cyclin-d1 and Nevus--Pigmented

The Clark model for melanoma progression emphasizes a series of histopathological changes beginning from benign melanocytic nevus to melanoma via dysplastic nevus. Several models of the genetic basis of melanoma development and progression are based on this Clark's multi-step model, and predict that the acquisition of a BRAF mutation can be a founder event in melanocytic neoplasia. However, our recent investigations have challenged this view, showing the polyclonality of BRAF mutations in melanocytic nevi. Furthermore, it is suggested that many melanomas, including acral and mucosal melanomas, arise de novo, not from melanocytic nevus. While mutations of the BRAF gene are frequent in melanomas on non-chronic sun damaged skin which are prevalent in Caucasians, acral and mucosal melanomas harbor mutations of the KIT gene as well as the amplifications of cyclin D1 or cyclin-dependent kinase 4 gene. Amplifications of the cyclin D1 gene are detected in normal-looking 'field melanocytes', which represent a latent progression phase of acral melanoma that precedes the stage of atypical melanocyte proliferation in the epidermis. Based on these observations, we propose an alternative genetic progression model for melanoma.

Topics: Animals; Cell Transformation, Neoplastic; Cyclin D1; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Melanoma; Mutation; Nevus, Pigmented; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-kit; Skin Neoplasms

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.

Topics: Antigens, Neoplasm; Cyclin D1; Diagnosis, Differential; Humans; Immunohistochemistry; Melanoma; Melanoma, Cutaneous Malignant; Nevus, Pigmented; Proto-Oncogene Proteins c-kit; Skin Neoplasms

Deep penetrating nevus (DPN) is not a widely recognised lesion on the conjunctiva and only a few cases consistent with combined DPN have been reported.. A review of all excised and histopathologically diagnosed conjunctival melanocytic lesions between 2003 and 2018 was performed in order to identify melanocytic nevi morphologically consistent with DPN.. Thirty-four DPN were identified among 361 histopathologically examined conjunctival nevi (9.4%), including 33 (97%) combined with a common nevus and 1 (3%) pure DPN. The patients' age ranged from 7 to 51 years (median, 22 years). Clinically, 21 of 29 (72%) lesions with available data were darkly pigmented, and an increase in size and/or pigmentation was noted in 13 of 18 (72%) lesions with known history. All 24 lesions in which an immunohistochemical analysis was possible were diffusely positive for BRAFV600E (in DPN and common nevus components) and showed a diffuse nuclear positivity for beta catenin and cyclin D1 in the DPN component. None of the 21 lesions with available follow-up data recurred during a follow-up period from 0.3 to 16.3 years (median, 7.5 years).. DPN of the conjunctiva is a relatively common lesion and usually presents as a combined nevus. Genetically, DPN of the conjunctiva are characterised by a combination of BRAFV600E mutation and activation of the beta catenin pathway. Recognition of DPN of the conjunctiva is important in order not to overdiagnose it as a melanoma, and to explain its potential atypical clinical features. DPN of the conjunctiva seems to be a benign lesion.

Topics: Adolescent; Adult; beta Catenin; Child; Conjunctival Neoplasms; Cyclin D1; Female; Humans; Immunohistochemistry; Male; Middle Aged; Mutation; Nevus, Pigmented; Proto-Oncogene Proteins B-raf

Deep penetrating nevus (DPN) is an intradermal, sometimes compound benign melanocytic lesion, which involves the reticular dermis, occasionally reaching the subcutis, which can raise concern for melanoma both clinically and histologically. Recently, it has been genetically defined by the combination of MAPK activating and β-catenin activating mutations. We sought to investigate genetic alterations in 2 cases of combined nevi of congenital melanocytic and DPN. Case 1 was a 16-year-old woman with a pigmented lesion on the trunk since birth, which was completely excised. Histopathological examination revealed a combined congenital nevus with a DPN. Comparative genomic hybridization showed no major genetic alterations, except for gain of 6q11.1 and point mutation of B-RAF V600E. Case 2 was a 62-year-old woman with a congenital pigmented lesion on the back. The lesion was diagnosed as a combined nevus of congenital and DPN. Comparative genomic hybridization showed no genetic alterations, and the NRAS Q61K was detected in both components. DPN is in most cases part of a combined nevus. Our cases showed strong and uniform nuclear expression of β-catenin and cyclin D1 in the DPN component suggesting the evolution of the congenital nevus to the DPN clone by acquiring β-catenin activating mutation.

Topics: Adolescent; beta Catenin; Biomarkers, Tumor; Comparative Genomic Hybridization; Cyclin D1; Female; Gain of Function Mutation; Genetic Predisposition to Disease; GTP Phosphohydrolases; Humans; Immunohistochemistry; Membrane Proteins; Middle Aged; Neoplasm Invasiveness; Nevus, Pigmented; Phenotype; Point Mutation; Proto-Oncogene Proteins B-raf; Skin Neoplasms

Intraocular melanocytoma is a rare naevus variant that can be located at the optic disc or within the uvea, and belongs to the group of non-epithelial-associated melanocytic lesions. We wanted to gain an understanding of the role of GNAQ, GNA11 and BRAF V600E in the pathogenesis of uveal melanocytoma and in cases of transformation to uveal melanoma and also to perform a differential immunohistochemical study comparing melanocytoma with uveal melanoma.. Two patients were identified with melanocytoma, one of which had transformed to melanoma. In the latter case, the melanocytoma exhibited an immunophenotype that featured nuclear p27 and no HMB45 staining, with very low Cyclin D1 expression compared with the melanoma that featured little nuclear but more cytoplasmic p27 positivity, much higher Cyclin D1 expression and HMB45 positivity. The melanocytomas were negative for CD68 allowing distinction from melanophages. Both melanocytomas and the melanoma harboured mutations in GNAQ, with no mutations of GNA11 or BRAF V600E.. GNAQ mutations are present in uveal melanocytomas and in a case of transformation to melanoma, implicating GNAQ-dependent mitogen activation signals, in the pathogenesis of uveal melanocytoma. This assists in explaining why a proportion of uveal melanocytoma can transform to uveal melanoma, known to harbour high-frequency GNAQ mutations at exon 5, codon 209.

Topics: Adolescent; Adult; Cell Transformation, Neoplastic; Chromosomes, Human, Pair 3; Chromosomes, Human, Pair 8; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p27; gp100 Melanoma Antigen; GTP-Binding Protein alpha Subunits; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Immunoenzyme Techniques; In Situ Hybridization, Fluorescence; Male; MART-1 Antigen; Melanoma; Melanoma-Specific Antigens; Mutation; Nevus, Pigmented; Polymerase Chain Reaction; Proto-Oncogene Proteins B-raf; Retrospective Studies; Uveal Neoplasms

Even in experienced hands, the classification of some melanocytic lesions of the conjunctiva remains challenging. In skin pathology, the recent application of fluorescence in situ hybridisation (FISH) has been demonstrated to be of use for the analysis and diagnosis of ambiguous melanocytic neoplasms of the skin. This study set out to evaluate this method on seven prospective conjunctival cases that were histologically equivocal.. 18 unequivocal retrospective melanocytic controls were exposed to FISH. Commercially available probes assessing copy numbers of RREB1 (6p25), MYB (6q23) and CCND1 (11q13) genes compared with CEP6 (a chromosome six centromeric reference point) were used. After control verification, seven prospective, equivocal cases were identified and exposed to FISH.. There was complete correlation between FISH result and the control section histopathology report. Control cases of melanoma cases were all positive for FISH and control benign lesions were negative. Of the seven equivocal cases, five were positive and classed as invasive melanoma or melanoma-in situ, one was negative and one tetraploid, classed as negative (these last two cases were classed as naevi with careful clinical observation).. FISH is very useful in classifying equivocal conjunctival melanocytic lesions, especially those with atypical junctional activity and naevoid melanocytic proliferations of the conjunctiva.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Conjunctival Neoplasms; Cyclin D1; DNA Probes; DNA-Binding Proteins; Female; Humans; In Situ Hybridization, Fluorescence; Male; Melanoma; Middle Aged; Neoplasm Proteins; Nevus, Pigmented; Prospective Studies; Proto-Oncogene Proteins c-myb; Retrospective Studies; Transcription Factors; Young Adult

A decrease in the level of the ROC1 protein, which is involved in cyclin D1 degradation, might explain an increase in cyclin D1 protein in the absence of gene overexpression. This study aimed to investigate the relationship between ROC1 and cyclin D1 expression in skin melanomas. A total of 62 cases of primary skin melanomas and 58 cases of compound melanocytic nevi were assessed. Immunohistochemistry was performed using cyclin D1 and ROC1 antibodies, and fluorescent in situ hybridization was used to assess the amplification of the CCND1 gene. ROC1 was expressed in >50% of cells in 87.9% of the melanocytic nevus cases and in 45.2% of the melanoma cases (p=0.0014). There was a significant negative correlation between ROC1 and cyclin D1 expression in all cases (p=0.0008985). In comparison with cyclin D1, ROC1 expression was increased in 86.2% of the melanocytic nevi and in 45.2% of the melanomas (p<0.001). Among the non-amplified melanomas, 50% expressed cyclin D1 in >50% of the cells and expressed ROC1 in <25%. ROC1 expression is negatively correlated with cyclin D1 expression, demonstrating its importance in the degradation of cyclin D1 in melanomas.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Brazil; Carrier Proteins; Chi-Square Distribution; Child; Child, Preschool; Cyclin D1; Gene Amplification; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Melanoma; Middle Aged; Nevus, Pigmented; Skin Neoplasms; Young Adult

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cyclin D1; Diagnosis, Differential; DNA-Binding Proteins; Female; Fluorescent Dyes; Humans; In Situ Hybridization, Fluorescence; Male; Melanoma; Middle Aged; Nevus, Pigmented; Proto-Oncogene Proteins c-myb; Skin Neoplasms; Transcription Factors; Young Adult

Accurate classification of primary melanocytic tumours as benign or malignant is crucial for prognostic prediction and appropriate patient management. Several chromosomal aberrations have been frequently identified in melanomas, but are absent in melanocytic naevi. We performed four-colour fluorescence in situ hybridisation (FISH) analysis of melanocytic tumours to determine the accuracy of the technique in classifying melanocytic tumours as benign or malignant.. FISH was performed on paraffin-embedded tissue from 40 histologically unequivocal melanocytic tumours (10 metastatic melanomas, 10 primary melanomas and 20 benign melanocytic naevi) using the product Vysis LSI RREB1/LSI MYB/LSI CCND1/CEP 6 probes (Abbott Molecular Laboratories, USA), which is designed to detect the copy number of the RREB1 (6p25), MYB (6q23), and CCND1 (11q13) genes and FISH positivity is defined by means of a scoring algorithm.. FISH distinguished the melanomas and the naevi with a sensitivity of 90% (10/10 primary melanoma cases and 8/10 metastatic melanoma cases, respectively), and a specificity of 95%. The most common abnormalities in the melanomas were increased copies of 11q (70%) and 6p (70%), followed by 6q loss relative to cep6 (50%). Fifteen of the 18 positive melanomas were positive by more than one criterion.. The results of this study show that FISH, using a panel of four probes, is a sensitive and specific method of classifying benign and malignant melanocytic tumours. The four-colour FISH technique has the potential to assist in the stratification of the subgroup of melanocytic tumours which are difficult to classify using conventional histology.

Topics: Adolescent; Adult; Aged; Child; Cyclin D1; DNA-Binding Proteins; Female; Gene Dosage; Genes, myb; Humans; In Situ Hybridization, Fluorescence; Male; Melanoma; Middle Aged; Nevus, Pigmented; Sensitivity and Specificity; Skin Neoplasms; Transcription Factors; Young Adult

Familial acquired dysplastic nevi carry a risk for the development of melanoma. However, the results in various studies regarding the significance of sporadic dysplastic nevi as a precursor of malignant melanoma (MM), are controversial. The aim of this study is to investigate cyclin D1 expression and Ki67 proliferative index in a group of melanocytic lesions to address the biologic significance of sporadic dysplastic nevi in the progression of melanocytic lesions. Formalin-fixed paraffin-embedded material from 21 common melanocytic nevi, 42 dysplastic nevi, and 17 primary cutaneous MMs were examined. Standard streptavidin-biotin immunoperoxidase method was used for immunostaining with cyclin D1 and Ki-67 antibody. Nuclear cyclin D1 immunostaining was scored and Ki-67 proliferative index was calculated. Cyclin D1 expression was significantly higher in melanoma than those in other lesions. However, there was no significant difference between dysplastic nevi and common melanocytic nevi in terms of cyclin D1 expression. Ki-67 index was significantly higher in dysplastic nevi compared with common melanocytic nevi and to melanoma compared with dysplastic nevi. There was a significant positive correlation between cyclin D1 expression and Ki-67 proliferative index for each group. The present study indicates significant differences in cyclin D1 expressions and Ki-67 indices among melanocytic lesions. We think that dysplastic nevi are biologically separate from common melanocytic nevi in terms of proliferative activity. Additionally, our results suggest that cyclin D1 expression may be related to malignant phenotype and is associated with high proliferation rate in MM.

Topics: Biomarkers, Tumor; Cyclin D1; Dysplastic Nevus Syndrome; Humans; Immunohistochemistry; Ki-67 Antigen; Melanoma; Nevus, Pigmented

The tumour suppressor gene product, p16, is often inactivated during melanoma malignant progression. Although the importance of p16 in melanomas is well documented, its relationship with cyclin D1, beta-catenin and ultraviolet radiation (UVR) remains unclear.. To determine the role of these cell cycle-related proteins and high-risk sun exposure in the biological behaviour of melanocytic lesions.. We used immunohistochemistry to examine 28 melanocytic naevi (MN; 9 congenital and 19 acquired types) and 24 primary cutaneous malignant melanomas (CMM; 19 nodular melanomas, 3 lentigo maligna melanomas, 1 acral lentiginous melanoma and 1 superficial spreading melanoma) for the presence of p16, cyclin D1 and beta-catenin. The melanocytic lesions were classified into two groups to examine the effects of UVR on these three proteins: high risk of sun exposure (chronically sun damaged; CSD), or low risk of sun exposure (nonchronically sun damaged; non-CSD). We evaluated the relationship between the production of these proteins and the histopathological and clinical characteristics of the lesions.. Production of p16 was repressed in most CMM, but not in MN (P < 0.0001). Cyclin D1 was overproduced in CMM but not in MN, and beta-catenin was frequently overproduced both in MN and CMM. Overproduction of beta-catenin was not common in CSD melanocytic lesions, but was more frequent in non-CSD melanocytic lesions (P = 0.027).. An immunohistochemical panel including melanocytic markers enriched by p16 and cyclin D1 could be used to differentiate some borderline melanocytic lesions. In addition, the Wnt/beta-catenin pathway was more frequently activated in non-CSD than in CSD melanocytic lesions.

Topics: Adult; Aged; beta Catenin; Biomarkers, Tumor; Cell Cycle Proteins; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Disease Progression; Female; Gene Expression; Humans; Male; Melanoma; Middle Aged; Neoplasm Proteins; Nevus, Pigmented; Skin Neoplasms; Sunlight

Progression through the cell cycle is controlled by cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitory proteins. The role of cyclin D1 in the development and progression of melanomas is controversial. The goal of this study is to evaluate the role of cyclin D1 in benign and malignant melanocytic lesions of the skin.. A total of 126 pigmented lesions of the skin including compound nevi (21), intradermal nevi (18), melanoma in situ (28), primary invasive melanomas (30), and metastatic melanoma (29) were evaluated for cyclin D1 expression. The following tiered system was used for scoring: 0% nuclear staining (score 0), 1% to 19% nuclear staining (score 1), 20% to 49% nuclear staining (score 2), and 50% or greater nuclear staining (score 3).. Average scores were significantly higher for primary melanomas compared with nevi and for in situ melanomas compared with primary invasive melanomas. The average score for metastatic melanomas was not significantly different compared with primary invasive melanomas. Scores for primary invasive melanomas did not correlate with depth of invasion or presence of metastases. Compound nevi exhibited a slightly higher level of cyclin D1 expression compared with intradermal nevi.. Although primary melanomas show a higher level of cyclin D1 expression compared with nevi, cyclin D1 appears to have little role in development of a metastatic phenotype. It is not clear why lesions localized near the dermal-epidermal junction express higher levels of cyclin D1. Further studies are indicated to ascertain the biologic role and practical utility of cyclin D1 in melanocytic lesions of the skin.

Topics: Biomarkers, Tumor; Cyclin D1; Humans; Immunohistochemistry; Melanocytes; Melanoma; Nevus, Pigmented; Skin Neoplasms