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PReferentially expressed Antigen in Melanoma (PRAME) is a cancer testis antigen, first isolated in tumor-reactive T-cell clones from a metastatic melanoma patient. It has been widely studied in skin pathology as an immunohistochemical marker capable of distinguishing between benign nevi and malignant melanomas. PRAME has been found to be also expressed in non-melanocytic tumors, including lung, breast, kidney and ovarian cancer. However, less is known about the diagnostic and/or prognostic role of this protein in uveal melanoma (UM); few studies have reported that PRAME expression seems to give to UM patients an additional metastatic risk beyond the other already-known prognostic parameters. In the present retrospective study, we aimed to correlate PRAME immunoreactivity to other clinico-pathologic features and follow-up data on a large series of 85 cases (45 non-metastasizing and 40 metastasizing tumors) of primary UM. A statistically significant correlation was found between PRAME expression and higher metastatic risk and lower metastasis-free survival. We propose to include PRAME in the immunohistochemical panel of UM as an easily usable marker capable of predicting higher metastatic risk and stratifying patients' outcome., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Neuroblastoma (NB) and malignant cutaneous melanoma (CMM) are neural crest cells (NCC)-derived tumors and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association studies (GWAS). We took a three-staged approach to conduct cross-disease meta-analysis of GWAS for NB and CMM (2101 NB cases and 4202 controls; 12 874 CMM cases and 23 203 controls) to identify shared loci. Findings were replicated in 1403 NB cases and 1403 controls of European ancestry and in 636 NB, 508 CMM cases and 2066 controls of Italian origin. We found a cross-association at locus 1p13.2 (rs2153977, odds ratio = 0.91, P = 5.36 × 10-8). We also detected a suggestive (P < 10-7) NB-CMM cross-association at 2q37.1 with opposite effect on cancer risk. Pathway analysis of 110 NB-CMM risk loci with P < 10-4 demonstrated enrichment of biological processes such as cell migration, cell cycle, metabolism and immune response, which are essential of human NCC development, underlying both tumors. In vitro and in silico analyses indicated that the rs2153977-T protective allele, located in an NB and CMM enhancer, decreased expression of SLC16A1 via long-range loop formation and altered a T-box protein binding site. Upon depletion of SLC16A1, we observed a decrease of cellular proliferation and invasion in both NB and CMM cell lines, suggesting its role as oncogene. This is the largest study to date examining pleiotropy across two NC cell-derived tumors identifying 1p13.2 as common susceptibility locus for NB and CMM risk. We demonstrate that combining genome-wide association studies results across cancers with same origins can identify new loci common to neuroblastoma and melanoma arising from tissues which originate from neural crest cells. Our results also show 1p13.2 confer risk to neuroblastoma and melanoma by regulating SLC16A1., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine, whose role in melanoma is controversial. Although high-dose TNF-α is approved for the treatment of patients with in transit-metastatic melanoma confined to the limb, diverse preclinical models of melanoma have shown that TNF-α can induce cell invasion. Biomarkers that can differentiate between the dual role of TNF-α are needed. TRAF2 is critical to TNF receptor-induced activation of nuclear factor-κB (NF-κB), allowing shifting from death to survival-signaling cascades. The large immunophilin FKBP51 acts as a scaffold and catalyst in the IκB kinase complex assembly and activation. Here, using microscopy and an electrophoretic mobility-shift assay, we provide further evidence in support of the essential role of FKBP51 in sustaining the TNF-α NF-κB signaling in melanoma. Through the cross-linking reaction with the chemical linker disuccinimidyl glutarate, we show that a direct interaction occurs between FKBP51 and TRAF2 in melanoma cells. Immunohistochemistry of tumor samples from 24 patients with cutaneous melanomas showed a correlation between the expressions of the two proteins. Given the association of FKBP51 and TRAF2 with TNF-α-induced NF-κB signaling and their correlation in tumor samples, we propose that the two proteins can be exploited as useful markers for the identification of those melanoma tumors that can benefit from TNF-α inhibition. Future studies will address this hypothesis.

Background: Scalp/neck melanomas have a poor prognosis, possibly because of a rich vascular supply that prompts tumor cells' dissemination., Methods: We compared the accuracy of immunohistochemical (IHC) staining with morphology for the identification of lymphovascular invasion in 156 scalp/neck melanomas. We then analyzed the association of vessel invasion and density with pathological features and survival., Results: IHC-detected lymphatic vessel invasion (LVI) and blood vessel invasion (BVI) were identified in 34.6% and 13.5% of cases, respectively. IHC increased the LVI/BVI detection compared to morphology (40.4% vs 16.6%; p < .001). The degree of peritumoral and intratumoral blood vessel density (BVD) was greater than lymphatic vessel density (LVD). Ulceration was the only factor independently associated with intratumoral (p = .029) and peritumoral (p = .047) BVD. Tumor thickness was the only independent predictor of survival (p = .002)., Conclusion: IHC allows accurate assessment of lymphovascular invasion in scalp/neck melanomas. In these tumors, we observed a high incidence of BVI, which deserves further investigations., (© 2014 Wiley Periodicals, Inc.)

FKBP51 (gene FKBP5) is an immunophilin capable of immunosuppression expressed in melanoma and lymphocytes. We found increased levels of a spliced FKBP5 variant in the PBMCs of 124 patients with melanoma. This variant encodes for an unknown isoform (FKBP51s). We hypothesized that FKBP51s resulted from tumour interaction with immune cells, through PDL-1/PD-1. To address this issue, we performed melanoma/PBMC cocultures. Furthermore, the immunohistochemistry of 76 melanoma specimens served to investigate whether FKBP51s stained tumour infiltrating lymphocytes. Our results showed that PBMCs expressed FKBP51s when cocultured with melanoma. Tumour PDL-1 knockdown or anti-PD-1 reduced FKBP51s expression in cocultured PBMCs. IHC showed a strong FKBP51s signal in tumour infiltrating lymphocytes, and lymphocytes of the invasion front of the tumour, along with melanoma PDL-1 expression. When overexpressed in melanoma, FKBP51s facilitated PDL-1 expression on the cell surface. In conclusion, our study shows that FKBP51s marks the PBMCs of patients with melanoma and is exploited by the tumour to immunomodulate through PDL-1., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

FKBP51 (FKBP5 Official Symbol) is large molecular weight member of the FK506 binding protein family, a subfamily of the immunophilin proteins. FKBP51 exerts multiple biological functions in the cell, including modulation of steroid hormone response, immune regulation, cell proliferation, regulation of pAkt levels and control of NF-κB activation. Several lines of evidence support a role for this protein in cancer biology, especially in resistance to chemo- and radio-therapy. Recent research studies highlighted functions of FKBP51 in promoting the epithelial to mesenchymal transition (EMT) transdifferentiation program in melanoma. This process, which is classically regulated by Transforming Growth Factor (TGF)-β, enables cancer cells to disseminate from primary tumors and spread to distant locations, acquiring resistance to therapy and self-renewal capability. This last, in turn, is crucial to their subsequent expansion at sites of dissemination. The aim of the present article is to review recent literature data that involve FKBP51 in the mechanisms that switch the TGF-β from a tumor suppressor to a pro-metastatic invader.

Melanoma is resistant to most standard chemotherapeutics. We analysed the combined effect of doxorubicin and enzastaurin on cell death of four melanoma cell lines, namely G361, SK-MEL3, A375 and SAN. Enzastaurin IC50 was calculated by measure of growth inhibition with MTS assay and corresponded to 2 μM; the half maximal cytotoxicity of doxorubicin was obtained at 3 μM dose. Evaluation of combination index showed synergism (CI > 1) or additive effect (CI = 1) with all melanoma cell lines, with enzastaurin doses ≥0.6 μM and doxorubicin doses ≥1 μM. Combination of the two drugs resulted in increase in caspase 3 and 8 activation, in comparison with activation by single agents. Caspase 8 activation was impaired by TNFR-1 blocking. Our results show doxorubicin-stimulated production of TNFα, whereas enzastaurin-stimulated TNFR-1 expression on plasma membrane. The effect on TNFR-1 appeared to be mediated by PKCζ inhibition. Taken together, our findings suggest that enzastaurin increases doxorubicin-induced apoptosis of melanoma by a mechanism involving, at least in part, activation of the TNF-α signal., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To understand the role of angiogenesis and hypoxia in cancer progression of primary oral melanoma (POM)., Materials and Methods: Sixteen malignant primary melanomas were immunostained with markers CD34, VEGF and HIF-1α. Stained cells were counted in the invasive front and inside the tumour, and the differences were compared and correlated with histological parameters and disease-specific survival of the patients., Results: Tumour invasive front showed increased MVD and increased vessel VEGF and HIF-1α expression compared with the intratumoural compartment. No such differences were seen in tumoural melanocytes of the two compartments. Positive correlations were observed between CD34 and VEGF, CD34 and HIF-1α and VEGF and HIF-1α expression in invasive front vessels. CD34 expression was statistically correlated with the level of infiltration. A significant trend to worse disease-free survival was also determined with increased invasive front vessel expression of CD34, VEGF and HIF-1α., Conclusions: Our data highlight the importance of the invasive margin in POM biology. The high angiogenic activity and endothelial VEGF and HIF-1α expression in invasive front vessels have a significant impact on patient survival and future agents targeted against VEGF pathway may represent a novel and effective therapeutic opportunity. Larger studies are needed to further address our findings., (© 2012 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Melanoma is the most aggressive skin cancer; there is no cure in advanced stages. Identifying molecular participants in melanoma progression may provide useful diagnostic and therapeutic tools. FK506 binding protein 51 (FKBP51), an immunophilin with a relevant role in developmental stages, is highly expressed in melanoma and correlates with aggressiveness and therapy resistance. We hypothesized a role for FKBP51 in melanoma invasive behaviour. FKBP51 promoted activation of epithelial-to-mesenchymal transition (EMT) genes and improved melanoma cell migration and invasion. In addition, FKBP51 induced some melanoma stem cell (MCSC) genes. Purified MCSCs expressed high EMT genes levels, suggesting that genetic programs of EMT and MCSCs overlap. Immunohistochemistry of samples from patients showed intense FKBP51 nuclear signal and cytoplasmic positivity for the stem cell marker nestin in extravasating melanoma cells and metastatic brains. In addition, FKBP51 targeting by small interfering RNA (siRNA) prevented the massive metastatic substitution of liver and lung in a mouse model of experimental metastasis. The present study provides evidence that the genetic programs of cancer stemness and invasiveness overlap in melanoma, and that FKBP51 plays a pivotal role in sustaining such a program.

Purpose: The prevalence of BRAF, NRAS, and p16CDKN2A mutations during melanoma progression remains inconclusive. We investigated the prevalence and distribution of mutations in these genes in different melanoma tissues., Patients and Methods: In all, 291 tumor tissues from 132 patients with melanoma were screened. Paired samples of primary melanomas (n = 102) and synchronous or asynchronous metastases from the same patients (n = 165) were included. Tissue samples underwent mutation analysis (automated DNA sequencing). Secondary lesions included lymph nodes (n = 84), and skin (n = 36), visceral (n = 25), and brain (n = 44) sites., Results: BRAF/NRAS mutations were identified in 58% of primary melanomas (43% BRAF; 15% NRAS); 62% in lymph nodes, 61% subcutaneous, 56% visceral, and 70% in brain sites. Mutations were observed in 63% of metastases (48% BRAF; 15% NRAS), a nonsignificant increase in mutation frequency after progression from primary melanoma. Of the paired samples, lymph nodes (93% consistency) and visceral metastases (96% consistency) presented a highly similar distribution of BRAF/NRAS mutations versus primary melanomas, with a significantly less consistent pattern in brain (80%) and skin metastases (75%). This suggests that independent subclones are generated in some patients. p16CDKN2A mutations were identified in 7% and 14% of primary melanomas and metastases, with a low consistency (31%) between secondary and primary tumor samples., Conclusion: In the era of targeted therapies, assessment of the spectrum and distribution of alterations in molecular targets among patients with melanoma is needed. Our findings about the prevalence of BRAF/NRAS/p16CDKN2A mutations in paired tumor lesions from patients with melanoma may be useful in the management of this disease.

Background: Early excision is the only strategy to reduce melanoma mortality, but unnecessary excision of benign lesions increases morbidity and healthcare costs., Objective: To assess accuracy in melanoma detection based on number-needed-to-excise (NNE) values over a 10-year period., Methods: Information was retrieved on all histopathologically confirmed cutaneous melanomas or melanocytic nevi that were excised between 1998 and 2007 at participating clinics. NNE values were calculated by dividing the total number of excised lesions by the number of melanomas. Analyses included changes in NNE over time, differences in NNE between specialized clinical settings (SCS) versus non-specialized clinical settings (NSCS), and patient factors influencing NNE., Results: The participating clinics contributed a total of 300,215 cases, including 17,172 melanomas and 283,043 melanocytic nevi. The overall NNE values achieved in SCS and NSCS in the 10-year period were 8.7 and 29.4, respectively. The NNE improved over time in SCS (from 12.8 to 6.8), but appeared unchanged in NSCS. Most of the effect on NNE in SCS was due to a greater number of excised melanomas. Higher NNE values were observed in patients younger than 40 years and for lesions located on the trunk., Limitations: No data concerning the use of dermatoscopy and digital monitoring procedures were collected from the participating centers., Conclusion: Over the 10-year study period, accuracy in melanoma detection improved only in specialized clinics maybe because of a larger use of new diagnostic techniques such as dermatoscopy., (Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Fourier transform infrared (FTIR) microspectroscopy has been employed to investigate benign (ordinary dermal and Reed nevi), dysplastic and malignant (invasive melanoma) skin lesions through the analysis of spectral changes of melanocytes as well as in the evaluation of the presence of melanin. Hierarchical cluster analysis and principal component analysis led to a satisfactory separation of malignant from dysplastic and normal melanocytes. Also, on enlarging the clustering with spectra from Reed and dermal nevi, the multivariate analysis segregated well the spectral data into discrete clusters, allowing the obtaining of reliable average spectra for analysis at the molecular level of the main groups or components responsible for the biological and biochemical changes. The most significant spectral characteristics appear to be related to differences in secondary protein structures, in nucleic acid conformation, in intra- and intermolecular bonding. In all cases, supervised and unsupervised spectral analyses resulted in satisfactory agreement with histopathological findings.

Background: Cutaneous melanoma (CM) is the most lethal form of skin malignancy, which registers a constant increase in incidence worldwide. The identification of molecular alteration(s) involved in its biological aggressiveness represents a major challenge for researchers, considering that existing therapies are ineffective to treat metastasizing cases. The epigenetic control of chromatin dynamics during DNA synthesis, replication, and repair is fundamental for the orderly progression of cell proliferation. The Chromatin Assembly Factor 1 (CAF-1) complex acts as a major regulator of this process; its intermediate (p60) subunit has been recently proposed as a novel proliferation and prognostic marker for several tumors. We aimed to establish if the evaluation of the expression of CAF-1/p60 in primary CM may help define the prevision of outcome of patients., Methods: Immunohistochemistry with anti-CAF-1/p60 was performed on paraffin-embedded tissue sections of 130 cases of primary CM retrieved from the archive files of the Department of Biomorphological and Functional Sciences, Section of Pathology, University "Federico II" of Naples, Italy. Results were compared with histopathological and follow-up data of patients., Results: CAF-1/p60 was expressed in all CM. A significant statistical association between the overexpression of the protein and the occurrence of skin, node and/or distant metastases (P < 0.05) emerged, independently from histopathological prognostic factors., Conclusions: CAF-1/p60 looks promising as a new prognostic marker for CM and sheds new light on the molecular events associated with photocancerogenesis and melanoma biology.The screening for CAF-1/p60 might contribute to the molecular sub-classification of CM, with improved translational outcomes.

FK506-binding protein 51 (FKBP51) is an immunophilin with isomerase activity, which performs important biological functions in the cell. It has recently been involved in the apoptosis resistance of malignant melanoma. The aim of this study was to investigate the possible role of FKBP51 in the control of response to ionizing radiation (Rx) in malignant melanoma. FKBP51-silenced cells showed reduced clonogenic potential after irradiation compared with non-silenced cells. After Rx, we observed apoptosis in FKBP51-silenced cells and autophagy in non-silenced cells. The FKBP51-controlled radioresistance mechanism involves NF-kappaB. FKBP51 was required for the activation of Rx-induced NF-kappaB, which in turn inhibited apoptosis by stimulating X-linked inhibitor of apoptosis protein and promoting authophagy-mediated Bax degradation. Using a tumor-xenograft mouse model, the in vivo pretreatment of tumors with FKBP51-siRNA provoked massive apoptosis after irradiation. Immunohistochemical analysis of 10 normal skin samples and 80 malignant cutaneous melanomas showed that FKBP51 is a marker of melanocyte malignancy, correlating with vertical growth phase and lesion thickness. Finally, we provide evidence that FKBP51 targeting radiosensitizes cancer stem/initiating cells. In conclusion, our study identifies a possible molecular target for radiosensitizing therapeutic strategies against malignant melanoma.

Purpose: Although relatively rare, uveal melanoma is the most common ocular tumor of adults. Up to half of uveal melanoma patients die of metastatic disease. CXCR4, a chemokine receptor, is a prognostic factor in cutaneous melanoma involved in angiogenesis and metastasis formation. The aim of this study was to evaluate the expression of CXCR4 in uveal melanoma., Methods: CXCR4 was detected by immunohistochemistry in 44 samples of uveal melanoma. Staining was categorized into three semiquantitative classes based on the rate of stained (positive) tumor cells: absence of staining, <50% of cell (+) and >50% (++). Correlations between CXCR4 expression, data on patient and tumor features were studied by contingency tables and the chi2 test. Time-to-event curves were studied using the Kaplan-Meier method. Univariate analysis was performed using the log-rank test. Ninety-five percent confidence intervals (95% CI) of hazard ratios were also reported., Results: Staining for CXCR4 protein was absent in 18 tumors (40.9%), present in <50% of cells in 19 (43.2%) and in >50% of cells in 7 (15.9%) tumors. CXCR4 expression correlated to the epithelioid-mixed cell type (P=0.030). No statistically significant relation emerged between CXCR4 expression, largest tumor diameter (LTD) and extracellular matrix patterns as evaluated through histological patterns stained with periodic acid-Schiff (PAS). Events occurred in 2 out of 18 patients (11.1%) with negative tumors (2 deaths), in 3 out of 19 patients (15.8%) with <50% of positive tumor cells (2 deaths and 1 occurrence of metastases) and in 1 out of 7 patients (14.3%) with >50% of positive tumor cells (1 occurrence of metastases). The cell type (P=0.0457) but not CXCR4 showed prognostic value at univariate analysis., Conclusion: This study shows that CXCR4 is commonly expressed in uveal melanoma and correlates with cell type a well-established prognostic factor.

Experimental and clinical evidence indicate that immunological mechanisms might be important in the clinical course of uveal malignant melanoma (UMM). We analyzed the amount and phenotype of tumor infiltrating lymphocytes (TIL) and the expression of the apoptosis-inducing molecule Fas and its ligand, FasL, on tumor cells and TIL in a selected series of UMM with the aim to establish if a correlation between their expression and the clinical behavior of UMM exists. TIL phenotype and Fas/FasL expression were evaluated by immunohistochemistry in 61 cases of formalin-fixed, paraffin-embedded UMM. Results were compared with the follow-up data of patients. Most of the UMM showed a prevalence of CD8+ CD3+ T lymphocytes, or CD4+ and CD8+ cells in equal amounts. UMM showed a variable expression of FasL, ranging from 0 to > 40% of neoplastic cells. Fas was always expressed in TIL, although with a variable extent. A subgroup of UMM showed in TIL a strongly reduced or even absent expression of TCR zeta-chain, involved in activation of T-lymphocytes. This subgroup was characterized by a worse outcome. We hypothesized that an impaired cytotoxic immune response due to the loss of the zeta-chain expression plays a primary role in the biological course of UMM. Our results indicate that the overcoming of the impairment of TCR function may represent a prerequisite for the development of new therapeutic strategies for managing UMM, suggesting that elimination of tumor cells may be possible by activation of cytotoxic cells present within ocular melanomas.

The family of the poly(adenosine diphosphate-ribose) polymerase (PARP) proteins is directly involved in genomic stability, DNA repair, and apoptosis by DNA damage. In this study, we evaluated the role of PARP-1 in melanoma and its prognostic importance. We studied by immunohistochemistry and Western blot analysis PARP-1 expression in a selected series of 80 primary melanoma of the head and neck region. The results were correlated with tumor thickness and patient's outcome. A follow-up of at least 3 years was available. Fifteen cases of benign melanocytic nevi were used as controls. Normal melanocytes showed only scattered, focal nuclear positivity and were considered as negative for PARP-1 expression by immunohistochemistry (score, 0). Thirty cases of melanoma (37.5%) showed nuclear expression of PARP-1 in both radial and vertical growth phases. Western blot analysis showed the presence of a high signal for full-length PARP-1 only in the cases with high immunohistochemical (nuclear) expression of protein (score, ++/+++) in both radial and vertical growth phase. A significant correlation was present between PARP-1 expression in vertical growth phase and the thickness of tumor lesion (P = .014); all but one tumor measuring less than 0.75 mm showed no or low PARP-1 expression. No correlation was found between PARP-1 expression in radial growth phase and tumor thickness (P = .38, data not shown). These data suggest that PARP-1 overexpression is a potential novel molecular marker of aggressive cutaneous malignant melanoma and a direct correlation between PARP-1-mediated inhibition of the apoptosis and biologic behavior of cutaneous malignant melanoma.

Purpose: To determine the efficacy of echography with new generation contrast agents in visualizing vascularization of choroidal malignant melanomas., Methods: An echographic contrast medium consisting of phospholipidic microbubbles filled with sulphur hexafluoride (Sonovue) was used to visualize microcirculation in 25 cases of choroidal lesions already diagnosed with standardized echography (21 choroidal malignant melanomas, four disciform lesions)., Results: In untreated malignant melanomas contrast agent echography revealed the presence of a dense microcirculation inside the mass. In one case vitreal seeding of the contrast agent was detectable before enucleation and histological examination revealed the presence of tumoral cells. In 12 cases treated with transpupillary thermotherapy, contrast agent echographic evaluation showed heavy regression of microcirculation after 1 week, confirmed in one case by histology, and a reduction of 70-80% in dimensions after 6 months (which appeared to have stabilized at subsequent examinations). In four cases treated with proton beam brachytherapy 2 years prior to our examination, contrast agent echography showed the absence of a microvascular network and the presence of large vessels and blood lakes. In four cases of disciform lesion, deep and superficial retina-associated vascularization was observed, with a weak spread of contrast agent inside the lesion., Conclusion: Live representation with good resolution of choroidal malignant melanoma microcirculation was obtained.

Background: Benign melanocytic skin lesions may be difficult to differentiate from melanoma both clinically and dermoscopically. One of the most confounding dermoscopic features, commonly seen in melanoma but in our experience also in melanocytic naevi, is represented by the so-called blue-white structures (BWS)., Objectives: To evaluate diagnostic significance and histopathological correlates of BWS seen by dermoscopy in a series of clinically equivocal melanocytic skin lesions that were excised., Methods: Patients were recruited from six specialized pigmented lesion clinics in Austria, Italy and Spain over a period of 9 months. All consecutive patients showing one or more melanocytic lesions with BWS, but not classified as melanoma dermoscopically, were included. Each lesion was photographed clinically and dermoscopically. All images were reviewed by one of us and the degree, type and location of BWS evaluated for each lesion. A panel of four experienced dermatopathologists independently reviewed all specimens for diagnosis and one of them evaluated presence and degree of melanosis and/or fibrosis. The main outcome measures were the percentage and histopathological correlates of lesions with different degree, type and location of BWS., Results: All included lesions with BWS (n = 158) showed partial or focal regression histopathologically. One hundred and thirty-five (85.4%) lesions were diagnosed as melanocytic naevi (complete histopathological interobserver agreement), whereas 23 (14.6%) were defined as equivocal because at least one of four pathologists diagnosed the given lesion as melanoma. Only one lesion was diagnosed as melanoma by all four pathologists. The majority of naevi exhibited blue areas (84.4%) with a central distribution (57%) and involving < 50% of the lesion surface (89.6%). By contrast, 78.3% of equivocal lesions revealed a combination of white and blue areas with an irregular distribution (60.9%) and involving > 50% of the lesion surface (47.8%)., Conclusions: Using degree and type of BWS, an algorithm was constructed that can be applied for the management of lesions exhibiting dermoscopic features of regression.

Background: Uveal malignant melanoma (MM) is characterized by a marked variability in biological behavior and by an unpredictable clinical course. Therefore the search for reliable prognostic parameters is active. In this study we investigated the immunohistochemical expression of cyclin D1, a cell cycle regulatory molecule, to analyze the possible significance of the protein in the prognostic evaluation of these neoplasms., Materials and Methods: Forty-five selected uveal MM were incubated with the anti-cyclin D-1 antibody; the findings were compared with the follow-up data, with the cell type and with the largest tumor dimension., Results: The overexpression of cyclin D1 was found to be inversely related to disease-free interval (p < 0.001) and to the spindle A/B tumors with good prognosis (p = 0.05). On the other hand, a direct correlation was found with epithelioid/spindle B melanomas with poor clinical course (p = 0.05) and with sclera infiltration (p = 0.01). No statistically significant relation emerged between cyclin D1 expression and LTD., Conclusion: These data may suggest a possible role of the overexpression of cyclin D1 in the tumorigenesis of uveal MM and in the prognostic evaluation of these tumors, representing a useful tool to subclassify lesions with similar morphological features.

Background: There is a need for better standardization of the dermoscopic terminology in assessing pigmented skin lesions., Objective: The virtual Consensus Net Meeting on Dermoscopy was organized to investigate reproducibility and validity of the various features and diagnostic algorithms., Methods: Dermoscopic images of 108 lesions were evaluated via the Internet by 40 experienced dermoscopists using a 2-step diagnostic procedure. The first-step algorithm distinguished melanocytic versus nonmelanocytic lesions. The second step in the diagnostic procedure used 4 algorithms (pattern analysis, ABCD rule, Menzies method, and 7-point checklist) to distinguish melanoma versus benign melanocytic lesions. kappa Values, log odds ratios, sensitivity, specificity, and positive likelihood ratios were estimated for all diagnostic algorithms and dermoscopic features., Results: Interobserver agreement was fair to good for all diagnostic methods, but it was poor for the majority of dermoscopic criteria. Intraobserver agreement was good to excellent for all algorithms and features considered. Pattern analysis allowed the best diagnostic performance (positive likelihood ratio: 5.1), whereas alternative algorithms revealed comparable sensitivity but less specificity. Interobserver agreement on management decisions made by dermoscopy was fairly good (mean kappa value: 0.53)., Conclusion: The virtual Consensus Net Meeting on Dermoscopy represents a valid tool for better standardization of the dermoscopic terminology and, moreover, opens up a new territory for diagnosing and managing pigmented skin lesions.

Background: Dermoscopy (dermatoscopy, epiluminescence microscopy) is increasingly employed for the preoperative detection of cutaneous melanoma; dermoscopic features of pigmented skin lesions have been previously defined using histopathology as the key to the code. In a preliminary study on 10 cases evaluated by nine dermoscopists and nine histopathologists, the authors experienced that when at least two dermoscopists disagree in evaluating a melanocytic lesion, even histopathologic consultations may give equivocal results., Methods: One hundred seven melanocytic skin lesions, consecutively excised because of equivocal clinical and/or dermoscopic features, were retrospectively examined by eight dermoscopists and eight histopathologists; the diagnostic interobserver agreement was calculated by means of the Schouten k statistics. After histopathologic consultations, all 107 lesions underwent unblinded dermoscopic re-evaluation in order to find which dermoscopic features had given rise to histopathologic diagnostic difficulties., Results: The interobserver ageement was good for both dermoscopy (k = 0.53) and histopathology (k = 0.74). Out of 48 cases evaluated by the dermoscopists in complete accordance, only 8 (16.7%) received at least one conflicting histopathologic diagnosis. Instead, among the remaining 59 cases with at least one disagreeing dermoscopic diagnosis, 21 (35.6%) received at least one disagreeing histopathologic diagnosis. The unblinded dermoscopic re-evaluation showed that five out of seven lesions with clear-cut regression structures were histopathologically controversial., Conclusions: At least for selected and reasonably difficult lesions, a diagnostic discrepancy among formally trained dermoscopists seems to be predictive for a diagnostic disagreement among histopathologists. Lesions showing clear-cut regression structures are prone to give some histopathologic disagreement., (Copyright 2002 American Cancer Society.)

We describe 5 cases of "compound blue nevus" (CBN) ("superficial blue nevus with prominent intraepidermal dendritic melanocytes," "Kamino nevus"). Dermoscopically in 2 of 4 cases the bluish pigmentation characteristic of blue nevi was centrally replaced by a black lamella, with black dots and brown globules also observed in one case, thus revealing a structural asymmetry suggestive of melanoma. Histopathologically, pigmented parakeratosis was the underlying histopathologic finding of black lamella and dots/globules. Immunohistochemistry highlighted the unique histopathologic feature of CBN, namely, single dendritic melanocytes at the dermoepidermal junction with striking intraepidermal prolongations. Our findings confirm that CBN is a distinctive variant of blue nevus that may mimic cutaneous melanoma both clinically and dermoscopically.

Ultraviolet (UV) radiation plays a pivotal role in skin damage and photocarcinogenesis. The basic mechanism of phototoxicity lies in DNA damage, and involves mutation of tumor suppressor genes, oncogenes and genes directly involved in the control of the stability of genome, such as the mismatch repair (MR) genes. The goal of this study was to evaluate the role of p53 and hMSH2 in the UV-related carcinogenetic process. An immunohistochemical study for p53 and hMSH2 was performed in a series of 43 basal cell carcinomas (BCC) and 60 melanomas (MM) from photoexposed areas of head and neck region, comparing the findings with follow-up. A deregulated p53 expression characterized less differentiated, more aggressive BCC (BCC2) but not the well-differentiated ones (BCC1). The hMSH2 protein was present, though expressed at varying levels, in 18 out of 21 BCC1 cases and in 4 out of 22 BCC2. In the remaining 3 cases of BCC1 and 18 cases of BCC2, a complete absence of hMSH2 expression was found, correlating directly with the presence of recurrence and/or death of the disease in case of melanoma (p<0.05). Overall, the expression of hMSH2 correlated inversely with the p53 overexpression (p<0.01). In MM, p53 was found overexpressed in 81.6% of the cases, and this correlated positively with the level of infiltration and with the presence of relapses (p<0.01) or metastasis (p<0.01) and inversely with the disease-free interval (p<0.05). These results are in agreement with the reported association between p53 deregulation and a more aggressive cancer phenotype. The evaluation of the expression of p53 and hMSH2 could improve the management of patients with BCC and MM, and could have a role also in the evaluation of the early cutaneous photo-inducted damage, contributing to the identification of presymptomatic patients predisposed to the development of UV-related new skin tumors, who could become candidates for chemoprevention trials.

Aims and Background: Dermoscopy (dermatoscopy, skin surface microscopy, epiluminescence microscopy) has been increasingly employed in recent years for the preoperative detection of cutaneous melanoma, and dermatoscopic features of pigmented skin lesions have been previously defined using histopathology (HP) as the "key to the code". The aim of the present study was to evaluate the interobserver agreement on the HP diagnosis in a series of epiluminescence microscopy equivocal melanocytic skin lesions., Study Design: Ten melanocytic skin lesions were selected on the basis of diagnostic disagreement of at least 2 out of 9 epiluminescence microscopy observers. The histologic specimens from the 10 lesions were examined by 9 HP observers. The agreement of the HP diagnoses was calculated by means of Fleiss' k statistics., Results: The overall HP agreement was less than excellent (k = 0.5). When considering the prevailing epiluminescence microscopic and HP diagnoses, 2 cases were shown to be epiluminescence microscopy false-negative melanomas. Virtually no agreement was found among epiluminescence microscopy observers in 4 cases (40%) or among HP observers in 3 cases (30%). However, only one pigmented skin lesion remained unclassifiable on epiluminescence microscopy as well as HP., Conclusions: When at least 2 epiluminescence microscopy experts disagree in the evaluation of a given melanocytic skin lesion, even HP consultations may give equivocal results. The need to establish more reliable epiluminescence microscopic and HP criteria by performing an improved and meticulous clinicopathologic correlation, e.g. by using telecommunication via Internet, is emphasized.

Background: The DNA mismatch repair system (MMR) plays an important role in the maintenance of genomic stability. To date few studies have been performed on hMSH2 and hMLH1 expression and melanoma of the head and neck region. A study of two cases revealed no mutations of the mismatch repair genes hMSH2 and hMLH1., Materials and Methods: To verify the possibility of implication of hMSH2 and hMLH1 alterations in melanocytic cancerogenesis, the authors examined the protein expression pattern of hMSH2 and hMLH1 by immunohistochemistry in 9 paraffin-embedded oral melanoma., Results: One case (11%) showed nuclear positivity for hMSH2, 3 cases (33%) showed cytoplasmic positivity, and five cases (55%) showed no staining in the tumoral cells, even if normal squamous epithelium available in this section showed a nuclear positivity. Four cases (44%) showed no hMLH1 staining in the tumoral cells, even if normal squamous epithelium available in this section showed a nuclear positivity. Two cases (22%) showed nuclear positivity, and three cases (33%) showed cytoplasmic positivity., Conclusions: The analysis of mismatch repair genes can be a new molecular diagnostic tools for the detection of patients at high risk of developing melanoma and other neoplasia, or metastasis and recurrences.

Epiluminescence microscopy (ELM, skin surface microscopy, dermoscopy, dermatoscopy) is a valuable method for improving the diagnostic accuracy in pigmented skin lesions. Specific ELM criteria are already recognized for differentiating pigmented Spitz naevi (PSN) from cutaneous melanomas (CM). Our purpose was to describe the ELM appearance of a series of PSN with emphasis on PSN and CM with overlapping features. Thirty-six consecutive patients with PSN, and three cases of CM (selected from a larger database) exhibiting ELM 'spitzoid' features, were evaluated clinically, dermatoscopically and histopathologically. Most PSN (27 of 36; 75%) displayed two typical ELM patterns, namely, the starburst (19 of 36; 53%) or the globular pattern (eight of 36; 22%), which were correlated to different histopathological findings. In nine of 36 (25%) PSN, atypical ELM features which are more commonly seen in CM were observed. These PSN with an atypical pattern were characterized by an uneven distribution of colours and structures, and an irregular diffuse pigmentation resembling blue-white veil or irregular extensions (black blotches). These atypical lesions mostly occurred in children and showed no history of growth. In contrast, in three examples of CM, the typical ELM criteria of malignancy were less recognizable and either the characteristic starburst or globular pattern usually seen in PSN was present. These three lesions occurred in adults and had a recent history of change in colour, shape or size. The overlap in ELM features of some PSN and CM represents a major diagnostic pitfall when ELM examination is considered alone. In these atypical cases, clinical history including the age of the patient may be the only clue to enable a correct diagnosis.

Objective: To define the value of silver-stained nucleolar organizer regions (AgNOR) in the evaluation of uveal malignant melanomas (MM)., Study Design: Morphometric analysis of AgNORs was performed on 30 uveal MM of spindle A, B, epithelioid and mixed cell types. Findings were compared with cytotype, largest tumor dimension (LTD) and clinical outcome., Results: AgNOR mean perimeter (MP) was 3.76 microns (SD 1.21, range 1.79-8.51 microns) in A, 5.05 microns (SD 1.96, range 1.79-16.41 microns) in B and 6.15 microns (SD 3.86, range 1.79-33.80 microns) in epithelioid MM; mean area (MA) was 0.86 micron 2 (SD 0.60, range 0.20-2.78 microns 2) in A, 1.58 microns 2 (SD 1.11, range 0.20-9.63 microns 2) in B and 2.34 microns 2 (SD 2.10, range 0.20-15.27 microns 2) in epithelioid MM; the aspect ratio (AR) was 3.10 (SD 0.19, range 2.90-3.35) in A, 5.80 (SD 2.07, range 3.77-9.32) in B and 12.22 (SD 2.84, range 8.11-15.81) in epithelioid MM. From comparing MA and RA with follow-up, it seemed that MM with a good prognosis (spindle A and a subgroup of B tumors, B1) exhibited the lowest MA and AR values, while MM with poorer clinical behavior (epithelioid and a second subgroup of spindle B MM, B2) showed the highest. No correlation was found between AgNORs and LTD., Conclusion: AgNORs may contribute to the prognostic evaluation of uveal MM.

Primary malignant melanoma of the ovary is an exceedingly rare pathologic event: only eight cases have been reported in literature and in every case they arised in a cystic mature teratoma. The differential diagnosis of primary malignant melanoma is a challenge for pathologist: in fact it must be differentiated by metastatic melanoma and by numerous primary ovarian tumours. We report a rare case of primary malignant melanoma of the ovary with immunohistochemical and ultrastructural study and with a review of the literature.