Small congenital nevi associated with melanoma: case reports and considerations

Melanocytic nevi, both congenital and acquired, are considered to be precursors of melanomas. Data about the malignant potential of these nevi are conflicting, particularly with reference to the nevus of the smallest size. Patients with preexisting melanocytic nevi (both congenital and acquired) have risks of developing melanoma that differ from those of subjects without them. The purpose of this study was to verify the presence of melanoma in preexisting nevi both congenital (congenital nevus associated melanoma) (CNAM) and acquired (ANAM). In particular, we investigated melanomas associated with small congenital nevi (SCN). A cohort of 190 patients with primary melanomas was studied. Congenital nevi were called "small" (SCN) when their diameters were less than 1.5 cm. Epiluminescence microscopy (ELM) was performed to further improve the clinical diagnosis and to observe the more subtle changes in the preexisting nevi. Forty of the 190 cases of melanoma were associated with preexisting nevi; of these, 15 had congenital features with a CNAM largest diameter of 1.5 cm. These 15 cases were melanomas of the superficial type with a mean tumor thickness lower than that of ANAM (0.33 vs 1.50). There were no differences between the locations of CNAM and other melanomas. Male patients were significantly more affected. ELM microscopy permitted us to detect the early malignant changes in nevi and thus to improve our diagnosis. A high percentage of small congenital nevi were found to be associated with melanomas. They may be considered as melanomas precursors. Because of their large number and frequency, prophylactic removal of all SCN is not feasible. However, they should be removed as soon as possible when clinical or ELM changes are observed.     

Lipomatous melanocytic nevomatosis

Giant congenital melanocytic nevi (GCMN) are rare and occur in about one out of every 200,000-500,000 births. Their importance resides in the aesthetic alteration they produce and in the possibility of malignant transformation or in their association with nevi in the central nervous system as a distinctive syndrome: neurocutaneous melanoblastosis or nevomatosis, due to the fact that nervous system lesions are produced by infiltration of nevus cells. We present here a patient with a combination of GCMN with an outstanding lipomatosis located on the same area.     

Histogenesis of congenital and acquired melanocytic nevi based on histological study of lesion size and thickness

The histogenesis of melanocytic nevi is poorly understood. It is important to determine the differences and similarities in histogenesis between congenital and acquired nevi. To clarify the histogenic differences between acquired melanocytic nevi (AMN) and congenital melanocytic nevi (CMN), diameter and depth of nevus cells (tumor thickness) were examined in histological specimens from 80 cases of CMN and 71 cases of AMN, and these nevi were classified according to Mark's pathological CMN criteria. In all cases, giant CMN nevus cells were found in the lower marginal portion of excised specimens. The mean diameter and lesional thickness were significantly higher in CMN than in AMN. AMN diameter showed a significant correlation (r = 0.567, P < 0.05) with lesional thickness, while no such relation was observed in CMN. In addition, a significant correlation between lesion diameter and thickness was observed in small (<10 mm) non-Mark's type CMN (r = 0.626, P < 0.05). CMN may be classified into three subtypes: (i) caused by increased proliferation of melanoblasts during the course of migration from the neural crest to the epidermis; (ii) proliferation of nevus cells after arrival at the epidermis, and nevus cell distribution affected by adnexa and dermal differentiation; and (iii) arising after completion of skin development before birth.     

Installation of a network for patients with congenital melanocytic nevi in German‐speaking countries

In 2005, an Internet‐based network for the support of patients with congenital melanocytic nevi in German‐speaking countries was started ( http://www.naevus‐netzwerk.de ). Along with detailed information for patients and parents, the home‐page includes a nevus registry which is based on an electronic questionnaire and which aims at providing data on the long‐term course of nevi estimated to reach > 10 cm in largest diameter. In the past, congenital melanocytic nevi have been subject to various mythological interpretations (“Tierfellnävus”, lit.”animal coat nevus”;”Muttermal”). Today an increasing body of reliable scientific data allows a differentiated reflection of the risk of malignant transformation and has led to progress in the diagnostic and therapeutic management. Recent findings from the literature and considerations from scientific meetings are reviewed.     

Coexistence of Plaque-Type Blue Nevus and Congenital Melanocytic Nevi

A rare case of development of plaque-type blue nevus adjacent to congenital nevi in a 44-year-old woman is presented.     

Congenital melanocytic nevi and nevus spilus have a tendency to follow the lines of Blaschko: an examination of 200 cases

There have been few reports about the characteristics of the pigmentary arrangement of congenital melanocytic nevi (CMN) and nevus spilus (NS). Though the lines of Blaschko, which don't correspond to other lines such as Langer's lines and skin dermatomes, are well known to be followed by some rare pigmentary disorders, the relationship between these two disorders and the lines of Blaschko has not been discussed. Therefore, through an examination of 200 cases, we investigated whether or not the arrangement of CMN and NS follow the lines of Blaschko. Thirty-nine out of 92 cases (42.4%) of CMN and 67 out of 108 cases (62.0%) of NS were considered to follow the lines of Blaschko. Today, the idea is widely accepted that two functionally different cells proliferate during early embryogenesis of the skin which is caused from mosaicism and, as a result, the lines of Blaschko appear visually. In our results, we found that there were some cases of CMN and NS which showed a relationship with the lines of Blaschko, which is meaningful considering that the lesions and the lines are both related to pigmentary gene anomalies. The result was compared with CMN and NS by the chi(2) test. NS showed a predominant tendency to follow the lines with a significant difference (P = 0.0055). This may indicate that the lines of Blaschko reflect more clearly the proliferation of the epidermal cells than other cells in growth of the skin of the embryo. Further studies are required to elucidate the reason why some cases follow these lines and others do not.     

SCALP syndrome with a germline heterozygous DOCK6 mutation and somatic mosaic NRAS Q61R mutation

We present a case of SCALP syndrome, which was diagnosed in a male infant with the characteristic findings of sebaceous nevi, central nervous system malformations, aplasia cutis congenita, limbal dermoid, and giant congenital melanocytic nevi, or pigmented nevi. We identified a germline compound heterozygous DOCK6 mutation and a somatic mosaic NRAS Q61R mutation in the giant congenital melanocytic nevus. This report will increase clinician awareness of SCALP syndrome and augment the literature in characterizing this rare syndrome, including its genetic background.     

Hypophosphatemic rickets: A rare complication of congenital melanocytic nevus syndrome

We report the case of a child who presented with a giant melanocytic nevus with numerous satellite nevi at birth and developed hypophosphatemic rickets due to excessive secretion of the FGF23 hormone. A NRAS c.182A>G (Q61R) mutation was identified in the lesional skin. The functional outcome was favorable with medical treatment.     

EGFR通路在相关皮肤病发病机制中的研究进展

表皮生长因子受体（EGFR）是一种受体酪氨酸激酶，存在于几乎所有上皮细胞和多种间充质细胞的细胞膜上，EGFR通路的失调可能导致细胞增殖、血管生成、细胞凋亡受损、细胞侵袭性增强，影响银屑病、特应性皮炎等炎症性皮肤病和皮肤鳞状细胞癌、黑素瘤等肿瘤性皮肤病的发生与发展，本文综述了EGFR通路在相关皮肤病发病机制中的研究进展。     

Early excision of congenital melanocytic nevi under tumescent anesthesia and skin expansion by intracutaneous double butterfly sutures

Background: Excision of large congenital melanocytic nevi is recommended because of the risk of malignant transformation and for aesthetic reasons. Our treatment concept includes 1) excision in one or more steps preferably before the age of one year, 2) skin expansion through high‐tension wound closure with intracutaneous double butterfly sutures and 3) performing surgery with tumescent or general anesthesia. Patients and Methods: A retrospective survey was conducted among all parents with children treated for congenital melanocytic nevi in 2004 or 2005 with a maximum age of 6.0 years. The parents were asked to evaluate the trauma associated with their child's surgery and the aesthetic result. Results: Fifty‐nine families were contacted, of whom 51 replied. Forty‐two parents assessed surgery‐associated trauma as light or very light. Thirty‐nine parents rated the aesthetic results as good to very good. Severe complications did not occur. Conclusion: The proposed surgical concept is a safe procedure with good aesthetic results and low surgery‐associated trauma for the child.     

巨大先天性黑素细胞痣恶变并淋巴结转移1例

报告1例巨人先天性黑素细胞痣恶变淋巴结转移，患儿男，14个月，出生后即发现腰骶部有巨人黑素细胞痔，14个月时皮损组织病理检查示，黑素细胞痣恶变并有右侧腹股沟淋巴结转移。     

Reasons for rarity of anal melanocytic naevi

In the last 16 years only seven definite cases of anal melanocytic naevi have been reported in the literature. We describe three new cases, none of which were suspected clinically and were incidentally diagnosed on histological examination of haemorrhoidectomy specimens. The infrequency of these special site flexural melanocytic lesions may be related to changes in the involutionary mechanisms of the anal melanocyte proliferation. However, other factors related to the low detection rates by clinicians and pathologists need also to be considered.     

Dermoscopy is a suitable method for the observation of the pregnancy-related changes in melanocytic nevi

BACKGROUND: It is a common opinion that expansion and darkening in melanocytic nevi may occur during pregnancy. The main problem is that whether it is a usual finding, or it is a condition that requires suspicion about melanoma. OBJECTIVES: It was aimed to find the changes that might occur in the sizes and structures of melanocytic nevi during pregnancy. METHODS: Ninety-seven nevi of the 56 pregnant women in the first trimester were evaluated in the study. The localization and size of the nevi were recorded on a standard body diagram. After clinical examination, dermoscopic analyses were applied. Pattern analyses were done, and total dermoscopy scores (TDS) were calculated by applying ABCD scoring system. All subjects were seen again during the third trimester. RESULTS: There was a statistically significant difference between the mean diameters of nevi in the first and third trimester (P = 0.001). Of nevi whose diameters increased, 10 (50.00%) were localized on the front of body, 6 (30.00%) on the face and neck, 3 (15.00%) on the legs, and 1 (5.00%) on the back. The enlargement in diameters was more significant on the front of the body, but there was no statistically significant difference. Compared according to the pattern analysis, new dot formation was observed only on the structure of six nevi during the last trimester. Four of them were localized on the front of the body. There was statistically significant increase in mean TDS in comparison between the first and third trimesters (P = 0008). CONCLUSIONS: During the pregnancy, widening in diameters and structure changes of nevi may be seen especially on the front of the body. We also think that these findings might be connected with expansion of the skin during pregnancy. Dermoscopic controls are the first choice of method to analyse the nevi since the patient may not recognize these changes.     

Melanocytic nevi clinically simulating melanoma

Melanoma and other benign or malignant pigmented skin tumors can significantly overlap in their clinical and dermoscopical presentations. Thus, pigmented skin lesions may be misdiagnosed in a large number of cases. An extensive review of the published work provides numerous examples of benign lesions mimicking melanoma. Although a number of melanocytic nevi may have been identified as melanomas, information about their clinical appearance is limited. In this report, we present the clinical appearances of two melanocytic nevi on the vulva and the upper extremity that were difficult to diagnose clinically. Detecting melanoma at an early stage is of the utmost importance. However, more attention should be given to the diagnostic accuracy of benign pigmented skin lesions, which otherwise may be diagnosed and treated as melanoma.     

A giant melanocytic nevus treated with combined use of normal mode ruby laser and Q-switched alexandrite laser

We report a combination procedure that can improve the effectiveness of laser removal of giant congenital melanocytic nevi (CMN). A 2-year-old girl with a giant CMN was seen in our outpatient clinic. Histological findings showed a compound nevus without any evidence of malignancy or dysplastic changes. The patient was treated with the normal mode ruby laser and Q-switched alexandrite laser. The lesion was significantly improved in color and cosmetic appearance. Partial hypopigmentation and texture changes were observed. Histological findings showed a marked decrease in the number of junctional melanocytes and the nests in the papillary and reticular dermis. The combined laser treatment is an effective method for the treatment of giant CMN, but further study is warranted to follow-up questions of recurrence and malignant change.     

Proliferative nodule resembling angiomatoid Spitz tumor with degenerative atypia arising within a giant congenital nevus

Proliferative nodules arising within congenital melanocytic nevi often present a diagnostic challenge given a close resemblance to melanoma. Several morphologic variants have been characterized. In difficult cases, ancillary molecular tests can be used to better exclude the possibility of malignant degeneration. Herein, we report a case of an unusual proliferative nodule with overlapping features of angiomatoid Spitz tumor and ancient melanocytic nevus, which demonstrated normal findings on both chromosomal microarray and a gene expression profiling assay.     

Epidermal growth factor-induced matrix metalloproteinase-1 expression is negatively regulated by p38 MAPK in human skin fibroblasts

Background

Many extracellular stimuli, including epidermal growth factor (EGF), are known to induce MMP-1 expression. Recently, several reports have shown that ERK activity plays an important role in EGF-induced MMP-1 expression. However, EGF is also known to activate many signaling pathways in addition to the ERK pathway, but the roles of these pathways during the induction of MMP-1 by EGF are unclear.

Objective

We investigated the role of JNK, p38 MAPK, and PI3K/Akt pathways in EGF-induced MMP-1 expression in human skin fibroblasts. Then, we further explored the inhibitory effect of p38 MAPK pathway on EGF-induced MMP-1 expression and studied the molecular mechanisms involved in the processes.

Methods

Human skin fibroblasts were pretreated with various chemical inhibitors or small interfering RNA (siRNA) at the indicated concentrations and then treated with EGF, TNF-alpha, or IL-1beta for the indicated times. Protein and mRNA levels of various target molecules were assessed by Western blotting and quantitative real-time PCR, respectively.

Results

We found that EGF-induced MMP-1 expression was positively regulated by JNK as well as ERK but negatively regulated by p38 MAPK in human skin fibroblasts. On the other hand, the PI3K/Akt pathway did not significantly affect MMP-1 induction by EGF. Then we found that the inhibition of p38 MAPK pathway specifically increased the MMP-1 expression stimulated by EGF but not by TNF-alpha or IL-1beta, indicating that the effect of p38 MAPK on MMP-1 expression may be stimulus-type specific in human skin fibroblasts. In addition, the inhibitory effect of p38 MAPK on EGF-induced MMP-1 expression was shown to be mainly mediated by p38-alpha MAPK. Our further studies showed that the inhibition of p38 MAPK but not PI3K specifically increased EGF-induced ERK and JNK activations, and that the augmentation of EGF-induced MMP-1 expression by p38 MAPK inhibition was significantly attenuated by inhibiting the activities of ERK and/or JNK.

Conclusions

Our results indicate that EGF-induced MMP-1 expression is differentially regulated by the JNK, p38 MAPK, and PI3K/Akt pathways, and suggest that p38 MAPK negatively regulates EGF-induced MMP-1 expression by suppressing the activations of ERK and JNK.