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.

Early Angiosarcoma of the Scalp: A Clinicopathological Pitfall.

Angiosarcoma (AS) is a rare malignant vascular tumor, which affects mainly elderly patients. After the diagnosis, the mean overall survival of patients is 30 months. The variable presentation of the malignancy, the benign appearance of the cutaneous lesions, and the minimal histological changes in early lesions can sometimes delay the correct diagnosis. The authors report a case of an 80-year-old white male patient, with a painless and ecchymotic lesion of the scalp, which histologically showed minimal pathological atypia, conclusive for a diagnosis of AS with minimal histological changes. The authors discuss the main and most emblematic cases of AS initially misdiagnosed for other cutaneous diseases reported in the literature, noting that in some cases, also the histology can be treacherous and a trap for the dermatopathologist. The recent findings on MYC, FLT4 and KDR amplification, and the relative therapeutic perspectives are also discussed. Finally, the authors draw up some pathological cornerstones, which could improve the diagnosis, above all in early lesions with minimal atypia.

Biliopancreatic diversion: when a cure becomes a disease.

Phrynoderma is a type of follicular hyperkeratosis located primarily on the extensor surfaces of the extremities. It is most commonly seen in Africa and Southeast Asia, where it is correlated with malnutrition; however, it is rare in developed countries, where it is often the result of malabsorption secondary to pancreatic insufficiency, colectomy, chronic giardiasis, and bariatric surgery. Here, we report a case of a 51-year-old white male patient, who presented to our Institute with a 1-year history of diffuse, reddish-brown asymptomatic papules associated with follicular nodules. In association with cutaneous symptomatology, the patient complained of also having night blindness. The patient, 4 years before, underwent a bariatric surgical treatment, which included a biliopancreatic diversion. Histologic examination of skin biopsy revealed hyperkeratosis and irregular acanthosis of the epidermis in association with dilated follicular infundibulum filled with keratinous material, whereas the laboratory investigations showed hypovitaminosis A. Based on the patient's history and cutaneous biopsy, a final diagnosis of phrynoderma was made. The steady increase of obesity in developed countries results in a relative increase in bariatric surgery. This must involve a multidisciplinary team to manage nutrition deficiencies and prevent possibly important complications, as mentioned in this report.

Mycobacterium abscessus hand-and-foot disease in children: rare or emerging disease?

Mycobacterium abscessus is emerging as an important cause of cutaneous infections in sporadic cases and outbreak settings. Although immunosuppressed or elderly patients are most commonly affected, in 2006 an outbreak of clinically distinct cutaneous lesions on the hands and feet caused by M. abscessus in a population of healthy children using a public swimming pool was reported. This article describes an outbreak of skin infection in a population of healthy Italian children attending the same school and using the same swimming pool. In January 2010 we identified three children with multiple, painful nodules on the palms and soles. M. abscessus was isolated from one child's lesions. A public health investigation was conducted and a team of dermatologists and public health officers visited all of the children; 514 children were screened and 29 cases were identified overall. All of the affected children had used the school's swimming pool. These children were treated with oral clarithromycin for 4 to 8 weeks. Because of the long period of time between the presentation and diagnosis of the first cases, the possibility that the number of cases may have been underestimated cannot be excluded. To our knowledge, this is the second largest reported cluster of M. abscessus skin infection suspected to be related to swimming pool exposure in a population of otherwise healthy children. It is unclear whether this disease is rare or should be considered as an emerging clinical entity.

Merkel cell polyomavirus in Merkel cell carcinoma of Italian patients.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare but very aggressive human malignancy of elderly or immunosuppressed patients. Clonal integration of a new human polyomavirus, the Merkel cell polyomavirus (MCPyV), has been reported in MCC patients. The main objective of the study was the detection of MCPyV and viral expression in clinical samples of Italian patients who were diagnosed MCC. FINDINGS: DNA and RNA were extracted from nine MCCs to detect the presence of MCPyV. Viral large T gene (LT1 and LT3), and viral capsid gene (VP1) were detected by polymerase chain reaction (PCR) based methods, and the amplified PCR products were subjected to direct sequencing. The presence of viral T antigen and/or viral capsid DNA sequences was demonstrated in eight of the nine MCC lesions, whereas RNA transcripts were detected in three MCCs. CONCLUSIONS: These findings indicate a potential role of MCPyV in the pathogenesis of at least a subset of MCCs.

Eccrine syringofibroadenoma and clear cell acanthoma: an association by chance?

A 58-year-old white woman with stasis dermatitis developed a solitary, slowly growing keratotic nodule of the dorsum of the foot. The excision biopsy specimen of this lesion showed a biphasic pattern of eccrine syringofibroadenoma and clear cell acanthoma. Such a previously unreported association is neither necessarily by chance nor necessarily a collision. Because a reactive histogenesis has been postulated for both eccrine syringofibroadenoma and clear cell acanthoma, this case could represent a morphologically biphasic pattern of epidermal and ductal hyperplasia as a consequence of the stasis-induced chronic inflammation coupled with the footwear-induced chronic trauma.

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.

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.

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.

Obesity-associated lymphoedematous mucinosis.

BACKGROUND: Mucin deposition on the shins is considered as an indicator of pretibial myxoedema, which is typically seen in patients with Graves' disease. OBJECTIVE: The purpose of this study was to report the clinical and histopathological features of a group of patients with pretibial mucinosis in the absence of thyroid disease. METHODS: Five patients are included in this series and studied both clinically and histologically and compared with similar cases in the literature. RESULTS: All patients were middle aged or elderly. Four patients were women. They were characterized clinically by morbid obesity and bilateral lower extremity pitting oedema sparing the feet. Semitranslucent papules and/or nodules and sometimes vesicles were found on the shins. Characteristic histological features include (i) hyperorthokeratosis with epidermal atrophy and effacement of the rete ridge pattern, (ii) oedema in the papillary and upper part of the reticular dermis with mucin deposition stained positively with alcian blue and colloidal iron, (iii) angioplasia in the upper part of dermis with upward-running, increased and thickened capillary vessels and (iv) variable fibrosis in the reticular dermis with separation of collagen bundles and increased stellate or linear fibroblasts. A hypocaloric diet was given in two cases, and an important weight loss was observed, which was accompanied by a marked improvement of the pretibial mucinosis. CONCLUSIONS: Pretibial mucinosis is a histological feature associated with morbid obesity and lymphoedematous features of the legs that should be distinguished from true pretibial myxoedema. The term of 'obesity-associated lymphoedematous mucinosis' seems to be appropriate for this condition.

Angiomatous reaction Kaposi-sarcoma-like as a side effect of topical corticosteroid therapy in lichen sclerosus of the penis.

Lichen sclerosus (LS) is a chronic inflammatory skin condition usually located in the anogenital area. Topical corticosteroid therapy is the first choice treatment which may arrest or delay the progression of the disorder. We report the case of a 74-year-old man presented with a 6-month history of nodular lesions localized on penis. The man had a previous history of genital lesions that had been diagnosed as LS and treated with long-term topical corticosteroid therapy. After 3 months of corticosteroid therapy, the patient observed the appearance of several nodular erythematous lesions on the penis with progressive disappearance of the clinical symptoms of LS. These purple to red asymptomatic angiomatoid nodules resembled the clinical features of Kaposi sarcoma.

Detection of HPV-15 in painful subungual tumors of incontinentia pigmenti: successful topical therapy with retinoic acid.

Incontinentia pigmenti (IP) is an X-linked dominant disorder, which occurs in female patients. We present a typical case of IP with subungual tumors (STIP) together with a short review on subungual tumors in IP. The diagnosis was achieved on the basis of the onset in adult life of STIP together with the other specific symptoms like ocular and dental abnormalities and achromic lesions of the legs. In the STIP lesions the presence and, in one of them, the expression, of HPV type 15 were detected. Topical therapy with retinoic acid cured the tumoral lesions. To the best of our knowledge this is the first report of HPV in STIP, opening a new scenario in the pathogenesis and the treatment of STIP. In conclusion, in our opinion, all painful subungual tumors should be considered as a possible late manifestation of IP.

Milia en plaque: three new pediatric cases.

Milia en plaque (MEP) is an unusual and extremely rare clinical variant of milia, characterized by multiple milia-like lesions overlying an erythematous edematous plaque with histologic findings consistent with milia. MEP tends to affect the middle-aged patients and shows a predilection for women. Among children, this entity is rarely described and, to our knowledge, only four cases have been reported to date in the dermatologic literature. We add three new cases of children, one of whom had an unusual site of presentation.

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.

Birt-Hogg-Dubé (BHD) syndrome: report of two novel germline mutations in the folliculin (FLCN) gene.

Molecular analysis of the folliculin (FLCN) gene was performed in four consenting patients from two families with Birt-Hogg-Dubé (BHD) syndrome, showing the occurrence of two frameshift mutations located respectively in exons 5 (802insA) and 9 (1345delAAAG) of the FLCN gene. A novel homozygous sequence variant in the intron 9 (IVS9 +5C>T) was also found. 1345delAAAG was associated with a wide variety of tumors, including stomach, colon, breast and parotid cancer. Conversely, the family carrying 802insA only had clinical evidence of dermatological lesions. These findings further suggest the relevance of exon 9 mutations in cancer predisposition for BHD.