Proliferation Of Melanocytes Research Articles

In vivo reflectance confocal microscopy role for early to advanced lentigo maligna melanoma spectrum: A systematic review and pooled analysis.

Lentigo maligna (LM) is a growing problem worldwide and the main type of melanoma insitu in some Caucasian populations. It presents as a spectrum from atypical intraepidermal melanocytic proliferation (AIMP) to invasive lentigo maligna melanoma (LMM). Accurate diagnosis and staging are crucial for determining appropriate management strategies. To assess the role of invivo reflectance confocal microscopy (RCM) in differentiating early and advanced stages of lentigo maligna. A systematic search was conducted on Medline, PubMed, Scopus, Web of Science, Proquest Central, Embase, Cochrane and Google Scholar. References of included and excluded studies were reviewed for additional sources. Studies involving RCM for AIMP, LM and LMM diagnosis published until 1 December 2023, were selected for analysis. Publications on other non-invasive imaging techniques, other skin diseases or those addressing only RCM surgical margins and therapeutic response without reporting RCM features were excluded. Each article was reviewed by two experts, with disagreements resolved by a third expert. Data for each RCM feature were pooled, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Features were stratified for architecture, cellular morphology and distribution. Twenty-seven articles involving 303 lesions were included. Features favouring LM over AIMP included (1) Architecture: the presence of non-edged papillae (OR 4.50, 95% CI 1.92-10.52) and (2) Cellular distribution: widespread pagetoid cells and junctional atypical cells (OR 25.06, 95% CI 4.19-148.45) and junctional nests (OR 18.06, 95% CI 3.04-106.32). Features favouring LMM over LM included (1) Architecture: epidermal disarray (OR 5.03, 95% CI 1.90-13.22), junctional disarray (OR 4.19, 95% CI 1.54-11.33) and destroyed collagen fibres (OR 3.91, 95% CI 1.80-8.44) and (2) cellular distribution: widespread pagetoid and junctional atypical cells (OR 2.71, 95% CI 1.27-5.75) and junctional nests (OR 4.48, 95% CI 2.12-9.43). This study identifies the RCM features associated with the LM/LMM spectrum.

Successful Adjunctive Treatment of Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) with High-Dose Intravenous Immunoglobulin Therapy (IVIG).

Purpose: The management of bilateral diffuse uveal melanocytic proliferation is controversial, with most earlier reports advocating for plasmapheresis. Here, we report a case of bilateral diffuse uveal melanocytic proliferation secondary to gastric adenocarcinoma that was successfully treated with adjunctive intravenous immunoglobulin, using a loading dose followed by a treat-and-extend strategy. Methods: Clinical case report with 3 years of follow-up including serial ophthalmologic examinations. Functional assessments included visual acuity and subjective visual complaints. Periodic anatomic assessments were performed including serial optical coherence tomography, ultra-widefield fundus imaging, multimodal angiography, and ophthalmic ultrasound. Results: A 75-year-old man presented with a 6-month history of blurry vision and difficulty with dark and light adaptation in both eyes. A diagnosis of bilateral diffuse uveal melanocytic proliferation was established based on clinical findings and subsequent discovery of an underlying gastric malignancy; the diagnosis of a paraneoplastic syndrome was further substantiated by documentation of cancer-associated antiretinal antibodies and serum reactivity against human retina by immunohistochemistry. Treatment with high-dose (2 g/kg) intravenous immunoglobulin was initiated with biweekly, followed by monthly, then q2-3 monthly dosing intervals. Meanwhile, the patient received surgical resection and systemic chemotherapy resulting in complete radiographic remission of the primary cancer. Over the course of 3 years, the patient has demonstrated clinically significant improvements in visual acuity and subjective visual function. Rapid and sustained anatomic improvements were observed in serous retinopathy and choroidal thickness. Conclusion: Intravenous immunoglobulin may be a viable adjunctive treatment option for some patients with bilateral diffuse uveal melanocytic proliferation.

Effect of Amygdalin on Murine Melanoma Cancer Cell Line and Normal Human Fibroblast Cells

Background and Objectives: Melanoma is the most aggressive and fatal type of skin cancer caused by the uncontrolled proliferation of melanocytes. The ineffectiveness of existing therapies has encouraged researchers to use herbal medicines. Amygdalin is a natural cyanogenic glycoside that is found in fruits and seeds of different plants and has antiproliferative, antioxidant, and immune-regulating activities. In this study, we aim to evaluate the effect of amygdalin against murine melanoma cancer cell line and normal human fibroblast cells. Methods: The murine melanoma cancer cell line (B16F10) and human foreskin fibroblasts (HFF) cells were exposed to different concentrations of amygdalin and dacarbazine (a standard anticancer drug) for 24 and 48 hours. The half-maximal inhibitory concentration (IC50) of amygdalin was obtained using the MTT assay and analyzed in GraphPad Prism and Excel applications. Results: Amygdalin had a high cytotoxic effect on the melanoma cell line within 48 hours of exposure, which is comparable to the cytotoxicity of dacarbazine at the same time. Amygdalin had no cytotoxic effect on HFF cells, while dacarbazine caused a high toxicity on HFF cells. Conclusion: Amygdalin, by inhibiting the proliferation of cancer cells in a dose-dependent manner, may prevent the adverse effects of chemical drugs on healthy cells and can be an appropriate treatment option for melanoma.

Tanshinone IIA inhibits H2O2-induced ferroptosis in melanocytes through activating Nrf2 signaling pathway.

Melanocyte ferroptosis has been proven to contribute to the development of vitiligo. Tanshinone IIA (TSA), a Chinese herbal extract, has been shown to inhibit vitiligo progression. Whether TSA regulates ferroptosis in melanocytes remains unclear. Hydrogen peroxide (H2O2) was used to induce melanocytes to stimulate vitiligo cell model in vitro. Cell proliferation was examined by 5-ethynyl-2'-deoxyuridine assay. The levels of malondialdehyde (MDA), reactive oxygen species (ROS), glutathione peroxidase (GSH) and iron (Fe2+) were detected by corresponding commercial kit. The protein levels of ferroptosis-related markers and Nrf2 pathway-related markers were examined using western blot and immunofluorescence staining. Cell viability and cytotoxicity were analyzed using cell counting kit 8 assay and lactate dehydrogenase (LDH) detection. Mitochondrial morphology was examined using a transmission electron microscope. After H2O2 treatment, melanocyte proliferation was reduced, while oxidative stress and ferroptosis were enhanced. TSA treatment could inhibit ferroptosis in H2O2-induced melanocytes. Besides, TSA could activate Nrf2 pathway and promote Nrf2 nuclear translocation, and Nrf2 specific inhibitor (ML385) also reversed the inhibitory effect of TSA on H2O2-induced melanocyte ferroptosis. Our data showed that TSA alleviated H2O2-induced melanocyte ferroptosis via activating Nrf2 pathway.

CLINICAL CASES OF SPITZOID NEOPLASMS

Spitz nevi account for about 2% of the total number of melanocytic skin neoplasms. There are benign Spitz nevi, atypical Spitz tumour, and malignant Spitz melanoma. These clinically similar lesions, usually represented by a flesh-coloured, pink or brownish-black spot or nodule, are often heavily vascularised, grow rapidly in size and change in structure, raising concerns about malignancy. Dynamic observations have revealed the possibility of long-term stabilisation and periods of regressive changes. Dermoscopy is used for early diagnosis due to the initially small size of nevi. When examining the magnified image of the tumour surface, the structure of the neoplasm is recognized. In the case of Spitz nevi, special patterns of “starburst” and “stardust” are identified, which allow to suspect the diagnosis and the period of involution, respectively. Pathohistologically, Spitz nevi are defined as melanocytic proliferations with large epithelioid or spindle-shaped melanocytes with large nuclei, vesicular chromatin and prominent nucleoli. However, the differentiation between different subtypes of spitzoid neoplasms remains a difficult issue. As of today, the review of H&E-stained structures still prevails over immunohistochemical and molecular genetic diagnostic methods. Even nowadays, Spitz nevi still cause difficulties in clinical and morphological diagnosis and management approaches. The publication considers several interesting cases from personal clinical practice. Case 1: Patient A, a 24-year-old woman. She complained of a single rash on the outer surface of the right thigh, which gradually increased in size over the last year. On clinical examination, a small erythematous, partially pigmented, heterogeneous nodule was observed in this area. The demonstrated Spitz nevus is heterogeneous in structure. Being in the phase of active growth, it showed an asymmetrical “starburst” pattern formed by vascular elements in a linear arrangement, and white reticular lines or structureless zones. Case 2: Patient B, 34 years old. A full examination of the right popliteal fossa revealed a heterogeneous spot up to 4 mm in diameter, which caused concern. A case of Spitz nevus is represented by a globular pattern in the centre and a reticular pattern on the periphery, which is more common for lesions that have been on the skin for some time, but no longer show signs of active growth. Case 3: Patient C, a 25-year-old woman, skin phototype 2, with a family history of skin tumours in several previous generations. The examination revealed a heterogeneous nodule of suspicious morphology in the left scapula. Dermoscopically, the above-described lesion is represented by two zones of different structure. The central zone has the signs of radial markings formed by various pattern elements; the polychromatic zone has areas of negative pigment network, white lines, dots and globules. There was also an eccentrically located area with a radially oriented hyperchromatic pigment network and a clear border along the outer edge. Most Spitz nevi are independent lesions, but some of them can be associated with other skin neoplasms. This is likely to be the example in the above-mentioned case, so it was the nevus-associated Spitz melanoma. Spitz nevi are an urgent problem of modern medicine. The similarity of the clinical, dermoscopic and pathological picture to malignant skin neoplasms causes diagnostic difficulties. Visual variability requires considerable clinical experience of a specialist.

Diffuse meningeal melanocytosis – a silent culprit

Abstract Introduction/Objective Diffuse meningeal melanocytosis is a rare melanocytic proliferation that poses significant risk of severe hydrocephalus and mortality among children and young adults. Although the clonal melanocytes do not typically exhibit malignant morphological features, their capability for extensive invasion and malignant-like behavior necessitates tissue biopsy alongside immunohistochemical and molecular testing for definitive diagnosis. Methods/Case Report A 17-year-old male presented with progressive headaches, photophobia, and nausea, initially attributed to migraines. Neuro-opthalmological assessment revealed papilledema, leading to a diagnosis of idiopathic intracranial hypertension. Serial imaging showed fluctuating leptomeningeal enhancement and moderate communicating hydrocephalus without parenchymal lesions. Therapeutic lumbar punctures provided modest symptom improvement; increased opening pressure was observed. Evaluation of seven CSF specimens showed low glucose levels, increased cellularity consisting of bland appearing epithelioid cells of unknown etiology, and increased lymphocytes. Infectious causes were excluded. Due to the indeterminate CSF findings, discussion between the cytopathologist and neuro-opthamologist was crucial to facilitate tissue biopsy to exclude a neoplastic process. Subsequent shunt placement and cerebral cortex biopsy revealed neoplastic cells with sheet-like architecture coating the dura without overt brain invasion. The tumor cells had eosinophilic cytoplasm without pigment and enlarged nuclei with irregular contours, vesicular chromatin, and prominent nucleoli. No high-grade features were seen. Immunohistochemical stains were positive for MART1, HMB45, and PRAME, consistent with a melanocytic lesion. FISH melanoma panel was negative. The final diagnosis was diffuse meningeal melanocytic neoplasm, most consistent with meningeal melanocytosis. The patient received chemotherapy with improved symptoms and stable disease. Results (if a Case Study enter NA) NA Conclusion Diffuse meningeal melanocytosis is a challenging cytologic diagnosis as melanocytes can morphologically mimic lymphocytes and monocytes, and the low cellularity of CSF specimens often results in insufficient cell blocks for ancillary tests. The direct communication of the pathologist with the clinical team to correlate pathology, radiology, and clinical symptoms was essential to ensure the proper management of this patient.

Treatment Options in Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP): Case Presentation and Review of the Literature

ABSTRACT Purpose To outline the therapeutic approach for a rare case of Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) and examine the current management recommendations of this uncommon condition. Methods-Results Literature review on the current treatment options in BDUMP cases. An 82-year-old woman was referred to our clinic due to bilateral visual loss. She was treated elsewhere with anti-vascular endothelial growth factors (anti-VEGF) in both eyes for presumed choroidal neovascularization (CNV) without improvement. Her past medical history (PMH) entailed colon cancer, treated with surgical resection and adjuvant chemotherapy 15 years ago. The patient presented with low visual acuity in both eyes, multiple oval orange patches in the fundus with striking hyperfluorescent pattern in fluorescein angiography (FA), giraffe pattern in fundus autofluorescence (FAF) and rapidly progressive cataracts. Intravitreal dexamethasone implants were administered with mild improvement and subretinal fluid absorption. Conclusions The management strategy in BDUMP should focus on the systemic, often occult malignancy. There is no standard treatment protocol for BDUMP; however, plasmapheresis in combination with primary malignancy treatment seems to yield promising results in current literature reports. Anti-VEGF injections failed to control BDUMP sequelae, however intravitreal dexamethasone implants may offer temporary relief.

Modulatory effects of oxytocin on normal human cultured melanocyte proliferation, migration, and melanogenesis

Melanocytes are specialized melanin-producing neural crest-derived cells. Melanocyte proliferation and melanin production (i.e., melanogenesis) are crucial for determining skin color. Disruption of these processes can cause pigmentary skin disorders, including hypo-pigmentary disorders such as vitiligo and hyper-pigmentary disorders such as melasma. Understanding these processes is important for discovering new targets to tackle these skin disorders. Therefore, this study aimed to investigate the effects of oxytocin (OXT) on melanocyte functions. Normal Human Cultured Melanocytes (NHCM) were treated with different OXT doses to investigate OXT effects and mechanisms on NHCM proliferation, migration, and on melanogenesis. OXT significantly increased NHCM proliferation and migration in a dose-dependent manner after 72 h of treatment. In addition, OXT dose-dependently upregulated melanogenesis-related microphtalmia-associated transcription factor, tyrosinase, tyrosinase-related protein (TYRP)-1, and TYRP-2 expression accompanied by an increased trend in melanosome number and maturation stage. Furthermore, OXT at concentrations (62.5–125 nM) increased melanin production. These findings suggest the involvement of OXT receptor (OXTR). In addition, this study demonstrates that OXT stimulates melanocyte proliferation, migration, with a tendency toward melanosome maturation, while it modulates melanin production in a dose-dependent manner. Thus, OXT system including its receptor OXTR may be a potential therapeutic target for skin pigmentary disorders.

Spitz melanoma with MAP3K8::ABLIM1 rearrangement: a case report with review of the literature

BackgroundSpitz tumors are relatively uncommon melanocytic lesions, typically affecting a relatively younger population but can be encountered at any age. They are characterized by a proliferation of melanocytes with epithelioid and/or spindled cytomorphology features, and interpretation is often challenging. The majority of these tumors are driven by kinase fusions or HRAS mutations. MAP3K8 fusions, although rare, are characteristic genomic events in Spitz tumors, especially in more atypical or malignant lesions.Case presentationHere, we present the case of a 43-year-old woman with a clinically cystic mass in her right groin, histologically characterized as a spindle and epithelioid cell malignant tumor. Immunohistochemistry revealed diffuse expression of S100 protein, tyrosinase and SOX10, patchy weak PRAME, HMB45 and Melan-A reactivity, and negative staining for BRAF V600E. Next-generation sequencing analysis revealed the presence of a MAP3K8::ABLIM1 fusion gene, as well as GRIN2A and TERT promoter mutations. The morphology, immunohistochemistry and molecular analysis confirmed Spitz melanoma with molecular features suggesting a worse prognosis.ConclusionThis case introduces a novel fusion partner of MAP3K8 in the context of Spitz melanoma and expands the morphologic and molecular spectrum of Spitz melanoma.

The role of signaling pathways mediated by the GPCRs CysLTR1/2 in melanocyte proliferation and senescence.

In contrast with sun exposure-induced melanoma, rarer melanocytic tumors and neoplasms with low mutational burden present opportunities to study isolated signaling mechanisms. These include uveal melanoma and blue nevi, which are often driven by mutations within the G protein-coupled signaling cascade downstream of cysteinyl leukotriene receptor 2. Here, we review how the same mutations within this pathway drive the growth of melanocytes in one tissue but can inhibit the growth of those in another, exemplifying the role of the tissue environment in the delicate balance between uncontrolled cell growth and senescence.

Hair regrowth in alopecia areata and re-pigmentation in vitiligo in response to treatment: Commonalities and differences.

Both alopecia areata (AA) and vitiligo share common pathogenesis involving, interferon-γ (IFN-γ) and interleukin-15 (IL-15) signalling pathways that activate cytotoxic CD8+ T lymphocytes. These shared mechanisms may explain why both diseases respond to currently available treatments (e.g. topical/systemic corticosteroid) and emerging treatment modalities. As compared with the speed of re-pigmentation in vitiligo lesions, the regeneration of pigmented terminal hair follicles in AA lesions appears fast in response to treatments targeting the inhibition of the Janus kinases (JAKs) and other kinases. We summarize the commonalities and differences between AA and vitiligo focusing on the treatment modalities, followed by recent findings associated with hair follicle stem cells (HFSC) in hair bulge (HBg) and melanocyte stem cells (McSC) in HBg and hair germ (HGm). We then discuss how HFSC and HGm-McSC are involved in the initiation of anagen phase, followed by pigmented terminal hair regrowth in the recovering AA lesions in association with immunology. We also discuss how HBg-McSC contribute to the migration of fully dendritic mature melanocytes into interfollicular epidermis and the equal distribution of melanin in recovering vitiligo lesions. Finally, we present four hypotheses to elucidate the delayed distribution of melanin by mature melanocytes in depigmented vitiligo lesions from the aspects of stem cell biology, as compared with quick hair recovery in AA: (1) McSC are less abundant than HFSC. (2) McSC require a long travel, whereas HFSC reside close to hair regeneration trigger point. (3) Keratinocyte scaffold to accept melanin is not well preserved, whereas scaffold for hair regrowth is well preserved. (4) Inhibitors targeting JAKs and other kinases have less direct effects on melanocyte proliferation and differentiation in vitiligo than hair regrowth in AA. Our review provides an overview of treatment modalities and bridges the gap between scientific advancement and clinical practice in AA and vitiligo management.

Refractory solar lentigines successfully treated with 532-nm nanosecond Nd:YAG Vasculature Salvage Laser Surgery (VSLS) system: Case series.

Solar lentigo, a common epidermal hyperpigmented lesion found in sun-exposed areas, results from the proliferation of melanocytes and the accumulation of melanin. Although various treatments for solar lentigo have been explored, they often lead to complications, including prolonged erythema and post-inflammatory hyperpigmentation (PIH), posing significant concerns. This study evaluated the safety and efficacy of the Vasculature Salvage Laser Surgery (VSLS) system. We treated six Korean patients, each with solar lentigo, in a single session using the 532-nm nanosecond neodymium-doped yttrium aluminum garnet (Nd:YAG) VSLS system, with follow-up periods ranging from 3 to 10weeks. The treatment led to the complete removal of pigmented lesions in all patients without resulting in PIH, even in cases where previous laser treatments had failed. The only side effect observed was mild erythema, which resolved over the long term in most instances. The VSLS system emerges as a safe and effective treatment for pigmented lesions, including refractory solar lentigines. Nonetheless, additional studies are required to verify its long-term efficacy.

Phosphodiesterase-4 Inhibitors Increase Pigment Cell Proliferation and Melanization in Cultured Melanocytes and within a 3-Dimensional Skin Equivalent Model

Vitiligo is a common chronic autoimmune disease characterized by white macules and patches of the skin, having a negative impact on patients' life, and without any definitive cure at present. Identification of new compounds to reverse depigmentation is therefore a pressing need for this disease. The pharmacologic compounds phosphodiesterase-4 inhibitors (PDE4i) are small molecules with immunomodulatory properties, used for treatment of inflammatory dermatoses. PDE4i have shown repigmentation effects in vitiligo patients, in some case reports. We characterized the proliferative and melanogenic potential of two known PDE4i, crisaborole and roflumilast, and of a more recently designed compound, PF-07038124. We used two in vitro model systems, the primary human melanocyte culture and a 3D co-cultured skin model (MelanoDermTM), with an exploratory testing platform composed of complementary assays (spectrophotometry, melanin and proliferation assays, immunostaining, Fontana-Masson staining, qRT-PCR, western blot and whole transcriptome RNA-Sequencing). We identified that the treatment with PDE4i was associated with increased melanocyte proliferation and melanization in both in vitro models, and with increase in the melanogenic genes and proteins expression in cultured melanocytes. These effects were found to be enhanced by addition of α-MSH. Our findings support the further evaluation of PDE4i with or without α-MSH agonists in vitiligo trials.

54191 Nail Unit Atypical Intraepidermal Melanocytic Proliferation: Diagnostic Change to Melanoma and Local Recurrence Rate After Mohs Micrographic Surgery

54191 Nail Unit Atypical Intraepidermal Melanocytic Proliferation: Diagnostic Change to Melanoma and Local Recurrence Rate After Mohs Micrographic Surgery

S100 protein expression in PKC-fused blue naevi, cellular blue naevi and PRKAR1A-inactivated pigmented epithelioid melanocytomas

Recent data have redefined the genetic spectrum of pigmented epithelioid melanocytomas (PEMs). PEM is now defined by a secondary genetic event, a protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A) inactivation, that confers the specific cytomorphology of the entity, but this event can arise within a naevus with a genetic background of common, blue or Spitz type. PKC-fused melanocytic proliferations, although they can exhibit PEM-like morphological features, have now been regrouped within the blue group of tumours. Past studies have shown that the latter group tends to lose S100 expression. Herein, we studied the nuclear expression of S100 by immunohistochemistry in 73 PKC-fused benign blue naevi. Histologically, the most frequent pattern found in PKC-fused blue naevi (51%) was a dermal biphasic architecture associated with a horizontal band of medium-sized bland melanocytes in the upper papillary dermis, with a deeper dermal expansion combining spindled and dendritic melanocytes with occasional small nests of bland melanocytes within a fibrous background. A PEM-like hyperpigmented hyperplasia of the epidermis was seen in 32% of cases. The immunohistochemical study found in 31 of the 37 (84%) dermal biphasic PKC-fused melanocytic tumour cases a significant loss of nuclear expression of S100 (in more than 50% of cells) in the superficial horizontal dermal band area and in 68% of the biphasic dermal component. However, the hyperpigmented PEM-like junctional components were not assessable by immunohistochemistry. An exploratory analysis of S100 expression in 21 blue naevi and in 25 PEM with confirmed PRKAR1A inactivation was also performed. In blue naevi, a loss of nuclear S100 expression in more than 50% of melanocytes was found in over 70% of these lesions both in the dendritic and epithelioid dermal components. By contrast, nuclear expression of S100 was most often preserved in PEM with PRKAR1A inactivation (85% preservation in the epithelioid component). These results suggest that searching for S100 expression loss by immunohistochemistry may be helpful in the diagnosis of PKC-fused blue naevus similarly as in dendritic and cellular blue naevi. This simple test, especially if a band-like structure is present in the upper dermis, can effectively support this diagnosis, as a genetic confirmation of these benign tumours is not warranted.

Malignant blue melanoma

Malignant blue melanomas (MBMs) arise from blue nevi and all related intradermal melanocytic proliferations. They harbor specific, mutually exclusive mutations in the G-coupled protein pathway, mainly involving GNAQ or GNA11. Other rare genetic drivers include CYSLTR2 or PCLB4 mutations. PKC and GRM1-gene fusions have been recently added to this list. MBMs have a predilection for the scalp area, presenting as rapidly growing nodules within a pre-existing lesion. Histopathologically, these tumors are located in the dermis and subcutaneous fat and consist of large nodules or expanding dense sheets. Tumor necrosis is commonly seen. Large spindle-shaped and epithelioid melanocytes with high-grade cytological atypia and frequent mitotic figures are at higher magnification. A benign blue nevus or intermediate-grade blue melanocytoma is frequently found on the side of the central mass. Loss of nuclear BAP1 immunoreactivity is a poor prognostic factor.

Exosomal miR-222-3p derived from dermal papilla cells inhibits melanogenesis in melanocytes by targeting SOX10 in rabbits.

Dermal papilla cells (DPCs) play a pivotal role in hair follicle development and can modulate melanogenesis in melanocytes (MCs) through their microenvironment. Our previous studies have demonstrated that the level of exosomal miR-222-3p derived from DPCs of white Rex rabbits are significantly higher than those of black Rex rabbits. However, the specific role and underlying molecular mechanisms of exosomal miR-222-3p in melanogenesis remain elusive. DPCs and MCs were isolated from hair follicles of Rex rabbits and identified using western blotting (WB) and immunofluorescent staining. Exosomes derived from DPCs (DPCs-exos) were characterized using nanoparticle tracking analysis, transmission electron microscopy, and WB. To investigate cell-cell crosstalk mediated by exosomes, MCs were co-cultured with CM-Dil-labeled DPCs-exos. The expression of miR-222-3p in skin tissue and exosomes was quantitatively assessed using quantitative real-time PCR (qRT-PCR). The transmission of DPCs-secreted exosomal miR-222-3p to MCs was demonstrated using Cy3-labeled miR-222-3p in conjunction with transwell assays. The impact of miR-222-3p on melanin synthesis was evaluated using the NaOH method, CCK-8, and Annexin V-FITC/PI assays. SOX10, a potential target gene regulated by miR-222-3p, was validated using a dual-luciferase reporter assay, site-specific mutation, and WB. Increased levels of miR-222-3p were observed in the skin and DPCs-exos of white Rex rabbits compared to those of black Rex rabbits. Effective internalization of CM-Dil-labeled DPCs-exos by MCs was observed. Furthermore, exosomal miR-222-3p derived from DPCs was transferred to MCs. Functionally, miR-222-3p significantly inhibited MCs proliferation, induced apoptosis and inhibited melanin synthesis. SOX10 was confirmed as a direct target of miR-222-3p in this regulatory cascade. The findings demonstrate that exosomal miR-222-3p, derived from DPCs, suppresses melanogenesis in MCs by targeting SOX10, thus unveiling a novel mechanism of exosome involvement in melanogenesis.

Subungual melanoma: molecular analysis of 31 cases from early stage to invasive melanoma.

The distinction between the benign subungual melanocytic lesions and an early lesion of subungual melanoma (SUM) remains a diagnostic challenge. We evaluated the routine diagnostic utility of array Comparative Genomic Hybridization (aCGH) to detect whole-genome copy number variations (CNV) as well as targeted next-generation sequencing (NGS) in SUM. This retrospective study included 20 cases of in situ SUM and 11 cases of invasive SUM. Analysis by aCGH detected common oncogene amplifications in all but one case of invasive SUM (n = 10) and in all cases of in situ SUM with a melanocyte count (MC) >45/mm (n = 4 true positive) and the average number of CNV was 8.5. Thirteen remaining cases of in situ SUM gave false negative results (n = 13), owing to a lack of sufficient melanocytes to analyse (median MC of 35.35; range: 10.16-39.5). Molecular analysis failed in four cases (three in situ SUM and one invasive SUM) due to insufficient amounts of DNA. Across the whole cohort, the sensitivity of aCGH was 52%, but when adjusting the cutoff to MC >45/mm, the sensitivity was 93%. Targeted NGS was less informative than aCGH analyses in our series of SUM. To distinguish malignant from benign lesions, especially in situ SUM versus atypical lentiginous melanocytic proliferations, aCGH analysis should be performed when the MC is above 45 melanocytes per linear millimetre. This pangenomic method can detect oncogene amplifications, as well as a number of CNV >3, which strongly support the diagnosis of malignancy.

Bilateral Diffuse Uveal Melanocytic Proliferation with Oral Mucosal Pigmentation

Bilateral Diffuse Uveal Melanocytic Proliferation with Oral Mucosal Pigmentation

Melanocyte lineage dynamics in development, growth and disease.

Melanocytes evolved to produce the melanin that gives colour to our hair, eyes and skin. The melanocyte lineage also gives rise to melanoma, the most lethal form of skin cancer. The melanocyte lineage differentiates from neural crest cells during development, and most melanocytes reside in the skin and hair, where they are replenished by melanocyte stem cells. Because the molecular mechanisms necessary for melanocyte specification, migration, proliferation and differentiation are co-opted during melanoma initiation and progression, studying melanocyte development is directly relevant to human disease. Here, through the lens of advances in cellular omic and genomic technologies, we review the latest findings in melanocyte development and differentiation, and how these developmental pathways become dysregulated in disease.