Biological Implications and Functional Significance of Transglutaminase Type 2 in Nervous System Tumors.

Transglutaminase type 2 (TG2) is the most ubiquitously expressed member of the transglutaminase family. TG2 catalyzes the transamidation reaction leading to several protein post-translational modifications and it is also implicated in signal transduction thanks to its GTP binding/hydrolyzing activity. In the nervous system, TG2 regulates multiple physiological processes, such as development, neuronal cell death and differentiation, and synaptic plasticity. Given its different enzymatic activities, aberrant expression or activity of TG2 can contribute to tumorigenesis, including in peripheral and central nervous system tumors. Indeed, TG2 dysregulation has been reported in meningiomas, medulloblastomas, neuroblastomas, glioblastomas, and other adult-type diffuse gliomas. The aim of this review is to provide an overview of the biological and functional relevance of TG2 in the pathogenesis of nervous system tumors, highlighting its involvement in survival, tumor inflammation, differentiation, and in the resistance to standard therapies.

The Morphology of Nasal Polyps in Different Age Groups: Histopathological Features.

BACKGROUND: Nasal polyps (NPs) represent the end-stage manifestation of chronic rhinosinusitis (CRS), a relatively common pathological condition encountered in all ages of life. METHODOLOGY: The aim of our study was to evaluate the histological features and inflammatory cellular components of NPs in a retrospective cohort (143 cases) of pediatric, adult and elderly populations in order to discuss the possible morphological age-related differences statistically documented. RESULTS: In the pediatric group, the inflammatory infiltrate presented many eosinophils mixed with lymphocytes, while in the adult population, lymphocytes and plasma cells were mainly evident, frequently with a perivascular distribution or with the formation of subepithelial lymphoid nodules. In the elderly population, inflammation was less evident and was associated with cavernous-like angecthatic structures with thrombotic stratification. Nearly all morphological findings exhibited statistically significant values among differently aged subgroups. CONCLUSIONS: Our results support the presence of histological specificities of NPs at different ages of life, providing new insight into the etiopathogenesis of NPs. The future role of biological therapies, mainly in cases refractory to already available standard medical and surgical treatments, may be analyzed by a prospective study using a larger cohort with a long-term evaluation also in relation to a possible relapse.

Pilocytic astrocytoma: The paradigmatic entity in low­grade gliomas (Review).

Among low-grade gliomas, representing 10-20% of all primary brain tumours, the paradigmatic entity is constituted by pilocytic astrocytoma (PA), considered a grade 1 tumour by the World Health Organization. Generally, this tumour requires surgical treatment with an infrequent progression towards malignant gliomas. The present review focuses on clinicopathological characteristics, and reports imaging, neurosurgical and molecular features using a multidisciplinary approach. Macroscopically, PA is a slow-growing soft grey tissue, characteristically presenting in association with a cyst and forming a small mural nodule, typically located in the cerebellum, but sometimes occurring in the spinal cord, basal ganglia or cerebral hemisphere. Microscopically, it may appear as densely fibrillated areas composed of elongated pilocytic cells with bipolar 'hairlike' processes or densely fibrillated areas composed of elongated pilocytic cells with Rosenthal fibres alternating with loosely fibrillated areas with a varied degree of myxoid component. A wide range of molecular alterations have been encountered in PA, mostly affecting the MAPK signalling pathway. In detail, the most frequent alteration is a rearrangement of the BRAF gene, although other alterations include neurofibromatosis type-1 mutations, BRAFV600E mutations, KRAS mutations, fibroblast growth factor receptor-1 mutations of fusions, neurotrophic receptor tyrosine kinase family receptor tyrosine kinase fusions and RAF1 gene fusions. The gold standard of PA treatment is surgical excision with complete margin resection, achieving minimal neurological damage. Conventional radiotherapy is not required; the more appropriate treatment appears to be serial follow-up. Chemotherapy should only be applied in younger children to avoid the risk of long-term growth and developmental issues associated with radiation. Finally, if PA recurs, a new surgical approach should be performed. At present, novel therapy involving agents targeting MAPK signalling pathway dysregulation is in development, defining BRAF and MEK inhibitors as target therapeutical agents.

Programmed Cell Death Ligand 1 Immunohistochemical Expression and Cutaneous Melanoma: A Controversial Relationship.

Cutaneous melanoma (CM) is traditionally considered one of the most "immunogenic" tumors, eliciting a high immune response. However, despite the presence of tumor-infiltrating lymphocytes (TILs), melanoma cells use strategies to suppress antitumor immunity and avoid being eliminated by immune surveillance. The PD-1 (programmed death-1)/PD-L1 (programmed death-ligand 1) axis is a well-known immune escape system adopted by neoplastic cells. Therefore, immunotherapy with PD-1 and PD-L1 inhibitors is quickly becoming the main treatment approach for metastatic melanoma patients. However, the clinical utility of PD-L1 expression assessment in CM is controversial, and the interpretation of PD-L1 scores in clinical practice is still a matter of debate. Nonetheless, the recent literature data show that by adopting specific PD-L1 assessment methods in melanoma samples, a correlation between the expression of such a biomarker and a positive response to PD-1-based immunotherapy can be seen. Our review aims to describe the state-of-the-art knowledge regarding the prognostic and predictive role of PD-L1 expression in CM while also referring to possible biological explanations for the variability in its expressions and related treatment responses.

Low and Ultra-Low HER2 in Human Breast Cancer: An Effort to Define New Neoplastic Subtypes.

HER2-low and ultra-low breast cancer (BC) have been recently proposed as new subcategories of HER2 BC, supporting a re-consideration of immunohistochemical negative scores of 0, 1+ and the 2+/in situ hybridization (ISH) negative phenotype. In the present review, we outline the criteria needed to exactly distinguish HER2-low and ultra-low BC. Recent clinical trials have demonstrated significant clinical benefits of novel HER2 directing antibody-drug conjugates (ADCs) in treating these groups of tumors. In particular, trastuzumab-deruxtecan (T-Dxd), a HER2-directing ADC, has been recently approved by the US Food and Drug Administration as the first targeted therapy to treat HER2-low BC. Furthermore, ongoing trials, such as the DESTINY-Breast06 trial, are currently evaluating ADCs in patients with HER2-ultra low BC. Finally, we hope that new guidelines may help to codify HER2-low and ultra-low BC, increasing our knowledge of tumor biology and improving a targetable new therapeutical treatment.

Unusual localization and clinical presentation of primary central nervous system extranodal marginal zone B­cell lymphoma: A case report.

Primary central nervous system (CNS) extranodal marginal zone B-cell lymphoma (MZBL) is a rare low-grade non-Hodgkin lymphoma, characterised predominantly by small B cells, plasma cells, monocytoid cells and scattered large immunoblasts. Primary CNS MZBL is a slow-growing tumour that remains localised and is characterised by an excellent clinical prognosis. The present study describes the case of a 48-year-old HIV-negative female patient with a history of head trauma 1 year prior, who presented with worsening neurological symptoms and a magnetic resonance imaging finding of a ~3-cm extra-axial mass within the left lateral ventricle. From histopathology and immunohistochemistry, the lesion was diagnosed as a CNS MZBL; as no other primary lesions were found, the base of the choroid plexuses of the left lateral ventricle was considered the primary site. To the best of our knowledge, the current case is the first study to report on primary CNS MZBL arising in this anatomical site and paves the way for further studies on the role of chronic inflammation (in the present case resulting from trauma) in the pathogenesis not only of primary CNS MZBL but also of lymphoma in general. Additionally, this report could serve as a starting point for studies analysing the role of meningothelial cells in the pathogenesis of primary CNS MZBL.

Bladder Epicheck Test: A Novel Tool to Support Urothelial Carcinoma Diagnosis in Urine Samples.

Bladder cancer and upper urothelial tract carcinoma are common diseases with a high risk of recurrence, thus necessitating follow-up after initial treatment. The management of non-muscle invasive bladder carcinoma (NMIBC) after transurethral resection involves surveillance, intravesical therapy, and cytology with cystoscopy. Urinary cytology, cystoscopy, and radiological evaluation of the upper urinary tract are recommended during follow-up in the international urological guidelines. Cystoscopy is the standard examination for the first assessment and follow-up of NMIBC, and urine cytology is a widely used urinary test with high sensitivity for high-grade urothelial carcinoma (HGUC) and carcinoma in situ (CIS). In recent years, various urinary assays, including DNA methylation markers, have been used to detect bladder tumors. Among these, the Bladder EpiCheck test is one of the most widely used and is based on analysis of the methylation profile of urothelial cells to detect bladder neoplasms. This review assesses the importance of methylation analysis and the Bladder EpiCheck test as urinary biomarkers for diagnosing urothelial carcinomas in patients in follow-up for NMIBC, helping cytology and cystoscopy in doubtful cases. A combined approach of cytology and methylation analysis is suggested not only to diagnose HGUC, but also to predict clinical and histological recurrences.

First-line ICIs in renal cell carcinoma.

Treatment of metastatic renal cell carcinoma (mRCC) has radically changed, switching from interferon alfa (IFN-α) and high-dose interleukin-2 (HD IL-2) to new targeted therapies directed against tumoral neoangiogenesis, the mammalian target of the rapamycin (mTOR) pathway and immune checkpoints. Of note, the inhibition of immune checkpoints restores antitumor immune response, therefore promoting immune-mediated elimination of neoplastic cells. The best example of this targeted treatment is represented by PD-1/PD-L1 inhibition that has become the standard of care in mRCC treatment and has improved mRCC patients' prognoses after failure of other targeted therapies. In this manuscript, we review the main therapeutic protocols adopted for mRCC, based on the use of immune checkpoint inhibitors (ICIs) alone or combined with other drugs.

BRAF-AXL-PD-L1 Signaling Axis as a Possible Biological Marker for RAI Treatment in the Thyroid Cancer ATA Intermediate Risk Category.

The use of radioiodine therapy (RIT) is debated in intermediate-risk differentiated thyroid cancer (DTC) patients. The understanding of the molecular mechanisms involved in the pathogenesis of DTC can be useful to refine patient selection for RIT. We analyzed the mutational status of BRAF, RAS, TERT, PIK3 and RET, and the expression of PD-L1 (as a CPS score), the NIS and AXL genes and the tumor-infiltrating lymphocytes (TIL, as the CD4/CD8 ratio), in the tumor tissue in a cohort of forty-six ATA intermediate-risk patients, homogeneously treated with surgery and RIT. We found a significant correlation between BRAF mutations and a less than excellent (LER, according to 2015 ATA classification) response to RIT treatment (p = 0.001), higher expression of the AXL gene (p = 0.007), lower expression of NIS (p = 0.045) and higher expression of PD-L1 (p = 0.004). Moreover, the LER patient group had a significantly higher level of AXL (p = 0.0003), a lower level of NIS (p = 0.0004) and a higher PD-L1 level (p = 0.0001) in comparison to patients having an excellent response to RIT. We also found a significant direct correlation between the AXL level and PD-L1 expression (p < 0.0001) and a significant inverse correlation between AXL and NIS expression and TILs (p = 0.0009 and p = 0.028, respectively). These data suggest that BRAF mutations and AXL expression are involved in LER among DTC patients and in the higher expression of PD-L1 and CD8, becoming new possible biomarkers to personalize RIT in the ATA intermediate-risk group, as well as the use of higher radioiodine activity or other possible therapies.

Autophagic-Related Proteins in Brain Gliomas: Role, Mechanisms, and Targeting Agents.

The present review focuses on the phenomenon of autophagy, a catabolic cellular process, which allows for the recycling of damaged organelles, macromolecules, and misfolded proteins. The different steps able to activate autophagy start with the formation of the autophagosome, mainly controlled by the action of several autophagy-related proteins. It is remarkable that autophagy may exert a double role as a tumour promoter and a tumour suppressor. Herein, we analyse the molecular mechanisms as well as the regulatory pathways of autophagy, mainly addressing their involvement in human astrocytic neoplasms. Moreover, the relationships between autophagy, the tumour immune microenvironment, and glioma stem cells are discussed. Finally, an excursus concerning autophagy-targeting agents is included in the present review in order to obtain additional information for the better treatment and management of therapy-resistant patients.

Colorectal carcinoma to pituitary tumour: tumour to tumour metastasis.

We document a patient with colon adenocarcinoma who presented with rapidly worsening visual impairment. Staging computer tomography and subsequent magnetic resonance scans documented a sellar, suprasellar lesion compressing the optic chiasm. The patient underwent trans-sphenoidal surgery to relieve optic chiasm compression and obtain tissue for diagnosis. Histological examination revealed a metastatic mucinous adenocarcinoma in a gonadotroph pituitary neuroendocrine tumour (PitNET, formerly pituitary adenoma). The patient underwent adjuvant radiotherapy to the sella and chemotherapy but he died nine months after pituitary surgery. This report highlights the diagnostic and management challenges of metastases to PitNET.

Expanding the spectrum of "mesenchymal" tumors of the central nervous system.

In this review, we summarize the clinical, histopathological, and molecular features of central nervous system (CNS) tumors with BCOR internal tandem duplication, intracranial mesenchymal tumor with FET/CREB fusion, CNS CIC-rearranged sarcomas and primary intracranial sarcoma DICER1-mutant, now included in the 2021 WHO classification of CNS tumors. Possible relationships between tumors occurring in the CNS and their systemic counterparts are discussed.

Immunoexpression of p62/SQSTM1/Sequestosome-1 in human primary and recurrent IDH1/2 wild-type glioblastoma: A pilot study.

p62/SQSTM1/Sequestosome-1 is an autophagic protein that serves a crucial role in cellular metabolism, proliferation and malignant growth. Notably, autophagy may influence the development and resistance to therapy of numerous types of human cancer. In the present pilot study, the immunohistochemical pattern of p62 was analyzed in a cohort of patients with isocitrate dehydrogenase (IDH)1/2 wild-type glioblastoma (GBM), in primary and recurrent samples, in order to verify the concordance or discordance between the primary and recurrent tumors. In addition, the association between p62, and patient outcome and O6-methylguanine-DNA methyltransferase (MGMT) status was assessed. The results revealed p62 immunoexpression in the nucleus and cytoplasm of neoplastic elements in 45% of primary and 55% of recurrent cases of GBM. A discordant p62 immunoreactivity was detected in 35% of cases, with a variation either with positive or negative conversion of p62 status. Statistically, p62 expression and MGMT status exhibited a significant prognostic value by univariate analysis, whereas only MGMT promoter methylation status emerged as an independent prognostic factor by multivariate analysis. Finally, the most favorable prognosis was documented when the same GBM case was positively concordant for both p62 expression and MGMT methylated status. Since little data are available regarding the association between p62 expression and MGMT in GBM, further investigations may be required to determine if new targeted therapies may be addressed against autophagy-related proteins, such as p62.

Aggressive variants of follicular cell-derived thyroid carcinoma: an overview.

PURPOSE: The incidence of thyroid carcinoma has increased globally in the past years. Papillary thyroid carcinoma (PTC) is the most frequent neoplasm of the thyroid gland comprehending the 90% of the thyroid carcinoma and has an indolent clinical behaviour. However, some variants of follicular cell-derived thyroid carcinoma, including variants of classic of PTC, have been identified that show a more aggressive biological behaviour. An accurate diagnosis of these entities is crucial for planning a more aggressive treatment and improving patients' prognosis of patients. The aim of this review is to present the main clinical, histological, and molecular features of aggressive variants of follicular cell-derived thyroid carcinoma, and to provide useful histological parameters for determining the most suitable therapeutic strategy for patients affected by these forms. RESULTS: Variants of classic PTC such as the diffuse sclerosing variant (DSV), the tall cell variant (TCV), the columnar cell variant (CCV), the solid/trabecular variant (STV) and the hobnail variant (HV), and other variants of follicular cell-derived thyroid carcinoma, such as poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC), are associated with aggressive behaviour. CONCLUSIONS: The correct identification and diagnosis of aggressive variants of follicular cell-derived thyroid carcinoma is important, as they allow the clinician to adopt the most refined therapeutic strategies in order to the survival of the patients.

Autophagy-related Prognostic Signature in HER2 Positive Gastric Carcinomas.

BACKGROUND: The immunohistochemical analysis of autophagy-related proteins (ATGs) has been recently applied in human pathology to study differentiation and cancer progression. The aim of the present study is to analyze a cohort of gastric carcinomas (GC) by five ATG antisera (Beclin-1, LC3A/B, p62, ULK-1 and AMBRA-1), also evaluating their possible relationship with clinicopathological parameters, HER2 status and final outcome of patients. METHODS: A cohort of 123 GCs has been studied by ATG antisera utilizing Masuda's criteria that define positive cases in which at least two out of five protein expressions were documented. RESULTS: The immunohistochemical signature for autophagy (A-IHC) was 49.59% as a whole. The percentage of A-IHC ranged from 31% for poorly cohesive carcinomas to 56% for adenocarcinomas. The performance of each ATG immunomarker documented high values for sensitivity, specificity and efficiency for LC3A/B, Beclin-1 and p62. In univariate analysis of GC, grade, stage, Ki67 expression, HER2 status as well as A-IHC appeared as emerged as relevant parameters with a high p-value (p < 0.001). Finally, in multivariate analysis, HER2 status, stage and A-IHC emerged as independent prognostic variables. In the comparison of survival curves, GC cases immunoreactive for A-IHC exhibited a shorter survival with a worse outcome. CONCLUSIONS: We have hypothesized that A-IHC could represent an additional morphological tool to provide prognostic elements in order to identify patients affected by aggressive with shorter survival and worse outcome.

Larynx lymphoepithelial carcinoma: surgical management.

Lymphoepithelial carcinoma (LEC) is an entity mostly frequent in the nasopharynx, which represents 40% of all neoplasms. The incidence's not exclusive of a geographic area; however, it has an endemic distribution in Southeast Asia and Eskimos. LEC is not exclusive of the nasopharynx, has also been reported in other anatomical areas, such as the sinonasal tract, nasolacrimal duct, oral cavity, oropharynx, salivary glands, thymus, hypopharynx, oesophagus, stomach, trachea, lung and others. Non-nasopharyngeal and nasopharyngeal LEC have the same microscopic features, but the nasopharyngeal is more likely associated with Epstein-Barr virus. LEC has been approved by the WHO. LEC located in the larynx is quite rare and worthy of attention for its implication in the treatment and prognosis. We present a case of LEC treated in our ENT department in a middle-aged man.

Intratumoral Heterogeneity in Differentiated Thyroid Tumors: An Intriguing Reappraisal in the Era of Personalized Medicine.

Differentiated thyroid tumors (DTTs) are characterized by significant molecular variability in both spatial and temporal intra-tumoral heterogeneity (ITH), that could influence the therapeutic management. ITH phenomenon appears to have a relevant role in tumor growth, aggressive behavior and drug resistance. Accordingly, characteristics and consequences of ITH in DTTs should be better analyzed and understood in order to guide clinical practice, improving survival. Consequently, in the present review, we investigated morphological and molecular ITH of DTTs in benign, borderline neoplasms and in malignant entities, summarizing the most significant data. Molecular testing in DTTs documents a high risk for recurrence of cancer associated with BRAFV600E, RET/PTC 1/3, ALK and NTRK fusions, while the intermediate risk may be related to BRAFK601E, H/K/N RAS and PAX8/PPARγ. In addition, it may be suggested that tumor genotype is associated with peculiar phenotype.

HER2 Heterogeneity in Personalized Therapy of Gastro-Oesophageal Malignancies: An Overview by Different Methodologies.

Human epidermal growth factor receptor-2 (HER2)-expression gastro-oesophageal adenocarcinomas (GEA) gained interest as an important target for therapy with trastuzumab. In the current review, we focused the current knowledge on HER2 status in dysplastic and neoplastic gastric conditions, analyzing the methodological procedures to identify HER2 expression/amplification, as well as the proposed scoring recommendations. One of the most relevant questions to evaluate the useful impact of HER2 status on therapeutic choice in GEAs is represented by the significant heterogeneity of HER2 protein and gene expression that may affect the targeted treatment selection. Future development of biotechnology will continue to evolve in order to offer more powerful detection systems for the assessment of HER2 status. Finally, liquid biopsy as well as mutation/amplification of several additional genes may furnish an early detection of secondary HER2 resistance mechanisms in GEAs with a better monitoring of the treatment response.