Fordyce granules and hyperplastic mucosal sebaceous glands as distinctive stigmata in Muir-Torre syndrome patients: characterization with reflectance confocal microscopy.

BACKGROUND: The Muir-Torre syndrome (MTS), a variant of Lynch syndrome (LS), is characterized by the presence of sebaceous skin adenomas and/or carcinomas and keratoacanthomas associated with visceral malignancies. Fordyce granules (FGs) are oral mucosal lesions previously found in association with LS. The aim of this study was to analyze the specific frequency of FGs in sporadic individuals and gene carriers patients with MTS of known mismatch repair genes mutations. The secondary aim was to characterize FGs by means of reflectance confocal microscopy (RCM). METHODS: A total of 13 patients belonging to nine different genetically unrelated MTS kindreds (MLH1 gene mutation n = 2; MSH2 gene mutation n = 11) and 140 genetically unrelated healthy controls were examined. Depending on the clinical examination of the oral mucosa surface, subjects were categorized as either FGs positive or FGs negative. RESULTS: FGs were diagnosed in 13 of 13 (100%) of MMR gene carriers patients with MTS vs. 9 of 140 (6.4%) controls. The most common site for FGs in MTS was the vestibular oral mucosa, compared with the gingival mandibular and retromandibular pad in controls. RCM examination found multiple sebaceous acinar cells that appear as round or oval hyper-refractive globules and that create a lobular aspects of the sebaceous glands defined as 'moruliform' or 'berry-like' structures. CONCLUSIONS: Clinical and RCM evidences of our study suggest that an activation of the sebaceous glands system occurs in patients with MTS. Fordyce granules and intra-oral sebaceous hyperplasia may constitute an additional clinical parameter, which may be adopted to distinguish individuals with highest likelihood of being affected from MTS.

Comprehensive analysis of pseudoxanthoma elasticum: epidemiological, genetic, and clinical findings from the leading Italian center.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is a rare genetic autosomal recessive metabolic disease characterized by progressive mineralization and fragmentation of elastic fibers from soft connective tissues. The objective of our study was to analyze the epidemiological, genetic, cutaneous, and extracutaneous clinical data from the largest Italian monocentric cohort of PXE patients. METHODS: We included all patients diagnosed with PXE and referred to Neurocutaneous Rare Diseases at Umberto I Polyclinic Hospital (Rome, Italy) between January 1983 and February 2024. A retrospective analysis of their data was performed. RESULTS: We enrolled 86 patients (77.9% women), revealing compound heterozygosity in 19.8% of cases and homozygosity in 5.8%. Missense (34.9%), non-sense (5.8%), splice-site (5.8%), deletion (4.7%), and frameshift (2.3%) mutations were disclosed. Cutaneous alterations were noted in the neck (69.7%), axilla (33.7%), inguinal (17.5%), and cubital folds (11.7%). The most common ocular findings were angioid streaks (64.0%) and choroidal neovascularization (18.6%), with blindness reported in 5.8% of cases. Thicker intima-media was observed around the mid-fifties in the supra-aortic trunks (40.7%), lower limb arteries (32.6%), and renal arteries (4.7%). Regurgitation was more common in atrioventricular valves (48.8%) than in semilunar ones (10.5% and 9.3%). Dyslipidemia (19.8%), hypertension (18.8%), and fatty liver disease (12.8%) were prevalent, with calcifications found in the kidneys (25.6%), liver (15.1%), spleen (11.6%), and testicles (8.1% of males). Autoimmune diseases and depression were observed in 11.6% and 4.7% of cases, respectively. CONCLUSIONS: Enhanced understanding of PXE can improve patients' quality of life and facilitate the development of more effective therapeutic strategies.

HIV and syphilis: incidence rate of coinfection and syphilis reinfection in a cohort of newly diagnosed HIV patients.

BACKGROUND: Syphilis represents a major public health concern disproportionately affecting HIV positive patients and, in many cases, both infections are newly diagnosed at the same time. To date, limited studies are available on syphilis incidence in patients with a new HIV diagnosis. METHODS: Patients newly diagnosed with HIV in 2010-2018 were included in the study and screening tests for syphilis were performed at baseline and at least once a year. Primary aims were to analyze the incidence rate of HIV-syphilis coinfection and syphilis reinfection. Secondary objective was to identify characteristics independently associated with coinfection and reinfection. RESULTS: Of 500 newly diagnosed HIV patients, 20% presented a concomitant positive syphilis serology. Among them, 54 patients had a serology indicative for an active syphilis requiring therapy, while 46 had a history of prior treatments. The independent factors for syphilis acquisition were: MSM contact (OR=2.64; 95% CI: 1.48-4.72; P<0.001), male gender (OR=2.43; 95% CI: 1.08-5.48; P=0.032), and age (OR=1.03; 95% CI: 1.01-1.05; P=0.005 per year increasing). Presence of syphilis at the time of HIV diagnosis remained fairly stable during the study period (P for trend, P=0.689). We observed 52 syphilis reinfections related to 37 people. Patients with at least one reinfection were all males and 86.5% MSM. CONCLUSIONS: Males and MSM with HIV presented high rates of syphilis coinfection and reinfection suggesting persistent high-risk sexual behaviors and the need for appropriate intervention strategies in order to early detect and treat syphilis avoiding life-threatening complications and the spread of the infection in the community.

Effect of Reflectance Confocal Microscopy for Suspect Lesions on Diagnostic Accuracy in Melanoma: A Randomized Clinical Trial.

Importance: Previous systematic reviews and meta-analyses have concluded that given data paucity, a comparison of reflectance confocal microscopy (RCM) with dermoscopy is complex. They recommend comparative prospective studies in a real-world setting of suspect lesions. Objective: To test the hypothesis that RCM reduces unnecessary lesion excision by more than 30% and identifies all melanoma lesions thicker than 0.5 mm at baseline. Design, Setting, and Participants: This randomized clinical trial included 3165 patients enrolled from 3 dermatology referral centers in Italy between January 2017 and December 2019, with a mean (SD) follow-up of 9.6 (6.9) months (range, 1.9-37.0 months). The consecutive sample of 3165 suspect lesions determined through dermoscopy were eligible for inclusion (10 patients refused). Diagnostic analysis included 3078 patients (48 lost, 39 refused excision). Data were analyzed between April and September 2021. Interventions: Patients were randomly assigned 1:1 to standard therapeutic care (clinical and dermoscopy evaluation) with or without adjunctive RCM. Information available guided prospective clinical decision-making (excision or follow-up). Main Outcomes and Measures: Hypotheses were defined prior to study initiation. All lesions excised (baseline and follow-up) were registered, including histopathological diagnoses/no change at dermoscopy follow-up (with or without adjunctive RCM). Number needed to excise (total number of excised lesions/number of melanomas) and Breslow thickness of delayed diagnosed melanomas were calculated based on real-life, prospective, clinical decision-making. Results: Among the 3165 participants, 1608 (50.8%) were male, and mean (SD) age was 49.3 (14.9) years. When compared with standard therapeutic care only, adjunctive RCM was associated with a higher positive predictive value (18.9 vs 33.3), lower benign to malignant ratio (3.7:1.0 vs 1.8:1.0), and a number needed to excise reduction of 43.4% (5.3 vs 3.0). All lesions (n = 15) with delayed melanoma diagnoses were thinner than 0.5 mm. Conclusions and Relevance: This randomized clinical trial shows that adjunctive use of RCM for suspect lesions reduces unnecessary excisions and assures the removal of aggressive melanomas at baseline in a real-life, clinical decision-making application for referral centers with RCM. Trial Registration: ClinicalTrials.gov Identifier: NCT04789421.

Synergic effect of buccal fat pad pedicled flap and dermal acellular matrix for large cheek defect.

Reconstruction of large defects of the upper cheek defects still remains a challenge for the surgeon, who can apply different techniques. We present a new method involving the use of a dermal regeneration template to achieve an improved, faster healing of pedicled buccal fat flap in a 75-year-old woman affected by melanoma of the upper-middle cheek. The tumor involved soft tissue, zygomatic arch and periocular fact. The choice of the surgical technique consisted first in the creation of a buccal fat pad to restore the important lack of tissue over the underlying bones, and then in the position of a dermal acellular matrix (Integra® Dermal Regeneration Template; Integra LifeSciences Holdings Corporation, Plainsboro, NJ, USA). Three weeks later, once the neodermal formation was finished, a split thickness graft was placed. This is a not yet described association that represents a good surgical option for the restoration of large cheek defects that allows good functional and cosmetic result in older patient when minimal surgical invasion and operative duration are necessary because of a patient's general condition. The postoperative course with this surgical technique was regular and a good functional result was achieved. This technique provides an adequate functional coverage, a restoration of soft tissue lacking and an acceptable cosmetic result without ectropion.

Italian Guidelines in diagnosis and treatment of alopecia areata.

Alopecia areata (AA) is an organ-specific autoimmune disorder that targets anagen phase hair follicles. The course is unpredictable and current available treatments have variable efficacy. Nowadays, there is relatively little evidence on treatment of AA from well-designed clinical trials. Moreover, none of the treatments or devices commonly used to treat AA are specifically approved by the Food and Drug Administration. The Italian Study Group for Cutaneous Annexial Disease of the Italian Society of dermatology proposes these Italian guidelines for diagnosis and treatment of Alopecia Areata deeming useful for the daily management of the disease. This article summarizes evidence-based treatment associated with expert-based recommendations.

Imatinib-induced diffuse hyperpigmentation of the oral mucosa, the skin, and the nails in a patient affected by chronic myeloid leukemia: report of a case and review of the literature.

BACKGROUND: Imatinib mesylate is a tyrosine-kinase inhibitor used as the first-line treatment in chronic myeloid leukemia patients, but it is also indicated for other hematological diseases and solid tumors. Imatinib treatment is often associated with hypopigmentation, but only a few cases of hyperpigmentation are described in literature. METHODS: We are reporting the first case of imatinib-related hyperpigmentation involving the oral mucosa, skin, and nails in a patient affected by chronic myeloid leukemia and treated with imatinib since 2002. A review of all the available literature regarding the imatinib-related hyperpigmentation was performed, and one additional case was analyzed. Due to the possibility of a post-inflammatory hyperpigmentation, all cases of pigmentary changes previously characterized by a rash and/or pruritus in the same body areas were excluded. RESULTS: Thirty cases of well-documented imatinib-related hyperpigmentation were described in literature. In our case, imatinib therapy was well tolerated for several years, and it led to an excellent hematological and cytogenetic response. However, the patient gradually developed a blue-gray pigmentation that involved the nose, fingernails, toenails, pretibial regions, posterior axillary folds, and hard palate. Other causes of pigmentary changes were excluded, and histopathological examination confirmed the clinical suspicion of imatinib-related hyperpigmentation. CONCLUSIONS: Hyperpigmentation induced by imatinib is an adverse reaction rarely described in literature. The underlying pathogenetic mechanisms are not yet completely clear, and further studies are necessary to elucidate them. Currently, no treatment is required for this condition, and there is no indication to discontinue imatinib treatment.

Omalizumab in Chronic Spontaneous Urticaria Refractory to Conventional Therapy: An Italian Retrospective Clinical Analysis with Suggestions for Long-Term Maintenance Strategies.

INTRODUCTION: Omalizumab is indicated for the treatment of patients affected by chronic spontaneous urticaria (CSU) refractory to antihistamines. The aim of this study was to assess the efficacy, safety, and recurrence of symptoms in a real-life experience of omalizumab as an add-on therapy for H1-antihistamine-refractory CSU patients (refractory CSU). METHODS: A retrospective review of the clinical records of all refractory CSU treated with omalizumab at our dermatology center from June 2014 to April 2017 was performed. Patients previously treated with second-generation antihistamines at a fourfold increased dose without clinical responses at 4 weeks of treatment were selected. Omalizumab was administered at a single dosage of 300 mg every 4 weeks for 6 months. Disease severity was assessed using the 7-day Urticaria Activity Score (UAS7). RESULTS: Eighteen patients (14 women; mean age 51 years, range 25-74) were enrolled. Mean UAS7 at baseline was 27.3 (range 15-38). Symptoms improved in all patients at 4 weeks (UAS7 = 16.1, range 0-36). Treatment was completed in 17 patients (94.4%), and among these, a complete response (UAS7 = 0) was registered in 10 patients (58.8%). Adverse events included thrombocytopenia in 1 patient (5.6%) at 16 weeks; therapy was suspended after 20 weeks and the complication was resolved, resulting in a freedom from major adverse events of 94.4%. Symptom recurrence occurred in 3 patients (17.6%) at 4, 5, and 7 months from the end of the primary therapy. Retreatment with omalizumab was successful without any adverse effects. Mean follow-up was 9.5 months (range 1-28). CONCLUSION: Add-on omalizumab therapy for refractory CSU in a real-life setting seems to be effective and safe with a relatively low incidence of symptom recurrence. Further research should investigate personalized omalizumab treatment dosages and administration intervals, and the identification of biomarkers for future treatment algorithms.

Non-melanoma skin cancer of the head and neck: the aid of reflectance confocal microscopy for the accurate diagnosis and management.

BACKGROUND: Non-melanoma skin cancer (NMSC) represents the most common cutaneous neoplasms of the head and neck. In recent years, novel non-invasive diagnostic tool have been developed, and among these we have the reflectance confocal microscopy (RCM), that offers the evaluation of the skin at real time with cellular resolution. Numerous studies have identified the main confocal features of skin tumours, demonstrating the good correlation of these features with certain dermatoscopic patterns and histologic findings. EVIDENCE ACQUISITION: The aim of this analysis was to provide new insight into the role of RCM in the diagnosis and management of NMSC of the head and neck. Data comes from the most recent literature, taking into account previous essential reported information in this field. The study eligibility criteria were: studies providing update information, focusing on RCM findings in NMSC, without restrictions for age, sex, ethnicity. A search concerning the role of dermoscopy and RCM in the diagnosis of NMSC was performed on Medline. Duplicated studies, single case report and papers with language other than English were excluded from this study. EVIDENCE SYNTHESIS: RCM clues were analysed for NMSC in association with clinical, dermoscopic and histopathologic findings. Moreover, some new findings have been described and possible applications for NMSC of the head and neck have been discussed. CONCLUSIONS: RCM allows tissue imaging in vivo contributing to a more accurate diagnosis of NMSC of the head and neck, sparing time for the patient and costs for the public health system. RCM can also be used for selection of the biopsy site and it is helpful in defining the surgical safety margins to keep during the excision of skin cancers.

Confocal microscopy characterization of BRAFV600E mutated melanomas.

Thanks to modern techniques, molecular signatures for melanoma are now identifiable and have opened new horizons in the treatment of metastatic disease with molecular-targeted therapies. We distinguish different melanoma subtypes on the basis of genetic mutations such as BRAFV600E and we can therefore hypothesize the existence of corresponding morphological patterns that might be detected in vivo by noninvasive diagnostic tools such as dermoscopy and confocal microscopy. Eight BRAFV600E mutated melanomas (six primary and two metastases) were collected, matched in terms of age, sex, and thickness wild-type controls, and analyzed. In this preliminary study, regression, corresponding to fibrosis and melanophages in the dermis, was the predominant pattern and was also observed confocally when dermoscopy showed no peppering. In particular, confocal microscopy could not only detect regression but also provided a semiquantitative analysis of its grade through the count of melanophages. Confocal microscopy can be proposed as a useful tool in the preliminary screening and characterization of BRAFV600E mutated melanomas, providing new insights for patients' screening and follow-up.

Multiple primary melanomas versus single melanoma of the head and neck: a comparison of genetic, diagnostic, and therapeutic implications.

Single primary and multiple primary melanomas (MPMs) of the head and neck region may be confused at first glance because of the common clinical and dermoscopic patterns. An inaccurate diagnosis may lead the clinician to a wrong diagnostic and therapeutic pathway because MPMs occurring in familial or sporadic settings are often involved in individual cancer susceptibility. We investigated the clinical, demographic, histological, and survival differences between MPMs and single melanoma occurring in the head and neck region. A retrospective analysis of medical and histologic records from 217 melanomas of the head and neck region was carried out. Malignant neoplasms affecting MPMs patients were also reported. Mutational analysis of specific genes was carried out when clinical data and family history were suggestive for a familial/hereditary setting. Two hundred and five out of 217 (94.5%) patients were affected by single primary melanoma and 12 (5.5%) by MPMs of the head and neck region. Individuals affected by MPMs were distinguished by a significantly higher mutation frequency and a higher prevalence of malignant neoplasms such as renal cancer. Genetic testing showed germline mutations affecting MITF E318K, CDKN2A genes. Our data highlight the importance of strict cancer surveillance in individuals with MPMs and the role of appropriate genetic counseling and testing in selected patients. Finally, personalized clinical and instrumental screening and follow-up strategies should also be based on mutational status. A heightened level of suspicion is required in the clinical management of mutation carriers.