Prognosis in patients with sentinel node-positive melanoma is accurately defined by the combined Rotterdam tumor load and Dewar topography criteria.

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.

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Page 1

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,1,2is widely accepted as a highly accu-
rate diagnostic method of identifying early lymph
nodemicrometastasisinpatientswithmelanoma.
Sentinel node (SN) tumor burden is the most
important prognostic factor for patients with early-
stage melanoma.3Prognosis in patients with
SN-positivemelanomacorrelateswithseveralchar-
acteristics of the metastases in the SN such as size
and site. These factors reflect biologic behavior and
mayseparateoutpatientswhomayormaynotneed
additionallocoregionaland/orsystemictherapy.
SN positivity rates depend on median and
mean Breslow thickness of the primary, ulceration
rates, and the SN workup protocol and vary in the
literaturefrom14%to30%.4-6Approximately20%
of patients who are SN-positive have further nodes
involved, which are demonstrated by completion
lymph node dissection (CLND) findings, the so-
callednonsentinelnode(NSN)positivityrate.Many
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specialists in the melanoma field have tried to identify the correct
patientgrouptoundergoaCLNDandtoidentifythosepatientswho
cansafelybesparedunnecessaryCLNDanditsassociatedmorbidity,
such as wound infections and chronic lymph edema.6-39Ongoing
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-
tomyTrialII(MSLT-II)andtheEuropeanOrganisationforResearch
andTreatmentofCancer(EORTC)MINITUBstudies.40
In this study, two important morphometric parameters are
assessed: the microanatomic location (Dewar criteria)28and the
maximum diameter of the largest tumor lesion (Rotterdam crite-
ria).6,12TheEORTCMelanomaGroup(MG)recommendsthatall
pathologists report these criteria for each SN-positive patient.42
Theaimofthisstudy,whichusesthelargestreclassifieddatabaseof
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
melanomainninemajorcollaboratingEORTCMGcenterswereincludedin
thisretrospectivestudy.ParticipatingEORTCMGCentersarelistedinTable
1.Between1993and2008,1,080patientswerediagnosedwithtumorburden
intheSN.Adatabasewithpersonalinformationandinformationonprevious
medicalhistory,disease,andfollow-upwascreatedforthesepatients.Baseline
characteristicsaresummarizedinTable1.
In general, patients underwent the SNB in the same session as the re-
excision procedure after the diagnostic exaction of the primary melanoma.
Commonprocedurewastoachievemarginsof1cmformelanomas?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
histopathologicfeaturessuchasulcerationorClarklevelIVorVinvasion.
CLND was not performed in all SN-positive patients. In 71 patients
(6.6%),CLNDwasnotperformedforseveralreasons:refusaloffurthertreat-
ment, the diagnosis of distant metastasis between SNB and CLND, or the
presenceofminimaltumorburdenintheSN.
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.5,43,44In short, the triple technique consists of preoperative lympho-
scintigraphy, undertaken within 24 hours of the operation being performed;
perioperativeuseofpatentblue;anduseofahandheldgammadetectionprobe
todetecttheSNorSNs.AlymphnodewasidentifiedasanSNifitstainedblue,
ifithadaninsituradioactivitycountatleastthreetimesthatofthebackground
count, or if it had an ex vivo radioactivity count at least 10 times greater than
thebackgroundcount.
Afterthesurgicalprocedure,theSNsweresenttothepathologydepart-
ment for pathologic examination. SN tumor burden was reviewed, for the
purposeofthisstudy,byasecondpathologist,inalaterphase.
Pathology
In the nine EORTC centers, all SNs were worked up according to the
EORTC MG pathology protocol designed by Cook et al45First, the SNs were
fixedfor24hoursinbufferedformalin.Second,afterfixation,thelymphnodes
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,allsectionswerestainedwithhematoxylinandeosinandS100and/or
MelanA.TherewereslightlocaldifferencesintheCookprotocolregardingthe
Table 1. Baseline Characteristics of SN-Positive Patients (N ? 1,080)
Characteristic No. of Patients%
Sex
Male
Female
Center
DDHCC
CHUB
MMCCIO
RSCH
AVL
IGR
VU
UMCG
EIO
Age, years
? 50
? 50
Location
Extremity
Trunk
Head and neck
Histology
SSM
NM
Other
Breslow, mm
T1 (? 1.00)
T2 (1.01-2.00)
T3 (2.01-4.00)
T4 (? 4.00)
Clark
I
II
III
IV
V
Unknown
Ulceration
Absent
Present
Rotterdam criteria, mm
? 0.1
0.1-1.0
? 1.0
Dewar criteria
Subcapsular
Combined
Parenchymal
Multifocal
Extensive
Unknown
NSN status
Negative
Positive
Unknown
571
509
53
47
115
86
245
214
116
68
107
56
73
11
8
23
20
11
6
10
5
7
523
557
48
52
643
405
32
60
37
3
401
347
332
37
32
31
53
270
434
323
5
25
40
30
20
333
266
614
117
48
25
57
11
4
603
477
56
44
113
457
510
10
42
47
181
423
154
41
152
129
17
39
14
4
14
12
797
212
71
74
20
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(NetherlandsCancerInstitute,Amsterdam,theNetherlands);IGR,Institutde
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
mainprinciplesremainedunchanged.
All SNs with tumor burden were reviewed by different members of the
EORTCMG.InsevenofnineEORTCCenters,SNtumorloadwasreclassified
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
SNswereclassifiedaccordingtotheRotterdamcriteria.6,12Dewarcriteriawere
availablefor951patients(88%).
Dewar criteria define the microanatomic location of the melanoma
lesion.28Microanatomic 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)consistsofthemeasurementofthemaximumdiameterinanydirection
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
loadandusedothercutoffpoints.7-11,13-17,19-21Forthisreason,weusedother
cutoffpointsotherthan?0.1mminouranalyses(ie,?0.2mm[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-
DewarCombination(RDC)criteria(?0.1subcapsular,?0.1nonsubcapsu-
lar), combining the two most predictive and prognostic subgroups of the
parameters. Patients with tumors for which it was difficult to determine the
differentmicromorphometricparameterswerediscussedduringEORTCMG
meetings,whichtookplaceevery6months.
Statistics
UnivariateanalysesforNSNpositivitywereperformedbyusinga?2test.
Univariate analyses of end points for survival were performed by using the
Kaplan-Meier method and the log-rank test. Multivariate analyses to deter-
minetheprognosticvalueofcovariatesregardingmelanoma-specificsurvival
(MSS),disease-freesurvival(DFS),andoverallsurvival(OS)wereperformed
by using the Cox’s proportional hazards model. DFS and OS were calculated
fromtheoperationdateoftheSNBtothedateoffirstdiseaserecurrenceorthe
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-uptimewasdefinedasthedateoflastfollow-upordeathstartingfrom
thedateoftheSNprocedure.
For the survival analyses and analysis for NSN status, the following
variableswereincluded:sex(male,female),centers(nineEORTCcenters),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/unknownandpresent),Rotterdamcriteria(?0.1mm,
0.1to1.0mm,or?1.0mm),RotterdamcriteriaII(?0.2mm,0.2to1.0mm,
or?1.0mm),RotterdamcriteriaIII(?0.3mm,0.3to1.0mm,or?1.0mm),
RotterdamcriteriaIV(?0.4mm,0.4to1.0mm,or?1.0mm),Dewarcriteria
(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).StatisticswereperformedwithSTATAversion
11.1(STATA,CollegeStation,TX).
RESULTS
Patient Characteristics
Baseline characteristics are summarized in Table 1. This study
included 1,080 patients with melanoma (509 women and 571 men)
withapositiveSNprocedureovera16-yearperiod.Averageagewas51
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
3.1years(46and37months;range,1to172months).Themeanand
median times to first recurrence were 3.2 and 2.3 years (38 and 27
months).Atlastfollow-up,336(31%)of1,080patientsweredeceased.
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
ofSN-positivepatientswhohavetheworstprognosis.Thisisreflected
by the large proportion of patients with advanced SN metastases
(?1.0mmforRotterdamcriteria;extensiveforDewarcriteria).
Table 2. Characteristics per EORTC Center
Characteristic
Center
DDHCC CHUBMMCCIORSCHAVL IGR VUUMCG EIO
Median Breslow, mm
Ulceration percentage
Rotterdam criteria percentage
? 0.1 mm
0.1-1.0 mm
? 1.0 mm
Dewar criteria percentage
Subcapsular
Combined
Parenchymal
Multifocal
Extensive
3.00
45
3.34
50
4.00
64
2.40
31
3.00
40
2.90
47
2.10
25
2.50
30
3.00
49
17
48
35
26
35
40
3 11
46
43
49 11
49
40
23
57
20
4
33
64
32
64
50
41
52
44
30
30
13
12
15
40
29
12
8
12
4 18
50
17
1
13
34
41
0
5
21
15
50
26
3
6
15
56
19
0
10
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
47
22
4
24
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
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JOURNAL OF CLINICAL ONCOLOGY

Page 4

NSN Status
Of the 1,009 patients who underwent a CLND, 21% (212 pa-
tients)hadoneormorepositiveNSNs.Table3showsNSNpositivity
andnegativityratesforallfactorsassessedinthisstudy.Thefollowing
factors were significant regarding NSN status; age; center; histology
andlocationoftheprimary;Clarklevel;Breslowthickness;Rotterdam
criteria;RotterdamcriteriaII,III,andIV;Dewarcriteria;Dewarcrite-
riaII;andRDCcriteria.
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.Patientswith?0.2mm,?0.3mm,and?0.4mmhad14%,
14%,and13%positiveNSNs,respectively.NSNpositivitywas7%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
?0.1mm,whichshowedpositiveNSNsinonly2%ofpatients.
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
RDCcriteria,separatemultivariateanalyseswereperformed.Onmul-
tivariableanalysesofthecovariatesregardingMSS,sex,Breslowthick-
ness(T3andT4),ulceration,Rotterdamcriteria(withdifferenthazard
Table 3. Association Between Clinicopathologic Factors and the Detection
of Metastases in NSNs
Predictive Factor
NSN
P
PositiveNegative Unknown
No.%No.% No.%
Sex
Female
Male
Center
DDHCC
CHUB
MMCCIO
RSCH
AVL
IGR
VU
UMCG
EIO
Histology
SSM
NM
Other
Location
Extremity
Trunk
Head and neck
Age, years
? 50
? 50
Clark
II
III
IV
V
Unknown
Breslow
T1
T2
T3
T4
Ulceration
Absent
Present
Rotterdam criteria, mm
? 0.1
0.1-1.0
? 1.0
Rotterdam criteria II, mm
? 0.2
0.2-1.0
? 1.0
Rotterdam criteria III, mm
? 0.3
0.3-1.0
? 1.0
Rotterdam criteria IV, mm
? 0.4
0.4-1.0
? 1.0
111
101
22
18
360
437
71
77
38
33
7
6 .094
11
24
66
25
15
11
25
10
25
10
28
27
12
13
16
24
18
34
90
52
178
164
101
55
72
45
40
78
60
73
77
87
81
67
80
55
14
10
1
25
0
2
10
1
8
12
12
0
12
0
3
9
2
11
? .001
76
88
48
19
25
14
297
244
256
74
70
77
28
15
28
7
4
8 .003
123
82
19
20
22
466
310
21
72
77
66
54
13
4
8
3
713.011
101
111
19
20
398
399
76
72
24
47
5
8 .032
8 23
15
21
28
13
25
218
440
75
39
71
82
72
64
81
2
9
6
3
8
8
6
39
126
33
48
9
36.011
7 13
14
17
29
41
210
333
546
77
78
77
66
59
9
6
5
37
74
97
23
27
16
? .001
103
109
17
23
457
340
76
71
43
28
7
6 .052
10
73
129
9 87
349
361
77
76
71
16
35
20
14
8
4
16
25
? .001
27
56
129
14
15
25
140
296
361
73
78
71
24
27
20
13
7
4
? .001
38
45
129
14
15
25
202
234
361
75
78
71
30
21
20
11
7
4
? .001
43
40
129
13
17
25
253
183
361
76
78
71
38
13
20
11
6
4
? .001
(continued in next column)
Table 3. Association Between Clinicopathologic Factors and the Detection
of Metastases in NSNs (continued)
Predictive Factor
NSN
P
PositiveNegative Unknown
No.% No.%No.%
Dewar criteria
Subcapsular
Combined
Parenchymal
Multifocal
Extensive
Unknown
Dewar criteria II
Subcapsular
Nonsubcapsular
Unknown
RDC criteria
? 0.1-subcapsular
? 0.1-nonsubcapsular
? 0.1-unknown
12
80
25
7
53
35
7152
319
119
29
93
85
84
75
77
71
61
66
17
24
10
5
6
9
9
6
7
19
16
17
35
27
12
4
7
? .001
12
165
35
7 152
560
85
84
73
66
17
45
9
9
6
7
21
27
? .001
1247
402
797
80
77
74
11
41
71
19
8
7
82
129
16
26
? .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
significantonmultivariateanalyses.
The Kaplan-Meier 5- and 10-year OS rates were 91% and 81%
forpatientswithRotterdamcriteria?0.1mm,followedby71%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%forpatientswithRotterdamcriteria?0.1mm,followedby61%
and49%inthe0.1to1.0mmgroup,and40%and32%inthe?1.0
mm group. The Kaplan-Meier 5- and 10-year MSS rates were 92%
and87%forpatientswithRotterdamcriteria?0.1mm,followedby
74% and 57% in the 0.1 to 1.0 mm group and 59% and 48% in the
?1.0mmgroup(Fig1A).
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
subcapsularmetastasesand66%and52%forthosewithnonsubcap-
sularmetastases(Fig1B).TheKaplan-Meier5-and10-yearMSSrates
wereboth95%forpatientswithRDCcriteria?0.1mmsubcapsular,
althoughthe5-and10-yearOSrateswere88%and80%forpatients
withRDCcriteria?0.1mmnonsubcapsular(Fig1C).
DISCUSSION
Tothebestofourknowledge,thisisthelargeststudyeverperformed
in this field, evaluating almost three times more SN-positive patients
than reports of two studies performed in the United States,9,20a
previousreportoftheEORTCMG,6andareportfromtheMelanoma
Institute Australia in Sydney.22This study investigated prognostic
factorsforsurvivalandpredictivefactorsforNSNstatusbyaddressing
twodifferenthistologicparametersofclassifyingSNtumorload.
Table 4. Univariate and Multivariate Analyses of Covariates Regarding
Melanoma-Specific Survival
Variable
Univariate Multivariate
HR 95% CIP HR95% CIP
Sex
Female
Male
Center
DDHCC
CHUB
MMCCIO
RSCH
AVL
IGR
VU
UMCG
EIO
Histology
SSM
NM
Other
Location
Extremity
Trunk
Head and neck
Age, years
? 50
? 50
Clark
II
III
IV
V
Unknown
Breslow
T1
T2
T3
T4
Ulceration
Absent
Present
Rotterdam criteria
? 0.1
0.1-1.0
? 1.0
Rotterdam criteria II
? 0.2
0.2-1.0
? 1.0
Rotterdam criteria III
? 0.3
0.3-1.0
? 1.0
Rotterdam criteria IV
? 0.4
0.4-1.0
? 1.0
Dewar criteria
Subcapsular
Combined
Parenchymal
Multifocal
Extensive
Unknown
Dewar criteria II
Subcapsular
Nonsubcapsular
1
1.38
1
1.31 1.10 to 1.73 .0061.04 to 1.64 .022
1
1.75
1.93
1.53
1.09
1.07
1.54
0.83
1.78
1.02 to 3.01
1.23 to 3.04
0.95 to 2.46
0.65 to 1.84
0.51 to 2.22
0.93 to 2.55
0.43 to 1.60
1.02 to 3.10
.042
.004
.081
.74
.87
.091
.58
.041N/S
1
1.44
1.51
1.10 to 1.88
1.13 to 2.01
.009
.005 N/S
1
1.07
1.18
0.85 to 1.36
0.66 to 2.13
.55
.57N/S
1
1.240.99 to 1.55.063N/S
1
1.45
2.07
3.43
2.23
0.63 to 3.36
0.92 to 4.66
1.48 to 7.99
0.84 to 5.96
.39
.081
.004
.108 N/S
1
1.07
1.92
3.74
1
0.51 to 2.27
0.94 to 3.93
1.83 to 7.64
.85
.075
—
1.53
2.45
—N/S
.012
? .001
1.10 to 2.13
1.73 to 3.45
? .001
1
2.11
1
1.50 1.68 to 2.64
? .0011.18 to 1.92.001
1
3.28
5.36
1
2.65
3.30
1.72 to 6.25
2.83 to 10.13
? .001
? .001
1.38 to 5.06
1.73 to 6.31
.003
? .001
1
1.60
2.84
1
1.40
1.83
1.05 to 2.44
1.91 to 4.21
0.93 to 2.12
1.23 to 2.72
N/S
.003
? .001
1
1.67
2.75
1
1.42
1.77
1.14 to 2.45
1.96 to 3.88
0.98 to 2.05
1.26 to 2.50
N/S
.001
? .001
1
1.61
2.57
1
1.24
1.59
1.12 to 2.33
1.89 to 3.50
0.87 to 1.76
1.17 to 2.17
N/S
.003
? .001
1
1.88
1.94
1.46
3.62
1.61
1.29 to 2.76
1.23 to 3.05
0.72 to 2.95
2.38 to 5.51
1.02 to 2.56
.001
.004
.297
? .001
.042N/S
1
2.04 1.43 to 2.92
(continued in next column)
? .001N/S
Table 4. Univariate and Multivariate Analyses of Covariates Regarding
Melanoma-Specific Survival (continued)
Variable
UnivariateMultivariate
HR 95% CIPHR95% CIP
RDC criteria
? 0.1 subcapsular
? 0.1 nonsubcapsular
0.1-1.0 subcapsular
0.1-1.0 nonsubcapsular
? 1.0 nonsubcapsular
and subcapsular
NSN status
Negative
Positive
Unknown
1
2.57
5.23
5.92
1
0.66 to 9.95
1.60 to 17.15
1.87 to 18.69
N/S
.006
.002
—
4.53
5.01
—N/S
.013
.006
1.37 to 14.91
1.58 to 15.88
9.362.99 to 29.32
? .0016.171.95 to 19.45.002
1
2.46
1.45
1
2.12
1.68
1.89 to 3.22
1.09 to 1.93
? .001
.011
1.62 to 2.79
1.26 to 2.25
? .001
? .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
2210
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Page 6

This study confirms that patients with submicrometastases
(?0.1mm)hadanestimated5-yearOSrateof91%comparablewith
SN-negative patients.6The 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
RDCcriteria.Patientswithsubmicrometastasespresentinthesubcap-
sularareaonlyhadanNSNpositivityrateofonly2%andanestimated
5-and10-yearMSSof95%.Itishighlyunlikelythatthispatientgroup
benefitsfromaroutineCLND.Weproposethattheymightbeclassi-
fiedasSN-negativeinthenextAmericanJointCommitteeonCancer
(AJCC)classificationsystem.
Various micromorphometric parameters for tumor load in
theSNhavebeenstudied,suchasSNtumorburden,tumorpenetra-
tive depth, square area, percentage area, number of metastatic foci,
number of positive SNs, extracapsular spread, and capsular
invasion.14,17,18,20,23-26,32,33,36,39Otherstudiescombinedprimarymel-
anoma and/or SN characteristics into working models for predicting
survivaland/orNSNstatus.16,17,20,22,31,32,36,39Reproducibilityandac-
curacyareimportantaspectsintheassessmentofmicromorphomet-
ricparametersinthehistopathologicworkupandmeasurementofSN
tumor deposits.42,46Murali et al46observed 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
excellentdegreeofinterobserveragreement.Thus,besidescontaining
predictive and prognostic value, a measurement of SN tumor load
mustbesimpleandreproducible.
Manystudiesaddressedcutoffpointsotherthan0.1mmand1.0
mmusedbytheRotterdamcriteriameasuringthelargestdiameterof
the largest lesion6-21(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 cancer47,48and as
addressedinotherstudies,13,150.3mmasintheS-classification,24and
0.4mmassuggestedbyvanderPloegetal.21NSNpositivityincreased
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-
dictivevalue(Tables3and4).Theotherthreecutoffpointsaddressed
had worse survival than that in SN-negative patients (80% to 81%
comparedwith88%to94%),whilepatientswithsubmicrometastases
accordingtotheRotterdamcriteriahadsimilarsurvival(91%).
TumorloadandtopographycharacteristicspredictNSNpositiv-
ity,butwhethertheycanplayaroleinidentifyingpatientswhomayor
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
sameoutcomewithoutaCLND.Theoutcomeofagroupofpatients
with good prognosis but without CLND has never been published,
althoughtworecentstudiesdescribedthedifferencebetweenagroup
of SN-positive patients without CLND after a positive SN.49,50There
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
withnoCLNDwithhigh-volumeSNtumorburdenhaveworseout-
comethanpatientswithlow-volumeSNtumorburden.
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
underwaytofurtherinvestigatethepossibilityofreducingthe80%of
unnecessary CLND operations. The two most prominent studies are
the MSLT-II and the EORTC MINITUB studies.40When the out-
comes of these studies are final, alternative options to CLND can be
discussedandproposed.
Another issue is the biologic significance of minimal SN tumor
burden.Weposetwohypotheses:(1)Thesearedormantcellsthatwill
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)Thesearecellspresentedtotheimmunesystemthathasledto
A
113
457
510
No. at risk
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
12345678910
0
P < .001
P < .001
Melanoma-Specific
Survival (probability)
Time (years)
1.00
0.25
0.50
0.75
123456789 10
899
165
775
181149
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
123456789 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 7

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-
causetheSNhasbeenremovedinbothcasestoestablishthepresence
ofminimalSNtumorburden.
Thereareadditionalargumentsforclassifyingtumorloadinthe
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
lessdiseasehadthegreaterbenefit.51,52
In conclusion, this study of the EORTC MG proposes that
patients with tumor burden ? 0.1 mm might safely be spared a
routineCLND,especiallywhenfoundinthesubcapsularareaonly.
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 al7
Carlson et al8
13
15
14
16
? 3 mm
Isolated tumor cells
? 2 mm
? 2 mm
Micrometastasis
? 2 mm
? 0.1 mm
? 0.2 mm
? 2 mm
? 1 mm
(smallest
diameter)
? 0.2 mm
? 2 mm
? 2 mm
? 0.1 mm
? 1 mm
? 2 mm
? 2 mm
? 0.5 mm
? 2 mm
? 0.1 mm
? 0.1 mm
? 0.1 mm
Subcapsular
Combined
Sinusoidal
Nonextensive
Subcapsular
Subcapsular
Subcapsular
Subcapsular
Subcapsular
Subcapsular
—
—
—
16
2
6
0
0
18
13
86*
86*
90*
—
—
85
100
—
? 80
—
Lee et al9
Sabel et al10
Pearlman et al11
van Akkooi et al5,12
Govindarajan et al13
Debarbieux et al14
46
34
17
10
20
22
24
15
21
15
16
22
Scheri et al15
Roka et al16
Rossi et al18
Satzger et al17
N/A†
18
20
28
12
8
16
0
9
11
16
5
8
3
0
9
0
9
0
13
0
10
10
8
3
7
87
—
—
—
—
—
—
—
—
91
100
91
—
—
—
—
—
—
—
—
83
81
21
21
16
Guggenheim et al19,37
Gershenwald et al20
22
48
22
14
van Akkooi et al6
van der Ploeg et al21,27
This study
Dewar et al28
van Akkooi et al5,12
Govindarajan et al13
Roka et al16
Rossi et al18
Gershenwald et al20
Frankel et al29
van Akkooi et al8
van der Ploeg et al21,27
This study
91
15
184
24
10
20
18
20
48
29
91
15
184
23
13
17
16
15
16
21
21
14
21
23
13
17
Microanatomic location
(Dewar criteria)
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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JOURNAL OF CLINICAL ONCOLOGY

Page 8

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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