"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.

Non-Melanoma Skin Cancers: Biological and Clinical Features.

Non-melanoma skin cancers (NMSCs) include basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and Merkel cell carcinoma (MCC). These neoplasms are highly diverse in their clinical presentation, as well as in their biological evolution. While the deregulation of the Hedgehog pathway is commonly observed in BCC, SCC and MCC are characterized by a strikingly elevated mutational and neoantigen burden. As result of our improved understanding of the biology of non-melanoma skin cancers, innovative treatment options including inhibitors of the Hedgehog pathway and immunotherapeutic agents have been recently investigated against these malignancies, leading to their approval by regulatory authorities. Herein, we review the most relevant biological and clinical features of NMSC, focusing on innovative treatment approaches.

Tattoo-Associated Skin Reaction in a Melanoma Patient Receiving B-RAF and MEK Inhibitors: A Case Report with an Emphasis on Etiopathogenic and Histological Features.

Tattoo-associated cutaneous reactions have become quite frequent given the increasing percentage of tattooed subjects globally and also in Italy. On the other hand, the increasing use of target therapy is showing the ability of these drugs to affect the immune system and also cause adverse tattoo-related reactions. In this paper, we report a case of a 42-year-old patient with stage-IIID melanoma undergoing treatment with Dabrafenib and Trametinib. The patient reported erythema, oedema and scaling in areas of the body containing a black tattoo, and, conversely, no signs and/or symptoms in areas with tattoos of a different color. Histopathological and immunohistochemical features indicated a lympho-histiocytic reaction with a granulomatous morphology, mainly distributed around the vessels and hair adnexa. By discussing the cases reported in the literature prior to ours, we concluded and provided the possible indications of the pathogenesis.

Dystrophic Epidermolysis Bullosa (DEB): How Can Pregnancy Alter the Course of This Rare Disease? An Updated Literature Review on Obstetrical Management with an Additional Italian Experience.

Epidermolysis Bullosa (EB) is an extremely rare and disabling inherited genetic skin disease with a predisposition to develop bullous lesions on the skin and inner mucous membranes, occurring after mild friction or trauma, or even spontaneously. Within the spectrum of EB forms, dystrophic EB (DEB) represents the most intriguing and challenging in terms of clinical management, especially with regard to pregnancy, due to the highly disabling and life-threatening phenotype. Disappointingly, in the literature little focus has been directed towards pregnancy and childbirth in DEB patients, resulting in a lack of sound evidence and guidance for patients themselves and clinicians. The current study aims to contribute to the DEB literature with an updated summary of the existing evidence regarding the obstetrical and anesthesiological management of this rare disease. Furthermore, this literature review sought to answer the question of whether, and if so, in which way, the pregnancy condition may alter the course of the underlying dermatologic skin disease. Having all this information is indispensable when counseling a patient with DEB who desires a child or is expecting one. Finally, we reported own experience with a pregnant woman with a recessive DEB whom we recently managed, with a favorable outcome.

Endocrine Mucin-Producing Sweat Gland Carcinoma: Case Presentation with a Comprehensive Review of the Literature.

(1) Background: Endocrine Mucin-Producing Sweat Gland Carcinoma (EMPSGC) is a rare, low-grade, neuroendocrine-differentiated, cutaneous adnexal tumor, officially recognized by the World Health Organization (WHO) Skin Tumors Classification in 2018 as a separate entity and homologue of endocrine ductal carcinoma in situ (eDCIS)/solid papillary carcinoma of the breast. Although it is more frequent in the female sex, between 60 and 70 years old, in the peri-orbital region, EMPSGC has also been described in the male sex, in subjects under 60 and over 80, and in extra-eyelid localizations (cheek, temple, scalp), but also in extra-facial localizations (chest and scrotum). (2) Methods: We present the clinical case of a 71-year-old woman with an undated lesion of the scalp, which presented as a nodule, skin-colored, and 2.5 cm in maximum diameter. We also conduct a comprehensive literature review from 1997 to the end of 2022, consulting PubMed, Scopus, Web of Science (WoS), and Google Scholar using the following keywords: "Endocrine mucin-producing sweat gland carcinoma" and/or "EMPSGC" and/or "skin" and "cutaneous neoplasms". In addition, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 253 patients were recorded; 146 were females (57.7%) and 107 were males (42.2%). The vast majority of the lesions were in the eyelids (peri-ocular region), and only a minority of cases involved the cheeks, supra-auricular, retro-auricular, and occipital region, with very rare cases in the scalp, to which the present is also added. (4) Conclusions: The morphological and immunophenotypical features are essential both for the correct diagnosis and to be able to classify this lesion among the corresponding eDCIS/solid papillary carcinoma of the breast, with neuroendocrine differentiation. Recent papers have attempted to shed light on the molecular features of EMPSGC, and much remains to be conducted in the attempt to subtype the molecular profiles of these entities. Future studies with large case series, and especially with molecular biology techniques, will be needed to further add information about EMPSGC and its relationship in the PCMC spectrum.

Keratosis Pilaris-like Eruption during Treatment of Chronic Myeloid Leukemia with Tyrosine Kinase Inhibitors: Literature Review and Report of a Case Related to Imatinib.

The advent of tyrosine kinase inhibitors (TKIs) blocking BCR-ABL activity has revolutionized the therapeutic management of patients with chronic myeloid leukemia (CML). Adverse cutaneous reactions (ACRs) are common nonhematologic adverse events associated with the use of BCR-ABL TKIs. A characteristic pattern of eruption resembling keratosis pilaris (KP) has been described in patients treated with these drugs, especially nilotinib and dasatinib. The pathogenesis of this ACR is still unknown. This type of reaction appears to be uncommon with imatinib. Here, we report the case of an elderly patient with an asymptomatic KP-like eruption, which appeared one month after starting treatment with imatinib for CML. The case presentation is accompanied by a review of similar reactions in patients with CML treated with BCR-ABL inhibitors, attempting to make an excursus on the molecular targets of such drugs and possible mechanisms underlying this ACR.

Combination of immunotherapy and other targeted therapies in advanced cutaneous melanoma.

Cutaneous Melanoma (CM) is an aggressive cancer whose incidence is increasing worldwide. However, the knowledge of its biology and genes driving cell growth and survival allowed to develop new drugs that have improved PFS and OS of advanced disease. Both BRAF targeting agents and immune checkpoint inhibitors (ICIs) have been adopted for the treatment of metastatic disease and the adjuvant setting. Several melanoma patients show innate or acquired drug-resistance and thus new strategies are required for overcoming this complication. New ICIs have been developed, and strategies of combination or sequencing are under investigation in ongoing clinical trials. In addition, pre-clinical data have demonstrated that many strategies induce the release of neoantigens within the tumor microenvironment, thus suggesting the combination of new agents with ICIs. Here, we review the ongoing strategies in advanced CM including a dedicated section on treatment of brain metastases.

Squamous Cell Carcinoma in Patients with Inherited Epidermolysis Bullosa: Review of Current Literature.

Epidermolysis bullosa (EB) is a group of rare congenital diseases caused by mutations in structural proteins of the dermal/epidermal junction that are characterized by extreme epithelial fragility, which determines the formation of bullae and erosions either spontaneously or after local mechanical traumas. In EB patients, skin fragility leads to many possible complications and comorbidities. One of the most feared complications is the development of cutaneous squamous cell carcinomas (SCCs) that particularly in the dystrophic recessive EB subtype can be extremely aggressive and often metastatic. SCCs in EB patients generally arise more often in the extremities, where chronic blisters and scars are generally located. SCCs represent a big therapeutic challenge in the EB population. No standard of care exists for the treatment of SCC in these patients, and therapy is based on small case studies. Moreover, the pathogenesis of cSCC in EB patients is still unclear. Many theories have been indeed postulated in order to explain why cSCC behaves so much more aggressively in EB patients compared to the general population. cSCC in EB seems to be the result of many complex interactions among cancer cells, skin microenvironment, susceptibility to DNA mutations and host immune response. In this review, we analyze the different pathogenetic mechanisms of cSCC in EB patients, as well as new therapies for this condition.

Immune Disregulation in Cutaneous Squamous Cell Carcinoma of Patients with Recessive Dystrophic Epidermolysis Bullosa: A Single Pilot Study.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is one of the most devastating complications of recessive dystrophic epidermolysis bullosa (RDEB). We recently demonstrated a reduction in immune cell peritumoral infiltration in RDEB patients with cSCC, together with a reduction in CD3+, CD4+, CD68+ and CD20 lymphocytes as compared to primary and secondary cSCC in patients without RDEB. Recently, new molecules, such as high mobility group box 1 (HMGB1), T cell immunoglobulin, mucin domain 3 (TIM-3) and Heme oxygenase-1 (HO-1), have been shown to play a role in antitumoral immunity. OBJECTIVE: Patients with RDEB are known to be at increased risk of developing skin cancers, including the dreaded squamous cell carcinoma of the. Tendentially, cSCCs that arise in the context of EBDR are more aggressive and lead to statistically significant bad outcomes compared to cSCCs developed on the skin of patients without EBDR. In an attempt to study the microenvironment of these lesions, we conducted an immunohistochemical analysis study of proteins that could be actively involved in the genesis of this type of malignant neoplasms. METHODS: In this retrospective study, the OH1-HMGB1-TIM3 activation axis, as correlated to the T lymphocytes cell count, was assessed in biopsy samples from 31 consecutive cases consisting of 12 RDEB patients with cSCC, 12 patients with primary cSCC and 7 RDEB patients with pseudoepitheliomatous cutaneous hyperplasia. Parametric Student's t-test was applied for normally distributed values, such as CD4+ and CD8+, and non-parametric Mann-Whitney test for non-normally distributed values, such as HMGB-1, TIM-3 and HO-1. RESULTS: In RDEB patients with cSCC and with pseudoepitheliomatous hyperplasia, the expression of CD4 T helper lymphocytes was lower than in the peritumoral infiltrate found in primary cSCC. CD8 cytotoxic T lymphocytes were increased in primary cSCC compared to the other two groups. An increased HMGB1 expression was evident in both primary and RDEB cSCC. TIM3 expression was higher in RDEB patients with cSCC compared to the other two groups. A significantly reduced immunohistochemical expression of HO-1 was evident in the tumoral microenvironment of cSCC-RDEB as compared to primary cSCC. CONCLUSIONS: These data suggest that a reduced immune cell peritumoral infiltration in RDEB patients could be responsible, in the complexity of the mechanisms of carcinogenesis and host response, of the particular aggressiveness of the cSCC of RDEB patients, creating a substrate for greater local immunosuppression, which, potentially, can "open the doors" to development and eventual metastasis by this malignant neoplasm.

Primitive Cutaneous (P)erivascular (E)pithelioid (C)ell Tumour (PEComa): A New Case Report of a Rare Cutaneous Tumor.

Perivascular epithelioid cell tumours (PEComas) are a growing family of tumours composed of histologically and immunohistochemically distinctive perivascular epithelioid cells. Cutaneous primitive PEComas (cPEComas) are very rare, with 65 cases described in the English literature, and occur as a painless lesion predominantly in female patients, with a wide age range. We present a new case of cPEComa found on the left thigh of a 53-year-old patient with histopathological, immunohistochemical, and molecular information. The lesion was positive for HMB-45 and focal for smooth muscle actin and desmin but negative for melan-A, S-100 protein, CD31, and CD34. Next generation sequencing (NGS) analysis demonstrated the presence of genomic aberration for baculoviral IAP repeats containing BIRC3 splice site 1622-27_1631del37. Although there are little molecular data regarding this entity, our case adds to this knowledge, considering the importance of detecting genomic aberrations in the context of specific therapies such as mTOR inhibitors.

The Thousand Faces of Malignant Melanoma: A Systematic Review of the Primary Malignant Melanoma of the Esophagus.

Primary Malignant Melanoma of the Esophagus (PMME) is an extremely rare cancer of the esophagus, accounting for 0.1−0.8% of all oro-esophageal cancers and <0.05% of all melanoma subtypes, with an estimated incidence of 0.0036 cases per million/year. We conduct a careful analysis of the literature starting from 1906 to the beginning of 2022, searching the PubMed, Science.gov, Scopus and Web of Science (WoS) databases. A total of 457 records were initially identified in the literature search, of which 17 were duplicates. After screening for eligibility and inclusion criteria, 303 publications were ultimately included, related to 347 patients with PMME. PMME represents a very rare entity whose very existence has been the subject of debate for a long time. Over time, an increasing number of cases have been reported in the literature, leading to an increase in knowledge and laying the foundations for a discussion on the treatment of this pathology, which still remains largely represented by surgery. In recent times, the possibility of discovering greater mutations in gene hotspots has made it possible to develop new therapeutic strategies of which nivolumab is an example. Future studies with large case series, with clinicopathological and molecular data, will be necessary to improve the outcome of patients with PMME.

Dermatopathology of Malignant Melanoma in the Era of Artificial Intelligence: A Single Institutional Experience.

The application of artificial intelligence (AI) algorithms in medicine could support diagnostic and prognostic analyses and decision making. In the field of dermatopathology, there have been various papers that have trained algorithms for the recognition of different types of skin lesions, such as basal cell carcinoma (BCC), seborrheic keratosis (SK) and dermal nevus. Furthermore, the difficulty in diagnosing particular melanocytic lesions, such as Spitz nevi and melanoma, considering the grade of interobserver variability among dermatopathologists, has led to an objective difficulty in training machine learning (ML) algorithms to a totally reliable, reportable and repeatable level. In this work we tried to train a fast random forest (FRF) algorithm, typically used for the classification of clusters of pixels in images, to highlight anomalous areas classified as melanoma "defects" following the Allen-Spitz criteria. The adopted image vision diagnostic protocol was structured in the following steps: image acquisition by selecting the best zoom level of the microscope; preliminary selection of an image with a good resolution; preliminary identification of macro-areas of defect in each preselected image; identification of a class of a defect in the selected macro-area; training of the supervised machine learning FRF algorithm by selecting the micro-defect in the macro-area; execution of the FRF algorithm to find an image vision performance indicator; and analysis of the output images by enhancing lesion defects. The precision achieved by the FRF algorithm proved to be appropriate with a discordance of 17% with respect to the dermatopathologist, allowing this type of supervised algorithm to be nominated as a help to the dermatopathologist in the challenging diagnosis of malignant melanoma.

PRAME Immunoexpression in 275 Cutaneous Melanocytic Lesions: A Double Institutional Experience.

In recent years, the preferentially expressed antigen in melanoma (PRAME) has also been used in the histopathological diagnosis of melanocytic lesions, in order to understand if it could constitute a valid, inexpensive, and useful resource in dermatopathological fields. We performed a double-center study to evaluate whether the data on the usefulness and possible limitations of PRAME could also be confirmed by our group. From 1 December 2021 to 29 March 2022, we collected 275 cases of melanocytic lesions that were immunostained with PRAME (Ab219650) and rabbit monoclonal antibody (Abcam). To better correlate the PRAME expression with its nature (benign, uncertain potential for malignancy, or malignant), we categorized PRAME tumor cells' percentage positivity and intensity of immunostaining in a cumulative score obtained by adding the quartile of positive tumor cells (0, 1+, 2+, 3+, 4+) to the PRAME expression intensity in tumor cells (0, 1+, 2+, 3+). Of these 275 lesions, 136 were benign, 12 were of uncertain potential for malignancy (MELTUMP or SAMPUS or SPARK nevus), and 127 were malignant. The immunoexpression of PRAME was completely negative in 125/136 benign lesions (91.9%), with only a few positive melanocytes (1+) and intensity 1+ in the remaining 11 cases (8.1%). Of the 127 cases of melanoma (superficial spreading, lentigo maligna, and pagetoid histotypes), PRAME was strongly positive in 104/127 cases (81.8%) with intensity 4+ and 3+. In 17 cases (13.3%; melanoma spindle and nevoid cell histotypes), PRAME was positive in percentage 2+ and with intensity ranging from 2+ to 3+. In 7 cases (5.5%) of desmoplastic melanoma, PRAME was 1+ positive and/or completely negative. Of the 12 cases of lesions with uncertain potential for malignancy, the immunoexpression of PRAME was much more heterogeneous and irregularly distributed throughout the lesion. These data are perfectly in agreement with the current literature, and they demonstrate that the reliability of PRAME is quite high, but its use cannot cause physicians to disregard the morphological information and the execution of other ancillary immunohistochemical stains such as Melan-A, HMB-45, MiTF, and SOX-10.

Balloon Cell Melanoma: Presentation of Four Cases with a Comprehensive Review of the Literature.

BACKGROUND: balloon cell melanoma represents less than 1% of all histological forms of malignant melanoma and represents a diagnostic challenge for the dermatopathologist. METHODS: in this paper we present our cases of BCM found in our daily practice from 1 January 2008 to 31 December 2021, and we conduct a review of the literature relating to this entity in the period from the first description, 1970, to early 2022. RESULTS: four cases of melanoma balloon cell have been extrapolated from our electronic database, while in the review of the literature we have identified 115 cases of patients with primary and/or metastatic BCM. CONCLUSIONS: we believe that future studies with numerous case series are essential not only to increase the knowledge of the pathophysiology of this neoplasm but also to correctly evaluate the response of BCM patients to new oncological therapies.

Spitz Nevus with Features of Clark Nevus, So-Called SPARK Nevus: Case Series Presentation with Emphasis on Cytological and Histological Features.

Background: SPARK nevus represents a little-known and characterized entity, with few case series available in the literature. Methods and results: we present a case series of 12 patients (6 F and 6 M) between January 2005 and December 2020 and conduct a review of the current literature. Ten articles were selected on the basis of the adopted inclusion criteria and the PRISMA guidelines. Conclusions: The definition of histopathological and dermoscopic criteria are important to allow for an agreement to be reached among dermopathologists, and for the development of a consensus on higher case studies. To our knowledge, there are not many case series in the literature, and ours is part of the attempt to increase the knowledge of an entity that remains little-known and characterized.

The Great Mime: Three Cases of Melanoma with Carcinoid-Like and Paraganglioma-Like Pattern with Emphasis on Differential Diagnosis.

Melanoma is among the most aggressive tumors, with different histological patterns of presentation ranging from the usual and easily diagnosable pictures to complex patterns of difficult diagnostic interpretation. Here, we present three cases of a very rare melanoma variant described as "carcinoid-like" and "paraganglioma-like" in the literature, and a brief review of the current literature of the very few cases described to date.

The Multiple Faces of Nodular Trichoblastoma: Review of the Literature with Case Presentation.

Trichoblastoma (TB) is a rare biphasic benign adnexal neoplasm originating from follicular germ cells but clinically, it can simulate basal cell carcinoma (BCC), making the diagnosis more difficult. There are several variants of Trichoblastoma and a good knowledge of these is essential for correct diagnosis and management. We report two new cases observed in the last year at our Pathological Anatomy Operative Unit, and conduct a careful review of the literature, from the first description of this lesion by Headington in 1970 to the most recent classifications.

Dedifferentiated Melanoma: A Diagnostic Histological Pitfall-Review of the Literature with Case Presentation.

Dedifferentiated melanoma is a particular form of malignant melanoma with a progressive worsening of the patient's clinical outcome. It is well known that melanoma can assume different histo-morphological patterns, to which specific genetic signatures correspond, sometimes but not always. In this review we address the diagnostic difficulties in correctly recognizing this entity, discuss the major differential diagnoses of interest to the dermatopathologist, and conduct a review of the literature with particular attention and emphasis on the latest molecular discoveries regarding the dedifferentiation/undifferentiation mechanism and more advanced therapeutic approaches.