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.

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.

A Rare Case of Mediastinal Masson's Tumor Mimicking a Thymoma.

Masson's tumor or intravascular papillary endothelial hyperplasia is a rare nonmalignant pseudotumoral disease, arising in different anatomic sites, that can clinically and radiologically mimic various benign and malignant tumors. We report an exceptional case of mediastinal Masson's tumor, mimicking a thymoma, in a 48-year-old man, successfully treated with surgery. Though surgical removal may be technically difficult because of the intrinsic hypervascularized nature of these pseudotumoral benign lesions, resection is generally recommended, as they represent a locus minoris resistentiae of blood vessels, potentially causing fatal bleedings.

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.

Skin Mycetoma in an 11-Year-Old African Boy: Case Presentation with Emphasis on Histopathological Features and Differential Diagnosis.

Mycetoma is an uncommon, chronic infective disease of the skin and subcutaneous tissues, characterized by the triad of tumefaction, draining sinuses, and the presence in the exudate of colonial grains. In cases of long-term disease, the presence of colonial grains together with the host's derivative material can lead to the formation of real sinuses. Histological analysis is of fundamental importance to allow an accurate etiological diagnosis and to understand if the basic pathogen is an actinomycete (bacterium) or a real fungus (eumycetic mycetomas) and is also fundamental for therapy, which is quite different. Here, we present a case of Mycetoma in an 11-year-old patient who emigrated from Djibouti, Somalia, and showed the essential histopathological features of this rare and forgotten nosographic entity in the industrialized world and briefly discuss the major and most important differential diagnoses.

GLUT1, GLUT3 Expression and 18FDG-PET/CT in Human Malignant Melanoma: What Relationship Exists? New Insights and Perspectives.

BACKGROUND: Malignant melanoma is the most aggressive of skin cancers and the 19th most common cancer worldwide, with an estimated age-standardized incidence rate of 2.8-3.1 per 100,000; although there have been clear advances in therapeutic treatment, the prognosis of MM patients with Breslow thickness greater than 1 mm is still quite poor today. The study of how melanoma cells manage to survive and proliferate by consuming glucose has been partially addressed in the literature, but some rather interesting results are starting to be present. METHODS: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and a search of PubMed and Web of Sciences (WoS) databases was performed until 27 September 2021 using the terms: glucose transporter 1 and 3 and GLUT1/3 in combination with each of the following: melanoma, neoplasm and immunohistochemistry. RESULTS: In total, 46 records were initially identified in the literature search, of which six were duplicates. After screening for eligibility and inclusion criteria, 16 publications were ultimately included. CONCLUSIONS: the results discussed regarding the role and expression of GLUT are still far from definitive, but further steps toward understanding and stopping this mechanism have, at least in part, been taken. New studies and new discoveries should lead to further clarification of some aspects since the various mechanisms of glucose uptake by neoplastic cells are not limited to the transporters of the GLUT family alone.

Formalin-Fixed and Paraffin-Embedded Samples for Next Generation Sequencing: Problems and Solutions.

Over the years, increasing information has been asked of the pathologist: we have moved from a purely morphological diagnosis to biomolecular and genetic studies, which have made it possible to implement the use of molecular targeted therapies, such as anti-epidermal growth factor receptor (EGFR) molecules in EGFR-mutated lung cancer, for example. Today, next generation sequencing (NGS) has changed the approach to neoplasms, to the extent that, in a short time, it has gained a place of absolute importance and diagnostic, prognostic and therapeutic utility. In this scenario, formaldehyde-fixed and paraffin-embedded (FFPE) biological tissue samples are a source of clinical and molecular information. However, problems can arise in the genetic material (DNA and RNA) for use in NGS due to fixation, and work is being devoted to possible strategies to reduce its effects. In this paper, we discuss the applications of FFPE tissue samples in the execution of NGS, we focus on the problems arising with the use of this type of material for nucleic acid extraction and, finally, we consider the most useful strategies to prevent and reduce single nucleotide polymorphisms (SNV) and other fixation artifacts.

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.

Urological Melanoma: A Comprehensive Review of a Rare Subclass of Mucosal Melanoma with Emphasis on Differential Diagnosis and Therapeutic Approaches.

Melanoma is reported as the 19th most common cancer worldwide, with estimated age-standardized incidence rates of 2.8-3.1 per 100,000. Although the origin is most frequently cutaneous, mucosal melanoma has been described several times in literature, and despite its rarity (only 1% of all melanomas), increasing attention is being paid to this disease form. Within this subgroup, melanomas of the uropoetic apparatus are a rarity among rarities. Indeed, less than 50 cases of primary melanoma originating from the urinary bladder have been described, and even less originating from the kidney, renal pelvis and urethra. In this work, we present a detailed review of the literature related to this subclass of mucosal melanoma, delve into the biological landscape of this neoplasm and discuss current approaches, future perspectives and potential therapeutic approaches.

Papillary Meningioma: Case Presentation with Emphasis on Surgical and Medical Therapy of a Rare Variant of Meningioma.

Meningioma is one of the most frequent neoplasms of all in the central nervous system. Different variants are known, and of these some have peculiar characteristics, both from a morphological point of view and from a biological point of view. Here, we present a rare case of relapsed papillary meningioma in a young patient, focusing on histological characteristics, medical-surgical therapy and focusing on the risk of progression and/or recurrence of the lesion if not completely eradicated. Finally, we provide detailed molecular characteristics of the case in question.

Artificial Intelligence in Dermatopathology: New Insights and Perspectives.

In recent years, an increasing enthusiasm has been observed towards artificial intelligence and machine learning, involving different areas of medicine. Among these, although still in the embryonic stage, the dermatopathological field has also been partially involved, with the attempt to develop and train algorithms that could assist the pathologist in the differential diagnosis of complex melanocytic lesions. In this article, we face this new challenge of the modern era, carry out a review of the literature regarding the state of the art and try to determine promising future perspectives.

Purpuric Skin Rash in a Patient Undergoing Pfizer-BioNTech COVID-19 Vaccination: Histological Evaluation and Perspectives.

The COVID-19 pandemic has affected the entire planet, and within about a year and a half, has led to 174,502,686 confirmed cases of COVID-19 worldwide, with 3,770,361 deaths. Although it is now clear that SARS-CoV-2 can affect various different organs, including the lungs, brain, skin, vessels, placenta and others, less is yet known about adverse reactions from vaccines, although more and more reports are starting to emerge. Among the adverse events, we focused particularly on skin rashes. In this short report, we describe the case of a patient vaccinated with Comirnaty, who developed a purpuric rash resistant to oral steroid therapy after 2 weeks. To date, this is one of the very few cases in which skin biopsy was performed to better characterize the histopathological picture of this rash. Finally, we conduct a literature review of the cases of rashes from SARS-CoV-2 vaccines described in the literature, with the aim of laying foundations for future, larger case studies.

Granular Cell Dermatofibroma: When Morphology Still Matters.

Dermatofibroma, also known as "fibrous histiocytoma", is one of the most common cutaneous soft-tissue tumors. Many variants of dermatofibromas have been described, and knowledge of these variations is important to avoid misdiagnosis of a possibly more aggressive tumor. Histological features of different variants can coexist in the same lesion, but typical common fibrous histiocytoma features are generally found, at least focally, in all cases. However, when cellular changes make up the majority of the lesion, the histopathological diagnosis can become more complex and requires immunohistochemical investigations for correct nosographic classification. We present the case of a cutaneous fibrous histiocytoma, "granular cell" variant, found on the left leg of a 74-year-old woman.

HMGB1-TIM3-HO1: A New Pathway of Inflammation in Skin of SARS-CoV-2 Patients? A Retrospective Pilot Study.

The SARS-CoV-2 pandemic has completely disrupted the health systems of the entire planet. From the earliest months, it became increasingly clear that in addition to affecting the upper airways and lungs, there were other organs that could be affected. Among these, the skin became a real "sentinel signal" to be able to even suspect COVID-19. Background: this study deals with a little-explored issue for now: the study of skin immunopathology in SARS-CoV-2 positive subjects ascertained using the most reliable methods available. Methods: we used skin biopsy samples from SARS-CoV-2 positive and negative patients, studying morphology (Hematoxylin-Eosin), T lymphocyte population (CD4 and CD8), three markers such as HMGB-1, TIM-3 and HO-1 by immunohistochemistry. Results: although the presence of the CD4 and CD8 T population did not differ statistically significantly, we found greater activation and release of HMGB-1 in skin samples from SARS-CoV-2 positive patients, greater immunolabeling for TIM-3 at the level of CD4 and CD8 and a reduced expression of Heme oxygenase 1. Conclusions: these results support the possibility that there is immune deregulation in SARS-CoV-2 positive patients who develop skin manifestations of various kinds.

SARS-CoV-2 and Skin: The Pathologist's Point of View.

The SARS-CoV-2 pandemic has dramatically changed our lives and habits. In just a few months, the most advanced and efficient health systems in the world have been overwhelmed by an infectious disease that has caused 3.26 million deaths and more than 156 million cases worldwide. Although the lung is the most frequently affected organ, the skin has also resulted in being a target body district, so much so as to suggest it may be a real "sentinel" of COVID-19 disease. Here we present 17 cases of skin manifestations studied and analyzed in recent months in our Department; immunohistochemical investigations were carried out on samples for the S1 spike-protein of SARS-CoV-2, as well as electron microscopy investigations showing evidence of virions within the constituent cells of the eccrine sweat glands and the endothelium of small blood vessels. Finally, we conduct a brief review of the COVID-related skin manifestations, confirmed by immunohistochemistry and/or electron microscopy, described in the literature.

Cutaneous Metastases from Primary Liver Cancers: The Need for Knowledge and Differential Diagnosis.

Primary skin tumors are certainly more frequent than metastatic tumors, but the latter can sometimes be the first sign of otherwise unrecognized neoplastic pathology and always correspond to an advanced stage of the disease. Among the various neoplasms that can metastasize in cutaneous districts, skin metastases from primary malignant neoplasms from the liver and biliary tract are infrequent, and when they do occur they can pose differential diagnosis problems to the pathologist. Here we present two cases of metastatic skin lesions, respectively originating from the liver and the intrahepatic biliary tract, and we conduct a brief review of the current literature.

"Animal-Type Melanoma/Pigmented Epithelioid Melanocytoma": History and Features of a Controversial Entity.

Animal-type melanoma (ATM) was first described in the literature by Levene in 1979 in relation to a patient with a characteristic clinical presentation, and only later, rare and anecdotal case series have tried to shed light on an entity that has undergone several nosographic classification changes, and which, since 2018, is classified under the term "pigmented epithelioid melanocytoma". Here, we conduct a brief review of the current literature on ATM and present a new clinical case with histopathological, immunophenotypic, and molecular investigations.

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.

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.