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.

Immune disturbance leads to pulmonary embolism in COVID-19 more than classical risk factors: a clinical and histological study.

COVID-19 induces endotheliitis and one of the main complications is enhanced coagulation. The incidence of pulmonary embolism (PE) in COVID-19 (CPE) has increased and clinical features for a rigorous analysis still need to be determined. Thus, we evaluated the clinical characteristics in CPE and the immune infiltration that occurred. Between January 1 and December 31, 2021, 38 patients were affected by CPE (9 ICU, 19 males/19 females, 70.18 ± 11.24 years) out of 459 COVID-19 cases. Controls were subjects who were evaluated for PE between January 1 2015, and December 31, 2019 (92 patients, 9 ICU, 48 males/45 females, 69.55 ± 16.59 years). All patients underwent complete physical examination, pulmonary computed tomography, laboratory tests, D-dimer, and blood gas analysis. There were no differences in laboratory tests or D-dimer. In patients with CPE, pO2, alveolar-arterial oxygen difference (A-aDO2), oxygen saturation %, and the ratio between arterial partial pressure of oxygen (PaO2) and fraction of inspired oxygen (FiO2), P/F, were significantly increased. There were no differences in PaCO2. Platelet count was inversely correlated to P/F (r = - 0.389, p = 0.02) but directly to A-aDO2 (r = 0.699, p = 0.001) only in patients with CPE. Histology of lung biopsies (7 CPE/7 controls) of patients with CPE showed an increase in CD15+ cells, HMGB1, and extracellular MPO as a marker of NETosis, while no significant differences were found in CD3+, CD4+, CD8+, and intracellular MPO. Overall, data suggest that CPE has a different clinical setting. Reduced oxygen content and saturation described in Patients with CPE should not be considered a trustworthy sign of disease. Increased A-aDO2 may indicate that CPE involves the smallest vessels as compared to classical PE. The significant difference in NETosis may suggest the mechanism related to thrombi formation.

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.

Eosinophil-mast cell pattern of intraepithelial infiltration as a marker of severity in CRSwNP.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is defined as a Type 2 eosinophilic disease, while CRSsNP is considered a Type 1 neutrophilic disease. Since neutrophils are also activated in eosinophilic CRSwNP, the eosinophil-neutrophil dualism has been revaluated. Among the inflammatory cells infiltrating sinus-nasal tissues, the role of mast cells (MCs) is not already recognized, although Clinical-Cytological Grading, which defines the severity of CRSwNP, attributes to mixed eosinophil-MC forms of CRSwNP a greater risk of recurrence. We aimed to examine nasal polyps from both a cytological and histopathological point of view, to evaluate the presence and localization of MCs. Cytological and histological examination of 39 samples of nasal polyps were performed. Immunohistochemistry was used to evaluate the presence of Tryptase + CD117 + MCs, which were counted both in the epithelial layer and in the lamina propria. A statistically significant correlation was found between intraepithelial MCs and CRSwNP severity (p < 0.001) and between the total eosinophil count and the total mast cell count (p < 0.001). Cytological examination and immunohistochemistry were comparable in detecting the presence of intraepithelial MCs (p = 0.002). The histological cut-off of 6 intraepithelial MCs was identified to detect severe CRSwNP (p < 0.001). MCs have been shown to be located in the lamina propria of almost all eosinophilic nasal polyps without significantly affecting their severity. Intraepithelial MCs are associated with greater severity of CRSwNP. Histopathological criteria of the eosinophil-MC form of CRSwNP in addition to the eosinophilic one, should be defined to guarantee patients effective and tailored treatments.

Intracranial mesenchymal tumor with (novel) COX14::PTEN rearrangement.

Mesenchymal tumors of the central nervous system (CNS) include numerous entities, with different pathological features and biological behavior. Mesenchymal non-meningothelial tumors are rare and comprise neoplasms that are exclusive to the CNS or show peculiar features when occurring in the CNS compared with other sites. Within this group there are three new entities, classified on the basis of specific molecular alterations and included in the 5th edition of the WHO Classification of CNS Tumors: primary intracranial sarcoma; DICER1-mutant; CIC-rearranged sarcoma; intracranial mesenchymal tumor, FET::CREB fusion-positive. These tumors often show variable morphology, making diagnosis very challenging, although the implementation of molecular techniques has led to better characterization and more precise identification of these entities. However, many molecular alterations have yet to be discovered and some recently reported CNS tumors are currently missing an appropriate classification. Herein, we report the case of a 43-year-old man who presented with an intracranial mesenchymal tumor. Histopathological examination showed a wide spectrum of peculiar morphological features and a non-specific immunohistochemical profile. Whole transcriptome sequencing revealed the presence of a novel genetic rearrangement involving COX14 and PTEN genes, which has never been reported before in any other neoplasm. The tumor did not cluster in any defined methylation class of the brain tumor classifier, but resulted in a calibrated score of 0.89 for the methylation class "Sarcoma, MPNST-like", when analyzed by the sarcoma classifier. Our study is the first to report about this tumor with unique pathological and molecular features, characterized by a novel rearrangement between COX14 and PTEN genes. Other studies are necessary in order to define it as a new entity or as a novel rearrangement involving recently described and incompletely characterized CNS mesenchymal tumors.

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.

Prognostic Role of CDKN2A Deletion and p53 Expression and Association With MIPIb in Mantle Cell Lymphoma.

INTRODUCTION: Mantle cell lymphoma (MCL) is a rare type of lymphoma, which despite improvements in therapies in recent decades, remains an incurable disease. There is currently no reliable marker of chemoresistance available. In this study, we investigated the prognostic role of MIPIb and the association with biological markers including SOX11, p53 expression, Ki-67, and CDKN2A. MATERIALS AND METHODS: This retrospective study was focused on 23 patients with newly diagnosed classical MCL, treated at the University Hospital of Bari (Italy) between January 2006 and June 2019. RESULTS: We identified a MIPIb value ≥ 5.4440 as a prognostic parameter that correlates with p53 expression and CDKN2A deletion. We also observed that patients with p53 overexpression had a significantly higher MIPIb (5.52 ± 0.53) which in 80% of patients had a value higher than 5.4440. On the other hand, CDKN2A deletion was found more frequently (75%) associated with MIPIb ≥5.4440. Only the CDKN2A deletion was associated with a higher proliferation index, with 66.7% of samples having Ki67 ≥30%. From the survival analysis we found that patients with p53 overexpression and CDKN2A deletion have a significantly worse prognosis with a median overall survival of 50 (P = .012) and 52 months (P = .018), respectively. CONCLUSION: p53 expression and CDKN2A deletion represent a reliable pretreatment prognostic factor that identifies patients who do not benefit from currently used immunochemotherapy-based therapies and who are candidates for diversified treatments with the aim of improving prognosis. The MIPIb represents a prognostic index that correlates well with these biological alterations and can be used in clinical practice as their surrogate.

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.

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.

PReferentially Expressed Antigen in MElanoma (PRAME): preliminary communication on a translational tool able to early detect Oral Malignant Melanoma (OMM).

Oral malignant melanoma (OMM) has a prevalence less than 1% of all melanomas and it commonly develops on the oral mucosa following a slow and unspecific transformation of unstable melanocytic lesions, often resulting in a diagnostic delay. The marker PReferentially Expressed Antigen in MElanoma (PRAME) seems to be a valid tool to investigate the biological and histological nature of cutaneous melanocytic lesions, but to date its use to characterize pigmented lesions in the oral cavity is largely unexplored. The aim of this study was to create preliminary knowledge on the PRAME expression in OMM, and to compare its expression respect to other dysplastic pigmented lesions of the oral cavity. Interestingly, PRAME has been demonstrated to be reliable in the clinical conditions investigated in our pilot study; in fact, it has clearly differentiated the cases of Melanoma, which showed diffuse and intense positivity (score 6+/7+) to PRAME, from the other melanocytic nevi, which resulted to be mainly negative to PRAME. This means a better differential diagnosis, a reliable early diagnosis and a proper clinical/surgical management of the oncological lesions. In conclusion, PRAME can be a valid qualitative marker for differential diagnosis, not only in cutaneous melanomas, but also in malignant melanoma of the entire head and neck area.

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.

Oral lesions with immunohistochemical evidence of Sars-CoV-2 in swab-negative post-COVID syndrome.

OBJECTIVES: Growing evidence exists about post-COVID condition/syndrome as sequelae of Sars-CoV-2 infection in healed patients, possibly involving the lungs, brain, kidney, cardiovascular and neuromuscular system, as well the persistency of taste dysfunction. Such symptoms develop during or after infection and continue for more than 12 weeks with pathogenesis related to virus persistency but variable by organs or systems. MATERIALS AND METHODS: We recently observed six patients recovered from COVID-19 and with negative RT-PCR testing, showing oral mucosa lesions (mainly ulcers) overlapping those occurring in the acute phase, persisting up to 20 days and thus needing a biopsy with histological investigation and spike protein evaluation by immunohistochemistry. RESULTS: We found epithelial ulceration, inflammatory infiltrate, vessels with increased diameter and flattened endothelium but no thrombi formation; also, we found a weak epithelial SARS-CoV-2 positivity limited to the basal/spinosum layers, progressively decreasing toward the periphery, and the intraepithelial lymphomonocytes, endothelium, and perivascular pericytes too. CONCLUSIONS: Our findings provide evidence that SARS-CoV-2 can persist, as for other organs/systems, also in the oral epithelium/mucosa after the acute phase and can be responsible for lesions, although by a pathogenetic mechanism that should be better defined but certainly referable as the oral mucosa counterpart of post-COVID syndrome.

Metastatic Lung Cancer to the Head and Neck: A Clinico-Pathological Study on 21 Cases with Narrative Review of the Literature.

Metastases from lung cancer to the oral cavity and to the head and neck generally are very infrequent and usually manifest in advanced stages of the disease. Even more rarely, they are the first sign of an unknown metastatic disease. Nevertheless, their occurrence always represents a challenging situation both for clinicians, in the management of very unusual lesions, and for pathologists, in the recognition of the primary site. We retrospectively studied 21 cases of metastases to the head and neck from lung cancer (sixteen males and five females, age range 43-80 years; eight cases localized to the gingiva [two of these to the peri-implant gingiva], seven to the sub-mandibular lymph nodes, two to the mandible, three to the tongue, one case to the parotid gland; in eight patients, metastasis was the first clinical manifestation of an occult lung cancer) and proposed a wide immunohistochemical panel for a proper identification of the primary tumor histotype, including CK5/6, CK8/18, CK7, CK20, p40, p63, TTF-1, CDX2, Chromogranin A, Synaptophysin, GATA-3, Estrogen Receptors, PAX8, PSA. Furthermore, we collected data from previously published studies and narratively reviewed the relevant literature.

"GONE WITH THE WIND": The Transitory Effects of COVID-19 on the Gynecological System.

The coronavirus disease no longer seems to represent an insurmountable global problem. This is thanks to the advent of coronavirus vaccines, which have alleviated the most serious symptoms associated with this disease. On the other hand, there are still many extrapulmonary symptoms of COVID-19, and among these also those of a gynecological nature. At the moment, there are several questions in this field, one above all concerns the causal link between COVID-19, vaccines and gynecological alterations. Furthermore, another important aspect is represented by the clinical impact of post-COVID-19 gynecological alterations on the female population which, to date, would seem to be mainly due to their duration, even if the extent of these symptoms is still poorly understood. Furthermore, it is not possible to foresee eventual long-term aggravations, or more serious symptoms caused by other viral variants that may arrive in the future. In this review, we focus on this theme and attempt to reorganize the different pieces of a puzzle which, to date, does not seem to have shown us its complete picture.

Medication-related osteonecrosis of the jaw triggered by endodontic failure in oncologic patients.

OBJECTIVES: To describe the association between endodontic treatment failure and medication-related osteonecrosis of the jaw (MRONJ) in a cohort of oncologic patients in therapy with antiresorptive and antiangiogenic drugs. MATERIALS AND METHODS: Patients were selected as affected by MRONJ in absence of the common local risk factors (oral surgical procedures or ill-fitting dentures) but showing failure of previous endodontic treatment performed at least 6 months before the starting of antiresorptive/antiangiogenic therapies. Jaw lesions were all surgically treated and patients underwent a strict clinical and radiological follow-up. RESULTS: Among 18 patients, who developed 18 MRONJ, the only detectable local risk factor was the presence of teeth with failed endodontic treatment (more precisely, root canal underfilling in eight cases, root canal overfilling in two cases, root perforation in three cases, root fracture in five cases). All patients completely healed after surgical procedure and no recurrence was observed. CONCLUSIONS: Endodontic treatment failure should be considered a local risk factor for MRONJ development in oncologic patients. For such reason, it is mandatory to carefully evaluate them prior than the beginning of antiresorptive and antiangiogenic drugs administration.

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.

Angiomatoid Fibrous Histiocytoma (AFH) of the Right Arm: An Exceptional Case with Pulmonary Metastasis and Confirmatory EWSR1::CREB1 Translocation.

Angiomatoid fibrous histiocytoma (AFH) is a rare neoplasm described for the first time by Enzinger in 1979, and classified by World Health Organization 2020 as intermediate malignant potential neoplasm. It mostly occurs in the subcutis and is characterized by varying proportions of epithelioid, ovoid and spindle cells in a nodular and syncytial growth pattern, with some hemorrhagic pseudovascular spaces. In this paper, we report the clinical case of a 62-year-old man who presented with AFH on the right arm, and relapsed three years after first surgical excision. After a further three years, the patient presented with an intramuscular localization of AFH, and 12 months after this, a pulmonary metastasis of AFH was diagnosed. Given the rarity of the spreading of AFH, we performed Fluorescence In Situ Hybridization (FISH) and we detected EWSR1::CREB1 gene fusion.

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.

MUC1 Tissue Expression and Its Soluble Form CA15-3 Identify a Clear Cell Renal Cell Carcinoma with Distinct Metabolic Profile and Poor Clinical Outcome.

An altered metabolism is involved in the development of clear cell renal carcinoma (ccRCC). MUC1 overexpression has been found to be associated with advanced disease and poor prognosis. In this study, we evaluated the metabolomic profile of human ccRCC, according to MUC1 expression, and integrated it with transcriptomic data. Moreover, we analyzed the role of MUC1 in sustaining ccRCC aggressiveness and the prognostic value of its soluble form CA15-3. Integrated metabolomic and transcriptomic analysis showed that MUC1-expressing ccRCC was characterized by metabolic reprogramming involving the glucose and lipid metabolism pathway. In addition, primary renal cancer cells treated with a small interfering RNA targeting MUC1 (siMUC1) migrated and proliferated at a slower rate than untreated cancer cells. After cisplatin treatment, the death rate of cancer cells treated with siMUC1 was significantly greater than that of untreated cells. Kaplan-Meier curves showed significant differences in CSS and PFS among groups of patients with high versus low levels of CA15-3. In a multivariate analysis, CA15-3 was an independent adverse prognostic factor for cancer-specific and progression-free survival. In conclusion, MUC1 expressing ccRCC is characterized by a particular metabolic reprogramming. The inhibition of MUC1 expression decreases cell motility and viability and improves cisplatin susceptibility, suggesting that this pathway can regulate de novo chemotherapy resistance in ccRCC.

Molecular Features and Diagnostic Challenges in Alpha/Beta T-Cell Large Granular Lymphocyte Leukemia.

Large granular lymphocyte leukemia is a rare chronic lymphoproliferative disease of cytotoxic lymphocytes. The diagnosis, according to the WHO, is based on a persistent (>6 months) increase in the number of LGL cells in the peripheral blood without an identifiable cause. A further distinction is made between T-LGL and NK-LGL leukemia. The molecular sign of LGL leukemia is the mutation of STAT3 and other genes associated with the JAK/STAT pathway. The most common clinical features are neutropenia, anemia, and thrombocytopenia, and it is often associated with various autoimmune conditions. It usually has an indolent course. Due to the rarity of the disease, no specific treatment has yet been identified. Immunosuppressive therapy is used and may allow for disease control and long-term survival, but not eradication of the leukemic clone. Here, we discuss the clinical presentation, diagnostic challenges, pathophysiology, and different treatment options available for alpha/beta T-LGL leukemia, which is the most common disease (85%), in order to better understand and manage this often misunderstood disease.