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Agata Janowska,1 Valentina Dini,1 Teresa Oranges,1,2 Michela Iannone,1 Barbara Loggini,3 Marco Romanelli1 1Department of Dermatology, University of Pisa, Pisa, Italy; 2Department of Health Sciences, Anna Meyer Children University Hospital, University of Florence, Florence, Italy; 3Department of Pathology, University of Pisa, Pisa, ItalyCorrespondence: Agata JanowskaDepartment of Dermatology, University of Pisa, Via Roma 67, Pisa 56126, ItalyTel +39 050 992436Fax +39 050 992556Email dottoressajanowska@gmail.comAbstract: Atypical ulcers show atypical clinical features, histology, localization, and resistance to standard therapies. The persistence of a chronic ulcer despite treatment with standard therapies requires a more specific diagnostic investigation. Diagnosis involves obtaining the history and performing clinical examination and additional tests. A skin biopsy is frequently used to confirm unclear diagnosis. In difficult cases, microbiological and immunohistochemical examinations, laboratory blood tests, or instrumental tests should be evaluated. The treatment of atypical wounds is characterized by local systemic therapy and pain control. Our results highlight the need for early diagnosis, and standardized and targeted management by a multidisciplinary wound healing center.Keywords: atypical ulcers, wound healing, wound bed preparation, wound management

Dysplastic nevi represent one of the least agreed-upon entities in dermatopathology despite the existence of established criteria. This study explores preferentially expressed antigen in melanoma (PRAME) in dysplastic nevi, an uncharted area. We examined 22 common melanocytic nevi (CMN), 20 cutaneous melanomas (CM), 48 low-grade dysplastic nevi (LG-DN), and 40 high-grade dysplastic nevi (HG-DN). PRAME was immunohistochemically assessed using a five-tiered system (0 to 4 +). Among CMN, 59% scored 0, 32% scored 1 + , and 9% scored 2 + . CM had score 2 + and 4 + in 11% and 89% of cases, respectively. Among LG-DN, 38% presented score 0, 31% score 1 + , 17% score 2 + , 8% score 3 + , and 6% score 4 + . Thirty per cent of HG-DN demonstrated a score 0, 30% with score 1 + , 15% score 2 + , 10% score 3 + , and 15% score 4 + . Compared to CMN and CM, LG-DN and HG-DN showed heterogeneous expression profiles of PRAME. PRAME positivity effectively distinguished HG-DN from CM with 85% specificity and 80% sensitivity (p < 0.0001). Predictive values were 87% (negative) and 76% (positive). Furthermore, a trend of increased PRAME expression from LG-DN to HG-DN was observed. However, the applicability of PRAME in the differential diagnosis of dysplastic lesions remains unclear as can yield conflicting results with morphology, which remains the primary diagnostic tool for melanocytic lesions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Due to venous insufficiency, a vascular ulcer frequently occurs with the progression of stasis dermatitis. Achromic melanoma, a rare form of pigmentless melanoma frequently located on the sole of the foot, is often and easily confused with a typical wound. Diagnosis of ulcerated achromic melanoma is thus often delayed and associated with a poor prognosis., Case Report: The authors report a very rare case of malignant melanoma in a 70-year-old female with stasis dermatitis. The painless ulcer was present for 1 year before the first visit. Upon clinical examination, a 2-cm diameter hypergranulating ulcer with irregular and pigmented borders was present. Dermoscopy revealed the presence of red globules, a gray-to-blue veil, irregular vessels, and the remains of a pigmented ridge pattern. Histological analysis showed infiltration of atypical melanocytes in the dermis, 2 mitoses, and ulceration. Diagnosis of melanoma was confirmed by positive MART-1 immunochemistry. After removal of the melanoma, the area was covered with an autologous skin graft excised from the inner thigh. In accordance with the guidelines, sentinel lymph node biopsy was performed, and the result was negative for lymph node involvement. A comprehensive clinical dermoscopic evaluation led to the correct diagnosis., Conclusions: The current case highlights the importance of evaluating a chronic, atypical, nonhealing ulcer clinically and dermoscopically as well as through a biopsy procedure.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is an uncommon angioproliferative benign disorder. A 24- year-old Caucasian female patient presented with multiple itchy reddish pearly nodule., Competing Interests: Conflict of interest: The authors declare no potential conflict of interest., (©Copyright: the Author(s).)

Pyoderma gangrenosum (PG) is a neutrophilic dermatose (ND) characterized by a dense neutrophilic infiltrate in the affected tissue. Neutrophil extracellular traps (NETs) are web-like structures released by neutrophils and composed of cytosolic and granule proteins assembled on a scaffold of decondensed chromatin. Very little is known about the role of NETosis in PG. Here, we assessed the possible implication of NETosis in the pathogenesis of PG by investigating the NETosis in the ulcers of 26 PG patients. We demonstrated that neutrophils in the PG skin lesions undergo an aberrant level of NETosis in 100% of the analysed cases (N = 26). All control and abscess biopsies were instead negative for the NETosis. In addition, neutrophils from peripheral blood of PG patients showed a significantly higher rate of spontaneous, but not induced, NETosis. Overall, this study suggests that the NETosis may contribute to systemic inflammation and tissue destruction in PG, thus representing a possible novel therapeutic target., (© 2021 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Matrix metalloproteinases (MMPs) are a large family of ubiquitously expressed zinc-dependent enzymes with proteolitic activities. They are expressed in physiological situations and pathological conditions involving inflammatory processes including epithelial to mesenchymal transition (EMT), neuronal injury, and cancer. There is also evidence that MMPs regulate inflammation in tumor microenvironment, which plays an important role in healing tissue processes. Looking at both inflammatory and neuronal damages, MMP9 is involved in both processes and their modulation seems to be regulated by two proteins: tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6). However other important genes are involved in molecular regulation of transcription factors, protein-kinase B (AKT), and p65. In addition, Triticum vulgare extract (TVE) modulated the biological markers associated with inflammatory processes, including p65 protein. While there are no evidence that TVE might be involved in the biological modulation of other inflammatory marker as AKT, we would like to assess whether TVE is able to (1) modulate phosphorylation of AKT (pAKT) as an early marker of inflammatory process in vitro and (2) affect MMP9 protein expression in an in vitro model. The BV-2 cells (microglial of mouse) have been used as an in vitro model to simulate both inflammatory and neuronal injury pathologies. Here, MMP9 seems to be involved in cellular migration through inflammatory marker activation. We simulate an inflammatory preclinical model treating BV-2 cells with lipopolysaccharide (LPS) to induce proinflammatory activation affecting pAKT and p65 proteins. TVE is revealed to restore the native expression of AKT and p65. Additionally, TVE extract modulates also the protein concentration of MMP9. Nevertheless, immunofluorescence confocal analyses revealed that both AKT and MMP9 are regulated together, synchronously. This work seems to demonstrate that two important genes can be used to monitor the beginning of an inflammatory process, AKT and MMP9, in which TVE seems able to modulate their expression of inflammation-associated molecules., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Niccola Funel et al.)

Diabetic foot ulcerations (DFU) represent a major cause of hospitalization and amputation. In people with diabetes it's not uncommon to find chronic wounds due to pathogenic mechanisms different from diabetes. Here we report the case of a foot lesion misdiagnosed as DFU but actually caused by diffuse large B-cell lymphoma., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Case: Schwannomas are benign nerve myelin sheath tumors that can occur anywhere in the peripheral nervous system. It is very rare for Schwannomas to become malignant, but surgery is still the principal treatment to eliminate symptoms and to correctly diagnosis the tumor. We report an interesting case of a schwannoma of the saphenous nerve at the distal third of the posteromedial thigh: the patient complained of muscle weakness at left lower limb and vague anteromedial knee pain, mimicking a meniscal tear. Magnetic resonance images of the thigh showed a well-defined and oval mass lesion measuring 8.5 cm x 4.5 cm. Before investigating for a possible meniscal tear, we decided to remove the mass from the thigh, because we felt that it could itself be the cause of the mild pain complained about by the patient. Post-surgery, histological analysis conducted confirmed that this was a benign schwannoma., Discussion: Schwannomas generally can be asymptomatic or present as a mass. The clinical presentation of this rare tumor makes the diagnosis difficult., Conclusion: This reported case is particularly interesting because of the rarity of the lesion localization along the course of the saphenous nerve. The combination of the location, and especially the large size of the tumor, led us to believe that there is a correlation with the particular clinical presentation.

Eosinophilic granulomatosis with polyangitis (EGPA) is an uncommon ANCA-associated systemic small-vessel necrotizing vasculitis. At times, EGPA presenting manifestations can be very different from the usually recognized disease patterns. We report a 52-year-old female patient with 3 years history of itching. During the time occurred a chronic skin lichenification on her legs and gradually developed a full-blown ANCA-MPO positive EGPA in combination with blood hypereosinophilia, eosinophilic vasculitis at skin biopsy, subclinical asthma and chronic rhinosinusitis.

Skin malignant melanoma is a highly angiogenic cancer, necessitating early diagnosis for positive prognosis. The current diagnostic standard of biopsy and histological examination inevitably leads to many unnecessary invasive excisions. Here, we propose a non-invasive method of identification of melanoma based on blood flow dynamics. We consider a wide frequency range from 0.005-2 Hz associated with both local vascular regulation and effects of cardiac pulsation. Combining uniquely the power of oscillations associated with individual physiological processes we obtain a marker which distinguishes between melanoma and atypical nevi with sensitivity of 100% and specificity of 90.9%. The method reveals valuable functional information about the melanoma microenvironment. It also provides the means for simple, accurate, in vivo distinction between malignant melanoma and atypical nevi, and may lead to a substantial reduction in the number of biopsies currently undertaken.

The recently described telomerase reverse transcriptase (TERT) promoter mutations are recurrent in cutaneous melanoma. Several authors have described an association between these molecular alterations, some histological parameters, and patient survival. BRAF mutations are very frequent in melanoma, but their actual role in the evolution of the disease is still unclear. Here, we investigated the relationship of TERT promoter mutations and BRAF mutations with the most relevant clinicopathological parameters, individually and coexisting, in order to evaluate their role as independent prognostic markers and to determine the effect of their coexistence. A TERT promoter alteration was found in 20 of 53 cases (38 %), significantly associated with histological type, increasing tumor thickness and mitotic rate, more advanced pathologic tumor (pT) stage, and absence of regression. A BRAF mutation was found in 21 of 53 cases (40 %), significantly associated with tumor thickness and presence of metastases in the sentinel lymph node. Coexistence of a TERT promoter and BRAF mutation was detected in 11 of 53 cases (21 %). This was associated with increasing thickness, high mitotic rate, lymph node metastasis, presence of ulceration, and absence of regression. Coexistence of a mutation in the TERT promoter and in the BRAF gene correlated with more prognostically relevant factors than either mutation alone. Our data lead us to hypothesize that TERT promoter and BRAF mutations cooperate in cutaneous melanoma. Further studies in larger cohorts of patients are needed to investigate how this synergistic effect is involved in the evolution of the disease.

Adenocarcinoma is becoming the most common histologic type of lung cancer in both sex. Although most cases are seen in smokers, it develops more frequently than other histologic types in individuals who have never smoked. This evidence suggests that other putative etiologic factors, such as sex hormones, need to be investigated. Several subtypes of lung adenocarcinoma have been recently described with distinct clinicopathologic features and prognostic implications. The purpose of this study is to investigate the role of estrogen receptor beta in lung adenocarcinoma, with particular attention paid to its different histologic subtypes. Nuclear estrogen receptor beta expression was evaluated by immunohistochemistry in 112 lung adenocarcinomas, including both "single subtype" and "mixed subtype" samples. Using a 2-level (high/low) score system, estrogen receptor beta expression was high in most (75%) adenocarcinomas and turned out to be strongly related to the histologic subtypes. In fact, estrogen receptor beta expression was low or negative in 68.2% of solid subtypes, whereas it was high in 76.5% of nonmucinous bronchioloalveolar, in 69.4% of acinar, and in 61.2% of papillary patterns (P = .00004). Furthermore, a strong association between estrogen receptor beta expression and tumor histologic grade was observed: estrogen receptor beta was highly expressed predominantly in well- and moderately differentiated tumors (P = .0014). In conclusion, estrogen receptor beta expression has distinct patterns in lung adenocarcinoma, suggesting a specific role for estrogen receptor beta in the pathogenesis of different histologic subtypes of this type of cancer. Moreover, loss of estrogen receptor beta expression in poorly differentiated (G3) tumors could represent a crucial step in the dedifferentiation process of lung adenocarcinoma.

Glomus tumours are uncommon neoplasms usually arising in the dermis and subcutaneous tissues where glomus bodies are generally found. Occasionally glomus tumours can occur in extracutaneous sites such as the gastrointestinal tract, bone, genitourinary system and respiratory tract. Primary pulmonary glomus tumours are very rare (only 17 cases reported in the literature), and are often confused with other solid neoplasms such as carcinoids, hemangiopericytomas and tumours belonging to the family of Ewing's sarcoma/primitive neuroectodermal tumours. We present a case of a primary pulmonary glomus tumour originating in the right main bronchus with focal invasion of the submucosa in a 69-year-old man. Histological and immunohistochemical features are reported. The current literature is briefly reviewed, with special attention to differential diagnosis and malignancy criteria.

Purpose: Although most Leydig cell tumors are benign, radical orchiectomy is currently considered the standard therapy. We retrospectively analyzed the long-term followup of a series of patients with Leydig cell tumors electively treated with testis sparing surgery., Materials and Methods: Between November 1990 and December 2005, 17 consecutive patients with Leydig cell tumors underwent testis sparing surgery on an elective basis. Preoperative evaluation included physical examination, serum markers for germ cell tumors, scrotal ultrasound, abdominal computerized tomography, chest x-ray and hormonal profile if clinically required. Testis sparing surgery was performed via an inguinal approach with spermatic cord clamping. Frozen section examination was performed in all cases, revealing Leydig cell tumors. Followup consisted of physical examination, scrotal ultrasound, abdominal computerized tomography and chest x-ray every 6 months for the first 2 years, then annually. Tumor recurrence and survival were evaluated., Results: Mean patient age was 41.6 years (range 28 to 55). Medical referral was prompted by symptoms/signs such as infertility, gynecomastia or self-palpation of scrotal mass in 11 patients (64.7%), while in the remaining 6 (35.3%) the lesions were incidentally diagnosed. Hormonal profile was performed in 9 patients, showing abnormalities in all. Mean tumor diameter was 13.4 mm (range 5 to 31). Definitive pathological examination confirmed benign Leydig cell tumor in all cases. After a mean followup of 91 months (range 12 to 192), neither local recurrence nor distant metastases have been detected and all patients are alive without evidence of disease., Conclusions: In patients with Leydig cell tumors testis sparing surgery with frozen section examination provides an excellent long-term oncological outcome.

Background: There is considerable evidence that apoptosis plays an important role in the pathogenesis of a wide variety of skin diseases. Apoptosis failure may ensure the survival of transformed cells prone to sustain further genetic damage and it plays an important part in the development of tumors. Genetic alterations of Fas and p53, with consequent inactivation of gene protein products, may be involved in transcriptional downregulation of Fas., Objective: We investigated Fas and its ligand expression in 30 cases of nonmelanoma skin cancer, 19 basal cell and 11 squamous cell carcinomas, and we also analyzed Fas and p53 status, in an attempt to detect putative alterations., Method: Fas and its ligand expression were evaluated by RT-PCR; the promoter and the entire coding region of Fas, and the coding exons 4-9 of p53 were investigated by polymerase chain reaction, single strand conformation polymorphism, and DNA sequencing., Results: Fas alterations were found in 3/19 (15.8%) basal cell and in 4/11 (36.4%) squamous cell carcinomas. Five out of 25 cases (3/19 basal cell and 2/11 squamous cell carcinomas) were p53-mutated, and in the majority of these cases there were concomitant mutations of the Fas gene (c2 test; p = 0.035)., Conclusion: Taken together, our findings highlight an involvement of the Fas/Fas-ligand system in the development of skin cancer, suggesting that the loss of its apoptotic function, in some cases linked to p53 alterations, may contribute to the self-maintenance of cancer cells.

Angiogenesis is a central process in the growth of solid tumors. The purpose of our study was to analyze the angiogenic pattern in squamous and basal cell carcinomas and to point out differences in microvessel density that could explain their different biological behaviour. Thirty-nine skin tumors (26 basal and 13 squamous cell carcinomas) were analyzed. In all samples, the microvessels density (MVD) and the levels of vascular endothelial growth factor mRNA (VEGFmRNA) were analyzed, together with the inter-relationship between these two variables. Using the median value of the entire series (33 vessels per 2.22 mm2), tumors with low and high MVD were identified. The majority of cancers with high vascularization belonged to the squamous histotype (12 of 39), while 19 of the 26 basal cell carcinomas showed a lower number of microvessels than the median value (p = 0.0001). The median value of VEGFcDNA quantitation allowed us to distinguish tumors with high VEGF expression (> 470 molecules cDNA) from those with low (< or = 470 molecules) VEGF expression: 20 of the 26 basal cell carcinomas showed low VEGF expression, while 11 of the 13 squamous cell carcinomas showed high VEGFcDNA levels (p = 0.0003). Moreover, a significant association between a high microvessel density and high VEGFmRNA levels (p = 0.006) was found. Furthermore, when studying VEGF expression by immunohistochemistry, we obtained similar results and noted a correlation with VEGFmRNA expression (p < 0.0001). The association between high vascularization, high VEGF levels, and squamous cell histotype suggests the possible role of neoangiogenesis in determining the more aggressive biological behaviour of this type of cancer.

Lichen myxedematosus is a rare disease that is characterized by the formation of lichenoid papules and plaques. Histologic examination shows deposition of mucinous material in the dermis. We report the case of a patient with cutaneous and systemic involvement and examine the clinical and postmortem data.

Aims and Background: Thickness and level of invasion are the main morphological elements for an approximate but not sufficiently sensitive prognostic evaluation of cutaneous melanomas. By using immunohistochemical methods it is possible to detect biological markers related to prognosis. We have studied p53, PCNA, Bcl-2 and P-gp expression in 49 primary cutaneous melanomas., Materials: We used the immunophosphatase APAAP immunohistochemical method. The percentage of labeled cells (according to four classes of positivity: <5%; 5-25%; 25-50%; >50%) and the localization of immunoreactivity were expressed for each marker. Statistical analysis was performed to determine the correlations between markers and level or thickness of melanomas., Results: We found a good correlation between p53 expression and melanoma thickness (P <0.005), PCNA and P-gp expression. No relationship was observed between Bcl-2 expression and the different variables considered or other markers., Conclusions: Our data seem to indicate an unfavorable prognostic role of higher nuclear p53 expression. However, we believe that our results need to be integrated with patients' clinical follow-up and with the study of the expression of these markers in benign melanocytic lesions to gain more accurate information about their prognostic significance.