Congenital melanocytic nevi (CMN) are defined as neural crests derived benign naevomelanocytic proliferations being present at birth or emerging in the first weeks of life (Fig. 1). Uniquely, CMN can be present beyond the skin surface, spreading to the deep dermis, subcutaneous fat, fascia, or muscle, and the histological characteristics may be heterogeneous within single nevus [1]. The pigmentation of nevi can range from tan to dark brown, and clinically CMNs may vary considerably with respect to size, morphology, texture, and location [2]. CMNs can be distinguished by size: small, medium, large, and giant. Although initially the actual size of CMN was commonly evaluated at its current size, projected adult size (PAS) is now mostly used. This term refers to the largest diameter reached in adulthood and is calculated by multiplying actual CMN size by factors 1.7, 3.3, and 2.8, depending on lesion localisation (head, legs, and either trunk or arms and feet, respectively). According to this definition, large CMN (LCMN) have PAS ≥ 20 cm, while giant CMN (GCMN) are assigned if PAS exceeds 40–50 cm [3]. Some researchers also classify nevi covering over 2% of body surface area as LCMN or GCMN and nevi that cover a large portion of a major anatomical site as LCMN [2]. Large and giant CMN usually localise on the trunk, proximal parts of the limbs, scalp, or neck. GCMN often have “bathing trunks” and “glove stocking” distributions and are accompanied by multiple smaller satellite lesions, recently being called accompanying CMN [4]. The incidence of LCMN and GCMN is low (1/20,000 and 1/500,000 births, respectively); they are, however, considered a major health problem as they are connected with much higher risk of melanoma, neurocutaneous melanosis, other malformations of central nervous system, and greater therapeutic challenges [3]. For example, the lifetime risk of having melanoma for each individual with CMN equals 1–2%, while for those with larger CMN, the risk is higher and reaches 5–15% [4, 5]. Although the size of CMN was regarded as the single risk factor of those disorders for a long time, in 2013 an interdisciplinary group of experts elaborated a novel classification system that comprises more parameters to characterise CMN and determine risk of adverse events [6]. This classification includes also several satellite nevi in the first year of life (or actual), anatomic localisation, colour heterogeneity, surface rugosity, hypertrichosis, and presence of dermal or subcutaneous nodules. Nevertheless, as the authors themselves admit, the classification system would benefit greatly if genetic characteristics were part of it.
Examples of CMN: head localisation of the nevi (1, 2), anterior and posteriori view of neonate with bathing trunk localisation of the nevus before first operation (3, 4), neonate with back localisation of main nevus (5).
In recent years, few gain-of-function somatic variants have been reported as responsible for prenatal proliferation of melanoblasts. In particular, variants of codon 61 in
The archived affected skin samples taken from 18 children with large or giant congenital melanocytic nevi treated in Clinic of Surgery of Children and Adolescents Institute of Mother and Child in Warsaw in the years 2006 to 2017 were qualified for inclusion in the study. Localisation of main nevus was bathing trunk (five cases), back (seven patients), and head and/or neck in six patients. Age during first surgical intervention ranged from 1 month to 15 years. Surgical treatment was completed in 11 children (number of surgical procedures ranged from 2 to 21). Histological examination of excised nevus revealed compound nevus in all patients, but in two cases, in consecutive evaluations, melanoma arising in the nevus was additionally diagnosed. Accompanying neurocutaneous melanosis (NCM) was confirmed in six children (Table 1). Comprehensive clinical characteristics of the majority of our patients were published previously [9,10]. Resection specimens were taken from major lesions during surgery and fixed in formaline following paraffin embedment (FFPE samples). The samples were evaluated by a pathologist who marked regions containing the highest load of melanocytes, which were macro-dissected prior to DNA isolation. The material was collected and fixed in the years 2006 to 2017, therefore the majority of them were archive samples.
Characteristics of patients and results of molecular investigation
Patient No | Year of birth/sex | Localization of nevus | Melanoma arising in the nevus | Neurocutaneous melanosis (NCM) | Age during first operation | Number of operations | Treatment completed | CMN size | Satellite nevi | ||
---|---|---|---|---|---|---|---|---|---|---|---|
2011/m | B | 6/12 | 5 | + | >20 cm | + | none | p.Gln61Lys | |||
2012/m | H | + | 7/12 | 4 | > 0,5% PAS | 0 | none | none | |||
2012/m | H | 1/12 | 2 | + | 0,5 % PAS | 0 | none | p.Gln61Lys | |||
2009/f | BT | 4y | 6 | > 20 cm | ++ | none | none | ||||
1989/f | N | 15y | 4 | + | > 20 cm | 0 | none | none | |||
2003/f | B | 1/12 | 5 | + | > 20 cm | + | none | none | |||
2007/f | BT | + | 1/12 | 14 | > 20 cm | 0 | none | none | |||
2011/m | B | 3/12 | 2 | + | > 20 cm | 0 | none | p.Gln61Lys | |||
2009/f | B | 4/12 | 8 | + | > 20 cm | + | none | none | |||
2007/f | H | 2y | 8 | > 0,5% PAS | + | none | p.Gln61Lys | ||||
2011/f | B | 3/12 | 5 | + | > 20 cm | + | none | p.Gly12Asp | |||
2006/m | BT | + | 4/12 | 21 | > 20 cm | nd | none | none | |||
2009/m | B | + | 2y | 5 | > 20 cm | ++ | none | p.Gln61Lys | |||
2002/m | BT | 2y | 10 | + | not assessed | 0 | none | p.Gln61Arg | |||
2012/m | HN | 3/12 | 2 | > 0,5% PAS | 0 | none | none | ||||
2010/f | B | + | 6/12 | 4 | + | > 20 cm | + | none | none | ||
2006/f | BT | + | + | 6/12 | 13 | + | > 20 cm | nd | none | none | |
2008/m | H | + | + | 1/12 | 3 | + | > 0,5% PAS | - | none | none |
m = male
f = female
BT = bathing trunk
B = back
H = head
N = neck
ND = no data
PAS = projected adult size
none: refers to spectrum of variants analyzed within the frames of this study
DNA was extracted with the Qiagen QIAamp® DNA Mini-Kit, according to manufacturer instructions. Variant status in
Clinical and molecular characteristics of the patients are depicted in Table 1. Overall, we detected variants in 7/18 (38.9%) of the patients. All of them were found in
This study represents the first molecular study of large and giant CMN performed in Polish patients. In this study, we focused on detection of variants in the two genes:
In our group,
Overall, we detected
Hence, we cannot exclude that at least some of our patients harbour other variants as well. In one patient, we found the
In summary, our results indicate that
We present the results of the first mutational analysis of large/giant congenital melanocytic nevi in Polish patients.
Our results indicate that
Although further research is needed, considering worldwide trends toward precise medicine, our study is in line with public health policy. Within the next few years molecular studies may be included in a standard diagnostic/monitoring procedure of large/giant congenital melanocytic nevi.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.