Human Papillomavirus 42 Drives Digital Papillary Adenocarcinoma and Elicits a Germ Cell-like Program Conserved in HPV-Positive Cancers.

The skin is exposed to viral pathogens, but whether they contribute to the oncogenesis of skin cancers has not been systematically explored. Here we investigated 19 skin tumor types by analyzing off-target reads from commonly available next-generation sequencing data for viral pathogens. We identified human papillomavirus 42 (HPV42) in 96% (n = 45/47) of digital papillary adenocarcinoma (DPA), an aggressive cancer occurring on the fingers and toes. We show that HPV42, so far considered a nononcogenic, "low-risk" HPV, recapitulates the molecular hallmarks of oncogenic, "high-risk" HPVs. Using machine learning, we find that HPV-driven transformation elicits a germ cell-like transcriptional program conserved throughout all HPV-driven cancers (DPA, cervical carcinoma, and head and neck cancer). We further show that this germ cell-like transcriptional program, even when reduced to the top two genes (CDKN2A and SYCP2), serves as a fingerprint of oncogenic HPVs with implications for early detection, diagnosis, and therapy of all HPV-driven cancers. SIGNIFICANCE: We identify HPV42 as a uniform driver of DPA and add a new member to the short list of tumorigenic viruses in humans. We discover that all oncogenic HPVs evoke a germ cell-like transcriptional program with important implications for detecting, diagnosing, and treating all HPV-driven cancers. See related commentary by Starrett et al., p. 17. This article is highlighted in the In This Issue feature, p. 1.

Dermal lipofibromatosis-like neural tumor.

BACKGROUND: Lipofibromatosis-like neural tumor (LPF-NT) is a rare soft tissue typically occurring in the subcutis, characterized by a cellular proliferation of CD34- and S100-protein positive spindle-shaped tumor cells with an infiltrative growth pattern. OBJECTIVE: To describe five cases arising mainly in the dermis in order to expand their morphologic spectrum. METHODS: H&E slides were reviewed, and all cases were stained for CD34, SOX10, S100, ALK, and NTRK1 and some of them with additional staining. RESULTS: Patients were three males and two females with a mean age of 44.8 years (14-68 years). Histopathologically, all cases were characterized by a dense dermal infiltration by monomorphous, mildly atypical, plump to spindle-shaped tumor cells, staining diffusely positive for CD34, S100, and NTRK1 but were negative for S100, EMA, NKIC3, MNF116, SMA, ALK, and desmin. LIMITATIONS: Limited clinical information. CONCLUSION: LPL-NT can be located mainly in the dermis. Sixty percent of our cases showed typical areas of LPL-NT intermingled with more plump cells like the ones in fibrous hamartoma of infancy. We recommend a panel of CD34, S100, and NTRK1 antibodies not only in subcutaneous spindle cell neoplasms but also in the ones predominantly involving the dermis in order to make an accurate diagnosis.

Psoriasis is associated with fissured tongue but not geographic tongue: a prospective, cross-sectional, case-control study.

BACKGROUND AND OBJECTIVES: It has been postulated that psoriasis is associated with tongue lesions and geographic tongue might be "oral psoriasis". However, reports are inconclusive, prevalence rates vary and data for Europe are sparse. In this prospective case-control study we investigated the point-prevalence of tongue conditions in an Austrian cohort. PATIENTS AND METHODS: Psoriasis patients and healthy volunteers were assessed regarding tongue and skin lesions, age, sex, smoking habits, allergies, onset of psoriasis, PASI scores and anti-psoriatic treatment. RESULTS: We included 173 psoriasis patients, 58 women, 115 men (median age: 50 [37-60] years), and 173 volunteers, 79 women, 94 men (median age: 54 [43-64] years). Overall, 95 subjects had allergies, 64 psoriasis patients and 50 volunteers were smokers. Median age at onset of psoriasis was 26 (12-40) years, the median PASI score was 2 (0-4.1), most patients received ustekinumab (n = 47). Fissured tongue was significantly associated with psoriasis (25 [14.4 %] psoriasis patients, 13 [7.5 %] volunteers; P = 0.04). Geographic tongue was present in four individuals of each group (2.3%) and associated with smoking (P = 0.01) but not with psoriasis. CONCLUSIONS: Overall, we found a low point-prevalence of tongue lesions in this Austrian cohort. Psoriasis was associated with fissured tongue but not with geographic tongue. Thus, we cannot corroborate the hypothesis that geographic tongue is an oral manifestation of psoriasis.

The role of wide local excision for the treatment of severe hidradenitis suppurativa (Hurley grade III): Retrospective analysis of 74 patients.

BACKGROUND: Effective medical treatment for patients with severe hidradenitis suppurativa (HS) is limited. OBJECTIVES: We sought to measure the impact of wide local excision on quality of life in HS Hurley grade III patients and to examine the rate of postoperative complications, disease recurrences, and satisfaction with the cosmetic results. METHODS: Seventy-four patients were enrolled. Outcome measures included Dermatology Life Quality Index responses, disease duration, recurrence, previous therapies, postoperative complications, and satisfaction with cosmetic results. RESULTS: Most patients had inguinogenital/gluteal disease (68.9%, P < .001). Involvement of both the axillary and the inguinogenital/gluteal areas were pronounced in male patients (P = .018). None of the patients was treated with tumor necrosis factor-α inhibitors. Most patients (71.6%) had a disease history of >5 years at the time of presentation and multiple unsuccessful attempts with systemic and local therapeutic interventions. Wide local excision improved Dermatology Life Quality Index scores from initially 27.89 to 5.31 after surgery (P < .001), independent of localization (P = .195). Forty-seven percent of patients had postoperative complications, most frequently pain and scarring. The vast majority of patients (70.3%) were satisfied with the cosmetic results. LIMITATIONS: The retrospective nature of the study was a limitation. CONCLUSIONS: Wide local excision significantly improves the quality of life of HS patients. Local recurrence rates are low, and satisfaction with the cosmetic results is high.

Searching for the Chokehold of NRAS Mutant Melanoma.

Up to 18% of melanomas harbor mutations in the neuroblastoma rat-sarcoma homolog (NRAS). Yet, decades of research aimed to interfere with oncogenic RAS signaling have been largely disappointing and have not resulted in meaningful clinical outputs. Recent advances in disease modeling, structural biology, and an improved understanding of RAS cycling as well as RAS signaling networks have renewed hope for developing strategies to selectively block hyperactive RAS function. This review discusses direct and indirect blocking of activated RAS with a focus on current and potential future therapeutic approaches for NRAS mutant melanoma.

Acyl protein thioesterase 1 and 2 (APT-1, APT-2) inhibitors palmostatin B, ML348 and ML349 have different effects on NRAS mutant melanoma cells.

Oncogenic NRAS mutations are frequent in melanoma and lead to increased downstream signaling and uncontrolled cell proliferation. Since the direct inhibition of NRAS is not possible yet, modulators of NRAS posttranslational modifications have become an area of interest. Specifically, interfering with NRAS posttranslational palmitoylation/depalmitoylation cycle could disturb proper NRAS localization, and therefore decrease cell proliferation and downstream signaling. Here, we investigate the expression and function of NRAS depalmitoylating acyl protein thioesterases 1 and 2 (APT-1, APT-2) in a panel of NRAS mutant melanoma cells. First, we show that all melanoma cell lines examined express APT-1 and APT-2. Next, we show that siRNA mediated APT-1 and APT-2 knock down and that the specific APT-1 and -2 inhibitors ML348 and ML349 have no biologically significant effects in NRAS mutant melanoma cells. Finally, we test the dual APT-1 and APT-2 inhibitor palmostatin B and conclude that palmostatin B has effects on NRAS downstream signaling and cell viability in NRAS mutant melanoma cells, offering an interesting starting point for future studies.

The burden of malignant melanoma--lessons to be learned from Austria.

AIM OF STUDY: Incidence rates of melanoma, generated by cancer registries (CRs), are susceptible to reporting inconsistencies due to increasing decentralisation of diagnosis. We therefore independently assessed the burden of melanoma in Austria. METHODS: We collected histopathological reports on melanoma of all patients diagnosed in Austria in 2011. Demographic and clinical characteristics, histopathological tumour stages were assessed. Their regional distributions and incidence rates were analysed and compared with data of national and international CRs. RESULTS: A total of 5246 patients were diagnosed with 1951 in-situ and 3295 invasive melanomas in Austria in 2011 (population 8.4 million). Age, sex and anatomic distribution corresponded to findings in other European countries, however, the incidence of 25/100,000 (world age-standardised rate) for invasive melanomas was two-fold higher than published by the Austrian CR (12/100,000). Varying frequencies in diagnosing thin melanomas (≤1 mm; n = 4415) accounted exclusively for significant regional disparities, while advanced tumours (>1 mm; n = 761) were evenly distributed. Western Austria showed the highest rates (36/100,000). Patients from eastern Austria whose melanomas were diagnosed in laboratories in western Austria (n = 76) showed significantly higher proportions of in-situ lesions (n = 43; 57%) compared to those whose tumours were diagnosed in eastern Austria (n = 4014; in-situ = 1369; 34%) (p < 0.0001). CONCLUSIONS: In Austria, the melanoma burden and its potential socio-economic implications are significantly underestimated. Similarities of incidences indicate this could affect other European countries with well-established CRs and compromise international comparability of data. Austrian regional disparities suggest overdiagnosis of thin melanomas due to the variability of pathologists' thresholds for the diagnosis of early stage tumours.

Phrynoderma and acquired acrodermatitis enteropathica in breastfeeding women after bariatric surgery.

BACKGROUND AND OBJECTIVES: Women who have undergone bariatric surgery are susceptible to nutritional deficiencies in subsequent pregnancies. We highlight the importance of dermatologists in the early recognition of cutaneous signs of malnutrition occurring in this specific clinical setting. PATIENTS AND METHODS: We compare clinical characteristics of two young women with dermatological signs of combined post-gestational nutritional deficiencies following Roux-en-Y gastric bypass surgery. RESULTS: Patient 1 exhibited follicular papules on the extremities, perianal eczema, perlèche, alopecia, and depigmentation of hair. Patient 2 showed erythematous plaques in genitoanal and acral areas, perlèche, diffuse alopecia, and depigmentation of hair. Based on clinical and histopathological findings, decreased vitamin A (patient 1) and zinc levels (patient 2), we diagnosed phrynoderma and acquired acrodermatitis enteropathica, respectively. Comparison of the two patients revealed that both (i) were lacking follow-up after gastric bypass surgery, (ii) developed skin lesions as primary symptoms with (iii) mixed clinical manifestations due to combined deficiencies, and (iv) experienced initial symptoms during lactation suggesting a causal relationship. CONCLUSIONS: Our observations highlight the potentially increased risk of women to develop post-gestational dermatological manifestations of malnutrition following bariatric surgery. The awareness of dermatologists with respect to this emerging, susceptible patient group may help avert damage to mother and child.

Animal-type melanoma - tumor cell invasion of dermal lymphatics and molecular identification of lymph node metastasis.

Animal-type melanoma (ATM) represents a rare subtype within the wide spectrum of melanocytic tumors. Clinically, ATM lesions appear as sharply demarcated, brown, black and dark blue pigmented nodules, which show grey-white surface elements on dermatoscopy. The tumor is restricted to the dermis and arranged in irregular fascicles, which are composed of spindle-shaped and epithelioid melanocytes. Moderate tumor cell pleomorphism, mitoses and apoptotic cells all suggest a malignant process. Abundant, finely dispersed melanin pigment within tumor cells as well as numerous melanophages are strongly suggestive of ATM. Even though locoregional lymph node metastases are frequently found at diagnosis, the course of ATM is generally benign. Specific molecular changes may be detected in melanocytes from lesions and lymph nodes on fluorescence in situ hybridization (FISH). Such findings strongly indicate the malignant potential of ATM. The peculiar biology of ATM, as a moderately malignant tumor, is reflected in a new histopathological classification within the spectrum of dermal borderline melanocytic tumors (BMT).