Mucosal Alpha-Papillomavirus (HPV89) in a rare skin lesion.

BACKGROUND: Apocrine acrosyringeal keratosis is a rare skin lesion showing a unique benign keratotic lesion associated with syringocystoadenoma papilliferum. It is characterized by an exophytic proliferation of the epidermis with two distinct keratinocytic structures: a) columns of hyperkeratotic mass surrounded by acanthotic epidermis and b) papillated and/or cystic invaginations typical of syringocystoadenoma papilliferum. No causative agents were reported. FINDINGS: The present report describes a typical case of apocrine acrosyringeal keratosis localized in the right retro-auricular area of 57-year-old man in which the presence of HPV was evaluated. PCR analysis and direct sequencing revealed the presence of HPV 89. The presence of this low risk mucosal HPV in a skin localization was never reported as well as in association with this rare tumor. Furthermore rolling circle amplification, RT-PCR and in situ hybridization confirmed the presence of a transcriptionally active HPV 89. CONCLUSIONS: Taken together our results suggest that HPV89 plays a role in apocrine acrosyringeal keratosis with syringocystoadenoma papilliferum, in consideration of the documented biological activity of the virus. The association of low risk mucosal HPV infection with this skin lesion opens new perspectives in its clinical management. Further studies on samples from other patients are needed to confirm this association.

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.

Molecular characterization of 11 Italian patients with Darier disease.

Darier disease (DD) is an autosomal dominant genodermatosis characterized by multiple warty papules coalescing in seborrheic areas and specific histological skin changes. Heterozygous mutations in ATP2A2, encoding the sarco-endoplasmic reticulum calcium pumping ATPase type 2, are identified as the molecular basis of DD. In this study, molecular features in a large cohort of Italian patients are reported. Molecular data were collected along with the main clinical features. Genomic DNA was used for direct sequencing of ATP2A2. The effect of selected mutations was predicted by in silico analysis or investigated by gene expression studies. 10 different ATP2A2 mutations were identified. Three mutations (c.2300A>G, c.2794G>A, c.569delAins34) have been previously described, while 7, including 2 missense (c.545G>A and c.2116G>A), 2 nonsense (c.1372G>T and c.1675C>T), 1 small deletion (c.142delA), 1 duplication (c.2935_2949dup15) and 1 splice-site mutation (c.2742-1G>A), were novel. Collected data added new variants to the ATP2A2 repertoire and confirmed that ATP2A2 mutations are scattered over the entire gene and, in most cases, private.

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.

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.

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.

A kindred with familial progressive hyperpigmentation-like disorder: implication of fibroblast-derived growth factors in pigmentation.

Two patients with a generalized, progressive dyschromatosis disorder are described and investigated as a model to study the role of fibroblast-derived mediators on skin pigmentation. The patients (father and daughter) had had a widespread hyperpigmentation since early life which then progressively worsened with the appearance of hyperpigmented macules, café-au-lait macules and freckles, also involving the lips, palms and soles, intermixed with small hypopigmented spots. These features resembled those of familial progressive hyperpigmentation (FPH). Histology revealed a normal epidermis with pronounced keratinocyte hyperpigmentation and the presence of dermal melanophages. Ultrastructural analysis showed basal and suprabasal keratinocytes enriched in melanosome complexes. Immunohistochemical staining displayed an increased expression of hepatocyte growth factor (HGF), stem cell factor (SCF) and keratinocyte growth factor (KGF) in fibroblast-like cells of the upper dermis in hyperpigmented lesions of both patients, compared to control healthy skin. Our data suggest that a persistent activation of fibroblasts abnormally stimulating melanocyte functions is involved in hyperpigmentation disorders.

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.

The HtrA1 serine protease is down-regulated during human melanoma progression and represses growth of metastatic melanoma cells.

Differential gene expression of cell lines derived from a malignant melanoma or its autologous lymph node metastasis using cDNA arrays indicated down-regulation of PRSS11, a gene encoding the serine protease HtrA1, a homolog of the Escherichia coli protease HtrA, in the metastatic line. Stable PRSS11 overexpression in the metastatic cell line strongly inhibited proliferation, chemoinvasion and Nm23-H1 protein expression in vitro, as well as cell growth in vivo in nu/nu mice. A polyclonal anti-HtrA1 serum demonstrated a significantly higher expression in primary melanomas when compared to unrelated metastatic lesions in a human melanoma tissue array, and down-modulation of HtrA1 expression in autologous lymph node melanoma metastases in seven out of 11 cases examined. These results suggest that down-regulation of PRSS11 and HtrA1 expression may represent an indicator of melanoma progression.

Human herpesvirus 8 infection in patients with cutaneous lymphoproliferative diseases.

OBJECTIVE: To investigate the prevalence of human herpesvirus 8 (HHV-8; Kaposi sarcoma-associated herpesvirus) infection in patients with lymphoproliferative skin diseases such as large-plaque parapsoriasis (LPP) and mycosis fungoides compared with inflammatory cutaneous conditions or healthy control subjects. DESIGN: A survey study was undertaken in 123 subjects with various clinical conditions. SETTING: All patients had been seen in the Dermatology Department of the San Gallicano Dermatology Institute, Rome, Italy, in the last 2 years. PATIENTS: Forty-five patients with inflammatory or autoimmune cutaneous diseases, 50 healthy control subjects, 10 patients with LPP, 12 patients with mycosis fungoides, and 6 patients with classic Kaposi sarcoma were included in the study. MAIN OUTCOME MEASURES: The prevalence of HHV-8 infection was investigated with serologic studies using the gold standard assay based on body cavity-based B-cell lymphoma-1 cells latently infected with HHV-8. The presence of HHV-8 conserved sequence, corresponding to open reading frame 26, was also assessed in the peripheral blood and lesion tissue samples from patients with lymphoproliferative cutaneous diseases with nested polymerase chain reaction. The presence and distribution of cell types infected with HHV-8 in the lesion tissues was determined with immunohistochemical staining with the monoclonal antibody directed against the latent nuclear antigen-1 of HHV-8 encoded by open reading frame 73. RESULTS: In healthy control subjects and patients with inflammatory skin diseases, 13.9% were found to have antibody against HHV-8, consistent with the seroprevalence population in Italy. A highly significant association of HHV-8 infection and LPP was found (100%) compared with mycosis fungoides (25%). The peripheral blood mononuclear cells in 8 of 10 patients with LPP were found to harbor viral sequences at nested polymerase chain reaction, whereas none of them had a detectable serum viral load. All LPP lesion tissue samples were positive for HHV-8-encoded open reading frame 26, and the presence of HHV-8-infected cells was confirmed by immunohistochemistry profiles performed on paraffin-embedded tissues from 4 of 10 patients. The positive cell types included endothelial cells and the infiltrating dermal lymphocytes, characteristic hallmarks of LPP. Analysis of T-cell receptor gamma chain rearrangements in lesion tissue from our patients confirmed the lack of a significant association between T-cell clonality and LPP. CONCLUSION: These data suggest that HHV-8 may play a role in the onset of LPP, a disease whose cause and evolution are still undefined and which has often been considered the early stage of mycosis fungoides.

Epithelioma of Malherbe: new ultrasound patterns.

BACKGROUND: Calcifying epithelioma of Malherbe, or Pilomatricoma, is considered an uncommon cutaneous neoplasia, normally occurring in children as a solitary, firm, asymptomatic, hard, subcutaneous, slowly growing nodule on the face, neck, or proximal upper extremity. In literature, two Pilomatricoma ultrasound patterns are described: the totally calcified nodule and the hypoechoic nodule with internal calcific foci. High frequency ultrasound has not yet been applied for routine diagnosis of Pilomatricoma. The aim of the study was to retrospectively identify specific ultrasound features. METHODS: We retrieved 124 histologically Pilomatricoma cases: 28 patients with 32 lesions were preoperatively evaluated with ultrasound. RESULTS: 22/32 have shown a solid formation, hypoechoic, with a sharp outline. Of these 22, 10 lesions were completely calcifying and 12 partially calcified. In 3/32 lesions with uncertain diagnosis, ultrasounds showed a complex/mixed pattern with pseudo-fluid areas and microspots. 7/32 lesions with US different diagnosis included 3 complex lesions, 2 cystic lesions and 2 solid nodular lesions. CONCLUSION: In addition to well-known ultrasound patterns (completely calcified and partially calcified) we identified three new, not yet described, patterns that constitute the 31% of the cases: complex, pseudocystic and pseudotumoral.

Relation between animal-type melanoma and reduced nuclear expression of glutathione S-transferase pi.

BACKGROUND: Animal-type melanoma (ATM) is a rare variant of the tumor showing diffuse, heavily pigmented neoplastic cells in the dermis. Despite the high mean thickness of the lesions, reports seem to indicate a less aggressive behavior and a better survival rate for ATM compared with conventional melanoma, but the underlying pathways related to this favorable outcome are still unknown. OBSERVATIONS: Five women and 2 men aged 20 to 92 years presented with pigmented skin nodules (n = 5) or plaques (n = 2), varying in size from 1.0 to 4.5 cm. Findings from microscopic examination showed monotypic-appearing melanocytes with abundant intracytoplasmic melanin in a nodular or fascicular arrangement (mean Breslow thickness, 4.97 mm). Immunohistochemical analysis of ATM cells demonstrated the typical positive staining for S-100, vimentin, HMB-45, and melan-A. The investigation of the pi isoform of glutathione S-transferase, a family of enzymes involved in tumor progression, revealed that nuclear expression is reduced in ATMs compared with control melanomas, whereas results from cytoplasmic staining did not vary. One patient died of cardiac failure without evidence of disease progression; the remaining patients are disease-free at 3 (n = 4) and 5 years (n = 3). CONCLUSIONS: Our findings confirm that ATM is a variant of melanoma with distinctive clinical and histological features. Low nuclear expression of glutathione S-transferase pi expression is a characteristic of ATM and could add new insight to better understand the unusual biological behavior of this rare neoplasm.

Eccrine poroma: a clinical-dermoscopic study of seven cases.

Eccrine poroma can mimic benign and malignant melanocytic and non-melanocytic lesions. To date, little is known about the dermoscopic features of this condition. Seven histopathologically proven cases of eccrine poroma were examined using dermoscopy by three independent dermatologists. Both glomerular and hairpin vessels were observed in 71% of cases, whereas linear irregular vessels were observed in 43% of cases. A white-to-pink halo surrounding the vessels and multiple pink-white structureless areas were also frequently found (in 86% and 71% of cases, respectively). Three dermoscopic "profiles" were identified, all characterized by the presence of a white-to-pink halo surrounding the vessels, as well as by the association of two additional different features, namely: glomerular vessels and pink-white structureless areas, glomerular and linear irregular vessels, hairpin vessels and linear irregular vessels. However, due to the small number of lesions studied so far, we suggest that these profiles should be considered as likely, but not definitely pathognomonic signs of eccrine poroma.

High beta-HPV DNA loads and strong seroreactivity are present in epidermodysplasia verruciformis.

Epidermodysplasia verruciformis (EV) is a rare disease, characterized by cutaneous warts and associated with a strong predisposition to beta-genus human papillomavirus (HPV). Earlier studies reported high copy numbers of HPV-DNA in nearly all skin tumors from EV patients, but neither HPV replication status in non-lesional skin nor anti-HPV seroreactivity in these patients have been reported yet. We therefore performed a comprehensive viral load analysis for the more common beta-HPV types on skin samples and plucked eyebrow hairs from four EV patients treated at our dermatology department. The results clearly demonstrate that they carry a multiplicity (up to eighteen types) of beta-HPV genotypes in both skin sites. Worthy of note, a high intrapatient concordance for specific types between hair bulbs and skin biopsies was observed and the same beta-PV profile was maintained over time. Viral load analysis revealed a load range between less than one HPV-DNA copy per 100 cells to more than 400 HPV-DNA copies per cell in both eyebrow hairs and skin proliferative lesions. Evaluation of seroreactivity to beta-HPV types in the four EV patients revealed that antibodies against the 16 beta-HPV were significantly more prevalent and showed higher titers than in the controls.