ANALYTICAL AND QUANTITATIVE CYTOPATHOLOGY AND HISTOPATHOLOGY

1. 177
OBJECTIVE: Some melanocytic lesions can be diffi­
cult to diagnose because of ambiguous histological and
immunohistochemical features. Morphometric features
of melanocytes in the upper and lower parts of a chal­
lenging lesion may help to facilitate an accurate diag­
nosis.
STUDY DESIGN: We studied 32 cases of invasive
cutaneous melanoma, 35 cases of mild or moderate
dysplastic nevus, and 31 cases of benign melanocytic
nevus. All cases were immunostained with Sox10. The
nuclear areas of 30 melanocytes were measured on each
papillary (upper [U]) dermis and reticular dermis/sub-
cutaneous tissue (lower [L]) in all cases by using the
Image J analysis program. Then, a maturation index
(U/L) was calculated for each case. Also, cutaneous mel­
anomas were categorized into 2 groups that displayed
pseudo-maturation or the lack of it.
RESULTS: Mean maturation index was 1.04±0.29
in melanomas, 1.23±0.28 in dysplastic nevi, and
1.52±0.33 in benign melanocytic nevi, respectively.
There were statistically significant differences between
melanoma and dysplastic nevus (p=0.012) and be-
tween melanoma and benign melanocytic nevus
(p<0.001) for the maturation index. Although pseudo-
maturation was associated with low mitotic activity
and thin Breslow thickness, there was no significant
difference between survival distributions of 2 melanoma
groups.
CONCLUSION: Calculation of the maturation index
can be used as a supporting tool for the differential
diagnosis of challenging cases. However, it may possess
limitation for evaluation of nevoid melanoma, melanoma
in situ, or clonal nevus. (Anal Quant Cytopathol Hist-
pathol 2019;41:177–183)
Keywords: biomarkers, tumor; diagnosis; immu-
nohistochemistry; maturation; melanocytes; mela-
noma; morphometry; nevus, melanocytic; Schwann
cells; skin; skin neoplasms; Sox10 protein, human;
Sox10 transcription factor.
Analytical and Quantitative Cytopathology and Histopathology®
0884-6812/19/4105-0177/$18.00/0 © Science Printers and Publishers, Inc.
Analytical and Quantitative Cytopathology and Histopathology®
Can Numeric Maturation Value Be Used as a
Prognostic Indicator and Diagnostic Tool in
Cutaneous Melanomas?
A Morphometric Study
Mehmet Gamsizkan, M.D., Seyma Buyucek, M.D., Sinem Kantarcioglu Coskun, M.D.,
Mehmet Ali Sungur, Ph.D., Emin Ozlu, M.D., Atike Bahcivan, M.D., and
Binnur Onal, M.D.
From the Departments of Pathology, of Biostatistics, and of Dermatology, Düzce University, School of Medicine, Konuralp, Düzce, Tur-
key.
Dr. Gamsizkan is Associate Professor, Department of Pathology.
Drs. Buyucek and Bahcivan are Pathologists, Department of Pathology.
Dr. Kantarcioglu Coskun is Assistant Professor, Department of Pathology.
Dr. Sungur is Assistant Professor, Department of Biostatistics.
Dr. Ozlu is Associate Professor, Department of Dermatology.
Dr. Onal is Professor, Department of Pathology.
Address correspondence to: Mehmet Gamsizkan, M.D., Düzce Universitesi, Tıp Fakultesi, Patoloji AD 81000, Konuralp, Düzce/Turkey
(drgamsiz@yahoo.com).
Financial Disclosure: The authors have no connection to any companies or products mentioned in this article.

2. Melanomas, which constitute about 5.7% of all ma-
lignant tumors, are the most common neoplasm of
the skin after basal and squamous cell carcinoma.
Melanoma is reported to be the fifth most com-
mon cancer in men and the sixth most common
cancer among women in the United States.1 Tumor
thickness is the most important prognostic factor
in determining the risk of metastasis and progno-
sis. The histopathological diagnosis of melanocytic
lesions sometimes can be difficult and may even
cause medicolegal problems due to failure in diag-
nosis.
The cells of an ordinary melanocytic nevus
from the papillary dermis to reticular dermis dis-
play some morphologic variations. Type A nevus
cells, referred to as epithelioid cells, are round-to-
cuboidal shaped in the upper part of the dermis.
Type B cells resemble lymphoid cells and are gen-
erally present in the mid and lower parts of the
dermis. Type B cells are smaller as compared to
type A cells. They contain less cytoplasm and less
melanin, usually set in well-defined aggregates or
cords. Type C nevoid cells, when identified, are
set in the lower part of the dermis and tend to re-
semble fibroblasts or Schwann cells due to an elon-
gated and spindle-shaped nucleus; they do not
contain melanin.2 This configuration is called mat-
uration, and it is characteristic for a melanocytic
nevus. However, melanoma usually displays a lack
of maturation.
Although activating somatic point mutations
such as BRAF and NRAS can be seen in ordinary
melanocytic nevi, they are subject to senescence.3,4
Depending on the type and phenomenon, each mel-
anoma is accompanied by several genetic changes
such as point mutations, gene amplification, meth-
ylation, loss of heterozygosity, and chromosomal
imbalance.5 The content of the melanoma cell nu­
cleus increases by mutation burden, DNA copy
number, and chromosomal aberrations. In contrast
to melanocytic nevus, melanomas display TERT
promoter mutation or amplification.6 Depending
on the reflection of these genotypic changes in mel-
anomas, large nuclei and lack of maturation are
mostly seen in the hematoxylin and eosin (H&E)
slides.
Sox10 is an embryonic stem cell transcription
factor of neural crest stem cell lineage that is ex-
pressed in the neural crest, critical for maturation
and maintenance of melanocytes.7 It is routinely
used for the diagnosis of melanocytic lesions as
one of the most sensitive and specific nuclear mark-
ers.8,9 It is also useful for amelanotic and desmo-
plastic melanoma without melanin pigmentation.8
Therefore, Sox10 staining pattern facilitates the
evaluation of nuclear morphology by highlighting
the nucleus. Morphometric features of melano-
cytes immunostained with Sox10 may help to dif­
ferentiate challenging lesions from melanomas.
In this study we evaluated the maturation index
of cutaneous melanomas, dysplastic nevus, and
ordinary melanocytic nevus and compared them
to determine a cutoff value for diagnostic utility.
We also investigated the prognostic importance of
pseudo-maturation in melanomas.
Materials and Methods
Appropriate permission for the study was ob-
tained from the Committee of Ethics of Düzce
University School of Medicine (approval no. 62/
2018). The pathology department database was
searched for a period of 20 years. The inclusion
criteria for melanomas were (1) invasive skin mel-
anoma, (2) sufficient clinical history, and (3) suffi-
cient pathology material for analysis. H&E–stained
slides were reviewed by 2 of the authors (M.G. and
S.B.) to confirm the diagnosis and record histolog-
ical features based on WHO 2018. In addition to
extracutaneous melanoma, we excluded cutaneous
ones with insufficient tumor tissue or unsatisfying
clinical information from the study. We included
a total of 32 cases of invasive cutaneous melano-
ma, 35 cases of mild or moderate dysplastic nevus,
and 31 cases of benign melanocytic nevus includ-
ing congenital nevus and papillary nevus. There
was no special site nevus.
Following antibody incubation, immunoper-
oxidase staining was performed with an avidin-
biotinylated horseradish peroxidase complex as a
detection reagent. Sox10 (SP267) was used to sup-
port the melanocytic origin and to easily select the
cells. The thickness was measured in all melano-
cytic lesions (Figure 1A–B). The Image J analysis
program (National Institutes of Health, USA) was
also applied for morphometric analysis. The digi-
tal images were captured using a 40× objective
camera. Measurements were done on the Sox10
immunostained slides by counting 30 representa-
tive neoplastic melanocyte nuclei in the upper and
lower part (Figure 2). Due to different thicknesses
of melanocytic lesions, we measured in nuclei of
the lower part of a lesion as follows: 1 mm for T2
melanomas, 2 mm for T3 ones, 4 mm for T4 ones,
and the lowest border for T1 ones, dysplastic nevi,
178 Analytical and Quantitative Cytopathology and Histopathology®
Gamsizkan et al

3. and benign melanocytic nevi. Thus, a total of 60
nuclei (30 upper and 30 lower) were measured in
each slide. The crisp boundary of target neoplastic
cells was manually selected.
Because of the retrospective nature of the study,
there were no strict standards for fixation and pro-
cessing; we utilized the ratio of upper and lower
part values. Then, a maturation index (U/L) was
calculated for each case. Using the ratios, instead
of values of upper and lower part variables, a
new independent variable was provided which
can be used in receiver operating characteristic
(ROC) analysis. Also, cutaneous melanomas were
categorized into 2 groups that displayed pseudo-
maturation or the lack of it. Hence, we also in­
vestigated the relation of pseudo-maturation with
prognosis.
Statistical Analysis
Normality assumption for numerical data was ana-
lyzed with the Shapiro-Wilk test, and independent
samples t test or Mann-Whitney U test were used
to compare groups where appropriate. Numeri-
cal data were summarized with mean±standard
deviation or median (min-max) as appropriate,
and categorical data were summarized with fre­
quency and percentage. Pearson’s χ2 test or Fisher-
Freeman-Halton test was used to analyze cate-
gorical data according to the expected count rule.
Cutoff values to discriminate invasive cutaneous
melanoma from dysplastic nevus and melanoma
from benign melanocytic nevus were calculated by
ROC curve analysis. Survival times were analyzed
by using life tables and Kaplan-Meier survival
analysis. Survival times between groups were com-
pared by using a log-rank test. The effect of the age
factor on survival time was analyzed with a Cox
proportional hazards regression analysis. Statistical
Volume 41, Number 5/October 2019 179
Maturation Value in Melanomas
Figure 1 The measurement of thickness in benign melanocytic
nevus (A) and dysplastic nevus (B) from granular layer to the
lowest part (Sox10, ×40).
Figure 2
Nuclear gallery and
selection of melanocyte
(arrow) displaying Sox10
immunopositivity in Image J
analysis program (Sox10,
×400).

4. analyses were done with SPSS v.22 package, and
the level of significance was considered as 0.05.
Results
The mean age of the melanoma group was 54.9
years (range, 27–85 years). There were 21 (65.6%)
males and 11 (34.4%) females. The most common
site of melanoma was head and neck (n=9; 28.1%),
lower extremity (n=8; 25%), and trunk (n=8; 25%)
followed by upper extremity (n=4; 12.5%) and un-
known (n=3; 9.4%). The most common histopatho-
logical subtype was nodular melanoma, which was
found in 17 patients (53.1%), followed by superfi-
cial spreading melanoma with vertical phase in 10
(31.3%), acral lentiginous melanoma in 4 (12.5%),
and lentigo maligna melanoma in 1 (3.1%). Accord-
ing to the 8th Edition of the American Joint Com-
mittee on Cancer (AJCC) melanoma staging sys-
tem, 5 cases (15.6%) were in T1 (mean Breslow
thickness: 0.65 mm), 6 (18.8%) in T2 (mean Bres-
low thickness: 1.75 mm), 7 (21.9%) in T3 (mean
Breslow thickness: 2.77 mm), and 14 (43.8%) in T4
(mean Breslow thickness: 6.70 mm). Ulceration was
present in 17 (53.1%) cases. All these features and
other histopathological findings are summarized in
Table I.
The mean age of the dysplastic nevus group
was 31.7 years. The most common site of dysplas-
tic nevus was trunk (65.7%), followed by upper
extremity (8.5%), lower extremity (8.5%), head and
neck (5.7%), and unknown (11.4%). While 24 cases
had moderate dysplasia, 11 had mild dysplasia. The
mean thickness was 0.65 mm.
The mean age of the benign melanocytic nevus
180 Analytical and Quantitative Cytopathology and Histopathology®
Gamsizkan et al
Table I Clinical, Histopathological, and Maturation Findings of Melanomas
Histologic Breslow Mitoses/ Lymphocytic
Case Age/Sex Site subtype (mm) mm2 U LVI response R N MI
1 52/M UE NM 3.24 27 Yes Yes Non-brisk No No ≤1
2 63/M Trunk NM 4.66 4 Yes Yes Non-brisk No No ≤1
3 72/F H&N NM 5 6 Yes Yes Non-brisk No No ≤1
4 56/F LE NM 8.1 7 Yes Yes Non-brisk No No ≤1
5 64/M LE SSM-VP 2.16 22 Yes No Non-brisk No No ≤1
6 67/M Trunk NM 2.75 4 Yes No Non-brisk No No ≤1
7 64/M H&N NM 4.1 1 Yes No Non-brisk No No ≤1
8 56/F Trunk NM 4.03 1 Yes No Non-brisk No No ≤1
9 74/M UE ALM 6.5 1 Yes No Non-brisk No Yes ≤1
10 81/F Trunk NM 7.5 10 Yes No Non-brisk No No ≤1
11 85/F LE ALM 2 1 No No None No No ≤1
12 30/F Trunk NM 10 6 No No Non-brisk No No ≤1
13 54/F LE ALM 10 6 No No None No No ≤1
14 75/M LE NM 14 3 No No Non-brisk No No ≤1
15 38/M UE SSM-VP 3.5 1 No Yes Non-brisk Yes No >1
16 58/F H&N SSM-VP 1.21 1 No No Non-brisk No No >1
17 45/M ? SSM-VP 1.5 4 Yes No Brisk No No >1
18 34/M H&N NM 2 1 Yes No Non-brisk No No >1
19 34/F Trunk SSM-VP 2.22 1 Yes No Brisk No No >1
20 51/F UE NM 2.5 2 Yes No Brisk No No >1
21 35/M H&N NM 3 <1 Yes No Non-brisk No No >1
22 64/F ? SSM-VP 4.05 3 Yes No None No No >1
23 65/M LE ALM 5.4 6 Yes No Non-brisk No No >1
24 27/M LE NM 1.8 <1 No No Non-brisk No No >1
25 66/M Trunk NM 1.98 3 No No Non-brisk No No >1
26 35/M H&N NM 4.02 2 No No None No No >1
27 71/M H&N NM 6.5 2 No No Non-brisk No No >1
28 43/M Trunk SSM-VP 0.31 1 No Yes Non-brisk No No >1
29 63/M H&N LMM 0.5 <1 No No Non-brisk No No >1
30 49/M H&N SSM-VP 0.74 <1 No No Non-brisk No No ≤1
31 50/M ? SSM-VP 0.81 1 No No Brisk No No >1
32 36/M LE SSM-VP 0.9 1 No No None No No >1
ALM = acral lentiginous melanoma, H&N = head and neck, LE = lower extremity, LMM = lentigo maligna melanoma, LVI = lymphovascular invasion,
MI = maturation index, N = neurotropism, NM = nodular melanoma, R = regression, SSM-VP = superficial spreading melanoma with vertical phase,
U = ulceration, UE = upper extremity.

5. group was 40.4 years. The group consisted of 20
papillomatous nevi (11 compound, 9 intradermal)
and 11 congenital nevi (6 compound, 5 intrader-
mal). The most common site of benign melanocyt-
ic nevus was trunk (48.4%), followed by head and
neck (29%), lower extremity (3.2%), upper extrem-
ity (3.2%), and unknown (16.1%). The mean thick-
ness was 3.28 mm.
Diffuse and strong Sox10 immunopositivity was
found in all cases. The mean maturation index was
1.04±0.29 in melanomas, 1.23±0.28 in dysplastic
nevi, and 1.52±0.33 in benign melanocytic nevi,
respectively. According to the maturation index,
there was a statistically significant difference be-
tween the groups (melanoma versus dysplastic
nevus [p=0.012]; melanoma versus benign melano-
cytic nevus [p<0.001]).
In addition, melanomas were divided into 2 cat­
egories based on maturation values. Those “>1”
were considered as displaying pseudo-maturation.
Pseudo-maturation was found to be associated
with the lower mitotic activity (p=0.016) and thin
Breslow thickness (p=0.004). There was no sig-
nificant statistical relationship between pseudo-
maturation and other histopathological parame-
ters (Table II). The follow-up period ranged from
2 to 182 months. Mean overall survival was 61.3
months (95% CI 17.4–105.2) for ≤1 group and 113.8
months (95% CI 75.4–152.2) for >1 group. Accord-
ing to log-rank testing there was no significant
difference between the 2 melanoma groups (dis-
playing pseudo-maturation or not) in terms of sur-
vival time (p=0.160).
According to ROC analysis, cutoff value was
calculated as 1.22 between melanoma and benign
melanocytic nevus (sensitivity: 81.3%, specificity:
90.3%) and 1.13 between melanoma and dysplastic
nevus (sensitivity: 68.8%, specificity: 60%).
Discussion
Some melanocytic lesions may display ambiguous
histopathological features. Therefore, the diagnosis
of melanoma is not always easy, and supporting
methods such as image analysis may sometimes be
needed.
In our study we found a statistically significant
difference between melanocytic nevus, dysplastic
nevus, and melanoma for the mean nuclear area
Volume 41, Number 5/October 2019 181
Maturation Value in Melanomas
Table II Comparison of Maturation Index with Other Histopathological Parameters
Histopathological
Maturation index
parameters ≤1 (n=15) >1 (n=17) p Value
Breslow thickness 5.65 (0.74–14.00) 2.48 (0.31–6.50) 0.004
Mitosis/mm2 4 (1–27) 1 (0–6) 0.016
Ulceration 0.149
Present 10 (66.6%) 7 (41.2%)
Absent 5 (33.3%) 10 (58.8%)
LVI 0.383
Present 4 (26.7%) 2 (11.8%)
Absent 11 (73.3%) 15 (88.2%)
Lymphocytic response 0.138
None 2 (13.3%) 3 (17.6%)
Non-brisk 13 (86.7%) 10 (58.8%)
Brisk 0 (0.0%) 4 (23.5%)
Subtype 0.094
NM 10 (66.6%) 7 (41.2%)
SSM-VF 2 (13.3%) 8 (47.1%)
ALM 3 (20.0%) 1 (5.9%)
LMM 0 (0.0%) 1 (5.9%)
Regression —
Present 0 (0.0%) 1 (5.9%)
Absent 15 (100%) 16 (94.1%)
Neurotropism —
Present 1 (6.7%) 0 (0.0%)
Absent 14 (93.3%) 17 (100%)
ALM = acral lentiginous melanoma, LMM = lentigo maligna melanoma, LVI = lymphovascular invasion, NM = nodular melanoma,
SSM-VP = superficial spreading melanoma with vertical phase.

6. rate between the cells in the upper and lower part
of the dermis. In melanocytic nevi, the matura­
tion index (U/L) was significantly higher than that
in melanomas. Similar to our method, Leitinger et
al previously used and validated in convention-
al H&E slides.10 Our results were consistent with
their study.10 They reported statistical differences
in maturation index between ordinary melano-
cytic nevus as well as Spitz nevus compared with
melanoma; however, there were no cases of dys­
plastic nevi in their study. Li et al also reported
that maturation profiles could be used for sepa­
rating benign nevi from melanomas.11 On the
other hand, in conventional slides, nucleus selec-
tions may be difficult in pigmented lesions. Sox10
is a critical supportive tool for the melanocytic
origin, especially in tumors that lack pigment or
those with purely epithelioid or spindle cell mor-
phology. In our study all cases showed diffuse
and strong positive staining with the Sox10 an-
tibody, as previously reported.8,9 We also used a
red chromogen to demonstrate nuclei in the lesion
with dense melanin pigment for the evaluation of
maturation.
The frequency of histopathological subtypes of
melanomas varies worldwide. Superficial spread-
ing melanoma is the most common form in lighter-
skinned people (Fitzpatrick skin type I–III).12,13
Some far-east Asian studies have reported that
acral lentiginous melanoma is the most common
form and that its frequency varies from 41.8 to
48.4%.14-16 Nodular melanoma frequency has been
higher in Saudi Arabia, Egypt, and Ethiopia.17-19
The most common histopathological form in our
study is nodular melanoma (53.1%), followed by
superficial spreading melanoma (31.3%), acral len­
tiginous melanoma (12.3%), and lentigo maligna
melanoma (3.1%). Our results have revealed that
superficial spreading melanoma is lower than that
reported in our previous multicentric study.20
Genetic factors, relatively high fog weather com-
pared to other regions of Turkey, or cultural
dressing practices such as wearing a hijab might
explain this difference.
Due to the lack of maturation in melanoma, the
ratios obtained during the measurements were
expected to be around 1 in our study. Even if the
values >1 cannot be differentiated by the human
eye, it was accepted that it showed paradoxical
maturation as a result of the computer-assisted
morphometric evaluation, and pseudo-maturation
terminology was used for >1 values in our study.
We found that pseudo-maturation was related to
lower mitotic activity and thin Breslow thickness.
Nunes et al reported that the average area of large
nuclei was different from thin nonmetastatic tu-
mors to metastatic ones.21 Bedin et al showed that
the nuclear area was a poor prognostic factor in
addition to tumor thickness, vertical growth, and
lack of nuclear roundness.22 Smolle et al reported
that the nuclear size of the melanocytic cell was
related to the proliferative activity. However, in
our survival analyses between the 2 groups of
melanomas with pseudo-maturation or not, there
was no significant difference.23 These discrepant
conclusions can be a reflection of our patient pop-
ulations (predominantly thicker and nodular type
melanoma) rather than true biological differences.
Nevertheless, large case series may give more ac-
curate results on this issue.
A process from morphometric studies to deep
learning will develop more and more in the field
of routine practice. For instance, Steiner et al have
improved the deep learning based algorithm for
the detection of breast cancer metastases in lymph
nodes.24 That program shortened the time of
searching for metastases, especially in microme-
tastases. Digital image processing algorithms can
be used to facilitate and reduce time by detecting
the areas of nuclei. This method can be done more
effectively on immunohistochemical slides because
H&E sections do not display good contrast among
cytoplasm, nucleus, and stroma. The areas of nu-
clei from U and L parts can be coded to a deep
learning algorithm for calculating the ratio of ma­
turation index automatically using an image pro-
cessing technique.
Simple karyotypic morphometric measurement
using Sox10 provides reliable, reproducible, and
objective data as compared to conventional histo-
pathology. However, using this method has some
limitations. Nevoid melanoma can show paradox-
ical maturation. Additionally, a clonal nevus or
combined nevus with dermal components reveals
lack of maturation. Other histopathological criteria
and immunohistochemical features should be used
in combination for these kinds of rare lesions.25,26
Due to immunohistochemical staining features,
we could not evaluate the nuclear texture features
of melanocytes. Besides, we could not evaluate the
parameters related to the nuclear contour because
of the limitations of the Image J program. How-
ever, in this study we investigated the diagnostic
utility of a simple method that can be used practi-
182 Analytical and Quantitative Cytopathology and Histopathology®
Gamsizkan et al

7. cally for melanocytic lesions by an easily accessible
program.
As a result, the calculation of the maturation in-
dex can be used as an easy, practical supporting
tool for the diagnosis of challenging cases. In ad­
dition, deep learning-based algorithms can be de-
veloped in future studies.
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