Journal of Cancer Therapy, 2013, 4, 1490-1498
Published Online December 2013 (http://www.scirp.org/journal/jct)
http://dx.doi.org/10.4236/jct.2013.410180
Open Access JCT
The Prognostic Value of Minimally Involved Melanoma
Sentinel Lymph Nodes*
Alend Saadi1#, Didier Roulin1#, Essia Saiji2, Hanifa Bouzourene2, Nicolas Demartines1,
Maurice Matter1†
1Department of Visceral Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; 2University Institute of Pathol-
ogy, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Received November 26th, 2013; revised December 17th, 2013; accepted December 23rd, 2013
Copyright © 2013 Alend Saadi et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In accor-
dance of the Creative Commons Attribution License all Copyrights © 2013 are reserved for SCIRP and the owner of the intellectual
property Alend Saadi et al. All Copyright © 2013 are guarded by law and by SCIRP as a guardian.
ABSTRACT
Background: Sentinel node (SLN) status is the most important prognostic factor for early-stage melanoma patients. It
will influence follow-up and may change therapy. Positive SLNs present different degrees of involvement so that sub-
groups of patients may have minimal SLN invasion. The aim of this study was to evaluate survival in subgroups with
minimally involved SLNs and to compare them to negative SLN patients. Method: SLN biopsy was performed in 499
consecutive clinically N0 patients between 1997 and 2008. Following updated recommendations from the Melanoma
Group of the European Organization of Research and Treatment of Cancer, degrees of SLN involvement were fully re-
assessed for two anatomopathological parameters: tumour burden according to Rotterdam criteria (<0.1 mm, 0.1 - 1.0
mm, and >1.0 mm) and microanatomic location according to Dewar (subcapsular, combined subcapsular and paren-
chymal, parenchymal, multifocal, or extensive). Minimally involved SLNs were defined as those with tumor burden
<0.1 mm and/or subcapsular metastasis location. Kaplan-Meier and multivariable logistic regression analyses were per-
formed. Results: Out of 499 clinically N0 patients, positive SLNs were found in 123 patients (24.7 percent). With a
median follow-up of 52 months (range: 9 - 146), five-year disease-free (DFS), disease-specific survival (DSS) and
overall survival (OS) were 88.1, 93.9 and 89.9 percent for negative SLN patients, respectively. In minimally involved
SLNs, there were 21 with tumour burden <0.1 mm, and 52 with subcapsular metastasis. Five-year DFS, DSS and OS in
these sub-groups were 79.6, 86.6 and 86.6 percent, then 57.3, 69.8 and 67.8 percent respectively. DFS univariable
analysis of these sub-groups compared to negative SLNs showed: (HR1.89, 95 percent CI 0.75 - 4.79; p 0.175) and (HR
3.92, 95 percent CI 2.29 - 6.71; p < 0.0001) respectively. Minimally involved sub-groups were not predictive for NSLN
negativity. Conclusion: Rotterdam’s tumour burden stratification is an easy and useful prognostic factor of melanoma
survival. There was a trend showing that patients with SLN tumour burden <0.1 mm have a lower survival compared to
SLN negative patients. One might suggest that patients with minimally involved SLNs may not be managed similarly to
negative SLN patients. Subcapsular metastasis subgroup according to the microanatomic location has statistically sig-
nificant worst survival.
Keywords: Metastatic Melanoma; Sentinel Node; Minimally Involved
1. Introduction
Since the first report in 1992 for melanoma patients [1],
sentinel lymph node (SLN) biopsy has become a routine
procedure in specialized centers for the management of
intermediate risk, clinically localized cutaneous mela-
noma. Lymphatic mapping with sentinel lymphadenec-
tomy is a safe and effective surgical technique with lim-
ited morbidity [2]. The importance of the SLN status is
now widely accepted as the most important prognostic
factor [2,3]. In literature, positive SLN is found in 15
percent to 30 percent of patients [3-8]. In case of positive
*Sources of support and funding for this work: none.
#Both authors contributed equally to this work.
†Corresponding author.

The Prognostic Value of Minimally Involved Melanoma Sentinel Lymph Nodes 1491
SLN, most centers recommend a completion lymph node
dissection (CLND). However, additional positive non-
sentinel lymph nodes (NSLN) are found in only about 20
percent of CLND [3,5,7-10]. This means that radical
lymph node dissection, with its consecutive morbidity
[11], might be unnecessary in about three quarters of
patients with positive SLN. Seeking for the optimal prac-
tice, the SLN status was sharpened in order to better pre-
dict NSLN status, recurrence rate and survival. Different
classifications of positive SLN were proposed but none
of these have gathered a wide acceptance [5,7-17]. Re-
cently, the EORTC Melanoma Group recommended a
protocol to report the three following items per positive
SLN [18]: (1) The microanatomic location of the metas-
tases according to Dewar for the entire node (A = sub-
capsular, B = combined subcapsular and parenchymal, C
= parenchymal, D = multifocal, and E = extensive); (2)
the SLN tumour burden according to the Rotterdam Cri-
teria for the maximum diameter of the largest metastasis
expressed as an absolute number; and (3) the SLN tu-
mour burden stratified per category: <0.1 mm, 0.1 - 1.0
mm, or >1.0 mm.
The aim of this retrospective study of a prospective
cohort was to analyze the results of the positive SLNs in
a tertiary reference center for melanoma, to investigate
prognostic factors for disease-free survival (DFS), dis-
ease-specific survival (DSS) and overall survival (OS) in
light of the EORTC recommendations protocol and pri-
mary tumour criteria, and to compare minimally involved
subgroups, such as tumour burden <0.1 mm, subcapsular
metastasis, and SLN negative patients. Predictability of
positive NSLNs was also analyzed.
2. Patients and Methods
2.1. Patients
Between October 1997 and December 2008 all consecu-
tive SLN biopsy (SLNB) for melanoma patients were
included prospectively in a database. SLNB was per-
formed by a single surgical team at the Centre Hospi-
talier Universitaire Vaudois (CHUV) in Switzerland.
Inclusion criteria were primary skin melanoma >1.00
mm without palpable adenopathy and absence of distant
metastases (confirmed by CT scan or PET scan). Patients
with melanoma thickness <1.00 mm in the presence of
specific histopathologic factors, such as ulceration, re-
gression, or Clark level IV/V were also included. A
CLND was usually proposed to patients with metastatic
SLN. Patients with clinically metastatic lymph nodes
were offered a therapeutic lymph node dissection and
excluded from the present analysis. Patients with local
recurrence of an earlier melanoma who also had a SLNB
were excluded. The protocol of this study was accepted
by the Institutional Ethical Committee.
2.2. Surgical Technique and Pathological
Analysis
All patients underwent SLNB according to the triple
technique as previously described (3). The SLN was de-
fined as any blue node, the node with the highest radio-
active count, and any node with >10 percent count rate of
the most radioactive node. Any enlarged (>1 cm) suspi-
cious node and some adjacent nodes (mainly for ana-
tomical reason) were also dissected. SLNB was followed
by initial melanoma scar wide excision (WE) with safety
margins of 1 cm and 2 cm according to Breslow thick-
ness of < = 1 mm and >1 mm respectively. SLN(s) were
sent fresh or in formaldehyde solution directly to the
University Institute of Pathology. Lymph nodes were
bivalved and paraffin embedded. Three slices were cut
for hematoxylin and eosin (H & E) and immunohisto-
chemistry (IH) staining (Melan A and protein S100) at a
regular 50 m interval at least six times following a
SLNB protocol (3). No PCR analysis was performed.
The CLND’s nodes were only processed with H-E stain-
ing. An expert team from the Department of Pathology
(E.S. & H.B.) reviewed all positive SLNs for the purpose
of this study, according to the EORTC Melanoma Group
recommended protocol [18]. Degrees of SLN involve-
ment were fully re-assessed for two anatomopathological
parameters: tumour burden according to Rotterdam crite-
ria (<0.1 mm, 0.1 - 1.0 mm, and >1.0 mm) and microan-
atomic location according to Dewar (subcapsular, com-
bined subcapsular and parenchymal, parenchymal, mul-
tifocal, or extensive). Minimally involved SLNs were
defined as those with tumor burden <0.1 mm and/or sub-
capsular metastasis location.
2.3. Follow-Up
A clinical follow-up was performed every 3 months dur-
ing the first year after diagnosis, every 4 months during
the second year, every 6 months during the 3rd, 4th and 5th
years and then once a year. For patients with a Breslow
more than 4 mm and for patients with positive SLN, a
thoraco-abdominal scan was done once a year during the
first five years following diagnosis. Most patients were
followed at the outpatient clinic of the Oncology Unit in
the same institution. Some patients were followed by
their own dermatologists; their written follow-up was
obtained after consent. Duration of follow-up was de-
fined as time between date of SLN procedure and date of
the last follow-up or death.
2.4. Statistical Analysis
Quantitative variables were compared using the Student
or the Mann-Whitney test. Categorical variables were
compared using the χ2 test. Univariable analysis of po-
tential prognostic factors was performed (Table 1). A
Open Access JCT

The Prognostic Value of Minimally Involved Melanoma Sentinel Lymph Nodes
Open Access JCT
1492
Table 1. Clinical and anatomopathological characteristics of 123 positive sentinel lymph nodes (SLNs) patients and univari-
able analyses of disease-free (DFS), disease-specific (DSS) and overall survival (OS).
DFS DSS OS
Characteristics Level Patients
N = 123HR95% CI P HR95% CIP HR 95% CIP
Gender Female
Male
50
73
1
2.14 1.2 - 3.8 0.008
1
2.57 1.2 - 5.3 0.011
1
2.58 1.3 - 5.1 0.007
Age (mean ) ≤65 years
>65 years
84
39
1
1.68 1.0 - 2.83 0.052
1
1.50 0.8 - 2.9 0.230
1
1.57 0.9 - 2.9 0.153
Melanoma subtype
Superficial spreading
Nodular
Acral lentiginous
Others
42
50
15
16
1
1.05
1.63
0.76
0.6 - 1.9
0.7 - 3.6
0.3 - 1.9
0.870
0.220
0.545
1
1.22
1.82
0.95
0.6 - 2.5
0.6 - 5.2
0.3 - 3.0
0.601
0.265
0.935
1
1.24
1.67
1.10
0.6 - 2.5
0.6 - 4.7
0.4 - 3.1
0.544
0.331
0.861
Breslow thickness
<1 mm
1.01 - 2.0 mm
2.01 - 4.0 mm
>4.0 mm
4
41
49
29
1
1
1.82
1.82
1.3 - 2.5
1.3 - 2.5
<0.0001
<0.0001
1
1
3.68
3.68
1.1 - 2.3
1.1 - 2.3
0.002
0.002
1
1
1.64
1.64
1.1 - 2.4
1.1 - 2.4
0.008
0.008
Clark level
III
IV
V
23
89
11
1
1.23
1.37
0.6 - 2.5
0.5 - 3.8
0.552
0.551
1
1.41
1.21
0.6 - 3.4
0.3 - 4.9
0.440
0.787
1
1.56
1.63
0.7 - 3.7
0.5 - 5.9
0.316
0.448
Ulceration Absent
Present
49
74
1
2.21 1.3 - 3.7 0.003
1
2.16 1.1 - 4.1 0.018
1
2.38 1.3 - 4.3 0.005
Primary melanoma
location
Extremity
Head and neck
Trunk
63
5
55
1
1.68
1.09
0.5 - 5.5
0.7 - 1.8
0.393
0.729
1
2.93
1.50
0.9 - 10.1
0.8 - 2.9
0.089
0.226
1
2.41
1.32
0.7 - 8.2
0.7 - 2.5
0.157
0.379
Lymph node basin 1
>1
92
31
1
1.08 0.6 - 1.9 0.789
1
1.26 0.6 - 2.6 0.530
1
1.41 0.7 - 2.7 0.314
SLN Tumour Burden
<0.1 mm
0.1 - 1 mm
>1.0 mm
Not available
21
33
65
4
1
2.58
4.50
0.9 - 7.3
1.8 - 11.5
0.076
0.002
1
2.14
3.35
0.7 - 6.9
1.2 - 9.7
0.203
0.026
1
2.11
3.69
0.7 - 6.8
1.3 - 10.6
0.211
0.015
SLN Microanatomic
tumour location*
A
B
C
D
E
Not available
52
18
11
8
29
5
1
1.45
0.74
1.32
3.31
0.7 - 3.2
0.2 - 2.5
0.5 - 3.9
1.7 - 6.1
0.363
0.635
0.611
<0.0001
1
1.57
0.94
0.39
1.98
0.6 - 3.9
0.3 - 3.3
0.05 - 3.0
0.9 - 4.3
0.327
0.927
0.367
0.081
1
1.69
0.88
0.37
1.97
0.7 - 4.0
0.3 - 3.0
0.05 - 2.8
1.0 - 4.1
0.232
0.841
0.334
0.070
*SLN Microanatomic tumour location according to Dewar (8): A, subcapsular. B, combined subcapsular and parenchymal. C, parenchymal. D, multifocal or E,
extensive. HR, hazard ratio. CI, confidence interval. P, significance level.
multivariable logistic regression model was used for the
significant factors in the univariable analyses. Survival
analyses involved the Kaplan-Meier method combined
with log-rang test and multivariable Cox’s proportional
hazard regression models. Statistical analyses were per-
formed with Stata 11 software (Stata Corp®). P values
less than 0.05 were considered statistically significant.
3. Results
3.1. Patient Characteristics
During the study period, 499 consecutive patients with
primary skin melanoma and clinically N0 underwent a
SLNB and were included in this study. Metastases to
SLN(s) were detected in 123 (24.7 percent) patients. The
median (range) Breslow thickness was 1.7 mm (0.3 - 15),
1.5 mm (0.3 - 15), and 2.5 mm (0.8 - 12) for all patients,
SLN negative and SLN positive patients respectively.
For the same groups of patients, male ratios were 274/
499 (55 percent), 201/376 (54 percent) and 73/123 (59
percent) respectively; ulceration rates were 126/499 (25
percent), 77/376 (21 percent), 49/123 (40 percent) re-
spectively. Clinical and anatomopathologic characteris-
tics of the 123 SLN positive patients are presented in
Table 1. All positive SLN were classified according to
the recommendations from the EORTC Melanoma
Group protocol published in 2009 (15). In four cases the
pathological slides were not available for reassessment of
the tumour burden and in five cases for the micro-
anatomic location. The four SLN positive patients who
had melanoma with Breslow thickness 1.0 mm had a
Breslow thickness close to 1.0 mm (n = 2) or Clark level
IV (n = 2).
3.2. Prognostic Factors
The univariable Cox’s analysis of the 123 SLN positive

The Prognostic Value of Minimally Involved Melanoma Sentinel Lymph Nodes 1493
patients for DFS, DSS, and OS are presented in Table 1 .
Breslow thickness >2.0 mm, male gender, ulceration,
SLN tumour burden >= 0.1 mm, and extensive micro-
anatomic metastatic location (E) were significantly asso-
ciated with worse DFS, DSS, and OS (p < 0.05). An age
> 65 years was also significantly associated with worse
DFS. On the multivariable analysis, Breslow thickness
>2.0 mm (HR 3.01, 95 percent CI 1.51 - 6.04; p 0.002/
HR 3.27, 95 percent CI 1.40 - 7.66; p 0.006/HR 3.46, 95
percent CI 1.49 - 8.05; p 0.004), ulceration (HR 1.74, 95
percent CI 0.99 - 3.06; p 0.054/HR 2.13, CI 1.07 - 4.27; p
0.032/HR 2.50, 95 percent CI 1.28 - 4.89; p 0.007), and
SLN tumour burden >= 0.1 mm (HR 3.55, 95 percent CI
1.30 - 9.66; p 0.013/HR 3.04, 95 percent CI 1.03 - 8.94; p
0.044/HR 3.29, 95 percent CI 1.12 - 9.66; p 0.030) were
independent significant factors lowering DFS, DSS, and
OS. Male gender (HR 1.81, 95 percent CI 0.98 - 3.32; p
0.057/HR 2.95, 95 percent CI 1.39 - 6.27; p 0.005/HR
3.32, 95 percent CI 1.58 - 7.0; p 0.002) was an inde-
pendent significant factor lowering DSS and OS. Exten-
sive microanatomic metastatic location (E) was an inde-
pendent significant factor lowering only DFS (HR 1.87,
95 percent CI 1.05 - 3.35; p 0,033). The median SLN
tumour burden in the extensive microanatomic location
(E) was 7 mm (range: 0.8 - 15) compared to 0.15 mm
(range 0.09 - 4) in the subcapsular microanatomic loca-
tion (A) (HR 3.31, 95 percent CI 1.7 - 6.1; p < 0.001).
3.3. Survival Analyses
The median follow-up time for all 499 patients was 52
months (range: 9 - 146). The median follow-up time for
the 123 SLN positive patients was 41 months (range: 2 -
146). The 3- and 5 - year DFS for SLN positive patients
were 57.8 percent and 47.6 percent, compared to 92.3
percent and 88.1 percent respectively for patients with a
negative SLN. The 3- and 5-years DSS were 77.2 percent
and 61.8 percent compared to 97.2 percent and 93.9 per-
cent; and OS were 75.4 percent and 59.1 percent com-
pared to 95.4 percent and 89.9 percent for the same pa-
tients respectively.
3.4. Sentinel Lymph Node Positive Subgroups
Analyses
SLN positive subgroups DFS, DSS, and OS compared to
negative SLN are presented in Table 2. SLN tumour
burden subgroups 0.1 - 1 mm and >1 mm were signifi-
cantly associated with worse survival. However, it did
not reach statistical significance for the <0.1 mm sub-
group. SLN microanatomic tumour location subgroups
were all constantly significantly associated with a poorer
survival, except for subgroups C and D. The 3- and
5-years DFS, DSS, and OS for SLN positive subgroups
compared to SLN negative patients are presented in Ta-
ble 3. Tumour burden subgroups disease-free survival
curves are shown in Figure 1. Global recurrence rate was
5 (24 percent), 14 (42 percent), and 43 (66 percent) for
Rotterdam subgroups <0.1 mm, 0.1 - 1 mm, and >1 mm
respectively. Minimally involved SLN subcapsular sub-
group A presented 20 recurrences (39 percent). There
were 45 recurrences (12 percent) in the negative SLN.
3.5. Predictive Factors for Non-Sentinel Lymph
Node Metastasis
Among the 123 patients with a positive SLN, 111 un-
derwent a CLND. The procedure was not proposed to
Table 2. Univariable analyses of sentinel lymph node (SLN)-positive subgroups of disease-free (DFS), disease-specific (DSS)
and overall survival (OS) compared to SLN negative patients.
DFS DSS OS
SLN status Level NHR 95% CI P HR95% CI P HR 95% CI P
SLN negative 376 1 1 1
<0.1 mm 21 1.89 0.75 - 4.790.175 2.420.84 - 6.950.100 1.43 0.51 - 3.990.493
0.1 - 1.0 mm 33 4.55 2.45 - 8.47<0.00015.412.60 - 11.26<0.00013.29 1.65 - 6.560.001
SLN Tumour
Burden
>1.0 mm 65 8.97 5.83 - 13.80<0.00018.885.08 - 15.56<0.00016.04 3.72 - 9.79<0.0001
A 52 3.92 2.29 - 6.71<0.00013.202.64 - 9.44<0.00014.10 1.81 - 5.68<0.0001
B 18 6.07 2.96 - 12.48<0.00015.553.57 - 19.27<0.00018.30 2.60 - 11.86<0.0001
C 11 2.71 0.84 - 8.750.095 2.971.44 - 15.830.069 4.78 0.92 - 9.590.010
D 8 5.08 1.82 - 14.170.002 1.080.25 - 13.680.942 1.85 0.15 - 7.820.545
SLN
Microanatomic
tumour location*
E 29 13.93 8.38 - 23.17<0.00017.025.31 - 21.18<0.000110.60 3.75 - 13.14<0.0001
*SLN Microanatomic tumour location according to Dewar (8): A, subcapsular. B, combined subcapsular and parenchymal. C, parenchymal. D, multifocal or E,
extensive. HR, hazard ratio. CI, confidence interval. P, significance level.
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The Prognostic Value of Minimally Involved Melanoma Sentinel Lymph Nodes 1494
Figure 1. Kaplan-Meier curves with log-rank test of tumour burden subgroups disease-free survival compared to negative
sentinel nodes patients.
Table 3. Sentinel lymph node (SLN) subgroups primary characteristics: Breslow thickness (median and range) and ulcera-
tion, the 3 and 5 years rates of disease-free (DFS), disease-specific (DSS) and overall survival (OS).
3 years 5 years
SLN status Level Breslow U DFS DSS OS DFS DSS OS
SLN negative 1.5 (0.3 - 15) 20%92.3 97.2 95.4 88.1 93.9 89.9
<0.1 mm 2.3 (1.1 - 9) 38%86.3 93.4 93.7 79.6 86.6 86.6
0.1 - 1 mm2.0 (1.0 - 6) 30%64.4 83.1 83.4 52.7 68.7 68.5 SLN Tumour Burden
>1 mm 3.0 (0.8 - 12) 48%43.3 69.2 65.3 32.1 50.2 44.9
A 2.4 (1.0 - 9) 37%68.4 83.4 82.6 57.3 69.8 67.8
B 2.8 (1.1 - 8) 33%56.9 72.6 67.4 45.0 54.8 47.9
C 2.0 (1.2 - 6) 36%78.4 84.2 84.5 69.2 71.0 70.8
D 2.7 (1.5 - 5) 38%65.9 94.0 94.3 54.5 87.9 88.0
SLN Microanatomic
Tumour location*
E 3.1 (0.8 - 12) 52%32.0 66.7 63.9 22.6 47.9 44.0
*SLN Microanatomic Tumour location according to Dewar (8): A, subcapsular, B, combined subcapsular and parenchymal, C, parenchymal, D, multifocal, or E,
extensive. U, ulceration.
three patients due to their poor general condition, and six
further patients refused the procedure. A CLND was also
not proposed to three patients between 1997 and 2000
due to the very limited SLN invasion. Their SLNs were
negative with H-E and had few metastatic cells detected
in IH. One or more (median = 1, range = 1 - 4) positive
non-sentinel nodes (NSLN) were found in 20 patients (18
percent). The univariable analysis of these patients is
presented in Table 4. On the multivariable analyses, ul-
ceration (OR 6.51, 95 percent CI 1.91 - 22.13; p = 0.003)
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The Prognostic Value of Minimally Involved Melanoma Sentinel Lymph Nodes 1495
Table 4. Predictive factors of positive non-sentinel lymph nodes (NSLNs).
Positive NSLN = 20 Negative NSLN = 91
Characteristics Level N % N % OR P
Gender Female
Male
8
12
18
18
37
54
82
82
1
1.03 0.957
Age (mean ) ≤ 65 years
> 65 years
11
9
14
26
65
26
86
74
1
2.04 0.157
Melanoma subtype
Superficial spreading
Nodular
Acrallentiginous
Others
5
11
2
2
12
25
18
13
36
33
9
13
88
75
82
87
1
2.40
1.60
1.11
0.138
0.608
0.909
Breslow thickness
<1 mm
1.01 - 2.0 mm
2.01 - 4.0 mm
>4.0 mm
0
4
11
5
-
10
28
19
4
37
29
21
100
90
73
81
1
1
1.57
1.57
0.135
0.135
Clark level III
IV and V
3
17
14
19
19
72
86
81
1
1.50 0.552
Ulceration Absent
Present
6
14
9
31
60
31
91
69
1
4.52 0.005
Primary melanoma loca-
tion
Extremity
Head and neck
Trunk
10
3
7
18
60
14
45
2
44
82
40
86
1
6.75
0.72
0.051
0.533
SLN Tumour Burden
<0.1 mm
0.1 - 1 mm
>1.0 mm
Not available
1
5
12
2
6
17
20
16
25
49
1
94
83
80
1
3.20
3.92
0.308
0.206
SLN Microanatomic
Tumour location*
A
B
C
D
E
Not available
6
2
2
0
8
2
13
13
22
0
28
40
14
7
7
21
2
87
87
78
100
72
1
0.95
1.90
-
2.54
0.955
0.481
-
0.123
*SLN Microanatomic tumour location according to Dewar (8): A, subcapsular. B, combined subcapsular and parenchymal. C, parenchymal. D, multifocal or E,
extensive. OR, odd ratio. P, significance level.
and primary local tumour in the head and neck (OR
17.83, 95 percent CI 2.02 - 157.90; p = 0.010) were sig-
nificant predictive factors for NSLN positivity. The de-
gree of SLN involvement, with both studied classifica-
tions, was not a predictive factor of NSLN positivity.
Among the 12 patients who did not undergo a CLND,
four were in the minimally involved <0.1 mm subgroup
and two of them recurred at 2 months and 4 years then
deceased at 2 and 5 years respectively, another six pa-
tients were in the minimally involved subcapsular mi-
croanatomic location (A) and four of them recurred at 2,
5, 6, and 24 months while three of them deceased at 1, 2,
and 3 years.
4. Discussion
This single-institution-based study with surgical and an
atomopathological dedicated teams confirmed that tu-
mour burden stratification according to Rotterdam crite-
ria is a useful prognostic factor for survival. Patients with
SLN tumour burden <0.1 mm have a trend toward lower
survival and toward higher recurrence rate, compared to
SLN negative patients.
The clinical and anatomopathologic characteristics of
SLN positive patients in this study are comparable to
those described in literature [7-10,13,15] in terms of age,
primary melanoma location, male/female ratio, Clark
level, and ulceration rate. However, the median Breslow
thickness was 1.7 mm for all patients, and 2.45 mm for
SLN positive patients. These Breslow data are among the
lowest mentioned in literature [7,13,15], indicating that
primary tumours were probably detected at an earlier
stage. Despite this, 24.7 percent of metastatic SLN were
detected in clinically negative patients, which is among
the highest published rate [7-10,13,15]. The positive
NSLN rate is comparable to those previously reported.
The microanatomic location classification according to
Dewar was intended to predict NSLN metastatic in-
volvement in the CLND following a SLNB procedure [5].
The subgroup with subcapsular metastasis (A) is consid-
ered to be in the early stage of metastatic invasion, with
the hypothesis that metastatic cells have not yet contin-
ued to NSLN. However, in this study, 13 percent of the
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patients with subcapsular metastasis presented a positive
NSLN. Compared to negative SLN patients, the sub-
groups A, B, and E were associated with a higher recur-
rence rate and a poorer survival. The subgroups C and D
comprised of such a small number of patients that they
were therefore probably not associated with a poorer
survival than negative SLN patients.
Only subgroup E, with extensive metastasis, was an
independent significant factor on multivariable analysis
and negatively affected DFS. This was in fact partially
related to the diameter, with a median SLN tumour bur-
den significantly higher in the subgroup E compared to
subgroup A. Additionally, the distribution of the different
subgroups in this present study differed from its original
description: we found 42 percent of patients with sub-
capsular metastasis (i.e. subgroup A), as compared to 26
percent in Dewar’s publication. This can be explained by
the fact that this cohort of patients seems to have been
diagnosed at an earlier stage. One may also hypothesize
that the Dewar classification is difficult to reproduce,
despite the fact that expert pathologists (ES, HB) pre-
cisely reviewed all slides. This suggests that microana-
tomic location is not a useful tool for predicting survival
or the NSLN status.
Van Akkooi’s Rotterdam Criteria was specifically de-
signed for survival analysis [7]. He convincingly demon-
strated that the tumour burden threshold for SLN sub-
micrometastases in melanoma should be <0.1 mm. With
a slightly higher cut-off of <0.2 mm, the future of these
patients is differed significantly [15]. Tumour burden
within SLN is indeed an easy way to classify the degree
of the SLN metastatic invasion in contrast to many other
complicated classifications [16,19-21]. In his first publi-
cations, Van Akkooi concluded that sub-micrometastases
<0.1 mm could be considered as biologically false posi-
tive, identical to SLN negative patients. Therefore, these
patients could be spared a CLND and could be included
into adjuvant therapy trials as SLN negative patients
[7,22]. Van der Ploeg et al. [8-10] confirmed these con-
clusions in the same institution, and mentioned seven
patients from 2004 to 2008 who did not undergo CLND
because of the presence of minimal SLN tumour burden
(<0.1 mm). By interest, the issue of minimally involved
SLN was initially also debated in this institution. Three
among the earlier patients treated in this cohort were not
proposed a CLND. In the present study, only tumour
burden > = 0.1 mm was a significant independent factor
worsening DFS, DSS and OS. Sub-micrometastases
(<0.1 mm) was not a significant independent factor for
survival. However, there was a trend towards worse out-
comes for patients with sub-micrometastases in com-
parison to SLN negative patients. It could be hypothe-
sized that this trend did not reach statistical significance
due to the small number of patients (21 in the sub-mi-
crometastatic subgroup), therefore not permitting a gen-
eralization on a larger scale. Global recurrence rates also
rose following an increase of the metastatic charge ex-
pressed as tumour burden. However, even in the sub-
micrometastatic group, five patients recurred: four pa-
tients presented initially local recurrence, and one patient
had directly distant metastases. Only one patient in sub-
micrometastatic subgroup had a positive NSLN. The
Rotterdam criteria satisfactory allow a stratification of
the prognosis of patients with positive SLN. Although
CLND did not influence survival in cohort studies [23],
there is no data from randomized controlled trials. That is
why; the issue remains debated waiting for the ongoing
prospective study MLST II results. The European con-
sensus multidisciplinary based guideline 2012 did not cut
the issue of CLND for sub-micrometastatic subgroup
[24].
Some authors attempted to integrate various elements
in scores, taking into account the primary melanoma
characteristics and the metastatic charge of the SLN, but
until now these scores failed to reach two goals. The first
one is to find out the least invasive but the most secure
care program for a subgroup of positive SLN who are
unlikely to recur and have similar survival compared to
negative SLN. The second goal is to identify patients
with micrometastatic SLNs who have no positive NSLN
and thus can be considered as negative SLN. Taking into
account the present clinical data, one would challenge at
this point that such a classification might be possible. As
shown in this study, even a very limited SLN invasion
had a trend toward lower survival and could be associ-
ated with positive NSLN. If other primary tumour char-
acteristic restrictions are added to the sub-microscopic
subgroup, a real subgroup acting as negative SLN might
be found. In this case, it would restrict this subgroup so
much that it would apply to a very limited number of
patients and thus lose its clinical significance.
5. Conclusion
Tumour burden stratification according to Rotterdam
criteria is an easy and useful prognostic factor of survival
in melanoma. There was a trend showing that patients
with SLN sub-micrometastases <0.1 mm had a lower sur-
vival compared to SLN negative patients. One might
suggest that patients with minimally involved SLNs may
not be managed similarly to negative SLN patients. Our
results suggest that micro-anatomic location according to
Dewar is not a useful tool for predicting survival and the
NSLN status
6. Acknowledgments
We are grateful to Mohamed Faouzi for the statistical
analysis.
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