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Cancers Feb 2019The incidence of malignant melanoma, one of the deadliest cancers, continues to increase. Here we tested connexin (Cx) expression in primary melanocytes, melanoma cell...
The incidence of malignant melanoma, one of the deadliest cancers, continues to increase. Here we tested connexin (Cx) expression in primary melanocytes, melanoma cell lines and in a common nevus, dysplastic nevus, and thin, thick, and metastatic melanoma tumor progression series involving the tumor microenvironment by utilizing in silico analysis, qRT-PCR, immunocyto-/histochemistry and dye transfer tests. Primary melanocytes expressed /Cx43, /Cx46 and low levels of /Cx26 and /Cx30.2 transcripts. In silico data revealed downregulation of /Cx43 and /Cx26 mRNA, in addition to upregulated /Cx32, during melanoma progression. In three melanoma cell lines, we also showed the loss of /Cx43 and the differential expression of /Cx32, /Cx26, /Cx46 and /Cx30.2. The dominantly paranuclear localization of connexin proteins explained the ~10⁻90 times less melanoma cell coupling compared to melanocytes. In melanocytic tumor tissues, we confirmed the loss of Cx43 protein, fall of cell membrane and elevated paranuclear Cx32 with moderately increased cytoplasmic Cx26 and paranuclear Cx30.2 positivity during tumor progression. Furthermore, we found Cx43, Cx26 and Cx30 proteins upregulated in the melanoma adjacent epidermis, and Cx43 in the tumor flanking vessels. Therefore, differential connexin expression is involved in melanocytic tumor progression where varying connexin isotypes and levels reflect tumor heterogeneity-related bidirectional adaptive interactions with the microenvironment.
PubMed: 30717194
DOI: 10.3390/cancers11020165 -
Anais Brasileiros de Dermatologia 2023A lot of congenital melanocytic nevi (CMN) carry the somatic mutation in the oncogene BRAF V600E. But the detailed histopathologic characteristics and the proliferative...
BACKGROUND
A lot of congenital melanocytic nevi (CMN) carry the somatic mutation in the oncogene BRAF V600E. But the detailed histopathologic characteristics and the proliferative activity of CMN with BRAF V600E gene mutation have not been systematically documented.
OBJECTIVE
To identify the proliferative activity and histopathological features correlating them with BRAF V600E gene mutation status in CMN.
METHODS
CMN were retrospectively identified from the laboratory reporting system. Mutations were determined by Sanger sequencing. The CMN were divided into a mutant group and control group according to whether there was BRAF gene mutation and were strictly matched according to gender, age, nevus size, and location. Histopathological analysis, analysis of Ki67 expression by immunohistochemistry and laser confocal fluorescence microscopy were performed.
RESULTS
The differences in Ki67 index, the depth of nevus cell involvement and the number of nevus cell nests between the mutant group and the control group was statistically significant, with p-values of 0.041, 0.002 and 0.007, respectively. Compared with BRAF V600E negative nevi, BRAF V600E positive nevi often exhibited predominantly nested intraepidermal melanocytes, and larger junctional nests, but the difference in this data sets were not statistically significant. The number of nests (p = 0.001) was positively correlated with the proportion of Ki67 positive cells.
STUDY LIMITATIONS
A small sample of patients were included and there was no follow-up.
CONCLUSIONS
BRAF V600E gene mutations were associated with high proliferative activity and distinct histopathological features in congenital melanocytic nevi.
Topics: Humans; Child; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Retrospective Studies; Ki-67 Antigen; Nevus, Pigmented; Nevus; Mutation
PubMed: 37156689
DOI: 10.1016/j.abd.2022.01.016 -
The Journal of Investigative Dermatology May 2017Stunning technological advances in genomics have led to spectacular breakthroughs in the understanding of the underlying defects, biological pathways and therapeutic... (Review)
Review
Stunning technological advances in genomics have led to spectacular breakthroughs in the understanding of the underlying defects, biological pathways and therapeutic targets of skin diseases leading to new therapeutic interventions. Next-generation sequencing has revolutionized the identification of disease-causing genes and has a profound impact in deciphering gene and protein signatures in rare and frequent skin diseases. Gene addition strategies have shown efficacy in junctional EB and in recessive dystrophic EB (RDEB). TALENs and Cripsr/Cas9 have emerged as highly efficient new tools to edit genomic sequences to creat new models and to correct or disrupt mutated genes to treat human diseases. Therapeutic approaches have not been limited to DNA modification and strategies at the mRNA, protein and cellular levels have also emerged, some of which have already proven clinical efficacy in RDEB. Improved understanding of the pathogenesis of skin disorders has led to the development of specific drugs or repurposing of existing medicines as in basal cell nevus syndrome, alopecia areata, melanoma and EB simplex. These discoveries pave the way for improved targeted personalized medicine for rare and frequent diseases. It is likely that a growing number of orphan skin diseases will benefit from combinatory new therapies in a near future.
Topics: Animals; Dermatology; Drug Design; Drug Repositioning; Gene Editing; Genomics; High-Throughput Nucleotide Sequencing; Humans; Precision Medicine; Rare Diseases; Skin Diseases
PubMed: 28411843
DOI: 10.1016/j.jid.2016.08.038 -
Medicina (Kaunas, Lithuania) 2014In vivo reflectance confocal microscopy (RCM) is a promising novel technology for non-invasive early diagnostics of cutaneous melanoma. However, the possibility to...
BACKGROUND AND OBJECTIVE
In vivo reflectance confocal microscopy (RCM) is a promising novel technology for non-invasive early diagnostics of cutaneous melanoma. However, the possibility to detect melanocytic atypia in nevi by means of in vivo RCM remains unknown. The aim of the study was to evaluate the significance of in vivo RCM features of melanocytic atypia for the diagnosis of melanocytic nevi, dysplastic nevi and cutaneous melanoma.
MATERIALS AND METHODS
A total of 138 melanocytic skin lesions comprising 25 melanocytic nevi, 69 dysplastic nevi and 44 melanomas were analyzed by means of dermoscopy, in vivo RCM and routine histopathology. In vivo RCM images were analyzed for the arrangement of keratinocytes in epidermis, pagetoid cells and junctional melanocytic nests and correlated refractivity aspects of nests with histopathology.
RESULTS
Separately and all together taken the in vivo RCM features of melanocytic atypia were significant in differential diagnosis of benign and malignant melanocytic skin lesions, though none of the features was significant in discriminating nevi without cytologic atypia of dysplastic nevi. In vivo RCM feature of dense cell clusters corresponded with melanin containing nevomelanocytes on histopathology though exact correspondence of non-homogeneous and atypical sparse cell clusters remained questionable.
CONCLUSIONS
Nevus with histopathologically confirmed nevomelanocytic atypia (dysplastic nevus) could not be distinguished from nevus without atypia using analyzed in vivo RCM features of melanocytic atypia. More accurate diagnostics by means of in vivo RCM needs further investigation on reflectance of single and nested cutaneous melanocytes in benign and malignant skin lesions.
Topics: Diagnosis, Differential; Female; Humans; Male; Melanoma; Microscopy, Confocal; Nevus, Pigmented; Skin Neoplasms; Melanoma, Cutaneous Malignant
PubMed: 25458957
DOI: 10.1016/j.medici.2014.09.008 -
California Medicine Jun 1955Some melanomas arise from compound and junctional nevi. Since there is a relatively high incidence of malignant diseases on the soles of the feet and the genitalia,...
Some melanomas arise from compound and junctional nevi. Since there is a relatively high incidence of malignant diseases on the soles of the feet and the genitalia, routine removal of nevi developing in those areas is recommended."Juvenile melanomas" are active, cellular nevi occurring in prepubertal children. The clinical course is probably benign. The tenet of excision and dissection in continuity where feasible of the primary melanoma and the regional lymph nodes is reemphasized. When continuous dissection is not possible, regional node dissection is recommended as a separate procedure. Major amputations for melanomas of the extremities are not recommended for the usual case.
Topics: Amputation, Surgical; Dissection; Extremities; Foot; Humans; Incidence; Lymph Nodes; Melanoma; Nevus, Intradermal; Nevus, Pigmented; Skin Neoplasms
PubMed: 14379056
DOI: No ID Found -
Ocular Oncology and Pathology Sep 2017To report the clinical, pathological, and immunohistochemical features of the first pigmented spindle cell nevus (PSCN) of Reed documented to have appeared in the eyelid.
PURPOSE
To report the clinical, pathological, and immunohistochemical features of the first pigmented spindle cell nevus (PSCN) of Reed documented to have appeared in the eyelid.
METHODS
The findings of clinical and histopathological examination are presented, along with differential diagnoses and a review of the pertinent literature.
CASE
A 3-year-old boy presented with a rapidly growing, heavily pigmented left lower lid papule raising the concern of malignancy, warranting excisional biopsy. Nests of predominantly junctional Mart-1-positive spindle cells were identified by histopathological examination. The cells were largely uniform in size, elongated, surrounded by granular and coarse melanin, with a Ki-67 proliferation index of 0-2%. Five-month follow-up did not evidence any recurrence or invasive behavior of this benign melanocytic tumor.
CONCLUSION
This is the first documented case of PSCN of Reed, a distinct entity from Spitz nevus, presenting in the eyelid. The differential diagnoses include spindle cell and superficially spreading malignant melanoma as well as dysplastic nevus. Integration of clinical and histopathological findings with immunohistochemical and fluorescence in situ hybridization markers plays a central role in the diagnosis.
PubMed: 29134183
DOI: 10.1159/000454864 -
Journal of Biomedical Optics 2011In several human volunteers, photoacoustic microscopy (PAM) has been utilized for noninvasive cutaneous imaging of the skin microvasculature and a melanocytic nevus....
In several human volunteers, photoacoustic microscopy (PAM) has been utilized for noninvasive cutaneous imaging of the skin microvasculature and a melanocytic nevus. Microvascular networks in both acral and nonacral skin were imaged, and multiple features within the skin have been identified, including the stratum corneum, epidermal-dermal junction, and subpapillary vascular plexus. Several vascular and structural differences between acral and nonacral skin were also observed in the photoacoustic images. In addition, a nevus was photoacoustically imaged, excised, and histologically analyzed. The photoacoustic images allowed for in vivo measurement of tumor thickness, depth, and microvasculature-values confirmed by histologic examination. The presented images demonstrate the potential of PAM to aid in the study and evaluation of cutaneous microcirculation and analysis of pigmented lesions. Through its ability to three-dimensionally image the structure and function of the microvasculature and pigmented lesions, PAM can have a clinical impact in diagnosis and assessment of systemic diseases that affect the microvasculature such as diabetes and cardiovascular disease, cutaneous malignancies such as melanoma, and potentially other skin disorders.
Topics: Equipment Design; Equipment Failure Analysis; Humans; Microscopy, Acoustic; Microvessels; Nevus; Reproducibility of Results; Sensitivity and Specificity
PubMed: 21280921
DOI: 10.1117/1.3528661 -
Anais Brasileiros de Dermatologia 2020Spitz nevus is a benign melanocytic lesion, which presents in several ways: solitary, agminated, or disseminated. The disseminated variant is uncommon; it may have a...
Spitz nevus is a benign melanocytic lesion, which presents in several ways: solitary, agminated, or disseminated. The disseminated variant is uncommon; it may have a rapid evolution (the eruptive form) and be difficult to manage. This report presents the case of a 24-year-old patient with multiple papules on his limbs, which had appeared four years previously. On physical examination, 120 pink and skin-colored papules were seen, which under dermoscopy were observed to be homogeneous, pink vascular lesions. Histopathologic study revealed epithelioid cells arranged in groups or singly in the dermis and dermo-epidermal junction. They were HMB-45 positive in the superficial dermis, and Ki-67<1%. Given these findings, a diagnosis of eruptive disseminated Spitz nevi was made.
Topics: Biopsy; Dermoscopy; Humans; Immunohistochemistry; Male; Melanocytes; Nevus, Epithelioid and Spindle Cell; Skin Neoplasms; Young Adult
PubMed: 31899063
DOI: 10.1016/j.abd.2019.01.010 -
Scientific Reports Jan 2019Mutations in the gene (GJA1) encoding connexin43 (Cx43) are responsible for several rare genetic disorders, including non-syndromic skin-limited diseases. Here we used...
Mutations in the gene (GJA1) encoding connexin43 (Cx43) are responsible for several rare genetic disorders, including non-syndromic skin-limited diseases. Here we used two different functional expression systems to characterize three Cx43 mutations linked to palmoplantar keratoderma and congenital alopecia-1, erythrokeratodermia variabilis et progressiva, or inflammatory linear verrucous epidermal nevus. In HeLa cells and Xenopus oocytes, we show that Cx43-G8V, Cx43-A44V and Cx43-E227D all formed functional gap junction channels with the same efficiency as wild-type Cx43, with normal voltage gating and a unitary conductance of ~110 pS. In HeLa cells, all three mutations also localized to regions of cell-cell contact and displayed a punctate staining pattern. In addition, we show that Cx43-G8V, Cx43-A44V and Cx43-E227D significantly increase membrane current flow through formation of active hemichannels, a novel activity that was not displayed by wild-type Cx43. The increased membrane current was inhibited by either 2 mM calcium, or 5 µM gadolinium, mediated by hemichannels with a unitary conductance of ~250 pS, and was not due to elevated mutant protein expression. The three Cx43 mutations all showed the same gain of function activity, suggesting that augmented hemichannel activity could play a role in skin-limited diseases caused by human Cx43 mutations.
Topics: Animals; Connexin 43; Electric Conductivity; Epithelial Cells; Gap Junctions; HeLa Cells; Humans; Mutation, Missense; Oocytes; Skin Diseases; Xenopus
PubMed: 30631135
DOI: 10.1038/s41598-018-37221-2 -
Modern Pathology : An Official Journal... Apr 2011Atypical (dysplastic) melanocytic nevi are clinically heterogeneous malignant melanoma precursors, for which no topographic analysis of cell kinetic, cell cycle...
Atypical (dysplastic) melanocytic nevi are clinically heterogeneous malignant melanoma precursors, for which no topographic analysis of cell kinetic, cell cycle regulators and microsatellite profile is available. We selected low-grade atypical melanocytic nevi (92), high-grade atypical melanocytic nevi (41), melanocytic nevi (18 junctional, 25 compound) and malignant melanomas (16 radial growth phase and 27 vertical growth phase). TP53, CDKN2A, CDKN1A, and CDKN1B microsatellite patterns were topographically studied after microdissection; Ki-67, TP53, CDKN2A, CDKN1A, and CDKN1B expressions and DNA fragmentation by in situ end labeling for apoptosis were topographically scored. Results were statistically analyzed. A decreasing junctional-dermal marker expression gradient was observed, directly correlating with atypical melanocytic nevus grading. High-grade atypical melanocytic nevi revealed coexistent TP53-CDKN2A-CDKN1B microsatellite abnormalities, and significantly higher junctional Ki67-TP53 expression (inversely correlated with CDKN1A-CDKN1B expression and in situ end labeling). Malignant melanomas showed coexistent microsatellite abnormalities (CDKN2A-CDKN1B), no topographic gradient, and significantly decreased expression. Melanocytic nevi and low-grade atypical melanocytic nevi revealed sporadic junctional CDKN2A microsatellite abnormalities and no significant topographic kinetic differences. High-grade atypical melanocytic nevi accumulate junctional TP53-CDKN1A-CDKN1B microsatellite abnormalities, being progression TP53-independent and better assessed in the dermis. Melanocytic nevi and low-grade atypical melanocytic nevi show low incidence of microsatellite abnormalities, and kinetic features that make progression unlikely.
Topics: Adult; Apoptosis; Cell Cycle Proteins; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Disease Progression; Female; Humans; Immunohistochemistry; In Situ Hybridization; Kinetics; London; Male; Microdissection; Microsatellite Repeats; Middle Aged; Neoplasm Staging; Nevus, Pigmented; Retrospective Studies; Skin Neoplasms; Spain; Tumor Suppressor Protein p53
PubMed: 21336261
DOI: 10.1038/modpathol.2010.143