Novel insights into the BAP1-inactivated melanocytic tumor.

BAP1-inactivated melanocytic tumor (BIMT) is a group of melanocytic neoplasms with epithelioid cell morphology molecularly characterized by the loss of function of BAP1, a tumor suppressor gene located on chromosome 3p21, and a mutually exclusive mitogenic driver mutation, more commonly BRAF. BIMTs can occur as a sporadic lesion or, less commonly, in the setting of an autosomal dominant cancer susceptibility syndrome caused by a BAP1 germline inactivating mutation. Owing to the frequent identification of remnants of a conventional nevus, BIMTs are currently classified within the group of combined melanocytic nevi. "Pure" lesions can also be observed. We studied 50 BIMTs from 36 patients. Most lesions were composed of epithelioid melanocytes of varying size and shapes, resulting extreme cytomorphological heterogeneity. Several distinctive morphological variants of multinucleated/giant cells were identified. Some hitherto underrecognized microscopic features, especially regarding nuclear characteristics included nuclear blebbing, nuclear budding, micronuclei, shadow nuclei, peculiar cytoplasmic projections (ant-bear cells) often containing micronuclei and cell-in-cell structures (entosis). In addition, there were mixed nests of conventional and BAP1-inactivated melanocytes and squeezed remnants of the original nevus. Of the 26 lesions studied, 24 yielded a BRAF mutation, while in the remaining two cases there was a RAF1 fusion. BAP1 biallelic and singe allele mutations were found in 4/22 and 16/24 neoplasms, respectively. In five patients, there was a BAP1 germline mutation. Six novel, previously unreported BAP1 mutations have been identified. BAP1 heterozygous loss was detected in 11/22 lesions. Fluorescence in situ hybridization for copy number changes revealed a related amplification of both RREB1 and MYC genes in one tumor, whereas the remaining 20 lesions studied were negative; no TERT-p mutation was found in 14 studied neoplasms. Tetraploidy was identified in 5/21 BIMTs. Of the 21 patients with available follow-up, only one child had a locoregional lymph node metastasis. Our results support a progression of BIMTs from a conventional BRAF mutated in which the original nevus is gradually replaced by epithelioid BAP1-inactivated melanocytes. Some features suggest more complex underlying pathophysiological events that need to be elucidated.

Recurrent lentigo maligna in a young patient.

Lentigo maligna (LM) is usually diagnosed in sun-damaged skin of elderly patients and a correct excision of the lesion determines a complete healing from the disease. LM is very rare in young patients and, for this reason, it can be commonly misdiagnosed. We describe the case of a locally recurrent LM in a 19-year-old male patient, which initially arose at the age of 17 years. In order to avoid diagnostic pitfalls, clinicians have to put more emphasis on diseases which previously were prerogative only of elderly patients and that now could begin to engage a younger age, according to climate and behavior changes.

Ribociclib-Induced Erythema Dyschromicum Perstans (Ashy Dermatosis)-Like Pigmentation in a Metastatic Breast Cancer Patient.

Ribociclib is a selective cyclin-dependent kinase (CDK) 4/6 inhibitor that has been approved in combination with endocrine therapy for the treatment of hormone receptor-positive/human epidermal growth factor 2-negative advanced or metastatic breast cancer. The main dermatological adverse events associated with CDK 4/6 inhibitors that are described in the literature include skin rash, an increased risk of alopecia, and stomatitis. Erythema dyschromicum perstans (EDP), also known as ashy dermatosis, is characterized by acquired small and large slate-gray hyperpigmented macules with erythematous borders. There are currently no published reports of EDP-like or pigmentary changes induced by CDK 4/6 inhibitors. This report describes the first case of EDP-like pigmentation associated with ribociclib therapy.

Beta HPV Type 15 Can Interfere With NF-κB Activity and Apoptosis in Human Keratinocytes.

E7 protein from cutaneous as well as mucosal HPV types can alter NF-κB activity. Conflicting literature data show a HPV-induced up- or down-regulation of the NF-κB pathway in different cell lines. In a previous study we detected the expression of E7 gene of HPV15 in a subungual tumor of a patient affected by incontinentia pigmenti (IP). IP is a rare X-linked genodermatosis in which the IKKγ gene is altered. From observations in transgenic IKKγ defective mice, it was suggested that IKK-deficient cells may undergo rapid hyper-proliferation and apoptosis/necrosis, leading to increased pro-inflammatory cytokine production in the neighboring IKK-positive cells. The objective of this study was to ascertain if beta HPV 15 can alter apoptosis and NF-κB pathway in normal and IKKγ-deficient keratinocytes. The human immortalized keratinocyte cell line (HaCaT), and human primary keratinocyte (HPK) cells were transduced with a retrovirus expressing E6-E7 proteins of HPV 15 and IKKγ was successful silenced mimicking the HPV15 infection and IP. HPV15 E6-E7 gene expression improved NF-κB activity in human keratinocytes even when IKKγ was silenced by siRNA. In IKKγ silenced keratinocyte cells, TNF-α-induced apoptosis was strongly reduced by the expression of HPV15 E6-E7 genes. Beta HPV15 exerted this anti-apoptotic activity by decreasing pro-apoptotic BAK and cleaved Caspase 3 proteins. In conclusion, we can speculate that presence of persistent infection by beta papillomavirus might influence the biological fate of IP by altering NF-κB activation and apoptosis in IKKγ mutated cells, favoring their survival and possibly the development of tumors in the late stage of disease. Taken together, our data reinforce the importance of host genetic background in the pathogenesis of HPV-associated skin lesions.

MiRNAs as Potential Prognostic Biomarkers for Metastasis in Thin and Thick Primary Cutaneous Melanomas.

BACKGROUND/AIM: The identification of novel prognostic biomarkers for melanoma metastasis is essential to improve patient outcomes. To this aim, we characterized miRNA expression profiles in relation to metastasis in melanoma and correlated miRNAs expression with clinical-pathological factors. MATERIALS AND METHODS: MiR-145-5p, miR-150-5p, miR-182-5p, miR-203-3p, miR-205-5p and miR-211-5p expression levels were analyzed in primary cutaneous melanomas, including thin and thick melanomas, and in melanoma metastases by quantitative Real-Time PCR. RESULTS: A significantly lower miR-205-5p expression was found in metastases compared to primary melanomas. Furthermore, a progressive down-regulation of miR-205-5p expression was observed from loco-regional to distant metastasis. Significantly lower miR-145-5p and miR-203-3p expression levels were found in cases with Breslow thickness >1 mm, high Clark level, ulceration and mitotic rate ≥1/mm2 Conclusion: Our findings point to miR-205-5p as potential biomarker of distant metastases and to miR-145-5p and miR-203-3p as markers of aggressiveness in melanoma.

Metastases risk in thin cutaneous melanoma: prognostic value of clinical-pathologic characteristics and mutation profile.

BACKGROUND: A high percentage of patients with thin melanoma (TM), defined as lesions with Breslow thickness ≤1 mm, presents excellent long-term survival, however, some patients develop metastases. Existing prognostic factors cannot reliably differentiate TM patients at risk for metastases. OBJECTIVE: We aimed at characterizing the clinical-pathologic and mutation profile of metastatic and not-metastatic TM in order to distinguish lesions at risk of metastases. METHODS: Clinical-pathologic characteristics were recorded for the TM cases analyzed. We used a Next Generation Sequencing (NGS) multi-gene panel to characterize TM for multiple somatic mutations. RESULTS: A statistically significant association emerged between the presence of metastases and Breslow thickness ≥0.6 mm (p=0.003). None of TM with lymph-node involvement had Breslow thickness <0.6 mm. Somatic mutations were identified in 19 of 21 TM analyzed (90.5%). No mutations were observed in two not-metastatic cases with the lowest Breslow thickness (≤0.4 mm), whereas mutations in more than one gene were detected in one metastatic case with the highest Breslow thickness (1.00 mm). CONCLUSION: Our study indicates Breslow thickness ≥0.6 mm as a valid prognostic factor to distinguish TM at risk for metastases.

Expression and potential role of cellular retinol binding protein I in psoriasis.

Psoriasis is a diffuse chronic skin disorder characterized from accelerated epidermal turnover and inflammatory cell infiltrate. Retinoids influence keratinocyte proliferation and differentiation as well as inflammatory response. Cellular retinol binding protein (CRBPI) regulates intracellular vitamin A bioavailability and contributes to maintain skin homeostasis. The aim of present study was to investigate the expression of CRBPI and its role in the pathogenesis of skin psoriasis. Immunohistochemistry revealed more diffuse and increased CRBPI expression in all epidermal layers of human psoriatic lesions except in the stratum corneum. An imiquimod-induced psoriatic-like model documented the increase of skin lesional area and severity index score as well as of the severity of microscopic features as parakeratosis, papillomatosis and spongiosis in CRBPI-knockout compared to wild-type mice, associated to the increased keratinocyte CK17 and Ki-67 expression and the reduction of CK1, CRABPII and RXRα. Gene array of imiquimod-induced psoriatic skin documented the greater up-regulation of EGF/PDGF-related genes and down-regulation of EGR1 and pro-inflammatory IL-related genes in CRBPI-knockout compared to wild-type mice. Finally, CRBPI transfection in HaCaT cells increased AKT and NF-κB-related genes and proteins and down-regulated IL-2, IL-6 and IL-8 pro-inflammatory signalling. Although not recognized as a psoriatic susceptibility gene in our cohort of patients, the present data strongly supported the potential role of CRBPI to sustain keratinocyte proliferation and differentiation and to counteract pro-inflammatory genes expression in psoriatic lesions.

Linear ectopic sebaceous hyperplasia of the penis: the last memory of Tyson's glands.

Pathologists who find ectopic glands on the glans and/or on the prepuce, often describe them as Tyson's glands. In this regard, the term Tyson's glands can be replaced by two different descriptive expressions: papillomatosis corona penis and ectopic sebaceous glands. A 15-year-old Caucasian male patient presented to our Institute with multiple and asymptomatic circular skin colored-to-yellowish papules at the level of the foreskin, also affecting the shaft of the penis, where they assumed a linear feature. The histological examination revealed hyperplastic and dilated sebaceous glands, while in some areas these glands showed also a direct attachment with the epidermis. A lymphocytic infiltrate was also observed in one of the two specimens. A final diagnosis of linear ectopic sebaceous hyperplasia of the penis was made. According to the current report, the ectopic sebaceous hyperplasia of the penis can have a circular and a linear patter, as well as the presence and the absence of a lymphoid infiltrate. A correct clinical and pathological diagnosis are necessary to avoid unnecessary treatments and worries in the patients. In fact, not infrequently, this condition is confused with dermatological diseases as molluscum contagiosum, epithelioid granuloma, lymphangioma circumscriptum, multiple syringomas, lichen planus, and bowenoid papulosis.