Article

Prognosis in Patients With Sentinel Node-Positive Melanoma Is Accurately Defined by the Combined Rotterdam Tumor Load and Dewar Topography Criteria

Humboldt-Universität zu Berlin, Berlín, Berlin, Germany
Journal of Clinical Oncology (Impact Factor: 18.43). 06/2011; 29(16):2206-14. DOI: 10.1200/JCO.2010.31.6760
Source: PubMed
ABSTRACT
Prognosis in patients with sentinel node (SN)-positive melanoma correlates with several characteristics of the metastases in the SN such as size and site. These factors reflect biologic behavior and may separate out patients who may or may not need additional locoregional and/or systemic therapy.
Between 1993 and 2008, 1,080 patients (509 women and 571 men) were diagnosed with tumor burden in the SN in nine European Organisation for Research and Treatment of Cancer (EORTC) melanoma group centers. In total, 1,009 patients (93%) underwent completion lymph node dissection (CLND). Median Breslow thickness was 3.00 mm. The median follow-up time was 37 months. Tumor load and tumor site were reclassified in all nodes by the Rotterdam criteria for size and in 88% by the Dewar criteria for topography.
Patients with submicrometastases (< 0.1 mm in diameter) were shown to have an estimated 5-year overall survival rate of 91% and a low nonsentinel node (NSN) positivity rate of 9%. This is comparable to the rate in SN-negative patients. The strongest predictive parameter for NSN positivity and prognostic parameter for survival was the Rotterdam-Dewar Combined (RDC) criteria. Patients with submicrometastases that were present in the subcapsular area only, had an NSN positivity rate of 2% and an estimated 5- and 10-year melanoma-specific survival (MSS) of 95%.
Patients with metastases < 0.1 mm, especially when present in the subcapsular area only, may be overtreated by a routine CLND and have an MSS that is indistinguishable from that of SN-negative patients. Thus the RDC criteria provide a rational basis for decision making in the absence of conclusions provided by randomized controlled trials.

Full-text

Available from: Christiane A Voit
Prognosis in Patients With Sentinel Node–Positive
Melanoma Is Accurately Defined by the Combined
Rotterdam Tumor Load and Dewar Topography Criteria
Augustinus P.T. van der Ploeg, Alexander C.J. van Akkooi, Piotr Rutkowski, Zbigniew I. Nowecki,
Wanda Michej, Angana Mitra, Julia A. Newton-Bishop, Martin Cook, Iris M.C. van der Ploeg,
Omgo E. Nieweg, Mari F.C.M. van den Hout, Paul A.M. van Leeuwen, Christiane A. Voit,
Francesco Cataldo, Alessandro Testori, Caroline Robert, Harald J. Hoekstra, Cornelis Verhoef,
Alain Spatz, and Alexander M.M. Eggermont
See accompanying article on page 2199 and editorial on page 2137
From Erasmus University Medical
Center-Daniel den Hoed Cancer Center,
Rotterdam; Netherlands Cancer
Institute-Antoni van Leeuwenhoek
Hospital and Vrije Universiteit, Amster-
dam; University Medical Center
Groningen, Groningen, the Netherlands;
M. Sklodowska-Curie Memorial Cancer
Center and Institute of Oncology,
Warsaw, Poland; Royal Surrey County
Hospital, Guildford; European Organisa-
tion for Research and Treatment of
Cancer, Melanoma Group, Brussels,
Belgium; Charite´ , Humboldt University
of Berlin, Berlin, Germany; European
Institute of Oncology, Milan, Italy; Insti-
tut de Cance´ rologie Gustave Roussy,
Villejuif, France; and McGill University,
Montreal, Quebec, Canada.
Submitted July 19, 2010; accepted
October 27, 2010; published online
ahead of print at www.jco.org on April
25, 2011.
Written on behalf of the Melanoma
Group of the European Organisation for
Research and Treatment of Cancer.
A.P.T.V.D.P. and A.C.J.V.A. shared first
authorship.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Corresponding author: Alexander M.M.
Eggermont, MD, PhD, Institut de
Cancérologie Gustave Roussy, Villejuif
Cedex 94200, France; e-mail:
alexander.eggermont@igr.fr.
© 2011 by American Society of Clinical
Oncology
0732-183X/11/2916-2206/$20.00
DOI: 10.1200/JCO.2010.31.6760
ABSTRACT
Purpose
Prognosis in patients with sentinel node (SN) –positive melanoma correlates with several
characteristics of the metastases in the SN such as size and site. These factors reflect biologic
behavior and may separate out patients who may or may not need additional locoregional and/or
systemic therapy.
Patients and Methods
Between 1993 and 2008, 1,080 patients (509 women and 571 men) were diagnosed with tumor
burden in the SN in nine European Organisation for Research and Treatment of Cancer (EORTC)
melanoma group centers. In total, 1,009 patients (93%) underwent completion lymph node
dissection (CLND). Median Breslow thickness was 3.00 mm. The median follow-up time was 37
months. Tumor load and tumor site were reclassified in all nodes by the Rotterdam criteria for size
and in 88% by the Dewar criteria for topography.
Results
Patients with submicrometastases ( 0.1 mm in diameter) were shown to have an estimated
5-year overall survival rate of 91% and a low nonsentinel node (NSN) positivity rate of 9%. This is
comparable to the rate in SN-negative patients. The strongest predictive parameter for NSN
positivity and prognostic parameter for survival was the Rotterdam-Dewar Combined (RDC)
criteria. Patients with submicrometastases that were present in the subcapsular area only, had an
NSN positivity rate of 2% and an estimated 5- and 10-year melanoma-specific survival (MSS)
of 95%.
Conclusion
Patients with metastases 0.1 mm, especially when present in the subcapsular area only, may
be overtreated by a routine CLND and have an MSS that is indistinguishable from that of
SN-negative patients. Thus the RDC criteria provide a rational basis for decision making in the
absence of conclusions provided by randomized controlled trials.
J Clin Oncol 29:2206-2214. © 2011 by American Society of Clinical Oncology
INTRODUCTION
Sentinel lymph node biopsy (SNB), introduced by
Morton et al,
1,2
is widely accepted as a highly accu-
rate diagnostic method of identifying early lymph
node micrometastasis in patients with melanoma.
Sentinel node (SN) tumor burden is the most
important prognostic factor for patients with early-
stage melanoma.
3
Prognosis in patients with
SN-positive melanoma correlates with several char-
acteristics of the metastases in the SN such as size
and site. These factors reflect biologic behavior and
may separate out patients who may or may not need
additional locoregional and/or systemic therapy.
SN positivity rates depend on median and
mean Breslow thickness of the primary, ulceration
rates, and the SN workup protocol and vary in the
literature from 14% to 30%.
4-6
Approximately 20%
of patients who are SN-positive have further nodes
involved, which are demonstrated by completion
lymph node dissection (CLND) findings, the so-
called nonsentinel node (NSN) positivity rate. Many
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ORIGINAL REPORT
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specialists in the melanoma field have tried to identify the correct
patient group to undergo a CLND and to identify those patients who
can safely be spared unnecessary CLND and its associated morbidity,
such as wound infections and chronic lymph edema.
6-39
Ongoing
prospective multicenter studies aim to identify the group of patients
who can be considered for observation instead of CLND. The two
most prominent studies are the Multicenter Selective Lymphadenec-
tomy Trial II (MSLT-II) and the European Organisation for Research
and Treatment of Cancer (EORTC) MINITUB studies.
40
In this study, two important morphometric parameters are
assessed: the microanatomic location (Dewar criteria)
28
and the
maximum diameter of the largest tumor lesion (Rotterdam crite-
ria).
6,12
The EORTC Melanoma Group (MG) recommends that all
pathologists report these criteria for each SN-positive patient.
42
The aim of this study, which uses the largest reclassified database of
SN positivity, was to determine the role of tumor load and tumor
site in the SN as prognostic factors for survival and as predictive
factors for NSN positivity.
PATIENTS AND METHODS
Patients
Patients with a positive SNB after wide local excision of a malignant
melanoma in nine major collaborating EORTC MG centers were included in
this retrospective study. Participating EORTC MG Centers are listed in Table
1. Between 1993 and 2008, 1,080 patients were diagnosed with tumor burden
in the SN. A database with personal information and information on previous
medical history, disease, and follow-up was created for these patients. Baseline
characteristics are summarized in Table 1.
In general, patients underwent the SNB in the same session as the re-
excision procedure after the diagnostic exaction of the primary melanoma.
Common procedure was to achieve margins of 1 cm for melanomas 2mm
and margins of 1 to 2 cm for melanomas 2 mm. The SNB procedure was
offered to patients with Breslow thickness 1.0 mm or to patients with
histopathologic features such as ulceration or Clark level IV or V invasion.
CLND was not performed in all SN-positive patients. In 71 patients
(6.6%), CLND was not performed for several reasons: refusal of further treat-
ment, the diagnosis of distant metastasis between SNB and CLND, or the
presence of minimal tumor burden in the SN.
The Triple Technique
After wide local excision of the malignant melanoma, the SN surgical
procedure was done by using the triple technique, described in detail else-
where.
5,43,44
In short, the triple technique consists of preoperative lympho-
scintigraphy, undertaken within 24 hours of the operation being performed;
perioperative use of patent blue; and use of a handheld gamma detection probe
to detect the SN or SNs. A lymph node was identified as an SN if it stained blue,
if it had an in situ radioactivity count at least three times that of the background
count, or if it had an ex vivo radioactivity count at least 10 times greater than
the background count.
After the surgical procedure, the SNs were sent to the pathology depart-
ment for pathologic examination. SN tumor burden was reviewed, for the
purpose of this study, by a second pathologist, in a later phase.
Pathology
In the nine EORTC centers, all SNs were worked up according to the
EORTC MG pathology protocol designed by Cook et al
45
First, the SNs were
fixed for 24 hours in buffered formalin. Second, after fixation, the lymph nodes
were halved through the hilum in its longest dimension and embedded in
paraffin. From each face of the lymph node, five serial step sections of 4
m
each were cut with 50
m intervals between different numbers of sections.
Finally, all sections were stained with hematoxylin and eosin and S100 and/or
MelanA. There were slight local differences in the Cook protocol regarding the
Table 1. Baseline Characteristics of SN-Positive Patients (N 1,080)
Characteristic No. of Patients %
Sex
Male 571 53
Female 509 47
Center
DDHCC 115 11
CHUB 86 8
MMCCIO 245 23
RSCH 214 20
AVL 116 11
IGR 68 6
VU 107 10
UMCG 56 5
EIO 73 7
Age, years
50 523 48
50 557 52
Location
Extremity 643 60
Trunk 405 37
Head and neck 32 3
Histology
SSM 401 37
NM 347 32
Other 332 31
Breslow, mm
T1 ( 1.00) 53 5
T2 (1.01-2.00) 270 25
T3 (2.01-4.00) 434 40
T4 ( 4.00) 323 30
Clark
I20
II 33 3
III 266 25
IV 614 57
V 117 11
Unknown 48 4
Ulceration
Absent 603 56
Present 477 44
Rotterdam criteria, mm
0.1 113 10
0.1-1.0 457 42
1.0 510 47
Dewar criteria
Subcapsular 181 17
Combined 423 39
Parenchymal 154 14
Multifocal 41 4
Extensive 152 14
Unknown 129 12
NSN status
Negative 797 74
Positive 212 20
Unknown 71 7
Abbreviations: SN, sentinel node; DDHCC, Daniel Den Hoed Cancer Center (Eras-
mus University Medical Center, Rotterdam, the Netherlands); CHUB, Charité, Hum-
boldt University of Berlin (Berlin, Germany); MMCCIO, M. Sklodowska-Curie
Memorial Cancer Center and Institute of Oncology (Warsaw, Poland); RSCH, Royal
Surrey County Hospital (Guildford, United Kingdom); AVL, Antoni van Leeuwenhoek
Hospital (Netherlands Cancer Institute, Amsterdam, the Netherlands); IGR, Institut de
Cancérologie Gustave Roussy (Villejuif, France); VU, Vrije Universiteit (Amsterdam,
the Netherlands); UMCG, University Medical Center Groningen (Groningen, the
Netherlands); EIO, European Institute of Oncology (Milan, Italy); SSM, superficial
spreading melanoma; NM, nodular melanoma; NSN, nonsentinel node.
Classification of SN Tumor Load in SN-Positive Patients
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number and distance of step sections in different time periods; however, the
main principles remained unchanged.
All SNs with tumor burden were reviewed by different members of the
EORTC MG. In seven of nine EORTC Centers, SN tumor load was reclassified
by van Akkooi. In two EORTC centers (Antoni van Leeuwenhoek Hospital,
Netherlands Cancer Institute, Amsterdam, the Netherlands and University
Medical Center Groningen, Groningen, the Netherlands), other experienced
melanoma specialists reclassified the SN tumor load. SN tumor load was
classified according to the Rotterdam criteria and Dewar criteria. All positive
SNs were classified according to the Rotterdam criteria.
6,12
Dewar criteria were
available for 951 patients (88%).
Dewar criteria define the microanatomic location of the melanoma
lesion.
28
Microanatomic locations are subcapsular, parenchymal, combined,
multifocal, or extensive. Because Dewar criteria showed that the subcapsular
group had a better prognosis than any other, we have also grouped the loca-
tions into two groups: subcapsular and nonsubcapsular (which we called the
Dewar criteria II). The Rotterdam criteria ( 0.1 mm, 0.1 to 1.0 mm, 1.0
mm) consists of the measurement of the maximum diameter in any direction
of the largest lesion overall on a slide. Several other studies included the
maximum diameter of the largest tumor lesion as a parameter of SN tumor
load and used other cutoff points.
7-11,13-17,19-21
For this reason, we used other
cutoff points other than 0.1 mm in our analyses (ie, 0.2 mm [Rotterdam
criteria II], 0.3 mm [Rotterdam criteria III], and 0.4 mm [Rotterdam
criteria IV]). We also created a new variable after first analysis: Rotterdam-
Dewar Combination (RDC) criteria ( 0.1 subcapsular, 0.1 nonsubcapsu-
lar), combining the two most predictive and prognostic subgroups of the
parameters. Patients with tumors for which it was difficult to determine the
different micromorphometric parameters were discussed during EORTC MG
meetings, which took place every 6 months.
Statistics
Univariate analyses for NSN positivity were performed by using a
2
test.
Univariate analyses of end points for survival were performed by using the
Kaplan-Meier method and the log-rank test. Multivariate analyses to deter-
mine the prognostic value of covariates regarding melanoma-specific survival
(MSS), disease-free survival (DFS), and overall survival (OS) were performed
by using the Cox’s proportional hazards model. DFS and OS were calculated
from the operation date of the SNB to the date of first disease recurrence or the
date of death or the last follow-up, respectively. MSS was calculated from the
operation date of the SNB to the date of death caused by melanoma disease.
Follow-up time was defined as the date of last follow-up or death starting from
the date of the SN procedure.
For the survival analyses and analysis for NSN status, the following
variables were included: sex (male, female), centers (nine EORTC centers), age
( 50, 50 years), location of the melanoma (extremities, trunk, head and
neck), histology of the melanoma (superficial spreading melanoma, nodular
melanoma, other), Breslow thickness (T1, T2, T3, T4), Clark level (II, III, IV,
V), ulceration (absent/unknown and present), Rotterdam criteria ( 0.1 mm,
0.1 to 1.0 mm, or 1.0 mm), Rotterdam criteria II ( 0.2 mm, 0.2 to 1.0 mm,
or 1.0 mm), Rotterdam criteria III ( 0.3 mm, 0.3 to 1.0 mm, or 1.0 mm),
Rotterdam criteria IV ( 0.4 mm, 0.4 to 1.0 mm, or 1.0 mm), Dewar criteria
(subcapsular, parenchymal, combined, multifocal, extensive, unknown), De-
war criteria II (subcapsular, nonsubcapsular), RDC criteria ( 0.1 subcapsu-
lar, 0.1 nonsubcapsular) and, for survival analysis only, NSN status
(negative, positive, unknown). Statistics were performed with STATA version
11.1 (STATA, College Station, TX).
RESULTS
Patient Characteristics
Baseline characteristics are summarized in Table 1. This study
included 1,080 patients with melanoma (509 women and 571 men)
with a positive SN procedure over a 16-year period. Average age was 51
years (range, 6 to 88 years). Mean and median Breslow thicknesses
were 4.00 mm and 3.00 mm (range, 0.1 to 90 mm), respectively. The
mean and median follow-up times for the entire group were 3.8 and
3.1 years (46 and 37 months; range, 1 to 172 months). The mean and
median times to first recurrence were 3.2 and 2.3 years (38 and 27
months). At last follow-up, 336 (31%) of 1,080 patients were deceased.
In Table 2, the characteristics of Breslow thickness, ulceration
rate, and subgroups of the Rotterdam criteria and the Dewar criteria
are compared among the nine EORTC MG centers. With a median
Breslow thickness of 4.00 mm and an ulceration percentage of 64%,
the M. Sklodowska-Curie Memorial Cancer Center and Institute of
Oncology (MMCCIO; Warsaw, Poland) is the center with the group
of SN-positive patients who have the worst prognosis. This is reflected
by the large proportion of patients with advanced SN metastases
( 1.0 mm for Rotterdam criteria; extensive for Dewar criteria).
Table 2. Characteristics per EORTC Center
Characteristic
Center
DDHCC CHUB MMCCIO RSCH AVL IGR VU UMCG EIO
Median Breslow, mm 3.00 3.34 4.00 2.40 3.00 2.90 2.10 2.50 3.00
Ulceration percentage 45 50 64 31 40 47 25 30 49
Rotterdam criteria percentage
0.1 mm 17 26 3 11 4 9 11 23 4
0.1-1.0 mm 48 35 33 46 32 50 49 57 52
1.0 mm 35 40 64 43 64 41 40 20 44
Dewar criteria percentage
Subcapsular 30 40 4 18 34 15 15 N/A N/A
Combined 30 29 47 50 41 50 56 N/A N/A
Parenchymal 13 12 22 17 0 26 19 N/A N/A
Multifocal 12 8 4 1 5 3 0 N/A N/A
Extensive 15 12 24 13 21 6 10 N/A N/A
Abbreviations: EORTC, European Organisation for Research and Treatment of Cancer; DDHCC, Daniel Den Hoed Cancer Center (Erasmus University Medical
Center, Rotterdam, the Netherlands); CHUB, Charité, Humboldt University of Berlin (Berlin, Germany); MMCCIO, M. Sklodowska-Curie Memorial Cancer Center and
Institute of Oncology (Warsaw, Poland); RSCH, Royal Surrey County Hospital (Guildford, United Kingdom); AVL, Antoni van Leeuwenhoek Hospital (Netherlands
Cancer Institute, Amsterdam, the Netherlands); IGR, Institut de Cancérologie Gustave Roussy (Villejuif, France); VU, Vrije Universiteit (Amsterdam, the Netherlands);
UMCG, University Medical Center Groningen (Groningen, the Netherlands); EIO, European Institute of Oncology (Milan, Italy); N/A, not applicable.
van der Ploeg et al
2208
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NSN Status
Of the 1,009 patients who underwent a CLND, 21% (212 pa-
tients) had one or more positive NSNs. Table 3 shows NSN positivity
and negativity rates for all factors assessed in this study. The following
factors were significant regarding NSN status; age; center; histology
and location of the primary; Clark level; Breslow thickness; Rotterdam
criteria; Rotterdam criteria II, III, and IV; Dewar criteria; Dewar crite-
ria II; and RDC criteria.
The rate of additional positive lymph nodes in the group of
patients with submicrometastases ( 0.1 mm, Rotterdam criteria)
was 9%, although 16% of patients with Rotterdam criteria 0.1 to 1.0
mm had positive NSNs and 25% of patients had 1.0 mm of SN
tumor burden. NSN positivity rates for the other cutoff points were
similar. Patients with 0.2 mm, 0.3 mm, and 0.4 mm had 14%,
14%, and 13% positive NSNs, respectively. NSN positivity was 7% in
patients with subcapsular metastases and 22% in patients with non-
subcapsular metastases. The subgroup of patients with the best pre-
dictivity for NSN status was the group with subcapsular metastases
0.1 mm, which showed positive NSNs in only 2% of patients.
Survival
Results of univariate and multivariate analyses are provided in
Table 4. Because of multicollinearity in multivariate analyses due to
the covariates Rotterdam criteria (with different cutoff values) and
RDC criteria, separate multivariate analyses were performed. On mul-
tivariable analyses of the covariates regarding MSS, sex, Breslow thick-
ness (T3 and T4), ulceration, Rotterdam criteria (with different hazard
Table 3. Association Between Clinicopathologic Factors and the Detection
of Metastases in NSNs
Predictive Factor
NSN
P
Positive Negative Unknown
No. % No. % No. %
Sex
Female 111 22 360 71 38 7
Male 101 18 437 77 33 6 .094
Center
DDHCC 11 10 90 78 14 12
CHUB 24 28 52 60 10 12
MMCCIO 66 27 178 73 1 0
RSCH 25 12 164 77 25 12
AVL 15 13 101 87 0 0
IGR 11 16 55 81 2 3
VU 25 24 72 67 10 9
UMCG 10 18 45 80 1 2
EIO 25 34 40 55 8 11 .001
Histology
SSM 76 19 297 74 28 7
NM 88 25 244 70 15 4
Other 48 14 256 77 28 8 .003
Location
Extremity 123 19 466 72 54 8
Trunk 82 20 310 77 13 3
Head and neck 7 22 21 66 4 13 .011
Age, years
50 101 19 398 76 24 5
50 111 20 399 72 47 8 .032
Clark
II 823257126
III 39 15 218 82 9 3
IV 126 21 440 72 48 8
V 3328 7564 9 8
Unknown 6 13 39 81 3 6 .011
Breslow
T1 713417759
T2 37 14 210 78 23 9
T3 74 17 333 77 27 6
T4 97 29 546 66 16 5 .001
Ulceration
Absent 103 17 457 76 43 7
Present 109 23 340 71 28 6 .052
Rotterdam criteria, mm
0.1 10 9 87 77 16 14
0.1-1.0 73 16 349 76 35 8
1.0 129 25 361 71 20 4 .001
Rotterdam criteria II, mm
0.2 27 14 140 73 24 13
0.2-1.0 56 15 296 78 27 7
1.0 129 25 361 71 20 4 .001
Rotterdam criteria III, mm
0.3 38 14 202 75 30 11
0.3-1.0 45 15 234 78 21 7
1.0 129 25 361 71 20 4 .001
Rotterdam criteria IV, mm
0.4 43 13 253 76 38 11
0.4-1.0 40 17 183 78 13 6
1.0 129 25 361 71 20 4 .001
(continued in next column)
Table 3. Association Between Clinicopathologic Factors and the Detection
of Metastases in NSNs (continued)
Predictive Factor
NSN
P
Positive Negative Unknown
No. % No. % No. %
Dewar criteria
Subcapsular 12 7 152 84 17 9
Combined 80 19 319 75 24 6
Parenchymal 25 16 119 77 10 7
Multifocal 7 17 29 71 5 12
Extensive 53 35 93 61 6 4
Unknown 35 27 85 66 9 7 .001
Dewar criteria II
Subcapsular 12 7 152 84 17 9
Nonsubcapsular 165 21 560 73 45 6
Unknown 35 27 85 66 9 7 .001
RDC criteria
0.1-subcapsular 1 2 47 80 11 19
0.1-nonsubcapsular 82 16 402 77 41 8
0.1-unknown 129 26 797 74 71 7 .001
Abbreviations: NSN, nonsentinel node; DDHCC, Daniel Den Hoed Cancer
Center (Erasmus University Medical Center, Rotterdam, the Netherlands);
CHUB, Charité, Humboldt University of Berlin (Berlin, Germany); MMCCIO, M.
Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (War-
saw, Poland); RSCH, Royal Surrey County Hospital (Guildford, United King-
dom); AVL, Antoni van Leeuwenhoek Hospital (Netherlands Cancer Institute,
Amsterdam, the Netherlands); IGR, Institut de Cancérologie Gustave Roussy
(Villejuif, France); VU, Vrije Universiteit (Amsterdam, the Netherlands); UMCG,
University Medical Center Groningen (Groningen, the Netherlands); EIO,
European Institute of Oncology (Milan, Italy); SSM, superficial spreading
melanoma; NM, nodular melanoma; RDC, Rotterdam-Dewar Combined
(criteria).
Classification of SN Tumor Load in SN-Positive Patients
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ratios for different cutoff values), RDC criteria, and NSN status were
independent prognostic factors. Dewar or Dewar II criteria were not
significant on multivariate analyses.
The Kaplan-Meier 5- and 10-year OS rates were 91% and 81%
for patients with Rotterdam criteria 0.1 mm, followed by 71% and
54% in the 0.1 to 1.0 mm group and 57% and 46% in the 1.0 mm
group. The Kaplan-Meier 5- and 10-year DFS rates were 83% and
83% for patients with Rotterdam criteria 0.1 mm, followed by 61%
and 49% in the 0.1 to 1.0 mm group, and 40% and 32% in the 1.0
mm group. The Kaplan-Meier 5- and 10-year MSS rates were 92%
and 87% for patients with Rotterdam criteria 0.1 mm, followed by
74% and 57% in the 0.1 to 1.0 mm group and 59% and 48% in the
1.0 mm group (Fig 1A).
The Kaplan-Meier 5- and 10-year MSS rates of patients with
cutoff points 0.2 mm, 0.3 mm, and 0.4 mm were 81% and
73%, 81% and 74%, and 80% and 70%, respectively. The Kaplan-
Meier 5- and 10-year MSS rates were 81% and 71% for patients with
subcapsular metastases and 66% and 52% for those with nonsubcap-
sular metastases (Fig 1B). The Kaplan-Meier 5- and 10-year MSS rates
were both 95% for patients with RDC criteria 0.1 mm subcapsular,
although the 5- and 10-year OS rates were 88% and 80% for patients
with RDC criteria 0.1 mm nonsubcapsular (Fig 1C).
DISCUSSION
To the best of our knowledge, this is the largest study ever performed
in this field, evaluating almost three times more SN-positive patients
than reports of two studies performed in the United States,
9,20
a
previous report of the EORTC MG,
6
and a report from the Melanoma
Institute Australia in Sydney.
22
This study investigated prognostic
factors for survival and predictive factors for NSN status by addressing
two different histologic parameters of classifying SN tumor load.
Table 4. Univariate and Multivariate Analyses of Covariates Regarding
Melanoma-Specific Survival
Variable
Univariate Multivariate
HR 95% CI P HR 95% CI P
Sex
Female 1 1
Male 1.38 1.10 to 1.73 .006 1.31 1.04 to 1.64 .022
Center
DDHCC 1
CHUB 1.75 1.02 to 3.01 .042
MMCCIO 1.93 1.23 to 3.04 .004
RSCH 1.53 0.95 to 2.46 .081
AVL 1.09 0.65 to 1.84 .74
IGR 1.07 0.51 to 2.22 .87
VU 1.54 0.93 to 2.55 .091
UMCG 0.83 0.43 to 1.60 .58
EIO 1.78 1.02 to 3.10 .041 N/S
Histology
SSM 1
NM 1.44 1.10 to 1.88 .009
Other 1.51 1.13 to 2.01 .005 N/S
Location
Extremity 1
Trunk 1.07 0.85 to 1.36 .55
Head and neck 1.18 0.66 to 2.13 .57 N/S
Age, years
50 1
50 1.24 0.99 to 1.55 .063 N/S
Clark
II 1
III 1.45 0.63 to 3.36 .39
IV 2.07 0.92 to 4.66 .081
V 3.43 1.48 to 7.99 .004
Unknown 2.23 0.84 to 5.96 .108 N/S
Breslow
T1 1 1
T2 1.07 0.51 to 2.27 .85 N/S
T3 1.92 0.94 to 3.93 .075 1.53 1.10 to 2.13 .012
T4 3.74 1.83 to 7.64 .001 2.45 1.73 to 3.45 .001
Ulceration
Absent 1 1
Present 2.11 1.68 to 2.64 .001 1.50 1.18 to 1.92 .001
Rotterdam criteria
0.1 1 1
0.1-1.0 3.28 1.72 to 6.25 .001 2.65 1.38 to 5.06 .003
1.0 5.36 2.83 to 10.13 .001 3.30 1.73 to 6.31 .001
Rotterdam criteria II
0.2 1 1
0.2-1.0 1.60 1.05 to 2.44 1.40 0.93 to 2.12 N/S
1.0 2.84 1.91 to 4.21 .001 1.83 1.23 to 2.72 .003
Rotterdam criteria III
0.3 1 1
0.3-1.0 1.67 1.14 to 2.45 1.42 0.98 to 2.05 N/S
1.0 2.75 1.96 to 3.88 .001 1.77 1.26 to 2.50 .001
Rotterdam criteria IV
0.4 1 1
0.4-1.0 1.61 1.12 to 2.33 1.24 0.87 to 1.76 N/S
1.0 2.57 1.89 to 3.50 .001 1.59 1.17 to 2.17 .003
Dewar criteria
Subcapsular 1
Combined 1.88 1.29 to 2.76 .001
Parenchymal 1.94 1.23 to 3.05 .004
Multifocal 1.46 0.72 to 2.95 .297
Extensive 3.62 2.38 to 5.51 .001
Unknown 1.61 1.02 to 2.56 .042 N/S
Dewar criteria II
Subcapsular 1
Nonsubcapsular 2.04 1.43 to 2.92 .001 N/S
(continued in next column)
Table 4. Univariate and Multivariate Analyses of Covariates Regarding
Melanoma-Specific Survival (continued)
Variable
Univariate Multivariate
HR 95% CI P HR 95% CI P
RDC criteria
0.1 subcapsular 1 1
0.1 nonsubcapsular 2.57 0.66 to 9.95 N/S N/S
0.1-1.0 subcapsular 5.23 1.60 to 17.15 .006 4.53 1.37 to 14.91 .013
0.1-1.0 nonsubcapsular 5.92 1.87 to 18.69 .002 5.01 1.58 to 15.88 .006
1.0 nonsubcapsular
and subcapsular 9.36 2.99 to 29.32 .001 6.17 1.95 to 19.45 .002
NSN status
Negative 1 1
Positive 2.46 1.89 to 3.22 .001 2.12 1.62 to 2.79 .001
Unknown 1.45 1.09 to 1.93 .011 1.68 1.26 to 2.25 .001
Abbreviations: HR, hazard ratio; DDHCC, Daniel Den Hoed Cancer Center
(Erasmus University Medical Center, Rotterdam, the Netherlands); CHUB,
Charité, Humboldt University of Berlin (Berlin, Germany); MMCCIO, M.
Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (War-
saw, Poland); RSCH, Royal Surrey County Hospital (Guildford, United King-
dom); AVL, Antoni van Leeuwenhoek Hospital (Netherlands Cancer Institute,
Amsterdam, the Netherlands); IGR, Institut de Cancérologie Gustave Roussy
(Villejuif, France); VU, Vrije Universiteit (Amsterdam, the Netherlands); UMCG,
University Medical Center Groningen (Groningen, the Netherlands); EIO,
European Institute of Oncology (Milan, Italy); N/S, not significant; SSM,
superficial spreading melanoma; NM, nodular melanoma; RDC, Rotterdam-
Dewar Combined (criteria); NSN, nonsentinel node.
van der Ploeg et al
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This study confirms that patients with submicrometastases
( 0.1 mm) had an estimated 5-year OS rate of 91% comparable with
SN-negative patients.
6
The NSN positivity rate is 9%, which is com-
parable to a false-negative SN rate in patients who underwent SNB.
The most predictive and prognostic parameter in our study was the
RDC criteria. Patients with submicrometastases present in the subcap-
sular area only had an NSN positivity rate of only 2% and an estimated
5- and 10-year MSS of 95%. It is highly unlikely that this patient group
benefits from a routine CLND. We propose that they might be classi-
fied as SN-negative in the next American Joint Committee on Cancer
(AJCC) classification system.
Various micromorphometric parameters for tumor load in
the SN have been studied, such as SN tumor burden, tumor penetra-
tive depth, square area, percentage area, number of metastatic foci,
number of positive SNs, extracapsular spread, and capsular
invasion.
14,17,18,20,23-26,32,33,36,39
Other studies combined primary mel-
anoma and/or SN characteristics into working models for predicting
survival and/or NSN status.
16,17,20,22,31,32,36,39
Reproducibility and ac-
curacy are important aspects in the assessment of micromorphomet-
ric parameters in the histopathologic workup and measurement of SN
tumor deposits.
42,46
Murali et al
46
observed the agreement of assess-
ment of histologic parameters among seven different pathologists.
Quantitative parameters like the maximal size of largest SN deposit
(Rotterdam criteria), the tumor penetrative depth (S-classification),
and the estimated percentage area occupied by metastasis had an
excellent degree of interobserver agreement. Thus, besides containing
predictive and prognostic value, a measurement of SN tumor load
must be simple and reproducible.
Many studies addressed cutoff points other than 0.1 mm and 1.0
mm used by the Rotterdam criteria measuring the largest diameter of
the largest lesion
6-21
(Table 5). We scrutinized the cutoff point of 0.1
mm in this study and examined other cutoff points, for example, 0.2
mm as used for patients with SN-positive breast cancer
47,48
and as
addressed in other studies,
13,15
0.3 mm as in the S-classification,
24
and
0.4 mm as suggested by van der Ploeg et al.
21
NSN positivity increased
rapidly and in agreement with these other cutoff points, which had
positive NSNs in 13% to 14% of SN-positive patients (Table 3). Sur-
vival rates in these groups showed similar poor outcome. Five-year
MSS survival rates were 80% to 81% and 10-year MSS survival rates
were 70% to 74%. Of the four different cutoff points, 0.1 mm
according to the Rotterdam criteria had the best prognostic and pre-
dictive value (Tables 3 and 4). The other three cutoff points addressed
had worse survival than that in SN-negative patients (80% to 81%
compared with 88% to 94%), while patients with submicrometastases
according to the Rotterdam criteria had similar survival (91%).
Tumor load and topography characteristics predict NSN positiv-
ity, but whether they can play a role in identifying patients who may or
may not benefit from routine CLND is another important question.
Our study strongly suggests that some patients may not benefit from
routine CLND. Because almost all patients underwent CLND, the
question remains as to whether these patients would have had the
same outcome without a CLND. The outcome of a group of patients
with good prognosis but without CLND has never been published,
although two recent studies described the difference between a group
of SN-positive patients without CLND after a positive SN.
49,50
There
was no significant difference in locoregional control and disease-
specific survival between groups, indicating that CLND may not in-
fluence survival. It seems obvious that patients who are SN-positive
with no CLND with high-volume SN tumor burden have worse out-
come than patients with low-volume SN tumor burden.
Obviously, all retrospective studies including this one have the
traditional downside that can be overcome only by a prospective,
randomized controlled trial. Several prospective trials are currently
under way to further investigate the possibility of reducing the 80% of
unnecessary CLND operations. The two most prominent studies are
the MSLT-II and the EORTC MINITUB studies.
40
When the out-
comes of these studies are final, alternative options to CLND can be
discussed and proposed.
Another issue is the biologic significance of minimal SN tumor
burden. We pose two hypotheses: (1) These are dormant cells that will
inevitably become active metastatic cells after a long period of time.
Thus, the removal of such deposits (by excising the SN) can be cura-
tive. (2) These are cells presented to the immune system that has led to
A
113
No. at risk
457
510
106
398
437
91
335
328
76
256
218
64
201
156
44
153
100
33
115
64
18
83
43
14
59
33
12
44
22
10
27
15
B
No. at risk
C
No. at risk
< 0.1 mm
> 1.0 mm
0.1–1.0 mm
Subcapsular
Non-subcapsular/unknown
< 0.1 mm & subcapsular
0.1–1.0 mm & subcapsular
> 1.0 mm (both subcapsular & non-subcapsular)
< 0.1 mm & non-subcapsular
0.1–1.0 mm & non-subcapsular
0
P < .001
Melanoma-Specific
Survival (probability)
Time (years)
1.00
0.25
0.50
0.75
1 2 3 4 5 6 7 8 9 10
0
P < .001
P < .001
Melanoma-Specific
Survival (probability)
Time (years)
1.00
0.25
0.50
0.75
1 2 3 4 5 6 7 8 9 10
899
165181
775
149
604
123
426
97
323
70
226
53
158
36
107
27
78
21
56
15
35
0
Melanoma-Specific
Survival (probability)
Time (years)
1.00
0.25
0.50
0.75
1 2 3 4 5 6 7 8 9 10
59
54
108
349
510
55
52
99
300
437
51
41
89
247
328
42
35
74
183
218
35
30
58
144
156
25
20
43
111
100
16
18
38
78
64
8
11
29
55
43
6
9
22
38
33
5
8
17
28
22
4
7
12
16
15
Fig 1. Melanoma-specific survival for sentinel-node tumor burden according to
(A) Rotterdam criteria, (B) subcapsular location, and (C) Rotterdam-Dewar Com-
bination criteria.
Classification of SN Tumor Load in SN-Positive Patients
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Page 6
an immune response to destroy circulating tumor cells; therefore,
these cells will never progress to viable metastatic cells and should be
considered prognostically false positive. This is difficult to study, be-
cause the SN has been removed in both cases to establish the presence
of minimal SN tumor burden.
There are additional arguments for classifying tumor load in the
SN because it may help identify which patients could benefit from
adjuvant systemic therapy with interferon, since the large EORTC
18952 and 18991 trials both clearly demonstrated that patients with
less disease had the greater benefit.
51,52
In conclusion, this study of the EORTC MG proposes that
patients with tumor burden 0.1 mm might safely be spared a
routine CLND, especially when found in the subcapsular area only.
We acknowledge that long-term follow-up is necessary, and these
results need to be validated prospectively. We invite surgical on-
cologists to participate in studies, such as the MSLT-II or the
EORTC MINITUB study. The RDC criteria provide the strongest
prognostic information for survival and most accurately predict
NSN positivity. The simplicity of these classification systems is an
argument for their standard implementation.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Conception and design: Augustinus P.T. van der Ploeg, Alexander C.J.
van Akkooi, Alexander M.M. Eggermont
Provision of study materials or patients: Augustinus P.T. van der Ploeg,
Alexander C.J. van Akkooi, Piotr Rutkowski, Zbigniew I. Nowecki,
Wanda Michej, Angana Mitra, Julia A. Newton-Bishop, Martin Cook,
Table 5. Overview of Literature for Predictive Factors for NSN Involvement and 5-Year Estimated OS Rates
Parameters for Tumor
Burden in SN
Studies in Which
Parameter Was Assessed
for NSN Status
Analyzed NSN-
Positive
Patients
Most Prognostic
Subgroup of Variable
for NSN Status
NSN Positivity Rate
of Subgroup (%)
5-Year Estimated
OS Rate (%)No. %
Size as largest
diameter
of largest lesion
(Rotterdam criteria)
Ranieri et al
7
13 14 3 mm 86*
Carlson et al
8
15 16 Isolated tumor cells 86*
2 mm 90*
Lee et al
9
46 24 2mm 16
Sabel et al
10
34 15 Micrometastasis 2
Pearlman et al
11
17 21 2mm 6 85
van Akkooi et al
5,12
10 15 0.1 mm 0 100
Govindarajan et al
13
20 16 0.2 mm 0
Debarbieux et al
14
22 22 2mm 18 80
1mm
(smallest
diameter)
13
Scheri et al
15
N/A
0.2 mm 12 87
Roka et al
16
18 21 2mm 8
Rossi et al
18
20 21 2mm 16
Satzger et al
17
28 16 0.1 mm 0
1mm 9
2mm 11
Guggenheim et al
19,37
22 22 2mm 16
Gershenwald et al
20
48 14 0.5 mm 5
2mm 8
van Akkooi et al
6
91 23 0.1 mm 3 91
van der Ploeg et al
21,27
15 13 0.1 mm 0 100
This study 184 17 0.1 mm 9 91
Microanatomic location
(Dewar criteria)
Dewar et al
28
24 16 Subcapsular 0
van Akkooi et al
5,12
10 15 Combined 9
Govindarajan et al
13
20 16 Sinusoidal 0
Roka et al
16
18 21 Nonextensive 13
Rossi et al
18
20 21 Subcapsular 0
Gershenwald et al
20
48 14 Subcapsular 10
Frankel et al
29
29 21 Subcapsular 10
van Akkooi et al
8
91 23 Subcapsular 8
van der Ploeg et al
21,27
15 13 Subcapsular 3 83
This study 184 17 Subcapsular 7 81
Abbreviations: NSN, nonsentinel node; OS, overall survival; SN, sentinel node; N/A, not applicable.
*These rates are 3-year estimated overall survival rates.
Only the group of patients with isolated tumor cells and known NSN status were included. Six (12%) of 52 patients with tumors 0.2 mm had NSN positivity
in this study.
van der Ploeg et al
2212
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Page 7
Iris M.C. van der Ploeg, Omgo E. Nieweg, Mari F.C.M. van den Hout,
Paul A.M. van Leeuwen, Christiane A. Voit, Francesco Cataldo,
Alessandro Testori, Caroline Robert, Harald J. Hoekstra, Cornelis
Verhoef, Alain Spatz, Alexander M.M. Eggermont
Collection and assembly of data: Augustinus P.T. van der Ploeg,
Alexander C.J. van Akkooi, Angana Mitra, Iris M.C. van der Ploeg,
Christiane A. Voit, Harald J. Hoekstra, Alexander M.M. Eggermont
Data analysis and interpretation: Augustinus P.T. van der Ploeg,
Alexander C.J. van Akkooi, Iris M.C. van der Ploeg,
Alexander M.M. Eggermont
Manuscript writing: Augustinus P.T. van der Ploeg, Alexander C.J. van
Akkooi, Piotr Rutkowski, Zbigniew I. Nowecki, Wanda Michej, Angana
Mitra, Julia A. Newton-Bishop, Martin Cook, Iris M.C. van der Ploeg,
Omgo E. Nieweg, Mari F.C.M. van den Hout, Paul A.M. van Leeuwen,
Christiane A. Voit, Francesco Cataldo, Alessandro Testori, Caroline
Robert, Harald J. Hoekstra, Cornelis Verhoef, Alain Spatz,
Alexander M.M. Eggermont
Final approval of manuscript: Augustinus P.T. van der Ploeg, Alexander
C.J. van Akkooi, Piotr Rutkowski, Zbigniew I. Nowecki, Wanda Michej,
Angana Mitra, Julia A. Newton-Bishop, Martin Cook, Iris M.C. van der
Ploeg, Omgo E. Nieweg, Mari F.C.M. van den Hout, Paul A.M. van
Leeuwen, Christiane A. Voit, Francesco Cataldo, Alessandro Testori,
Caroline Robert, Harald J. Hoekstra, Cornelis Verhoef, Alain Spatz,
Alexander M.M. Eggermont
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    • "If SLND is positive, the prognosis is much worse [3]. Although the 5-year survival of SLND-positive patients is widely variable, from 64% to 91% [39], SLND is the standard procedure for stratifying primary melanoma patients. Our results showed that histological staining with BRAF (Stage I) and MMP2 (Stage 2) are strong prognostic factors. "
    [Show abstract] [Hide abstract] ABSTRACT: The melanoma staging system proposed by the American Joint Committee on Cancer (AJCC) (which classifies melanoma patients into four clinical stages) is currently the most widely used tool for melanoma prognostication, and clinical management decision making by clinicians. However, multiple studies have shown that melanomas within specific AJCC Stages can exhibit varying progression and clinical outcomes. Thus, additional information, such as that provided by biomarkers is needed to assist in identifying the patients at risk of disease progression.Having previously found six independent prognostic biomarkers in melanoma, including BRAF, MMP2, p27, Dicer, Fbw7 and Tip60, our group has gone on to investigate if these markers are useful in risk stratification of melanoma patients in individual AJCC stages. First, we performed Kaplan-Meier survival and Cox proportional multivariate analyses comparing prognostication power of these markers in 254 melanoma patients for whom the expression levels were known, identifying the best performing markers as candidates for stage-specific melanoma markers. We then verified the results by incorporating an additional independent cohort (87 patients) and in a combined cohort (341 patients).Our data indicate that BRAF and MMP2 are optimal prognostic biomarkers for AJCC Stages I and II, respectively (P = 0.010, 0.000, Log-rank test); whereas p27 emerged as a good marker for AJCC Stages III/IV (0.018, 0.046, respectively, log-rank test). Thus, our study has identified stage-specific biomarkers in melanoma, a finding which may assist clinicians in designing improved personalized therapeutic modalities.
    Full-text · Article · Feb 2015 · Oncotarget
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    • "Microanatomic location of metastases is evaluated according to the criteria by Dewar et al. [15]. SN tumour burden is assessed according to the Rotterdam criteria for SN tumour burden [16] [17]. Final histology of the SN or LND was considered as the golden standard. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Ultrasound guided fine needle aspiration cytology (US-guided FNAC) can identify microscopic involvement of lymph nodes as in breast cancer and avoid surgical sentinel node (SN). Its utility in melanoma patients is controversial and subject of this study. Methods: Between 2001 and 2010 over 1000 stage I/II consecutive melanoma patients prospectively underwent US-FNAC prior to SN biopsy. All patients underwent lymphoscintigraphy prior to US-FNAC. The Berlin US morphology criteria: Peripheral perfusion (PP), loss of central echoes (LCE) and balloon shaped (BS) were registered. FNAC was performed in case of presence of any of these factors. SN tumour burden was measured according to the Rotterdam criteria. All patients underwent SN or lymph node dissection (LND) in case of positive FNAC. Findings: Mean/median Breslow thickness was 2.58/1.57 mm. Mean/median follow-up was 56/53 months (1-132). SN positivity rate was 21%. US-FNAC Sensitivity was 71% (US only) and 51% (US-FNAC). Sensitivity of US-FNAC was highest for T4 (76%) and ulcerated melanomas (63%). PP, LCE and BS had sensitivity of 69%, 24% and 24% respectively. Sensitivity of US-FNAC increased with increasing SN tumour burden. PP was an early sign of metastasis (58% in <0.1mm metastases). Threshold size of a metastasis for FNAC was 0.3mm. Five-year survival correlated to US-FNAC status (95% in negative and 59% in positive). Interpretation: Ultrasound guided FNAC (US-FNAC) according to the Berlin morphology criteria could correctly identify at least half of all tumour positive sentinel nodes, prior to the surgical SN procedure. Peripheral perfusion is an early sign of metastasis, which is very sensitive, but with lower positive predictive value (PPV). It is responsible for the sensitivity of the procedure. Balloon shape is a sign of advanced metastases, with lower sensitivity, but high PPV. US-FNAC sensitivity correlated with increasing T-stage, ulceration of the primary and increasing SN tumour burden. US-FNAC status accurately predicts survival.
    Full-text · Article · Jul 2014 · European journal of cancer (Oxford, England: 1990)
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    [Show abstract] [Hide abstract] ABSTRACT: Background Selection for sentinel lymph node biopsy (SLNB) in cutaneous melanoma is currently based on histopathological variables specified in prognostic staging criteria. In 2009, these criteria were updated replacing Clark level with the tumour mitotic rate (TMR) when defining thin T1 tumours. This study aimed to determine the histopathological variables independently predictive of sentinel lymph node involvement and discusses which variables should influence our selection for SLNB. Methods One hundred and fifty-three patients with primary invasive localized cutaneous melanoma who underwent SLNB between 2003 and 2007 were reviewed from a prospectively collected database. We performed a multivariate binary logistic regression analysis to ascertain which variables independently predict sentinel status. Results SLNB positivity rate was 17.3%. No patient with a thin T1 tumour was SLNB positive. Breslow thickness was the only independent predictor of sentinel lymph node (SLN) status to reach significance (x 2, 10.555; p, 0.001). TMR and ulceration were not independent predictors of sentinel node status (x 2, 0.988; p, 0.320 and x 2, 2.082; p, 0.149, respectively). Conclusion Breslow thickness is the only variable that is consistently reported as an independent predictor of SLN status. The use of TMR and ulceration in staging criteria is intended to establish prognosis, not select for SLNB. Given the important implications of a positive SLNB on surgical management, accurate selection is imperative. Selection based solely on Breslow thickness, rather than staging criteria, may be valid. However, there is an urgent need for a well-designed large multi-centre analysis to validate this. Until then, we continue to select for SLNB within a multidisciplinary team accounting for multiple factors. Level of Evidence: Level II, Prognostic/Risk Study.
    Full-text · Article · Oct 2012 · European Journal of Plastic Surgery
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