Pulmonary Sclerosing Pneumocytoma: A Pre and Intraoperative Diagnostic Challenge. Report of Two Cases and Review of the Literature.

Pulmonary sclerosing pneumocytoma is a rare benign pulmonary tumor of primitive epithelial origin. Because of the unspecific radiological features mimicking malignancies and its histological heterogeneity, the differential diagnosis with adenocarcinoma and carcinoid tumors is still challenging. We report our experience of two cases of sclerosing pneumocytoma, as well as a review of the literature. Immunohistochemical findings showed intense staining of the cuboidal epithelial cells for cytokeratin-pool and TTF-1, with focal positivity for progesterone receptors. Round and spindle cells expressed positivity for vimentin, TTF-1 and focally for the progesterone receptor. Cytologic diagnosis of pulmonary pneumocytoma requires the identification of its dual cell population, made up of abundant stromal cells and fewer surface cells. Since the pre- and intraoperative diagnosis should guide surgical decision making, obtaining a sufficient specimen size to find representative material in the cell block is of paramount importance.

Kinase Fusions in Spitz Melanocytic Tumors: The Past, the Present, and the Future.

In recent years, particular interest has developed in molecular biology applied to the field of dermatopathology, with a focus on nevi of the Spitz spectrum. From 2014 onwards, an increasing number of papers have been published to classify, stratify, and correctly frame molecular alterations, including kinase fusions. In this paper, we try to synthesize the knowledge gained in this area so far. In December 2023, we searched Medline and Scopus for case reports and case series, narrative and systematic reviews, meta-analyses, observational studies-either longitudinal or historical, case series, and case reports published in English in the last 15 years using the keywords spitzoid neoplasms, kinase fusions, ALK, ROS1, NTRK (1-2-3), MET, RET, MAP3K8, and RAF1. ALK-rearranged Spitz tumors and ROS-1-rearranged tumors are among the most studied and characterized entities in the literature, in an attempt (although not always successful) to correlate histopathological features with the probable molecular driver alteration. NTRK-, RET-, and MET-rearranged Spitz tumors present another studied and characterized entity, with several rearrangements described but as of yet incomplete information about their prognostic significance. Furthermore, although rarer, rearrangements of serine-threonine kinases such as BRAF, RAF1, and MAP3K8 have also been described, but more cases with more detailed information about possible histopathological alterations, mechanisms of etiopathogenesis, and also prognosis are needed. The knowledge of molecular drivers is of great interest in the field of melanocytic diagnostics, and it is important to consider that in addition to immunohistochemistry, molecular techniques such as FISH, PCR, and/or NGS are essential to confirm and classify the different patterns of mutation. Future studies with large case series and molecular sequencing techniques are needed to allow for a more complete and comprehensive understanding of the role of fusion kinases in the spitzoid tumor family.

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.

Is It Time to Supersede the Diagnostic Term "Melanoma In Situ with Regression?" A Narrative Review.

Traditionally, the term melanoma in situ (MIS) is used to designate a horizontal (radial) growth phase of malignant melanoma (MM) in which there is no histological evidence of any invasion (or microinvasion) of neoplastic melanocytic cells into the superficial or papillary dermis. In daily dermatopathological practice, we are faced with misleading definitions, such as "melanoma in situ with regression," which risk affecting homogeneity for comparison purposes of pathological reports of malignant melanoma. The authors conducted a literature review using PubMed and Web of Science (WoS) as the main databases and using the following keywords: "Malignant Melanoma in situ" or "Melanoma in situ" and "regression" and/or "radial growth phase regression." A total of 213 articles from both analyzed databases were retrieved; finally, only eight articles in English were considered suitable for the chosen inclusion criteria. In consideration of the absence of studies with large case series, of reviews with meta-analyses, and, therefore, of a broad scientific consensus, expressions including "melanoma in situ with regression" should be avoided in the histopathological report. Instead, they should be replaced with clearer and more exhaustive definitions.

Cutaneous Metastasis from Internal Malignancies: The Revealing Role of the Skin.

Skin represents the heaviest organ of the human body, covering a surface area of 1 [...].

Giant Soft Tissue Leiomyosarcoma of the Left Lower Extremity: Case Presentation With a Review of the Literature.

Leiomyosarcoma (LMS) accounts for approximately 5-10% of soft tissue sarcomas, with an estimated incidence in the United States (US) of less than one case/200,000 persons, more frequent in women than men. Approximately two-thirds of LMSs are retroperitoneal, abdominal, and mediastinal. Localized, soft tissue LMSs represent a lower percentage, with the lower limbs and trunk being the most frequently involved sites. LMSs larger than 5 cm (so-called giants) are even rarer, and to date have been little reported in the literature. In this paper, we present the case of a giant LMS of the left lower limb in a 73-year-old patient, who had a mass for about two years, and who, after the first diagnostic biopsy, underwent limb amputation. Macroscopic and microscopic examinations confirmed the infiltration of the underlying tibial bone. We briefly discuss eight other cases described in the literature with similar size, pointing out that the parameters with the greatest impact on prognosis proved to be size >5 cm and depth of invasion. Due to the rarity of this neoplasm, little has yet been done in relation to the most suitable therapeutic treatment of such patients, and larger case series are mandated in order to be able to conduct broader-spectrum studies.

Partially Dedifferentiated Primitive Malignant Melanoma with Pseudo-Angiomatous Features: A Case Report with Review of the Literature.

Malignant melanoma (MM) is traditionally known as the "great mime" of human pathology, as it is potentially capable of imitating the most disparate neoplasms. It is known that in addition to the more classic histotypes of MM, there are also rare forms, including angiomatoid MM. Similarly, it has been amply demonstrated in the literature that MM is capable of dedifferentiating, losing melanocytic lineage markers, constituting a diagnostic challenge for the pathologist. Although 5 cases of primary angiomatoid MM have been described in the literature, to the best of our knowledge, no cases of dedifferentiated melanoma with pseudo-angiomatoid aspects have ever been described. In this paper, we present a very rare case of partially dedifferentiated MM in which the most dedifferentiated component lost melanocytic lineage immunohistochemical markers and assumed a pseudo-angiomatous morphology. Given the rarity of the case, we carried out a literature review of similar cases described, trying to draw new future perspectives not only about this particular variant of MM but also about the widest field of dedifferentiation/undifferentiation of MM.

Artificial Intelligence Applied to a First Screening of Naevoid Melanoma: A New Use of Fast Random Forest Algorithm in Dermatopathology.

Malignant melanoma (MM) is the "great mime" of dermatopathology, and it can present such rare variants that even the most experienced pathologist might miss or misdiagnose them. Naevoid melanoma (NM), which accounts for about 1% of all MM cases, is a constant challenge, and when it is not diagnosed in a timely manner, it can even lead to death. In recent years, artificial intelligence has revolutionised much of what has been achieved in the biomedical field, and what once seemed distant is now almost incorporated into the diagnostic therapeutic flow chart. In this paper, we present the results of a machine learning approach that applies a fast random forest (FRF) algorithm to a cohort of naevoid melanomas in an attempt to understand if and how this approach could be incorporated into the business process modelling and notation (BPMN) approach. The FRF algorithm provides an innovative approach to formulating a clinical protocol oriented toward reducing the risk of NM misdiagnosis. The work provides the methodology to integrate FRF into a mapped clinical process.

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.

Cutaneous Sarcoidosis-like Eruption Following Second Dose of Moderna mRNA-1273 Vaccine: Case or Relationship?

Various adverse reactions to SARS-CoV-2 vaccines have been described since the first months of the vaccination campaign. In addition to more frequent reactions, rare reactions, such as sarcoidosis-like, rashes have been reported. We present a case of a 23-year-old woman with a rash on the chin and peribuccal region, which developed approximately 3 weeks after the administration of the second dose of the Moderna mRNA-1273 vaccine. We briefly discuss other reports in the literature.

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.

Poorly Differentiated Cutaneous Squamous Cell Carcinoma (cSCC) or Lymphoepithelioma-like Carcinoma of the Skin (LELCS) with Squamous Pearls: A Case Presentation with Emphasis on Histomorphological Features and Classification Debates.

Lymphoepithelioma-like carcinoma of the skin (LELCS) is a rare primary skin cancer, with an annual incidence of 1/100,000 and about 85 cases published in the literature. It is considered the cutaneous counterpart of undifferentiated nasopharyngeal carcinoma (UNC, Schmincke-Regaud tumor) but has no association with EBV. We present an interesting case with features of LELCS in a 93-year-old man, right frontal-orbital region, diagnosed histologically and with immunohistochemical features. We also emphasize contrasting morphologic features for correct nosographic classification and address current issues, suggesting potential insights. Finally, we briefly reviewed other cases described in the literature.

Blastic Plasmocytoid Dendritic Cell Neoplasm (BPDCN): Clinical Features and Histopathology with a Therapeutic Overview.

Blastic Plasmacytoid Dendritic Cell Neoplasms (BPDCNs) are a rare, highly aggressive hematological malignant neoplasm that primarily involve the skin, bone marrow, lymph nodes and even extra-nodal sites. The rarity and relative poor description of cases in the literature make it necessary to review and further studies that deeply investigate this entity not only in a histopathological but also molecular field. In August-September 2023, we searched MEDLINE, PubMed and Scopus for randomized controlled trials (RCTs), narrative and systematic reviews, meta-analyses, observational studies (either longitudinal or retrospective), and case series published in English in the last 25 years using the keywords BPDCN, PDCs, Blastic NK-cell lymphoma, agranular CD4+ NK leukemia/lymphoma, agranular CD4+ CD56+ hematodermic neoplasm/tumor. Despite the progress made in recent years in the diagnosis and biological understanding of the disease, until 2018 there was no clear consensus regarding its treatment and the main therapeutic schemes used were based on chemotherapy regimens already used in the treatment of lymphomas, acute lymphoblastic leukemia (ALL) and/or acute myeloid leukemia (AML). In this narrative review, we address the definition and epidemiological features of BPDCN, provide the different theories on the etiopathogenesis with particular attention to the presumed cell of origin, discuss the main clinical manifestations that provide a sign of its presence, summarize the main histopathological and immunophenotypic characteristics with special attention to the most important markers, and finally, we provide some of the most effective information on the therapeutic treatment modalities of BPDCN.

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.

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.

Goblet Cell Carcinoma of the Appendix with Synchronous Adenocarcinoma of the Cecum: Distinct or Related Entities?

Goblet cell carcinoma (GCC) is a rare primary tumor of the appendix characterized by both epithelial and neuroendocrine components containing goblet cells. While in the past, the GCC has been associated with neuroendocrine tumors, recent studies consider that GCC is closer to adenocarcinoma than a neuroendocrine component. The association between gastro-intestinal (GI) carcinoids and second primary malignancies (SPMs) is widely described in the literature, but there is no reported case of GCC and synchronous adjacent adenocarcinoma of the colon. We describe the first case in the literature, to our knowledge, of synchronous colorectal adenocarcinoma of the cecum and GCC of the appendix that are incidentally discovered in the resected primary cancer specimen. The association between the two neoplasms seems to be not causal and maybe the "paracrine-effect theory" may explain the development of a second tumor close to the primary.

Development of Flat Warts on the Cheeks after BioNTech-Pfizer BNT162b2 Vaccine: Is There a Correlation?

The SARS-CoV-2 pandemic has affected health systems across the globe, making the use of vaccines more urgent and topical than ever. Since the first months after the introduction of vaccinations, several reactions, both local and systemic, have been reported although they were mostly very mild and only rarely harbingers of more serious complications. We present a case of multiple flat warts onset over the cheeks in a patient after the second dose of mRNA BioNTech-Pfizer BNT162b2 vaccine, and we discuss the possible temporal association between the two events, also considering the patient's antibody status.

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.

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.

Polymorphic Malignant Melanoma (PMM) of the Left Helix: Case Report with Clinical-Pathological Correlations.

Malignant melanoma (MM) is known to be the great mimic in dermatopathology. Over time, several variants have been described, not all of which have repercussions on the clinical/oncological management of the affected patient. The existence, however, of these alternative forms of MM is of great interest to the pathologist, as they are potentially capable of inducing diagnostic errors affecting the diagnostic-therapeutic care pathway (PDTC). In this paper, we present a very rare case of polymorphic MM, in which five different morphological aspects coexisted in the same lesion, confirmed by immunohistochemical investigation and by RT-PCR for mutation of the BRAF gene and discuss the importance of correct recognition of these different morphological features to avoid misdiagnosis.