Mesothelioma and Colorectal Cancer: Report of Four Cases with Synchronous and Metachronous Presentation.

There is evidence that asbestos could play a role in the carcinogenesis of digestive cancers. The presence of asbestos fibres in histological samples from gastric, biliary, colon cancers has been reported, but the mechanism is still controversial. It has been hypothesised that asbestos reaches these sites, especially through contaminated water; however, some experimental studies have shown that the inhaled fibres are mobile, so they can migrate to many organs, directly or via blood and lymph flow. We report four unusual cases of colorectal cancers in patients with a long history of asbestos exposure who also developed synchronous or metachronous mesothelioma. We evaluated the roles of BRCA associated protein-1 (BAP1) and cyclin-dependent kinase inhibitor 2A (CDKN2A) in colon cancer and mesothelioma to support the hypothesis that BAP-1 and CDKN2A are tumour suppressor genes involved in disease progression, recurrence, or death in both digestive cancers and mesothelioma. Potentially, these markers may be used as predictors of worse prognosis, but we also stress the importance of clinical surveillance of exposed patients because asbestos could induce cancer in any organ.

Mast cell density in Merkel cell carcinoma and its correlation with prognostic features and MCPyV status: a pilot study.

Merkel cell carcinoma (MCC) is a rare, highly aggressive, primitive neuroendocrine carcinoma of the skin, the origin of which is not yet fully understood. Numerous independent prognostic factors have been investigated in an attempt to understand which are the most important parameters to indicate in the histological diagnostic report of MCC. Of these, mast cells have only been studied in one paper before this one. We present a retrospective descriptive study of 13 cases of MCC, received at the Department of Pathology over a 20-year period (2003-2023 inclusive) on which we performed a study using whole-slide (WSI) morphometric analysis scanning platform Aperio Scanscope CS for the detection and spatial distribution of mast cells, using monoclonal anti-tryptase antibody and anti-CD34 monoclonal antibody to study the density of microvessels. In addition, we analyzed MCPyV status with the antibody for MCPyV large T-antigen (Clone CM2B4). We found statistically significant correlation between mast cell density and local recurrence/distant metastasis/death-of-disease (p = 0.008). To our knowledge, we firstly reported that MCPyV ( -) MCC shows higher mast cells density compared to MCPyV ( +) MCC, the latter well known to be less aggressive. Besides, the median vascular density did not show no significant correlation with recurrence/metastasis/death-of-disease, (p = 0.18). Despite the small sample size, this paper prompts future studies investigating the role of mast cell density in MCC.

Adverse Prognostic Impact of Transitional and Pleomorphic Patterns in Pleural Nonepithelioid Mesothelioma: Insights From Comprehensive Analysis and Reticulin Stain.

CONTEXT.­: Mesothelioma subtyping into epithelioid and nonepithelioid categories plays a crucial role in prognosis and treatment selection, with emerging recognition of the impact of various histologic patterns. OBJECTIVE.­: To investigate the prognostic implications of transitional and pleomorphic patterns in sarcomatoid mesothelioma. DESIGN.­: A total of 132 mesothelioma cases (87 biphasic, 45 sarcomatoid) were analyzed. Histologic slides were assessed, treatment data collected, and cases categorized into predominant epithelioid or sarcomatoid patterns. The sarcomatoid mesotheliomas were classified into usual, pleomorphic, and transitional patterns, with reticulin staining for the latter. Statistical analysis included Cox regression and Kaplan-Meier methods. RESULTS.­: Younger age (P = .02) and receiving therapy (P < .001) correlated with improved survival for both histotypes. Advanced stage was associated with shorter survival in sarcomatoid cases (P = .02). Predominant epithelioid pattern in biphasic cases led to longer survival (P < .001). Transitional and pleomorphic patterns were indicative of worse prognosis, with significantly lower survival in cases with both patterns than with usual sarcomatoid (P = .046). Multivariate analysis identified independent survival factors, including predominant epithelioid component in biphasic mesothelioma (P = .001) and chemotherapy (P < .001). CONCLUSIONS.­: Histologic subtyping in mesothelioma plays a pivotal role in prognosis. Transitional and pleomorphic patterns, even in low percentages, indicate poorer outcomes. This study highlights the need for standardized diagnostic support and suggests the potential utility of histochemical staining in identifying more aggressive morphologic aspects. Recognizing the significance of these patterns can guide treatment decisions and patient care strategies.

Congenital Cutis Verticis Gyrata in a Newborn with Turner Syndrome: A Rare Clinical Manifestation of This Chromosomal Disease with Trichoscopic Evaluation.

Cutis verticis gyrata (CVG) is a rare disorder of the scalp that entails the development of ridges and furrows, which mimic the anatomical conformation of the brain. This skin condition has been classified in primary essential, primary non-essential, and secondary CVG, depending on the presence or absence of other associated disorders. We present the case report of a one-month-old female newborn affected by congenital CVG (CCVG), who also received a diagnosis of Turner syndrome (TS). Skin folding was present at birth and located at the left frontal region of the scalp in the sagittal plane. Our purpose was to make this pathology clinically and tricoscopically better known, since it can be related to different genetic, inflammatory, and neoplastic conditions, etc. Non-invasive investigations, such as ultrasonography (U/S) of the brain and scalp and trichoscopy, were also used to obtain the important clues necessary to help in the CVG classification. The clinical diagnosis and trichoscopical investigation of CVG may also be useful for those patients who may have a genetic disease that is not screened for during prenatal examinations.

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.

Immunohistochemical Expression of Programmed Cell Death Ligand 1 (PD-L1) in Human Cutaneous Malignant Melanoma: A Narrative Review with Historical Perspectives.

Programmed death-ligand 1 (PD-L1) is the primary ligand of the receptor programmed death-1 (PD-1) which is constitutively expressed or activated in myeloid, lymphoid (T, B and NK), normal epithelial cells, and cancer. The PD-1/PD-L1 interaction is crucial for the physiological development of immunological tolerance but also in the development of the cancer. Among these, malignant melanoma represents a tumour in which the immunohistochemical expression of PD-L1 is important to guide future therapeutic choices based on the presence/absence of expression. Various clones have been used over time for immunohistochemical determination, and different results and heterogeneity remain among the various studies in the literature. We perform a narrative review of the present studies in order to discuss and take stock of what certain achievements have been made in this field, what challenges remain, and what possible solutions can be found.

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.

T Cell Immunoglobulin and Mucin Domain 3 (TIM-3) in Cutaneous Melanoma: A Narrative Review.

T cell immunoglobulin and mucin domain 3 (TIM-3) is an inhibitory immunocheckpoint that belongs to the TIM gene family. Monney et al. first discovered it about 20 years ago and linked it to some autoimmune diseases; subsequent studies have revealed that some tumours, including melanoma, have the capacity to produce inhibitory ligands that bind to these receptor checkpoints on tumour-specific immune cells. We conducted a literature search using PubMed, Web of Science (WoS), Scopus, Google Scholar, and Cochrane, searching for the following keywords: "T cell immunoglobulin and mucin-domain containing-3", "TIM-3" and/or "Immunocheckpoint inhibitors" in combination with "malignant melanoma" or "human malignant melanoma" or "cutaneous melanoma". The literature search initially turned up 117 documents, 23 of which were duplicates. After verifying eligibility and inclusion criteria, 17 publications were ultimately included. A growing body of scientific evidence considers TIM-3 a valid inhibitory immuno-checkpoint with a very interesting potential in the field of melanoma. However, other recent studies have discovered new roles for TIM-3 that seem almost to contradict previous findings in this regard. All this demonstrates how common and valid the concept of 'pleiotropism' is in the TME field, in that the same molecule can behave completely or partially differently depending on the cell type considered or on temporary conditions. Further studies, large case series, and a special focus on the immunophenotype of TIM-3 are absolutely necessary in order to explore this highly promising topic in the near future.

Histopathological Patterns of Cutaneous Adverse Reaction to Anti-SARS-CoV-2 Vaccines: The Integrative Role of Skin Biopsy.

The advent of vaccines represented a milestone to allow the slowing down and then containing of the exponential increase in ongoing infections and deaths of COVID-19. Since the first months of the vaccination campaign in various continents, there has been a certain number of reports of adverse events, including skin reactions. We conducted a systematic review, searching on PubMed, Web of Science, Scopus, and Cochrane Library for the words: COVID vaccine, dermatopathology, skin, eruptions, rash, cutaneous, BNT162b2 (Pfizer-BioNTech), ChAdOX1 (AstraZeneca), and mRNA-1273 (Moderna). A total of 28 records were initially identified in the literature search of which two were duplicates. After screening for eligibility and inclusion criteria, 18 publications were ultimately included. Various clinical cutaneous manifestations and histopathological patterns following vaccination have been described in literature. The most frequent clinical-pathological presentations were erythematous maculo-papular eruptions in different way of distribution with histopathological pictures mostly represented by interface changes and mixed peri-vascular and peri-adnexal cell infiltrate. Other presentations included new onset of pemphigoid bullous disease (n = 15), delayed T-cell-mediated hypersensitivity reaction (injection site reactions) (n = 10), purpuric skin rash (n = 13), mostly localized on the legs bilaterally and symmetrically with histological pictures characterized by extravasation of erythrocytes in the superficial and middle dermis, and other types of reactions. New studies with large case series and further literature reviews are needed to improve the clinical management of patients and optimize the timeline for carrying out histological biopsy for confirmatory, supportive, and differential diagnosis purposes.

Granulomatous Secondary Syphilis: A Case Report with a Brief Overview of the Diagnostic Role of Immunohistochemistry.

The diagnosis of syphilis can be challenging for dermatologists and dermatopathologists. In particular, secondary syphilis can have different clinical and histopathological presentations. A granulomatous tissue response is an unusual finding in secondary syphilis. We report the case of a 77-year-old man who presented with a 4-week history of non-pruritic generalised macules, papules, nodules and plaques. Histopathologically, there was a dense perivascular and periadnexal lympho-histiocytic dermal infiltrate with non-palisading and non-caseifying epithelioid granulomas and abundant plasma cells. The diagnosis of syphilis was confirmed by serology and immunohistochemical detection of Treponema pallidum in the biopsy specimen. A brief overview of the diagnostic role of immunohistochemistry is also provided, with particular emphasis on reported cases of granulomatous secondary syphilis.

Granular cell dermatofibroma: A potential diagnostic pitfall.

Dermatofibroma, also known as "fibrous histiocytoma", is one of the most common cutaneous soft-tissue tumours. Many variants of dermatofibromas have been described and knowledge of these variations is important to avoid a misdiagnosis of a possibly more aggressive tumour. 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 a correct nosographic classification. We report on the case of a cutaneous fibrous histiocytoma, "granular cell" variant, found on the left leg of a 74- year-old woman.

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.

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.

Peri-oral Monkeypox Virus Infection: A Clinical Report with Confirmatory Polymerase Chain Reaction Findings.

Mpox Virus (MPXV) is a zoonotic infectious disease first identified in 1970 in rural villages in rainforest areas of central and western Africa when smallpox was in the final stages of eradication. Since May 2022, cases and sustained transmission chains of monkeypox have been reported for the first time in countries where the disease is not endemic and without cases having direct or immediate epidemiological links to areas of West or Central Africa (travel, importation of mammals). On 23 July 2022, WHO declared monkeypox a "Public Emergency of International Concern" (PHEIC). In this paper, we report two cases of a Polymerase Chain Reaction (PCR)-confirmed MPXV infection. A 39-year-old Italian male came to our attention for a suspected herpetic infection, fever, headache, and malaise, which were followed by the development of an erythematous plaque covered by vesicles on the chin, an oval ulcer with a white peripheral border on the lower lip, and a central erosive area and three pustules on the arms and trunk. During the physical examination, cervical lymphadenopathy was also detected. PCR investigation of the patient and his partner confirmed the presence of MPXV infection. Our report describes a possible clinical feature of Mpox disease and illustrates the challenge of a disease that seems to present itself in different ways.

PRAME Immuno-Expression in Cutaneous Sebaceous Carcinoma: A Single Institutional Experience.

Background: In recent years, great research interest has been directed to the diagnostic, therapeutic and marker role of Preferentially expressed Antigen in Melanoma (PRAME) in the setting of various human neoplasms. Although it has been extensively studied mainly in the differential diagnosis setting of melanocytic pigmented lesions, still very few papers have analyzed the usefulness or otherwise of PRAME in the context of other non-melanoma skin cancers (NMSC). (2) Methods: In this paper, we report the data of our experience of 21 cases of sebaceous carcinoma (SC) classified in the three WHO grade and collected in the period between January 2005 and 31 October 2022, on which immunostaining for PRAME was performed; Non-parametric Mann−Whitney test for non-normally distributed values was performed. A comparison was made of the means between the three study groups (grade I, II and III). A value of p ≤ 0.05 was set as statistically significant (3) Results: Only seven cases (33.3%) were positive with an immunoscore of 2+/3+ for intensity and 1+/2+ for percentage cells positivity, while 14 cases (66.6%) were totally or nearly totally negative for PRAME with a few of sebaceous-like cells positive with an immunoscore of 1+. Eight cases of SC grade I were immunostaining for PRAME, a level of the cytoplasm of foci of sebaceous differentiation with a significant statical value (p < 0.0001) with respect to ten cases of SC grade II; furthermore, the eight cases of grade I were positive for PRAME in the same areas respect the 3 cases of SC grade III (p = 0.0303). There were no statistical significance between the 10 cases of grade II and 3 cases of grade III (p = 0.2028); (4) Conclusions: PRAME not seems to add particular information in the case of histopathological diagnostics of SC where other markers, including adipophylline, can be quite indicative. It seems, on the other hand, that PRAME can be useful in the subclassification setting of sebaceous carcinoma in grades I−II−III according to the directives of the latest WHO 2018, highlighting the foci of mature sebaceous differentiation most present in grades 1−2 and almost completely absent in grade 3 of the SC.

SARS-CoV-2, Placental Histopathology, Gravity of Infection and Immunopathology: Is There an Association?

(1) Background: As the pandemic months progress, more and more evidence shows that the placenta acts as a "barrier" to SARS-CoV-2, although rare cases of vertical transmission have been described. (2) Methods: In an attempt to investigate whether the symptoms' severity was related to different placental histological characteristics and the immune microenvironment, we subdivided 29 placentas from 29 mothers positive for SARS-CoV-2 into two groups, depending on the symptomatology (moderate/severe vs. asymptomatic/mild), performing immunohistochemical investigations for CD4 + and CD8 + T lymphocytes, as well as for CD68 + macrophage. We also evaluated the immuno-expression of the ACE2 receptor at the placental level. These two groups were compared to a control group of 28 placentas from 28 SARS-CoV-2-negative healthy mothers. (3) Results: The symptoms (likely to be related to viremia) were statistically significantly correlated (p < 0.05) with histopathological changes, such as maternal malperfusion, decidual arteriopathy, blood vessel thrombus of fetal relevance. Furthermore, the immuno-expression of ACE2 was significantly lower in SARS-CoV-2-positive groups vs. control group (p = 0.001). (4) Conclusions: There is still much to study and discover regarding the relationship between SARS-CoV-2 and histological changes in placentas and how the latter might contribute to various neonatal clinical outcomes, such as prematurity.

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.

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.

Preferentially Expressed Antigen in Melanoma (PRAME) and Human Malignant Melanoma: A Retrospective Study.

BACKGROUND: Preferentially expressed antigen in melanoma (PRAME) is a cancer testis antigen (CTA) identified in 1997 through analysis of the specificity of tumor-reactive T-cell clones derived from a patient with metastatic cutaneous melanoma. Although at first it seemed even more specific, various studies have shown that PRAME can also be expressed in the context of atypical lesions that do not correspond solely to the definition of malignant melanoma. METHODS: A systematic review of English articles was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: 126 records were identified in the literature search, of which 9 were duplicates. After screening for eligibility and inclusion criteria, 53 publications were included. CONCLUSIONS: The advent of a new marker such as PRAME is surely a step forward not only in the diagnostic approach, but also in the immunotherapeutic approach to MM. However, various studies have shown that PRAME can also be expressed in the context of atypical lesions apart from MM and, for this reason, the diagnostic sensitivity and specificity (hence accuracy) are clearly lower. Further studies with larger case series will be necessary to understand better what possibilities are offered in terms of diagnostic reliability by PRAME.

Advanced Cutaneous Leiomyosarcoma of the Forearm.

Leiomyosarcoma is a malignant smooth muscle neoplasm, which is traditionally divided into superficial and deep tumors. Superficial leiomyosarcomas are quite rare entities, accounting for approximately 7% of soft tissue neoplasms and 0.04% of all cancers. Here we describe a rare case of advanced primary cutaneous leiomyosarcoma (PCL) in a 93-year-old woman, highlighting the considerable size of the lesion and the correct surgical and oncological management. The clinical story began about 4 years ago, and the neoplasia was treated only with local radiotherapy, but the patient suffered from a dramatic volumetric increase of the right arm sarcoma one year ago. Then, an amputation of the limb was performed without following adjuvant chemotherapy. Currently, she does not show signs of recurrence and is in good shape.