A study of dermal melanophages in childhood nevi. Reassessing so-called "pigment incontinence".

In inflammatory dermatoses, dermal melanophages (MLP) are ascribed to "pigment incontinence," with melanin "dropping down" from the epidermis. Although this is analogous to the "dropping down" of melanocytic nevus cells (Abtropfung), MLP in ordinary nevi have not been systematically studied-so "pigment incontinence" may not apply to MLP in nevi. A total of 31 childhood nevi identified by pediatricians and family practitioners were evaluated for the distribution of MLP. We tested the hypothesis that a dermal origin of the melanin in MLP is more likely than dropping down from the epidermis. In our cohort, 90.3% (28/31) of childhood nevi had dermal MLP, a significantly higher frequency, compared to 31/60 ordinary adult nevi (P < 0.0001). Superficial dermis was the most common location (P < 0.001). However, only six specimens had MLP restricted to the superficial dermis, significantly less than predicted by the theory that melanin drops down from the epidermis (P < 0.00001). We also evaluated perivascular MLP, since nerves run together with vessels in neurovascular bundles (NVB), and it has been showed that precursors of melanocytes migrate from the neural crest to the skin as nerve sheath stem cells. Superficial NVB MLP correlated with deep NVB bundle MLP (P < 0.05), suggesting that NVB MLP represent "tombstones" for superficial and deep dermal nevus cells. Deep dermal, deep NVB, and deep periadnexal MLP may be valid biological criteria for diagnosis of congenital type (prenatal) nevi. Viewing prenatal nevi in children as a neurocristopathy fits a major principle of pediatric pathology: childhood diseases should be studied and understood based on what happens during tissue development.

Nevos melanocíticos palmoplantares: correlación dermatoscópica e histopatológica / Melanocytic nevi in palms and soles: dermatoscopy and histopathogic correlation

Introducción. El nevo se define como malformación circuscripta de los tegumentos, disembrioplásicos o hereditarios, transitorios o permanentes. Su importancia radica en su conocida relación casual con el melanoma. Un porcentaje de los melanomas proviene de nevos melanocíticos preexistentes. Por este motivo es importante distinguir aquellos que tienen alto riesgo de modificarse. La dermatoscopía es una técnica no invasiva, especialmente útil en la distinción de lesiones pigmentadas melanocíticas y no melanocíticas y, dentro de las primeras, entre nevos y melanoma. La piel volar presenta características especiales que producen imágenes dermatoscópicas peculiares. Objetivos, Descripción de los patrones dermatoscópicos acrales y frecuencia de presentación, correlación dermatoscópica e histopatológica de los nevos palmoplantares. Evaluar la concordancia dermatoscópica entre el investigador y un observador independiente. Material y métodos. Estudio observacional, prospectivo, transversal y analítico de pacientes con diagnóstico clínico de nevos melanocíticos palmoplantares. Se realizó en el hospital Privado de Córdoba entre mayo 2006 y abril 2007. Variables a estudiar: edad, sexo, antecedentes personales, fototipo, localización, patrón dermatoscópico y patrón histológico. Todos los pacientes fueron observados por el investigador y un observador independiente. Se realizó dermatoscopía y cirugía de todos los nevos. Resultados. En 74 pacientes, promedio de edad 32 años, con fototipo principal el II, se detectaron 83 nevos melanocíticos acrales. El patrón dermatoscópico más frecuente fue el paralelo del surco, y el patrón histológico fue el compuesto. La concordancia dermatoscópica fue excelente, calculada con el valor Kappa. Conclusión. Los patrones dermatoscópicos hallados en nuestro estudio coinciden con la literatura consultada.

Introduction.Nevus is defi ned as a circumscribed malformation, whichcan be dysembryoplastic or hereditary, temporary or permanent, of the teguments. Nevi are important given their well-known causal relationship with melanoma, a percentage of which results from preexisting melanocytic nevi. The refore, it is important to distinguish nevi which run the risk of undergoing a change. Dermoscopy is a non-invasive technique particularly useful to distinguish pigmented melanocytic lesions, which can be nevior melanomas, and pigmented non-melanocytic lesions. Volar skin exhib-its special dermoscopic features which produce particular images. Objectives. To describe the acral dermoscopic patterns, the frequency with which they occur and the dermoscopic and histopathologic correlation of nevi of the palms and soles, and to assess the dermatoscopic agreement between the investigator and an independent observer.Material and Methods. Observational, prospective, transverse and analytical study of patients with the clinical diagnosis of melanocytic nevi of the palms and soles. The study was conducted at Hospital Privado, in Córdoba, from May 2006 through April 2007. The variables to be studied were age, sex, personal history, phototype, location and dermoscopic and histologic patterns. All the patients were observed by the investigator as well as an independent observer, and dermoscopy and surgery were performed in all nevi. Results. 83 acral melanocytic nevi were detected in 74 patients with amean age of 32 and phototype II. The most frequent dermoscopic pat-tern was the parallel furrow pattern and the most frequent histologic pattern was the compound one. The dermoscopic agreement, calculated with Kappa values, was excellent. Conclusion.The dermoscopic patterns found in our study is consistedwith the literature reviewed.

Neurotized nevi of the oral mucosa: an immunohistochemical and ultrastructural analysis of nevic corpuscles.

BACKGROUND: Nevic corpuscle (NC), a stacked lamellar structure reminiscent of Meissner corpuscle, is frequently observed in dermal melanocytic nevi. Although the heading 'neurotized' is classically used for these nevi, the exact neural nature of NC has been a topic of considerable debate. Neurotized nevi have received little attention in the dental literature, and there was no information on NC in oral melanocytic nevi. METHODS: Six cases of oral intramucosal nevi with a significant number of NC (two completely and four partially neurotized nevi) were examined immunohistochemically and ultrastructurally. RESULTS: NC was composed of closely piled laminar cells devoid of visible melanin. NC and associated spindle nevus cells were immunopositive for S-100 protein but negative for HMB-45, myelin basic protein and epithelial membrane antigen. Within NC, no reactivity for neurofilament protein, protein gene product 9.5 or peripherin was evident. Numerous CD34-positive dendritic cells were located between nevus cells and often encircled NC. Ultrastructurally, NC consisted of concentrically layered elongated cells with a slender lamellated cytoplasm rich in thin filaments and pinocytotic vesicles. Their cytoplasmic processes were focally covered by external basal lamina and continuous to spindle nevus cells. Occasional NC cells contained a few melanosomes. There was no interposed axon in NC. CONCLUSIONS: Despite the close resemblance to Meissner corpuscle, NC showed no axonal supply. NC cells lacked terminal Schwannian differentiation and appeared to be modified melanocytes with some perineurial ultrastructural characteristics. The presence of CD34-positive cells, presumably corresponding to endoneurial fibroblasts, further supports an organizational relationship of NC and peripheral nerve sheath elements.

Nevo blanco esponja: revisión de la literatura y presentación de tres casos / White sponge nevus: review of the literature and report of three cases

El nevo blanco esponja (NBE) es una rara afección benigna, de naturaleza hereditaria autosómica dominante, que involucra la mucosa bucal y menos frecuentemente la nasal, esofágica, genital y rectal. Es un defecto de la queratina ocasionado por una mutación del gen codificante, que afecta el epitelio pavimentoso estratificado no queratinizado que reviste la mucosa bucal. Si bien su fisiopatología no está totalmente aclarada, la distribución y naturaleza de las lesiones en las mucosas sugieren que la mutación de la queratina 4 (K4) y/o queratina 13 (K13) serían las responsables de esta entidad. Se presentan tres nuevos casos, describiendo las alteraciones clínicas observadas en la mucosa bucal, sus aspectos histopatológicos y diferentes terapéuticas (AU)

Quantitative in situ evaluation of telomeres in fluorescence in situ hybridization-processed sections of cutaneous melanocytic lesions and correlation with telomerase activity.

BACKGROUND: Telomere length is correlated with cellular ageing and immortalization processes. In some human cancers telomere length measurement has proved to be of diagnostic and prognostic value. Results comparable with the traditional terminal restriction fragment length determination by Southern blotting have been obtained in metaphase and interphase cells in some studies by fluorescence in situ hybridization (FISH) analysis; FISH additionally allows for the quantification of telomeres at the cellular level. OBJECTIVES: In this study, 32 melanocytic lesions were analysed by FISH, aiming at investigating possible telomere differences among various benign and malignant lesions and correlation with telomerase activity (TA) level. METHODS: FISH was performed on paraffin sections from six common naevi, eight Spitz naevi, 12 melanomas, six melanoma metastases and nine control samples of normal skin. Telomere mean maximum diameter (Feret max), area and number per nuclear area were calculated by image analysis on fluorescent images elaborated through KS400 and in situ imaging system (ISIS) for FISH analysis programs. Mean TA level was also calculated in all lesions and correlated with telomere parameters. RESULTS: Telomere number per nuclear area was significantly lower in melanomas and metastases than in benign common and Spitz naevi and in control skin (7 small middle dot24 +/- 3.3; 6.11 +/- 3 vs. 14.46 +/- 5.6; 16.92 +/- 7.8; and 12.59 +/- 3.4, respectively; P < 0 .001). No significant differences were found for the other telomere parameters. In common and Spitz naevi, telomere number was positively correlated with Feret max (P = 0.046 and P < 0.0001, respectively). TA was significantly higher in melanomas and metastases than in the other groups (70.18 +/- 25.2; 105.07 +/- 30 vs. 2.16 +/- 2.4; 2 .99 +/- 2.1; 2 +/- 1.2, respectively; P< or = 0. 001) and it was inversely correlated with telomere number per nuclear area in melanomas (P = 0.0041). No other significant correlations were found. CONCLUSIONS: Encouraging results have been obtained from quantitative telomere evaluation in the diagnosis of melanocytic lesions, although an analysis of a larger number of cases would be necessary to provide more reliable data. An extreme shortening of some telomeres probably results in the decrease of telomeric signals and the lower mean number of detectable telomeres in melanomas and metastases. In melanomas, telomere number per nuclear area is also inversely correlated with TA levels. Quantitative FISH of melanocytic lesions could give more specific information at the cellular level in telomere and telomerase fields of investigation.

Discriminant analysis of image karyometric variables in benign and malignant melanocytic skin lesions.

OBJECTIVE: To perform a quantitative analysis to identify which of 7 nuclear morphometry-related variables are of diagnostic value in distinguishing benign from malignant melanocytic skin lesions. STUDY DESIGN: At the Institute of Pathology, University of Nis, formalin-fixed, paraffin-embedded skin biopsies from 23 cases of benign nevi (18 intradermal and 5 junctional) and 25 cases of primary nodular malignant melanomas were retrieved. Specimens were routinely stained with hematoxylin and eosin and analyzed using a computer-assisted interactive image analysis system. Nuclear area, equivalent diameter, volume of equivalent sphere, perimeter, mean chord, circularity and integrated optical density were estimated after manual editing of binary images. RESULTS: In univariate analysis, 6 features were found to be significantly different between the benign and malignant groups (P < .0001); all measured nuclear variables (except circularity) were higher in malignant melanomas. No significant differences were found among lesions with respect to nuclear shape. Using discriminant function analysis, a correct diagnosis was achieved in 95.8% of benign nevi cases and 84.0% of malignant melanoma cases. The best discriminant variable was nuclear area. CONCLUSION: Image analysis is diagnostically relevant to the evaluation of melanocytic lesions of the skin. The area of the nucleus appeared to have potential for differentiating benign from malignant tumors and can be estimated in the course of routine histology.

Hair follicle nevus occurring in frontonasal dysplasia: an electron microscopic observation.

We report a rare hair follicle nevus that occurred in a three-month-old Japanese boy with mild frontonasal dysplasia. It had been present since birth. Histologically, numerous tiny vellus hair follicles were found within the dermis. The constituent cells of these follicles showed the features of follicular germ cells under the electron microscope. The fibroblasts around the follicles were active and merged with the colloid substance. Many myofibroblasts were found in a collagenous stroma in the atrophic lesion of the frontonasal dysplasia.

Nevo epidermico asociado a queratosis pilar: a proposito de un caso / Epidermic nevus associate by pillar keratosic: a purpose of one case

Se presenta un paciente de 15 años de edad, quien presenta un nevo epidérmico hiperplásico, rodeado por áreas de queratosis pilar. Además presenta un nevo spilus en espalda. Todos los exámenes tendientes a detectar la presencia de alteraciones neurológicas, oftalmológicas u óseas, fueron negativas, se realiza tratamiento co 5 fluoracilo tópico asociado a tretinoina local, con buena respuesta

Nevo epidermico asociado a queratosis pilar: a proposito de un caso / Epidermic nevus associate by pillar keratosic: a purpose of one case

Se presenta un paciente de 15 años de edad, quien presenta un nevo epidérmico hiperplásico, rodeado por áreas de queratosis pilar. Además presenta un nevo spilus en espalda. Todos los exámenes tendientes a detectar la presencia de alteraciones neurológicas, oftalmológicas u óseas, fueron negativas, se realiza tratamiento co 5 fluoracilo tópico asociado a tretinoina local, con buena respuesta(AU)

Expression of fibroblast growth factor receptors in naevus-cell naevus and malignant melanoma.

In a previous study, we showed by immunohistochemical analysis that basic fibroblast growth factor (bFGF) is expressed strongly and homogeneously in naevus-cell naevus (NCN), while that in malignant melanoma (MM) is heterogeneous and sometimes non-existent. In order to elucidate the role of bFGF in these pigmented tumours, the expression of its receptors must be determined. In this study, we performed an immunohistochemical analysis of FGF receptors 1, 2 and 3 (FGFR-1, FGFR-2 and FGFR-3, respectively) in NCN and MM and compared their expression and localization with those of bFGF. The expression of bFGF and its three receptors was also examined in melanoma cell lines. None of the 10 NCN that showed strong, homogeneous staining for bFGF expressed FGFR-1 or FGFR-3 proteins; six weakly expressed FGFR-2 protein. Ten primary and 10 metastatic MM showed heterogeneous expression for the three receptors, with larger populations of FGFR-3-negative cells in the primary than in the metastatic tumours. Western blot analysis showed homogeneous expression of bFGF protein in all four melanoma cell lines tested, while FGFR proteins had a heterogeneous distribution in the different cell lines. Cultured NCN and normal melanocytes showed no immunoreactive band for FGFR-1 protein, the only protein tested. Our results suggested that tumour-derived bFGF is involved in melanoma formation through an autocrine mechanism, but is involved mostly through a paracrine or other mechanisms in NCN.

c-KIT receptor expression in cutaneous malignant melanoma and benign melanotic naevi.

To investigate the role of c-KIT receptor in melanocytic tumour development and progression, we analysed the expression and localization of c-KIT by immunohistochemistry and Western blotting. In contrast to the positive staining shown by melanocytes and naevus cells in the epidermis of common naevi (n=20), all dysplastic naevi (n=13) were negative, as were dermal melanocytic cells of blue naevi (n = 4) and common naevi (n = 26). Three out of four superficial spreading melanomas lost c-KIT expression both in the epidermal and dermal parts, while nodular melanomas showed no expression of c-KIT except in partially positive cells, and six out of seven metastatic melanomas were negative. In acral lentiginous melanomas (n = 8), in contrast to other types of melanoma, all cases with melanoma cells growing basally in the epidermis showed strong c-KIT positivity, but melanoma cells growing at the upper layers of the epidermis and vertically into the dermis lost c-KIT expression. Using the Western blot method on cultured pigment cells, human epidermal melanocytes, junctional naevus cells and one out of three metastatic melanoma cell lines showed 125 and 145 kDa bands corresponding to c-KIT, whereas dermal naevus cells did not. These results suggest that dysplastic naevi are distinct from ordinary naevi in terms of c-KIT expression and that basally growing cells in acral lentigenous melanomas could be at an initial stage of tumour progression, before c-KIT loss occurs.

Abnormal melanosomes: ultrastructural markers of melanocytic atypia.

To identify possible ultrastructural markers of melanocytic atypia, a quantitative ultrastructural study was made of melanocytes found at the dermal-epidermal boundary of normal skin and in benign, premalignant, and malignant melanocytic lesions. There was a significant increase (p < 0.05) in the number of melanosomes per melanocyte in the premalignant and malignant lesions compared with the number observed in the benign lesions. There was a significantly higher number (p < 0.05) of abnormal melanosomes (with irregularities in the laminar matrix or with a granular or clumpy matrix) in the premalignant and malignant lesions, which suggests that the presence of a high percentage of abnormal melanosomes might act as a useful ultrastructural marker in the diagnosis of melanocytic atypia.

Genetic and clinical mosaicism in a type of epidermal nevus.

BACKGROUND: Many skin disorders are characterized by a mosaic pattern, often with alternating stripes of affected and unaffected skin that follow the lines of Blaschko. These nonrandom patterns may be caused by a postzygotic mutation during embryogenesis. We studied the genetic basis of one such disorder, epidermal nevus of the epidermolytic hyperkeratotic type. Epidermolytic hyperkeratosis is an autosomal dominant blistering skin disease arising from mutations in the genes for keratin (K) 1 and 10. The offspring of patients with epidermal nevi may have generalized epidermolytic hyperkeratosis. METHODS: We studied the K1 and K10 genes in blood and in the keratinocytes and fibroblasts of lesional and nonlesional skin from three patients with epidermal nevi and four of their offspring with epidermolytic hyperkeratosis. RESULTS: In the patients with epidermal nevi, point mutations in 50 percent of the K10 alleles of epidermal cells were found in keratinocytes from lesional skin; no mutations were detected in normal skin. This mutation was absent or underrepresented in blood and skin fibroblasts. In the offspring with epidermolytic hyperkeratosis, the same mutations as those in the parents were found in 50 percent of the K10 alleles from all cell types examined. CONCLUSIONS: Epidermal nevus of the epidermolytic hyperkeratotic type is a mosaic genetic disorder of suprabasal keratin. The correlation of mutations in the K10 gene with lesional skin and the correlation of the normal gene with normal skin provide evidence that genetic mosaicism can cause clinical mosaicism.

PCNA expression and nucleolar organizer regions in malignant melanoma and nevus cell nevus.

The histogenesis of malignant melanoma with particular reference to the role of melanocytic nevus is still controversial in oncological pathology. In order to differentiate between the proliferative activity of malignant melanomas and benign melanocytic tumors, immunohistochemical analysis was carried out. We used monoclonal antibody PC10 to identify the Proliferating Cell Nuclear Antigen (PCNA), a highly conserved 36 KD acidic nuclear protein which correlates with cell proliferation, and the AgNOR method to stain the Nucleolar Organizer Regions (NORs) whose number and configurations may reflect protein synthesis activity. 47 cases of primary melanoma, 63 metastatic melanoma lesions, and 23 cases of nevi are included in this study. Spitz nevi showed a higher index of cell proliferation compared with other common benign nevi but a much lower index compared with malignant melanoma cells. The metastatic lesions of malignant melanomas had a higher index of proliferation and activity of cells than the primary lesions. Skin-metastatic lesions had higher indexes of cell proliferation and NOR activity than lymph node-metastatic lesions. These results support the idea that metastatic melanoma cells are derived from a more advanced stage of tumor progression. These data suggest that the combination of PCNA and AgNOR is an useful marker for differentiating benign melanocytic tumors from malignant melanomas.