Cutaneous Perivascular Hemophagocytosis: A Report of 2 Cases With Emphasis on Clinical and Histological Features.

ABSTRACT: Cutaneous perivascular hemophagocytosis (CH) is a histological manifestation that manifests as systemic hemophagocytic syndrome, also known as hemophagocytic lymphohistiocytosis, when accompanied by fever, hepatosplenomegaly, liver dysfunction, and cytopenia, and may rarely manifest independently of hemophagocytic lymphohistiocytosis. CH typically presents as purpuric or brownish macules and patches on the extremities, abdomen, and trunks. Histopathologically, the hallmark of CH includes extravasated erythrocytes and karyorrhectic debris phagocytized by histiocytes, associated with dermal capillary ectasia, perivascular infiltration of neutrophils, nuclear dust, and histiocytes without atypia. In this study, we report 2 cases of CH encountered in routine diagnostic practice and elucidate their significant clinical and histologic features. Our first patient had leukocytoclastic vasculitis with CH in the setting of Yersinia enterocolitis, and the second case represents CH in association with non-Hodgkin lymphoma. This study highlights the importance of considering CH as a potential indicator of underlying systemic pathology, including infectious and hematological disorders, in clinical practice.

Melasma and reflectance confocal microscopy: from baseline to treatment monitoring.

Melasma is a frequent condition worldwide, and it represents one of the most challenging disorders to treat in cosmetic dermatology. One of the critical factors for treatment prognosis is the assessment of the depth and distribution of pigment within the hyperpigmented area. Nowadays, non-invasive skin imaging techniques, such as reflectance confocal microscopy (RCM), have been used to estimate pigment distribution and depth within different skin layers. This article aims to provide a systematic review of RCM applications in melasma, providing terminology and investigating characteristics of melasma at baseline and after medical and laser treatment. Our results support the recognition of two main types of melasma, epidermal and mixed type, thanks to the role of RCM in highlighting the precise pigment depth location in the skin non-invasively. RCM treatment monitoring enables the objectification of pigment variations after treatment and the identification of prognostic factors for different treatment modalities. After the era of the application of RCM as a technique applied strictly to skin cancers, additional cosmetic applications are emerging, such as the application of melasma treatment monitoring.

Melanocortin-1 receptor (MC1R): a review for dermatologists.

Melanocortin-1 receptor (MC1R) and its variants have a pivotal role in melanin synthesis. However, MC1R has been associated to non-pigmentary pathways related to DNA-repair activities and inflammation. The aim of this review is to provide an up-to-date overview about the role of MC1R in the skin. Specifically, after summarizing the current knowledge about MC1R structure and polymorphisms, we report data concerning the correlation between MC1R, phenotypic traits, skin aging, other diseases and skin cancers and their risk assessment through genetic testing.

Diffuse Melanosis Cutis as the First Sign of Recurrence of Low-Risk Melanoma: Case Report and Systematic Review.

INTRODUCTION: Diffuse Melanosis Cutis (DMC) is a rare and late complication of metastatic malignant melanoma (MM) characterized by progressive pigmentation of skin and sometimes mucous membranes. The distinctive feature is the widespread and progressive deposition of melanin precursors in the dermis. OBJECTIVES: The purpose of this review is to define the clinical and demographic features of DMC and to promote a deeper insight into the clinical manifestation, histological findings, and pathophysiology behind DMC. METHODS: We have conducted a systematic review of the literature on published DMC in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. We also reported a case of DMC secondary to low-risk melanoma. RESULTS: Overall, including our case report, we reported 53 articles described 62 DMC patients. Breslow level of primary melanoma was reported having a mean value of 3.3 mm. The mean survival rate from onset of DMC resulted being 4.36 months. CONCLUSIONS: Among the most widely accepted etiopathogenetic hypotheses are deposition of melanic precursors in the dermis following tumor lysis, melanocyte proliferation induced by neoplastic growth factors, and the presence of diffuse dermal micro-metastases of MM. However, unanimous consensus on the proposed etiopathogenetic models of DMC is still lacking.

Unraveling the Complex Nexus of Human Papillomavirus (HPV) in Extragenital Keratinocyte Skin Tumors: A Comprehensive Analysis of Bowen's Disease and In Situ Squamous-Cell Carcinoma.

This comprehensive study delves into the intricate landscape surrounding the role of human papillomavirus (HPV) in extragenital keratinocyte skin tumors, specifically exploring Bowen's disease (BD) and in situ squamous-cell carcinoma (iSCC). Through a multifaceted examination, this research study elucidates the nuanced interplay of HPV, gender dynamics, anatomical site variations, and potential implications for the etiopathogenesis of these malignancies.

Dermatoscopy and reflectance confocal microscopy for basal cell carcinoma diagnosis and diagnosis prediction score: A prospective and multicenter study on 1005 lesions.

BACKGROUND: Basal cell carcinoma (BCC) is usually diagnosed by clinical and dermatoscopy examination, but diagnostic accuracy may be suboptimal. Reflectance confocal microscopy (RCM) imaging increases skin cancer diagnostic accuracy. OBJECTIVE: To evaluate additional benefit in diagnostic accuracy of handheld RCM in a prospective controlled clinical setting. METHODS: A prospective, multicenter study in 3 skin cancer reference centers in Italy enrolling consecutive lesions with clinical-dermatoscopic suspicion of BCC (ClinicalTrials.gov: NCT04789421). RESULTS: A total of 1005 lesions were included, of which 474 histopathologically confirmed versus 531 diagnosed by clinical-dermatoscopic-RCM correlation, confirmed with 2 years of follow-up. Specifically, 740 were confirmed BCCs. Sensitivity and specificity for dermatoscopy alone was 93.2% (95% CI, 91.2-94.9) and 51.7% (95% CI, 45.5-57.9); positive predictive value was 84.4 (95% CI, 81.7-86.8) and negative predictive value 73.3 (95% CI, 66.3-79.5). Adjunctive RCM reported higher rates: 97.8 (95% CI, 96.5-98.8) sensitivity and 86.8 (95% CI, 82.1-90.6) specificity, with positive predictive value of 95.4 (95% CI, 93.6-96.8) and negative predictive value 93.5 (95% CI, 89.7-96.2). LIMITATIONS: Study conducted in a single country. CONCLUSIONS: Adjunctive handheld RCM assessment of lesions clinically suspicious for BCC permits higher diagnostic accuracy with minimal false negative lesions.

Bone marrow metastases: a systematic review of a neglected involvement in malignant melanoma.

The occurrence of bone marrow metastases (BMM) in melanoma patients is often underestimated, with only 7% detected during in-vivo staging procedures but rising to 45% in autopsy cases. This systematic review aims to shed light on the clinical and laboratory features of BMM in melanoma by analyzing 73 studies selected from 2 482 initially retrieved from PubMed, Embase , and Cochrane CENTRAL databases. Our findings reveal a slight male predominance, with a median age at BMM diagnosis of 56 years. Primary melanoma sites included the skin (52%), mucosa (8.8%), uvea (20.5%) and unidentified (19%). BMM was preceded by lymph node involvement in 36.5% of cases, whereas 63% showed no nodal metastases, with direct BMM occurring in 22.5% and metastases to other sites in 41%. Common BMM symptoms included pain (60.7%), anemia (80%), thrombocytopenia, leukoerythroblastosis, pancytopenia and leukopenia, while disseminated intravascular coagulation was detected in 11% of cases. In 23.6% of cases, BMM was amelanotic. The prognosis for BMM is grim, with a median survival of only 2 months. Conventional therapies for BMM remain largely ineffective, emphasizing the importance of considering bone marrow as a potential metastatic site in melanoma patients.

Stevens-Johnson syndrome and toxic epidermal necrolysis: 11-year retrospective experience in a high-complexity tertiary hospital in Milan, Italy.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug-induced hypersensitivity reactions characterized by widespread epidermal necrosis, mucous membrane erosions, and systemic findings. We have provided our 11-year experience from a Milan, Italy tertiary hospital managing SJS/TEN, evaluating the clinical and histopathologic features plus the impact on mortality. We retrospectively analyzed 28 patients diagnosed with SJS/TEN based on the clinical and histopathologic findings, according to the classification criteria of multiple studies. We assessed the dermatographics, comorbidities, drug history, lesion characteristics, clinical findings, treatments, blood tests, and outcomes. Severity scores (SCORTEN, Re-SCORTEN, ABCD-10) were used for treatment evaluation and mortality prediction. Data were statistically analyzed, and significant factors associated with mortality were identified. We found that among the 28 patients, 89.2% had comorbidities, mainly cardiovascular diseases, and 21.4% had autoimmune disorders. All patients had received systemic therapy (46.6% monotherapy, 53.6% combination therapy), with systemic steroids (71.4%) and intravenous immunoglobulins (67.8%) being common treatments. There were complications, including systemic infections (67.9%) and septic shock (10.7%). The overall mortality rate was 17.8%. The statistical analysis indicated that malignancy, a high ABCD-10 score, and a high neutrophil-to-lymphocyte ratio were significantly associated with mortality. The extent of affected body surface area did not correlate significantly with mortality. This study provides insights into SJS/TEN management, revealing factors influencing mortality in a high-complexity tertiary hospital setting.

Unraveling the complexities of drug reaction with eosinophilia and systemic symptoms (DRESS): Insights into clinical, laboratory, and histopathologic features of a case series from an Italian tertiary center.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe and potentially life-threatening drug hypersensitivity reaction. The diagnosis and management of DRESS are complicated due to its heterogeneous clinical and pathologic presentations, delayed onset of signs and symptoms, and unpredictable outcome. This retrospective study aimed to analyze cases of DRESS from a single Italian referring tertiary hospital center (Grande Ospedale Metropolitano Niguarda, Milan, Italy) with a focus on clinical features, causative drugs, histopathologic findings, and treatment. We have included 18 of 32 patients with a probable or definite diagnosis of DRESS. The study observed a slight predominance of women, with antimicrobials and allopurinol identified as the main causative drugs. Clinical manifestations varied, with a monomorphic maculopapular eruption being the most common, whereas facial edema and mucosal involvement were less frequently observed. Multiple organs were commonly affected, with liver and kidney involvement being prominent. Cardiac involvement was associated with the severity of eosinophilia. Laboratory evaluations showed elevated eosinophil levels and increased eosinophil cationic protein levels, supporting the role of eosinophils in DRESS pathogenesis. Histopathologic analysis revealed various patterns often coexisting in the same biopsy in 83% of cases, with interface dermatitis being the most frequent, followed by the perivascular pattern and the spongiotic/eczematous pattern. We observed eosinophils in the biopsy samples in about 50% of patients, and the relationship between peripheral eosinophilia and eosinophils in skin biopsies was not significant. In addition to the RegiSCAR score, age may play a role in predicting disease severity, as older patients with lower scores had poorer outcomes. The prognosis of DRESS depended on early identification, discontinuation of the causative agent, and appropriate therapy. Systemic corticosteroids were the primary treatment option.

Annular dermatoses with rheumatologic implications.

A wide variety of cutaneous disorders present with annular (ringlike) skin lesions, and some of them carry rheumatologic implications because they may involve the joints or belong to the spectrum of connective tissue diseases. The diagnosis of an annular rheumatologic skin disease is possible with a correct clinicopathologic correlation, with a correct anamnesis of the patient, with the evaluation of systemic symptoms, laboratory and instrumental investigations, and finally with a cutaneous biopsy.

Laser Treatment Monitoring with Reflectance Confocal Microscopy.

Laser treatments have become popular in Dermatology. In parallel to technologic development enabling the availability of different laser wavelengths, non-invasive skin imaging techniques, such as reflectance confocal microscopy (RCM), have been used to explore morphologic and qualitative skin characteristics. Specifically, RCM can be applied to cosmetically sensitive skin areas such as the face, without the need for skin biopsies. For these reasons, apart from its current use in skin cancer diagnosis, our systematic review reveals how RCM can be employed in the field of laser treatment monitoring, being particularly suitable for the evaluation of variations in epidermis and dermis, and pigmentary and vascular characteristics of the skin. This systematic review article aims to provide an overview on current applications of RCM laser treatment monitoring, while describing RCM features identified for different applications. Studies on human subjects treated with laser treatments, monitored with RCM, were included in the current systematic review. Five groups of treatments were identified and described: skin rejuvenation, scar tissue, pigmentary disorders, vascular disorders and other. Interestingly, RCM can assist treatments with lasers targeting all chromophores in the skin and exploiting laser induced optical breakdown. Treatment monitoring encompasses assessment at baseline and examination of changes after treatment, therefore revealing details in morphologic alterations underlying different skin conditions and mechanisms of actions of laser therapy, as well as objectify results after treatment.

Lentigo maligna and lentigo maligna melanoma in vivo differentiation with dermoscopy and reflectance confocal microscopy: A retrospective, multicentre study.

INTRODUCTION: Dermoscopic predictors of lentigo maligna (LM) and lentigo maligna melanoma (LMM) have been recently reported, but these have not been reported in reflectance confocal microscopy (RCM). OBJECTIVES: (i) To validate dermoscopic predictors for LM/LMM, (ii) to identify RCM patterns in LM and LMM, and (iii) correlations between dermoscopic and RCM features in LM and LMM. MATERIALS AND METHODS: A retrospective, multicentre study of consecutive lesions with histologically proven LM or LMM subtypes of the head and face, with complete sets of dermoscopic and RCM images. RESULTS: A total of 180 lesions were included (n = 40 LMM). Previously reported differential dermoscopic features for LM subtypes were confirmed. Other features significantly associated with LMM diagnosis included irregular hyperpigmented areas, shiny white streaks, atypical vessels and light brown colour at dermoscopy and medusa head-like structures, dermal nests and nucleated cells within the papillae at RCM (p < 0.05). Correlations among LM lesions between dermoscopic and RCM features included brown to-grey dots and atypical cells (epidermis), grey colour and inflammation and obliterated follicles and medusa head-like structures. Among LMM lesions, significant correlations included obliterated follicles with folliculotropism, both irregular hyperpigmented areas and irregular blotches with widespread atypical cell distribution (epidermis), dermal nests and nucleated cells within the papillae (dermis). Irregular blotches were also associated with medusa head-like structures (dermal epidermal junction [DEJ]). CONCLUSIONS: Dermoscopic and RCM features can assist in the in vivo identification of LM and LMM and many are correlated. RCM three-dimensional analysis of skin layers allows the identification of invasive components in the DEJ and dermis.

Recurrent nasal basal cell carcinoma treated with standard surgery excision: evaluation of volume ratio.

BACKGROUND: Basal cell carcinoma (BCC) is the most common malignant skin tumor. Although it rarely evolves into a metastatic disease, BCC can lead to a significant morbidity due to local invasion. The risk of lesion recurrence depends on clinical and histopathological factors as described by the Nation Comprehensive Cancer Network (NCCN). The surgical excision margins have a well-known role: there is a close relationship between high recurrence rate of BCC and the tumor proximity to the surgical margins. Aim of our study was to assess whether there is a significative correlation between recurring BCC and volume ratio (VRb/t), defined as ratio between excisional biopsy volume and tumor volume, and if VRb/t is a useful parameter to assess the risk of recurrence of BCC. METHODS: Retrospective case-control study in 80 patients with history of recurrent basal cell carcinoma of the nose (cases), and 43 patients with history of basal cell carcinoma of the nose with no evidence of relapse (controls) in the following 8 years. RESULTS: Surgical excision margins, histological subtype, ulceration, depth of invasion and volume ratio (VRb/t) were evaluated in case and controls. The evaluation of VRb/t evidenced a significant difference between recurrent BCC and non-recurrent BCC. The mean values of VRb/t were 6.17 for cases and 11.94 for controls. The Binomial Logistic Regression has displayed, for values of VRb/t around 7, a probability of 75% to identify BCCs belonging to the recurrent group. CONCLUSIONS: Our data show a significant correlation between recurrent BCCs and VRb/t. VRb/t can help in the assessment of recurrence risk, used together with others prognostic factor. For values of VRb/t close to 7 it should be recommended a close follow-up to promptly identify a possible recurrence.

SARS-CoV-2 Detection by Digital Polymerase Chain Reaction and Immunohistochemistry in Skin Biopsies from 52 Patients with Different COVID-19-Associated Cutaneous Phenotypes.

BACKGROUND: COronaVIrus Disease 19 (COVID-19) is associated with a wide spectrum of skin manifestations, but SARS-CoV-2 RNA in lesional skin has been demonstrated only in few cases. OBJECTIVE: The objective of this study was to demonstrate SARS-CoV-2 presence in skin samples from patients with different COVID-19-related cutaneous phenotypes. METHODS: Demographic and clinical data from 52 patients with COVID-19-associated cutaneous manifestations were collected. Immunohistochemistry and digital PCR (dPCR) were performed in all skin samples. RNA in situ hybridization (ISH) was used to confirm the presence of SARS-CoV-2 RNA. RESULTS: Twenty out of 52 (38%) patients presented SARS-CoV-2 positivity in the skin. Among these, 10/52 (19%) patients tested positive for spike protein on immunohistochemistry, five of whom had also positive testing on dPCR. Of the latter, one tested positive both for ISH and ACE-2 on immunohistochemistry while another one tested positive for nucleocapsid protein. Twelve patients showed positivity only for nucleocapsid protein on immunohistochemistry. CONCLUSIONS: SARS-CoV-2 was detected only in 38% of patients, without any association with a specific cutaneous phenotype, suggesting that the pathophysiology of cutaneous lesions mostly depends on the activation of the immune system. The combination of spike and nucleocapsid immunohistochemistry has higher diagnostic yield than dPCR. Skin persistence of SARS-CoV-2 may depend on timing of skin lesions, viral load, and immune response.

The clinical and pathologic spectrum of mucocutaneous reactions after COVID-19 vaccinations in three tertiary referral centers of northern Italy.

Adverse cutaneous reactions after COVID-19 vaccinations have increased, highlighting not only how SARS-CoV-2 infection but also COVID-19 vaccines may induce adverse cutaneous manifestations. We evaluated the clinical and pathologic spectrum of mucocutaneous reactions after COVID-19 vaccinations, observed consecutively within three large tertiary centers of the Metropolitan City of Milan (Lombardy), comparing our results with the currently available literature. We retrospectively reviewed medical records and skin biopsies of patients diagnosed with mucocutaneous adverse events after COVID-19 vaccinations and followed at three Italian tertiary referral centers in the Metropolitan City of Milan. One hundred twelve patients (77 women and 35 men (112 total); median age, 60 years) have been included in the present study; a cutaneous biopsy was performed in 41 cases (36%). The trunk and arms were the most involved anatomic areas. Autoimmune reactions after COVID-19 vaccinations, urticaria, morbilliform eruptions, and eczematous dermatitis have been the most commonly diagnosed disorders. Compared to the currently available literature, we performed many more histologic examinations, allowing us to make more precise diagnoses. Most of the cutaneous reactions were self-healing and/or responded to topical and systemic steroids and systemic antihistamines, thus not discouraging the general population from carrying out vaccinations, which currently have a good safety profile.

"Your Skin Tells You" Campaign for Keratinocyte Cancers: When Individuals' Selection Makes the Difference.

BACKGROUND: Prevention campaigns for skin cancers have focused primarily on melanoma, and over time there has been increasing awareness of the need to select the population to be screened to maximize program effectiveness. OBJECTIVES: The objective of the study was to report the results of a free dermatological initiative, as part of an awareness campaign dedicated to keratinocyte cancers, targeting individuals pre-selected through a short questionnaire. METHODS: One day of dermatological consultations was held at 15 dermato-oncology referral centers during May 22-June 30, 2021. For selection, individuals answered a telephone interview consisting of 7 yes/no questions on risk factors. Demographics, clinical characteristics of suspicious tumors, and histopathologic diagnosis of excised lesions were collected. Suspicion rate, detection rate, and positive predictive values (PPVs) for any skin cancer, basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma were calculated. RESULTS: A total of 320 individuals (56.9% males; 43.1% females) with a median age of 69.6 (range 21-91) years qualified for the screening initiative. Overall, skin cancers and precancerous lesions were diagnosed in 65.9% of the patients. Suspicion rate was 28.7% for any skin cancer (92/320), 22.8% for BCC (73/320), 4.7% for cSCC (15/320), and 1.2% for melanoma (4/320). Detection rate was 23.4% for any skin cancer (PPV 93.7%), 18.1% for BCC (PPV 95.1%), 4.4% for cSCC (PPV 93.3%), and 0.9% for melanoma (PPV 75%). CONCLUSIONS: Selection of individuals at high risk is a cost-effective approach for early detection campaigns for keratinocyte cancers.