A Narrative Review of the State of the Art of CCR4-Based Therapies in Cutaneous T-Cell Lymphomas: Focus on Mogamulizumab and Future Treatments.

The CCR4 receptor is a pivotal target in cutaneous T-cell lymphoma (CTCL) therapy due to its role in impairing immune responses against malignant T-cells and expression profiles. Monoclonal antibodies like mogamulizumab effectively bind to CCR4, reducing tumour burden and enhancing patient outcomes by inhibiting the receptor's interaction with ligands, thereby hindering malignant T-cell migration and survival. Combining CCR4 antibodies with chemotherapy, radiation, and other drugs is being explored for synergistic effects. Additionally, small-molecular inhibitors, old pharmacological agents interacting with CCR4, and CAR-T therapies are under investigation. Challenges include drug resistance, off-target effects, and patient selection, addressed through ongoing trials refining protocols and identifying biomarkers. Despite advancements, real-life data for most of the emerging treatments are needed to temper expectations. In conclusion, CCR4-targeted therapies show promise for CTCL management, but challenges persist. Continued research aims to optimise treatments, enhance outcomes, and transform CTCL management. This review aims to elucidate the biological rationale and the several agents under various stages of development and clinical evaluation with the actual known data.

Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorders (SMPLPD), demographical, clinical, therapeutic and prognostic aspects: a retrospective monocentric analysis.

Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorders (SMPLPD), also known as PCS-TCLPD, represent a rare group of hematologic diseases primarily affecting the skin. In this retrospective single-centre case series study, we aimed to investigate the demographic, clinical, therapeutic, and prognostic aspects of SMPLPD. We collected data from cases diagnosed between 2010 and the present, employing histopathological and immunohistochemical methods following WHO criteria. We included 22 patients with a median age of 61.50 years and median time between clinical onset and diagnosis of 3.00 months. Surgical excision with conservative margins was the primary choice, showing clinical remission in 17 cases, while non-surgical treatments, including radiotherapy, high-potency steroid treatment and ablative laser, achieved clinical remission in four cases. Clinical presentations varied, but the most common one was a single violaceous nodule/papule on upper body parts. In conclusion, our single-centre case series provides valuable insights into SMPLPD, highlighting the effectiveness of surgical treatments and the potential of non-surgical ones. Even if controversial, the benign nature of SMPLPD emphasizes the importance of achieving tumour clearance with acceptable aesthetic outcomes.

Reflectance Confocal Microscopy Combined with Dermoscopy and Histology in the Diagnostic Setting of Pigmented Eccrine Poroma: A Retrospective Study.

INTRODUCTION: Pigmented eccrine poroma (PEP) is a unique variant of a benign adnexal tumor known as eccrine poroma. Distinguishing PEPs from other pigmented lesions can be challenging due to overlapping clinical and dermoscopic features. OBJECTIVES: To provide a comprehensive analysis of the dermoscopic, confocal (RCM), and histological features of PEPs. METHODS: We undertook a retrospective study of the clinical, dermoscopic, RCM and histopathological features of PEPs that were surgically excised and histopathologically recognized. Data on epidemiological, clinical, dermoscopic, RCM and histopathological features were collected from the databases of the Skin Cancer Unit, IRCCS Policlinico di Sant' Orsola, between January 2021 and May 2023. RESULTS: The study population consisted of 61 patients, including 34 females (55.7%) and 27 males (44.3%). Dermoscopic examination of 61 PEPs revealed the presence of irregular borders (55.7%), milia-like cysts (50.8%), brown pseudo-network (41%), cerebriform pattern (34.4%), comedo-like openings (29.5%), atypical vessels (26.2%), glomerular vessels (18%), fingerprint-like perifollicular structures (8.2%), dots (4.9%) and dotted vessels (4.9%). RCM imaging was collected from 11 cases and showed mostly well-defined tumor nests with small cells in 100% of cases, bright structures in the upper dermis representing melanocytes and melanophages (63.6%), dark round spaces within the tumor nests (54.5%), well-demarcated borders of the nest (45.5%) and dilated and prominent vessels in upper dermis (27.3%). Histopathological pattern analysis revealed PEP sensu stricto (PEPss) as the most frequent (54.1%). CONCLUSIONS: The distinctive dermoscopic patterns, along with the confocal features aid in the differentiation from other pigmented lesions.

Nb-UVB and PUVA therapy in treating early stages of Mycosis Fungoides: A single-center cross-sectional study.

INTRODUCTION: Mycosis fungoides (MF) and Sezary Syndrome are the most common forms of cutaneous T-cell lymphoma. Early-stage MF is known to have an indolent behavior, and the EORTC guidelines recommend treating patients with skin-directed therapies, such as phototherapy, instead of systemic therapies. Phototherapy is a popular therapeutic option, with two commonly used light sources-PUVA and narrow band-nb UVB. PUVA is less commonly used due to its potential carcinogenic role, but it has systemic effects, while nb-UVB has mostly skin-limited effects. There is ongoing debate regarding the role of UVB light, and in 2021, the Cutaneous Lymphoma Italian Study Group reached a consensus on technical schedules for NB-UVB and PUVA for MF. This study aims to analyze and compare the efficacy of the two phototherapy options in treating early-MF patients. MATERIALS AND METHODS: The study included patients diagnosed with stage IA/B MF in the last 10 years, who had at least 12 months of follow-up data and a minimum of 24 phototherapy sessions (PUVA or nb UVB) and treated with topical steroids apart from phototherapy. RESULTS: Results showed that the two phototherapy options were similarly effective in treating early MF, with no significant differences in clinical response, although PUVA was associated with more adverse effects. CONCLUSIONS: The study provides valuable insights into the use of phototherapy in early MF, and the results can be used to guide treatment decisions and improve patient outcomes.

BRAF V600K vs. BRAF V600E: a comparison of clinical and dermoscopic characteristics and response to immunotherapies and targeted therapies.

BACKGROUND: A number of mutations related to malignant melanoma (MM) have been identified, and of the mutated genes, BRAF has been found to be altered in > 50% of cases. Most of these have been BRAF V600E mutations, whereas the incidence of BRAF V600K may vary from 10% to 30%. Little is known about the clinical prognostic correlations of BRAF V600K MMs. We evaluated the clinical and dermoscopic features, incidence, therapy response and outcomes in the medium to long term. AIM: To compare the clinical and dermoscopic characteristics, the response to systemic therapies and the prognosis among MMs with BRAF V600E and BRAF V600K mutations. METHODS: We retrieved the data of patients tested in our centre for MM from 2012 to 2015, including clinical features, dermoscopic pictures, clinical history and tumour mutations. Only patients with BRAF V600E and BRAF V600K mutations were included. Any MMs positive for BRAF V600K mutation were collected, and the number of V600K cases and their features were used to extract the same number of patients with BRAF V600E from our database using a matching method. The clinical and dermoscopic presentation, therapy response and disease progression of the two groups were then evaluated. RESULTS: In total, 132 cases of BRAF V600E-mutated MMs were identified, and then randomized with a propensity-score method to match the 10 retrieved cases of BRAF V600K mutation. Both groups had a nodular appearance to the tumours and an advanced disease stage, and no significant differences in dermoscopic features were highlighted. During the follow-up period, four patients with BRAF V600K died of disease-specific causes. Moreover, we found a higher frequency of metastasis, a faster disease progression and more rapid mortality in patients with BRAF V600K. CONCLUSION: Despite the small size of this study, the results show similar clinical and dermoscopic characteristics between V600E and V600K mutations, but compared with BRAF V600E MMs, BRAF V600K MMs seem to be less responsive to therapy and have a worse prognosis.

Oral Manifestations in Melanoma Patients Treated with Target or Immunomodulatory Therapies.

BACKGROUND: BRAF (v-raf murine sarcoma viral oncogene homolog B1) and MEK (mitogen activated protein kinase) inhibitors, as well as immunotherapy against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1), have shown good results in improving the disease-free survival of patients with metastatic melanoma (MM). The aim of this review is to summarize the main oral adverse events (oAEs) occurring in patients undergoing target or immunotherapy. We proposed two separate sections: oAEs during the treatment with (1) target therapies with BRAF and MEK inhibitors and tyrosine kinase inhibitors (gingival hyperplasia, pigmentation disorders, squamo-proliferative lesions) and (2) immunotherapies with CTLA-4 or PD1 inhibitors (lichenoid reactions, immuno-bullous reactions, xerostomia and other reactions). Adverse events frequently include oAEs, although these are often misdiagnosed and under-reported. Indeed, the oral cavity is not routinely evaluated during clinical practice. The symptomatology related to oAEs is significant since it may represent the first manifestation of a severe systemic reaction, possibly leading to difficulties in nutrition with a consequent impact on patients' quality of life. A careful examination of the oral cavity is recommended during the evaluation of oncologic patients in order to promptly detect the onset of new manifestations.

The impact of the COVID-19 pandemic on dermatologic practice: an Italian survey.

BACKGROUND: Since December 2019, the global population has been experiencing an unprecedented challenge due to Corona virus disease (COVID-19). A pandemic was declared by the World Health Organization on March 11th 2020, with an escalation of new cases worldwide. Dermatology units experienced a reorganization of regular activity, also providing clinical diagnosis and medical assistance to COVID-19-positive patients who developed cutaneous manifestations. OBJECTIVE: To evaluate the impact of the COVID-19 pandemic on Italian dermatologic clinical practice. MATERIALS & METHODS: This was a prospective online survey, consisting of a questionnaire with 35 multiple-choice questions uploaded on the website of the Italian Society of Dermatology and Venereology - SIDeMaST. RESULTS: A total of 136 dermatologists, 78 women (57%) and 58 men (43%), participated in the survey. The mean age was 58 ± 14 years. In total, 60% of participants reported an impact of the pandemic on their practice, in most cases consisting of a remarkable reduction in routine clinical activity (58%). Concern regarding possible infection was evaluated with a score ranging from 0 (no concern) to 5 (extremely concerned): the fear of becoming infected was high (≥3 in 40%), as was the fear of infecting families, colleagues or patients (≥3 points in 45%). CONCLUSION: The COVID-19 pandemic is having a strong impact on dermatology practice in Italy. The identification of critical points may help scientific societies to improve the clinical scenario and create specific strategies to overcome the emergency.

Cutaneous and Mucosal Melanomas of Uncommon Sites: Where Do We Stand Now?

Melanomas arising at uncommon sites include a group of lesions related to unusual localizations in specific ethnic groups. The rarity of the disease often represents a limit to the participation of patients in specific trials. However, this peculiar genetic scenario has important therapeutic implications regarding new oncologic therapies. The aim of this article is to review the clinical features, somatic alterations and therapeutic options for melanomas of uncommon sites. They can be classified as cutaneous and mucosal lesions affecting the nail apparatus, palms/soles, oral mucosa, genital area and scalp. The prognosis may be worse compared to melanomas of other districts, and a prompt diagnosis may dramatically influence the outcome. Dermatologists and oncologists should therefore distinguish this melanoma subgroup in terms of surgical intervention and medical treatment. Due to the lack of mutations in genes usually found in cutaneous melanomas, the discovery of novel targets is required to develop new strategies and to change the prognosis of non-responders or wild-type patients.

Merkel cell carcinoma: an updated overview of clinico-pathological aspects, molecular genetics and therapy.

Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma of uncertain origin. MCC incidence varies by country and has been increasing among white populations over the last three decades. MCC occurs most commonly in elderly men and typically arises on sun-exposed areas. It is associated with a high mortality rate due to rapid growth and significant metastatic potential. Clinical and histopathological diagnosis are challenging, but prompt recognition of the disease is imperative for a correct management. Several hypotheses have been proposed to define the cell of origin, which still remains controversial. The discovery of Merkel cell polyoma virus, identified in the majority of MCCs, led to the hypothesis of the existence of two tumour subtypes showing biological, clinico-pathological and prognostic differences. Significant interest is nowadays directed to characterize MCC genomic alterations and microRNA (miRNA) expression profiles. Current treatment strategies for MCC depend on staging, and typically consist of surgery, radiation therapy, chemotherapy and/or, more recently, immunotherapy. The aim of this review is to provide an updated overview of MCC with a special focus on clinico-pathological aspects, molecular-genetics and therapy.