in Melanoma: Do They Reflect the Biology of the Tumor, the Lymph Node or the Surgeon?: Editorial to Accompany Ghaferi et al., ASO-2009-03-0312.R1

Nonsentinel Node Metastases in Melanoma: Do They Reflect the Biology of the Tumor, the Lymph Node or the Surgeon?: Editorial to Accompany Ghaferi et al., ASO-2009-03-0312.R1

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