Characteristics of dermal vascularity in melasma and solar lentigo.

BACKGROUND /PURPOSE: Melasma and solar lentigo (SL) are major benign hyperpigmented lesions, and both have been shown to involve the dermal vasculature. This review discusses current knowledge regarding the clinical characteristics of dermal vascularity in melasma and SL, as well as the results of relevant molecular biological investigations. METHODS: PubMed and Google Scholar were searched in December 2023 to identify articles related to melasma, SL, and the dermal vasculature in these lesions. RESULTS: Vascular morphologies in melasma and SL have been detected by histological and non-invasive methods, including modalities such as optical coherence tomography. Biological studies have indicated that factors secreted from vascular endothelial cells, such as stem cell factor and endothelin-1, can promote melanogenesis. With respect to phototherapy, blood vessel-targeting laser treatments are expected to provide long-term suppression of pigmentation, but this regimen is only effective when dilated capillaries are visible. CONCLUSION: In both melasma and SL, clinical and experimental investigations are revealing the contributions of dermal vascularity to hyperpigmentation. More effective treatment may require identification of hyperpigmentation subtypes. In the future, knowledge of treatment (including phototherapy) is expected to accumulate through reliable and validated non-invasive measurements.

Epidermal turnover and iron metabolism in senile lentigo.

Senile lentigo (SL) is a pigmentary disorder associated with disrupted epidermal turnover. Trace minerals in the skin are known to regulate keratinocyte proliferation and differentiation. To clarify the role of iron in SL, we compared the expression of molecules related to iron metabolism between SL lesion (lesion) and the surrounding normal skin (nonlesion). Our results revealed that proteins involved in iron uptake and utilization such as transferrin receptor 1, iron regulatory protein 1, mitoferrin 1, and divalent metal transporter 1 were expressed in the lower epidermis in the nonlesion, while expression of them was also observed in the upper epidermis in the lesion. Ferroportin (FPN), involved in iron export, was expressed in the upper epidermis in the nonlesion, but was only scarcely expressed in the upper epidermis in the lesion. Hepcidin, which promotes FPN degradation, was expressed in the lower epidermis in the nonlesion; however, its expression was also observed in the upper epidermis in the lesion. These changes in the expression of molecules involved in iron uptake/export/utilization might reflect the altered iron utilization state in SL, resulting in disruption of keratinocyte differentiation and disturbing epidermal turnover. Our results suggest that the metabolism of iron in keratinocytes in SL differs from that in the normal epidermis, and these changes could be associated with the abnormal epidermal turnover and decreased melanin excretion in SL.

Nevus Spilus With Dermatoheliosis: A Histologic Mimicker of Melanoma in Situ at Melanoma Excision Margins.

ABSTRACT: Nevus spilus, or speckled lentiginous nevus, is a relatively common lesion that presents at birth or in early childhood. It consists of a background tan patch, which appears similar to a café au lait macule or lentigo simplex on histology, studded with various types of nevi. Rarely, these nevi can undergo malignant transformation to melanoma. When melanoma develops within a heavily photodamaged nevus spilus, evaluating excision margins may be challenging because the combined histologic features of nevus spilus and severe dermatoheliosis can mimic melanoma in situ. We report a case of an elderly man with extensive sun damage who developed malignant melanoma within an occult nevus spilus, resulting in multiple excisions with false-positive margins.

Steroidogenic Factor-1 Lineage Origin of Skin Lesions in Carney Complex Syndrome.

Carney complex is a rare familial multineoplastic syndrome predisposing to endocrine and nonendocrine tumors due to inactivating mutations of PRKAR1A, leading to perturbations of the cAMP‒protein kinase A signaling pathway. Skin lesions are the most common manifestation of Carney complex, including lentigines, blue nevi, and cutaneous myxomas in unusual locations such as oral and genital mucosa. Unlike endocrine disorders, the pathogenesis of skin lesions remains unexplained. In this study, we show that embryonic invalidation of the Prkar1a gene in steroidogenic factor-1‒expressing cells leads to the development of familial skin pigmentation alterations, reminiscent of those in patients with Carney complex. Immunohistological and molecular analyses, coupled with genetic monitoring of recombinant cell lineages in mouse skin, suggest that familial lentiginosis and myxomas occur in skin areas specifically enriched in dermal melanocytes. In lentigines- and blue nevi‒prone areas from mutant mice and patients, Prkar1a/PRKAR1A invalidation occurs in a subset of dermal fibroblasts capable of inducing, under the influence of protein kinase A signaling, the production of promelanogenic EDN3 and hepatocyte GF signals. Our model strongly suggests that the origin of the typical Carney complex cutaneous lesions is the result of noncell-autonomous promelanogenic activity of a dermal fibroblast population sharing a community of origin with steroidogenic factor-1 lineage.

Eruptive facial lentiginosis-like repigmentation in a patient with longstanding generalized vitiligo without a detectable trigger.

Spontaneous appearance of hyperpigmented macules on chronic vitiligo lesions is a very rare phenomenon, which is described as eruptive lentiginosis. We describe the case of a patient with chronic non-segmental generalized vitiligo who presented with a sudden onset of hyperpigmented macules on depigmented areas of the face. A biopsy showed pigmented basal keratinocytes in the interfollicular epidermis, and immunohisochemistry with anti-SOX10 antibodies showed nuclei of single melanocytes. This case shows that even long-standing depigmented vitiligo lesions may contain functional melanocytes or their precursors.

Newborn infant with congenital lentigines as a manifestation of Carney Complex.

Carney Complex (CNC) is a rare syndrome characterised by skin pigmentation, endocrine over activity and myxomas, with the median age of detection being 20 years. We present a case of CNC diagnosed in infancy after being noted to have multiple lentigines over his face, abdomen, back and thighs at birth. We consider the differential diagnoses of similar cutaneous presentations in the well neonate and review the prognosis and suggested surveillance of patients with CNC.

Five novel mutations in SASH1 contribute to lentiginous phenotypes in Japanese families.

SASH1 has been reported as a causal gene of lentiginous phenotypes with and without heredity, including an autosomal dominant type characterized by lentigines predominantly on sun-exposed areas such as the face and limbs. Recently, cases of dyschromatosis with SASH1 mutations have been reported worldwide; however, only one case has been reported from Japan. Here, we analyzed six Japanese patients who characteristically showed many lentigines on sun-exposed areas, using next-generation sequencing. We identified five novel heterozygous mutations in SASH1 (p.I586M, p.S531Y, p.R644W, p.T525R, and p.S516I) in our patients and their families. The p.R644W substitution identified in two unrelated families was the first mutation located in the sterile alpha motif 1 (SAM1) domain. The degree and location of the lentigines were variable across individuals, even if they shared the same SASH1 mutation. All mutations were predicted to be deleterious by six different algorithms used to evaluate the functional impact of a variation. In addition, immunohistopathological findings and RNA sequencing results suggested that SASH1 mutations were associated with an increase in the number of melanocytes, acceleration of melanogenesis, and upregulated hair keratin expression.

Intraoral atypical lentiginous melanocytic lesion in a pediatric patient.

We present a rare case of intraoral atypical lentiginous melanocytic lesion affecting a pediatric patient, in which the diagnosis of lentiginous junctional melanocytic nevus with cytologic atypia was favored. The main differential diagnosis is lentiginous melanoma, which is a slowly progressing lesion, affecting mainly older adults, and microscopically presenting lentiginous growth pattern of moderately atypical melanocytes, with focal nesting and pagetoid spread. It is strongly recommended that melanocytic lesions showing features of atypical lentiginous growth pattern should be treated with wide excision; however, the impact of these guidelines on pediatric patients needs to be better defined with the report of further cases.

Three-dimensional structure analysis of melanocytes and keratinocytes in senile lentigo.

Senile lentigo or age spots are hyperpigmented macules of skin that commonly develop following long-term exposure to ultraviolet radiation. This condition is caused by accumulation of large numbers of melanosomes (melanin granules) produced by melanocytes within neighboring keratinocytes. However, there is still no consensus regarding the melanosome transfer mechanism in senile lentigo. To date, most pathohistological studies of skin have been two-dimensional and do not provide detailed data on the complex interactions of the melanocyte-keratinocyte network involved in melanosome transfer. We performed a three-dimensional reconstruction of the epidermal microstructure in senile lentigo using three different microscopic modalities to visualize the topological melanocyte-keratinocyte relationship and melanosome distribution. Confocal laser microscopy images showed that melanocyte dendritic processes are more frequently branched and elongated in senile lentigo skin than in normal skin. Serial transmission electron micrographs showed that dendritic processes extend into intercellular spaces between keratinocytes. Focused ion beam-scanning electron micrographs showed that dendritic processes in senile lentigo encircle adjacent keratinocytes and accumulate large numbers of melanosomes. Moreover, melanosomes transferred to keratinocytes are present not only in the supranuclear area but throughout the perinuclear area except on the basal side. The use of these different microscopic methods helped to elucidate the three-dimensional morphology and topology of melanocytes and keratinocytes in senile lentigo. We show that the localization of melanosomes in dendritic processes to the region encircling recipient keratinocytes contributes to efficient melanosome transfer in senile lentigo.

Reflectance confocal microscopy: Diagnostic criteria of common benign and malignant neoplasms, dermoscopic and histopathologic correlates of key confocal criteria, and diagnostic algorithms.

Reflectance confocal microscopy (RCM) is a high-resolution, noninvasive tool that is currently approved by the US Food and Drug Administration for obtaining and interpreting images of the skin and cutaneous neoplasms with the goal of decreasing unnecessary biopsy procedures in patients with benign lesions. The second article in this continuing medical education series focuses on identifying key criteria for the diagnosis of common skin cancers-melanoma, basal cell carcinoma, and squamous cell carcinoma. We contrast these findings with RCM features of common benign lesions-melanocytic nevi, solar lentigo, seborrheic keratosis, lichen planus-like keratosis, and sebaceous hyperplasia. We also correlate the dermoscopic and histopathologic findings with the RCM features.

Cutaneous Photoaging: A Notable Pattern of Distribution of Lentigines on the Face.

Importance: Facial lentigines are a common patient complaint encountered in general and cosmetic dermatology practices. Lentigines are a marker of photoaging and understanding their distribution will provide insight into the aging process in order to better counsel patients. Objectives: To compare the relative distribution of lentigines in facial cosmetic subunits. Methods: We reviewed clinical photographs of patients receiving Alexandrite laser treatment for facial lentigines during the time period 11/1/2017-12/1/2018. Individual lentigines were plotted for each patient into one of 21 aesthetic units. A "heat map" was created to compare the relative density of these lesions. Results: Grouped peripheral cosmetic subunits contained more lentigines compared to grouped central cosmetic units. The mean number of lentigines in the central units was 0.60 and in the peripheral units was 0.85. This finding was statistically significant with a p value of 0.0001. J Drugs Dermatol. 2020;19(7): doi:10.36849/JDD.2020.5193.

Clinicopathological diversity and outcome of longitudinal melanonychia in children and adolescents: analysis of 35 cases identified by excision specimens.

AIMS: Longitudinal melanonychia in paediatric patients often represents a difficult diagnostic challenge, and studies emphasising its clinical and histopathological features are limited due to its low incidence in childhood. METHODS AND RESULTS: We retrospectively analysed 35 paediatric cases identified by excision specimens on their clinicopathological features, and performed fluorescence in-situ hybridisation on 13 available cases. Fingernails (77.1%) were more likely to be affected. Total melanonychia and Hutchinson's sign were observed in 10 (28.6%) and 14 (40.0%) cases, respectively. Nail dystrophy at diagnosis was present in five cases. After complete excision of the lesions, four patients relapsed during follow-up (mean = 38 months). Seventeen cases were diagnosed as lentigines and 18 as naevi, among which 11 cases were categorised as lentigines/naevi with atypical melanocytic hyperplasia. Mild-to-moderate nuclear atypia, confluency of melanocytes, focal pagetoid spread and peri-ungual skin involvement were found in 25.7% (9 of 35), 40.0% (14 of 35), 40.0% (14 of 35) and 40.0% (14 of 35) of cases, respectively. Thirteen cases tested by fluorescence in-situ hybridisation showed no copy number aberration at the probed loci. There was a statistically significant difference in the following features between patients aged less and more than 10 years (P < 0.05): cytomorphology, mild-to-moderate nuclear atypia, confluency of melanocytes, focal pagetoid spread and melanocyte count. CONCLUSIONS: Some concerning clinicopathological characteristics, which are signs indicative of melanoma in adults, are not uncommon in paediatric longitudinal melanonychia, especially in patients aged ≤ 10 years. Owing to the extremely low incidence of melanoma in paediatric longitudinal melanonychia, in most circumstances a more conservative clinical management strategy should be adopted.

Epidermal keratin 5 expression and distribution is under dermal influence.

Human skin melanin pigmentation is regulated by systemic and local factors. According to the type of melanin produced by melanocytes, the transfer and degradation of melanosomes differ, thus accounting for most variations between ethnicities. We made the surprising observation that in a drastically changed environment, white and black phenotypes are reversible since Caucasian skin grafted onto nude mice can become black with all black phenotypic characteristics. Black xenografts differed essentially from other grafts by the levels of epidermal FGF-2 and keratin 5. In vitro analysis confirmed that FGF-2 directly regulates keratin 5. Interestingly, this phenomenon may be involved in human pathology. Keratin 5 mutations in Dowling-Degos Disease (DDD) have already been associated with the pheomelanosome-eumelanosome transition. In a DDD patient, keratin 5 was expressed in the basal and spinous layers, as observed in black xenografts. Furthermore, in a common age-related hyperpigmentation disorder like senile lentigo (SL), keratin 5 distribution is also altered. In conclusion, modulation of keratin 5 expression and distribution either due to mutations or factors may account for the development of pigmentary disorders.