Proliferation Of Melanocytes Research Articles

PRAME Immunohistochemical Expression and TERT Promoter Mutational Analysis as Ancillary Diagnostic Tools for Differentiating Proliferative Nodules From Melanoma Arising in Congenital Nevi.

Proliferative nodules (PNs) are benign melanocytic proliferations that typically develop within congenital melanocytic nevi. These tumors have overlapping histological features with melanoma. Ancillary immunohistochemistry and genomic sequencing are often used in diagnostically challenging cases. To assess the utility of preferentially expressed antigen in melanoma (PRAME) immunoreactivity and telomerase reverse transcriptase (TERT) promoter mutation analysis in distinguishing PNs from melanoma arising in congenital nevi cases. Twenty-one PNs and 2 melanomas arising in congenital nevi were immunohistochemically stained with PRAME. Cases with adequate tissue were also assessed for TERT promoter mutations through sequencing studies. The positivity rates in the PN cases were compared with those of the melanomas. Two of 21 PN cases were diffusely positive for PRAME (≥75% of the tumor cells positive). Two of 2 melanomas arising in congenital nevus cases were also diffusely PRAME positive. The difference was statistically significant using a Fisher exact test. None of the tumors harbored TERT promoter mutations. PRAME immunohistochemical marker may have diagnostic value in distinguishing diagnostically challenging PNs from melanoma, but diffuse expression is not specific for melanoma.

MicroRNA-370-5p inhibits pigmentation and cell proliferation by downregulating mitogen-activated protein kinase kinase kinase 8 expression in sheep melanocytes

In mammals, microRNAs (miRNAs) play key roles in multiple biological processes by regulating the expression of target genes. Studies have found that the levels of miR-370-5p expression differ significantly in the skins of sheep with different hair colors; however, its function remains unclear. In this study, we investigated the roles of miR-370-5p in sheep melanocytes and found that the overexpression of miR-370-5p significantly inhibited cell proliferation (P<0.01), tyrosinase activity (P=0.001) and significantly reduced (P<0.001) melanin production. Functional prediction revealed that the 3´-untranslated region (UTR) of MAP3K8 has a putative miR-370-5p binding site, and the interaction between these two molecules was confirmed using luciferase reporter assays. In situ hybridization assays revealed that MAP3K8 is expressed in the cytoplasm of melanocytes. The results of quantitative RT-PCR and Western blotting analyses revealed that overexpression of miR-370-5p in melanocytes significantly inhibits (P<0.01) MAP3K8 expression via direct targeting of its 3´ UTR. Inhibition of MAP3K8 expression by siRNA-MAP3K8 transfection induced a significant inhibition (P<0.01) of melanocyte proliferation and significant reduction (P<0.001) in melanin production, which is consistent with our observations for miR-370-5p. Target gene rescue experiments indicated that the expression of MAP3K8 in melanocytes co-transfected with miR-370-5p and MAP3K8-cDNA (containing sites for the targeted binding to miR-370-5p) was significantly rescued (P≤0.001), which subsequently promoted significant increases in cell proliferation (P<0.001) and melanin production (P<0.01). Collectively, these findings indicate that miR-370-5p plays a functional role in inhibiting sheep melanocyte proliferation and melanogenesis by downregulating the expression of MAP3K8.

The PER3rs772027021 SNP induces pigmentation phenotypes of dyschromatosis universalis hereditaria.

Dyschromatosis universalis hereditaria (DUH) is a pigmentary genodermatosis characterized by a mixture of hyperpigmented and hypopigmented macules distributed randomly over the body. Although Sterile Alpha motif- and SH3 domain-containing protein 1 (SASH1) and ATP-binding cassette subfamily B, member 6 (ABCB6) have been identified as causative genes for this disorder, some cases involve unknown pathogenic genes. In this study, whole-exome sequencing, data analysis, and Sanger sequencing were utilized for a four-generation extended Chinese family with DUH. A single-nucleotide polymorphism (SNP) (c. 517C > T (p.P173S), rs772027021) variant in exon 5 of Period Circadian Regulator 3 (PER3) (NM_001289861) was detected in each affected individual of the DUH family; the c. 517C > T SNP of PER3 (PER3rs772027021 SNP) and a novel mutation in exon 14 of SASH1 (c. 1574C > G (p.T525R)) were both found in the proband. The affected individuals carrying PER3rs772027021 SNP in this family demonstrated mild-pigmented phenotypes compared to those of the proband carrying PER3rs772027021 SNP and SASH1 T525R mutation. Increased melanin synthesis was induced by PER3rs772027021 SNP in the melanocytes of affected epithelial tissues. Mutated SASH1 or PER3rs772027021 SNP alone or cooperation of mutation of SASH1 and PER3rs772027021 SNP synergistically led to increased melanin synthesis and enhanced proliferation of melanoma cells in vitro. We also phenotypically characterized a commercially available zebrafish mutant line harboring the PER3rs772027021 SNP to induce melanocyte proliferation in vivo. Our results are the first to reveal that this PER3 SNP may be pathogenic for a novel DUH subtype with mild hyperpigmented and/or hypopigmented phenotypes and that mutation of SASH1 and PER3 cooperatively promotes hyperpigmentation phenotypes. KEY MESSAGES: PER3rs772027021 SNP is identified to be associated with hyperpigmentation and/or hypopigmentation phenotype and the novel pathogenic variant of PER3rs772027021 SNP probably contributed the pathogenesis of DUH. SASH1T525R mutation is confirmed to associate with DUH. A novel autosomal dominant inheritance DUH subtype with mild pigmentated phenotypes is caused by the PER3rs772027021 SNP.

The Complex Interplay between Nevi and Melanoma: Risk Factors and Precursors.

One effort to combat the rising incidence of malignant melanoma is focused on early detection by the clinical and dermoscopic screening of melanocytic nevi. However, the interaction between nevi, which are congenital or acquired benign melanocytic proliferations, and melanoma is still enigmatic. On the one hand, the majority of melanomas are thought to form de novo, as only a third of primary melanomas are associated with a histologically identifiable nevus precursor. On the other hand, an increased number of melanocytic nevi is a strong risk factor for developing melanoma, including melanomas that do not derive from nevi. The formation of nevi is modulated by diverse factors, including pigmentation, genetic risk factors, and environmental sun exposure. While the molecular alterations that occur during the progression of a nevus to melanoma have been well characterized, many unanswered questions remain surrounding the process of nevus to melanoma evolution. In this review, we discuss clinical, histological, molecular, and genetic factors that influence nevus formation and progression to melanoma.

Stardust Pattern as Evolution of Pigmented Spitz Nevi During Childhood.

Spitz nevi (SN) are benign melanocytic proliferations frequently occurring in children. Some pigmented SN with a starburst pattern evolve into the "stardust" one, which is characterized by a central, black to gray, hyperpigmented area and remnants of a brown network at the periphery. These dermoscopy changes are often the first alert to induce excision. The aim of this study is to enlarge the case series of stardust SN in children, in order to increase confidence with this new dermoscopic pattern and reduce unnecessary excisions. This retrospective observational study was conducted with SN cases received from IDS members. The inclusion criteria were: clinical and/or histopathologic diagnosis of Spitz naevus with starburst appearance in children <12 years old, availability of a dermoscopic image at baseline and after follow-up of at least 1 year, availability of patient data. The dermoscopic images and their changes over time were assessed by three evaluators in consensus. 38 SN were enrolled, with a median age of 7 years and a median FUP duration of 15,5 months. Comparing the evolution with time of FUP, no significant differences were found between growing and involuting lesions in terms of patient age and sex, location and palpability of lesions. The long follow-up reported in our study could really support the concept of benignity of changing SN. A conservative approach is acceptable for nevi showing the stardust pattern, because it may be considered a physiological evolution of pigmented Spitz nevus, and urgent surgeries could be avoided.

A rare case of esophageal melanocytosis – a case report

Esophageal melanocytosis is a rare but benign clinicopathologic entity, often presenting incidentally, with a reported incidence in 0.07% to 2.1% of gastrointestinal endoscopies. It is characterised by a non-atypical melanocytic proliferation and increased melanin deposition in the esophageal mucosa. We report a 71-year-old female who underwent oesophagogastroduodenoscopy for a progressive 1-year history of dysphagia and reflux symptoms. Endoscopically, blackish hyperpigmented spots were noted along the lower oesophagus.

Concentration-dependent stimulation of melanin production as well as melanocyte and keratinocyte proliferation by melatonin in human eyelid epidermis.

It remains unclear how the multifunctional indoleamine neurohormone, melatonin, alters melanin production and melanocytes within intact human epidermis under physiologically relevant conditions. In the current pilot study, we aimed to clarify this in long-term organ-cultured, full-thickness human eyelid skin, selected for its clinically recognized sensitivity to pigmentation-modulatory hormones. Warthin-Starry histochemistry showed that 100 μM melatonin significantly increased epidermal melanin content and melanocyte dendricity after 6 days of organ culture, even though tyrosinase activity in situ was inhibited, as assessed by quantitative immunohistomorphometry. While the higher melatonin dose tested here (200 μM) did not change epidermal melanization, but again inhibited tyrosinase activity, it increased the number and proliferation of both gp100+ epidermal melanocytes and keratinocytes as well as protein expression of the premelanosomal marker, gp100, ex vivo. Contrary to most previous studies, these eyelid skin organ culture results suggest that long-term melatonin application exerts overall stimulatory, dose-dependent effects on the epidermal pigmentary unit within intact human skin, which appear surprisingly tyrosinase-independent. While these provocative preliminary findings require further work-up and independent confirmation, they encourage one to systematically explore whether prolonged melatonin therapy can (re-)stimulate melanogenesis and increase the pool/activity of epidermal melanocytes in hypopigmented skin lesions.

BILATERAL DIFFUSE UVEAL MELANOCYTIC PROLIFERATION MISTAKEN FOR NIVOLUMAB-INDUCED VOGT-KOYANAGI-HARADA DISEASE-LIKE SYNDROME.

To describe a case of bilateral diffuse uveal melanocytic proliferation (BDUMP) that was mistaken for nivolumab-induced Vogt-Koyanagi-Harada disease-like syndrome. We present the case of a 58-year-old white man with metastatic renal clear cell carcinoma for which he was palliatively treated with IV nivolumab immunotherapy. The patient developed subacute onset of blurry vision and gray spots in the visual fields of both eyes, macular subretinal fluid, thickening of the retinal pigment epithelium, and swollen optic nerve heads. Differential diagnosis included nivolumab-induced Vogt-Koyanagi-Harada disease-like syndrome, and the patient was initially treated with steroids, which gave no improvement. Investigation showed the development of dark-gray patches in the peripheral retina of both eyes and cataract, which prompted reevaluation of the diagnosis, deeming BDUMP most likely. The patient was successfully treated with plasmapheresis. The initial presentation of the case was incorrectly diagnosed as nivolumab-induced Vogt-Koyanagi-Harada disease-like syndrome. On repeat studies of the patients' symptoms and imaging, we concluded we had missed signs of BDUMP. The diagnosis BDUMP was missed in the first evaluation. We present this case to discuss the similarities and differences between this disease and nivolumab-induced Vogt-Koyanagi-Harada disease-like syndrome. More importantly, we want to highlight that reevaluation of the diagnosis on worsening of a disease was key in this unusual case.

Review: The Key Factors to Melanomagenesis.

Melanoma is the most dangerous form of skin cancer that develops from the malignant transformation of the melanocytes located in the basal layer of the epidermis (cutaneous melanoma). Melanocytes may also be found in the meninges, eyes, ears, gastrointestinal tract, genito-urinary system, or other mucosal surfaces (mucosal melanoma). Melanoma is caused by an uncontrolled proliferation of melanocytes, that at first may form a benign lesion (nevogenesis), but in time, it may transition to melanoma, determining what it is named, melanomagenesis. Some tumors may appear spontaneously (de novo melanoma) or on preexisting lesions (nevus-associated melanoma). The exact cause of melanoma may not be fully understood yet, but there are some factors that initiate and promote this malignant process. This study aims to provide a summary of the latest articles regarding the key factors that may lead to melanomagenesis. The secondary objectives are to reveal the relationship between nevi and melanoma, to understand the cause of "de novo" and "nevus-associated melanoma" and highlight the differences between these subtypes.

Rapidly fatal metastatic melanoma arising from a congenital nevus in a young female

Melanoma is an aggressive and potentially fatal tumor of melanocytic origin. It may occur at any age yet more rarely at a young age. Melanomas in young patients have overall a more favorable prognosis than in older. However, progression to the metastatic stage and the death of the patient are not exceptional. One of the major risk factors for the development of melanoma in children and young adults is the congenital melanocytic nevus (CMN) [3]. The risk of malignant transformation of all congenital nevi ranges from 0.05% to 10.7%. The risk of malignant degeneration is correlated with size and location [4]. The size of the CMN above 40 cm as well as the presence of satellite nevi and the location in the trunk seem to increase the risk of developing MM. The role of surgical removal in inducing melanomas is controversial. In anatomopathology, melanomas arising from CMNs are usually located in the dermis and hypodermis, while melanocytic proliferation in a melanoma without a CMN starts in the epidermis [3]. Given the differences in the anatomical involvement of the disease, melanoma arising from congenital nevi may be considered a separate entity from the conventional case of melanoma and management may differ. Large excision may not be sufficient to remove all neoplastic cells from the nevi, and adjuvant aggressive systemic therapies may be essential to avoid a fatal outcome. A recent study revealed that congenital nevi preferentially harbor NRAS mutations rather than BRAF mutations commonly seen in other types of nevi, indicating an altered molecular basis of nevogenesis in congenital nevi. Herein, we report the case of a rapidly fatal metastatic melanoma in a young female arising from a congenital nevus of the trunk.

The Dark Areas of Esophagus

Esophageal melanocytosis characterized by melanocytic proliferation in the epithelium of esophagus is extremely rare disease. Aberrant migration of melanocytes during embryogenesis occurs in a small number of cases. Hence, the occurrence of benign and malignant melanocytic lesions is now known entities in esophagus. Melanocytosis is a benign entity and is very rare with an incidence of 0.07%–2.1%. The etiology of these lesions is not known. Endoscopic, histologic, and staining characteristics of two lesions are described. These cases were diagnosed from 450 endoscopic biopsies studied over a period of 10 months.

Lobulated intradermal nevus: A rare case report

Intradermal nevi are common benign proliferations of uniform melanocytes that are located initially at the dermal-epidermal junction and over time tend to migrate into the dermis and regress with subsequent morphological changes. At the end stage of this process, all the Naevus cells are completely detached from the overlying epidermis and is called intradermal nevus. We report a case of intradermal nevi in a 36 year old female presented to the Dermatology OPD with clusters of grapes like growth over the scalp for the last 5 years and confirmed with clinical and histopathological features.

Uticaj plave svetlosti iz prirodnih i veštačkih izvora na kožu

Blue light includes rays of lower energy in comparison to UV radiation, but it has a greater power of penetrating the dermis, even to a depth of 1mm. The aim of this review article was to analyze the biological effects of natural and artificial blue light on the skin based on the available literature, as well as to propose preventive measures in order to protect the skin from its harmful effects. The latest research has shown that blue light has various direct and indirect effects on the skin. The direct effects of blue light on the skin are the excessive creation of reactive oxygen species, nitrogen and hyperpigmentation, and it indirectly affects the skin by disrupting the circadian rhythm and secreting melatonin. Blue light has a direct effect on chromophores that are present in the skin and leads to their activation. Their activation leads to the excessive production of reactive oxygen species and release of reactive nitrogen species, that is, nitrogen monoxide (NO), which triggers melanogenesis and hyperpigmentation. Also, there comes to the decrease in cell vitality and/or proliferation of keratinocytes and melanocytes, then increased synthesis of pro-inflammatory interleukins and tumor necrosis factor alpha and altered collagen metabolism. Blue light reduces the antioxidative protection of the skin by causing the degradation of present carotenoids. It can be used in clinical practice in the prevention and treatment of certain dermatoses, as well as in photorejuvenation treatments in aesthetic medicine. Further research in this field is necessary.

Non-multiple medium-sized congenital melanocytic nevi: to excise or to follow up?

Congenital melanocytic nevi (CMN) are benign lesions composed of clonal proliferations of melanocytes. Although medium-sized CMN are common and generally remain benign throughout a person's lifetime, they may be precursors of melanoma. There is a limited number of studies focused on the risk of melanoma in solitary, medium-sized, congenital melanocytic nevus; therefore, the incidence of malignant transformation and guidelines for treatment are not well established. Prompted by the limited data, we conducted this study to gather more information about medium-sized CMN, to optimize clinical care. We share our analysis of surgically removed medium-sized CMN. A total of 10 patients with non-multiple, medium-sized, congenital melanocytic nevus were included in this study. Lesions were removed using surgical procedures. In most of the cases the reason for excision of the medium-sized CMN was evolution of the lesion or aesthetic considerations reported by the patients. In 2 cases, due to the large size of the lesions, serial excisions were performed, while other CMN were removed surgically using simple excision technique. Eight of 10 medium-sized CMN were histologically described as benign, and 2 cases of malignant transformations were reported. According to our clinical experience and knowledge, we recommend managing patients on an individual basis, taking into consideration multiple clinical attributes. In our opinion, long-lasting observation is the management of choice, and if there is need of surgery, we recommend total simple or staged excision depending on nevus size.

Eruptive lentiginosis in a young healthy woman—Revisiting causal associations

Lentigines are hyperpigmented macules, which represent the simplest form of increased melanocytic proliferation. The term “lentiginosis” is applied for the presence of lentigines in an exceptionally large number or in a distinctive configuration. Lentigines evolve slowly, but widespread occurrence over a short period of time is typical of eruptive lentiginosis. We report an unusual case of eruptive lentiginosis in a female patient with no prior systemic disorder or familial pattern, presenting with widespread hyperpigmented macules, symmetrically distributed over the face, neck, upper trunk, shoulders, and both arms and forearms. Clinicohistopathological features were consistent with eruptive lentiginosis. Our case report seems interesting as well as a rare one as it involved an otherwise healthy young woman.

Spatial Randomness in the Distribution of Acquired Melanocytic Nevi of the Back in a Population-Based Sample

It is assumed that body sites may differ in their susceptibility for melanocytic proliferation and malignant transformation (Green, 1992). Identifying areas where there is a high density (or cluster) of naevi, may aid in the early detection of melanoma. Recently, in a high-risk melanoma cohort (n=313; age range 30-49 years), Chousakos et al. (2022) assessed whether the distribution of melanocytic neoplasms (melanocytic naevi and melanomas) on the back followed the paradigm of complete spatial randomness.

Performance of PRAME immunohistochemistry compared with that of c-Kit, c-Myc, or cyclin D1 for the diagnosis of acral melanocytic tumors.

The diagnostic role of preferentially expressed antigen in melanoma (PRAME) immunohistochemistry has not been thoroughly evaluated for acral melanocytic tumors. The objective of this study was to evaluate the utility of this modality for the diagnosis of acral melanocytic tumors compared with other potential markers. Melanocytic tumors were classified as either acral nevi, challenging melanocytic tumors (superficial atypical melanocytic proliferation of uncertain significance (SAMPUS)-favor benign (SAMPUS-FB), SAMPUS-favor malignant (SAMPUS-FM)) or acral melanomas. A total of 106 acral melanocytic tumors including acral nevi (n = 32), SAMPUS-FB (n = 17), SAMPUS-FM (n = 20), and acral melanomas (n = 37) were included. Diagnostic power, assessed using an area under the receiver operating characteristic curve (AUC) for distinguishing acral melanomas and acral nevi, was highest for PRAME (AUC = 0.997), followed by c-Myc (AUC = 0.755), cyclin D1 (AUC = 0.652), and c-Kit (AUC = 0.573). At a PRAME expression level ≥30% as a positive test for acral melanoma, the sensitivity and specificity of this marker for discriminating acral melanoma from acral nevus were 100% and 96.9%, respectively. PRAME immunohistochemistry also discriminated SAMPUS-FM from SAMPUS-FB with a sensitivity and specificity of 90.0% and 76.5%, respectively. In conclusion, PRAME immunohistochemistry can be used effectively to distinguish between various spectra of acral melanocytic neoplasms.

NRAS promotes the proliferation of melanocytes to increase melanin deposition in Rex rabbits.

Melanocytes play a major role in the formation of mammalian fur color and are regulated by several genes. Despite playing the pivotal role in the study of melanoma, the mechanistic role of NRAS (neuroblastoma RAS viral oncogene homolog) in the formation of mammalian epidermal color is still elusive. First of all, the expression levels of NRAS mRNA and protein in the dorsal skin of different colored Rex rabbits were detected by qRT-PCR and Western blot. Then, the subcellular localization of NRAS was identified in melanocytes by indirect immunofluorescence. Next, the expression of NRAS was overexpressed and knocked down in melanocytes, and its efficiency was verified by qRT-PCR and Western blot. Subsequently, NaOH, CCK-8, and Annexin V-FITC were used to verify the changes in melanin content, proliferation, and apoptosis in melanocytes. Finally, we analyzed the regulation of NRAS on other genes (MITF, TYR, DCT, PMEL, and CREB) that affect melanin production. In silico studies showed NRAS as a stable and hydrophilic protein, and it is localized in the cytoplasm and nucleus of melanocytes. The mRNA and protein expression levels of NRAS were significantly different in skin of different colored Rex rabbits, and the highest level was found in black skin (P<0.01). Moreover, the NRAS demonstrated impact on the proliferation, apoptosis, and melanin production of melanocytes (P<0.05), and the strong correlation of NRAS with melanin-related genes was evidently observed (P<0.05). Our results suggested that NRAS can be used as a gene that regulates melanin production and controls melanocyte proliferation and apoptosis, providing a new theoretical basis for studying the mechanism of mammalian fur color formation.

153 Lower Levels of Calcidiol (Vitamin D2) Found in Patients with Vitiligo

Vitiligo is an autoimmune depigmenting disorder with a prevalence of 1% worldwide. While the exact pathogenesis of vitiligo remains unclear, it is caused by immune-mediated destruction of melanocytes. Vitamin D is known to have immunomodulatory effects on cells of both the innate and adaptive immune systems, thus deficiency is known to play a role in many autoimmune conditions. In the skin specifically, vitamin D has been shown to stimulate melanogenesis in vitro, and to regulate the activation, proliferation, and migration of melanocytes.

527 Long-term melatonin treatment stimulates melanin production as well as melanocyte dendricity and proliferation in human epidermis ex vivo

The pigmentary activities of the neurohormone, melatonin, have long fascinated dermatologists. Yet, cell culture reports are contradictory, and it remains unclear how melatonin alters melanocyte physiology in human epidermis. Thus, we have asked in healthy, organ-cultured, full-thickness human eyelid skin whether melatonin stimulates/inhibits melanin production by epidermal melanocytes that operate within their natural skin habitat. By assessing melanin content, tyrosinase activity in situ, melanocyte number, proliferation, and dendricity (gp100/Ki-67 IF), we show here that, after 3 days of organ culture, 200ug/mL melatonin initially reduces the epidermal melanin content, but without affecting tyrosinase activity or melanocyte proliferation/number (no significant changes seen for 100ug/mL).