The International Association for the Study of Lung Cancer (IASLC) Staging Project for Lung Cancer: Recommendation to Introduce Spread Through Air Spaces as a Histologic Descriptor in the Ninth Edition of the TNM Classification of Lung Cancer. Analysis of 4061 Pathologic Stage I NSCLC.

INTRODUCTION: Spread through air spaces (STAS) consists of lung cancer tumor cells that are identified beyond the edge of the main tumor in the surrounding alveolar parenchyma. It has been reported by meta-analyses to be an independent prognostic factor in the major histologic types of lung cancer, but its role in lung cancer staging is not established. METHODS: To assess the clinical importance of STAS in lung cancer staging, we evaluated 4061 surgically resected pathologic stage I R0 NSCLC collected from around the world in the International Association for the Study of Lung Cancer database. We focused on whether STAS could be a useful additional histologic descriptor to supplement the existing ones of visceral pleural invasion (VPI) and lymphovascular invasion (LVI). RESULTS: STAS was found in 930 of 4061 of the pathologic stage I NSCLC (22.9%). Patients with tumors exhibiting STAS had a significantly worse recurrence-free and overall survival in both univariate and multivariable analyses involving cohorts consisting of all NSCLC, specific histologic types (adenocarcinoma and other NSCLC), and extent of resection (lobar and sublobar). Interestingly, STAS was independent of VPI in all of these analyses. CONCLUSIONS: These data support our recommendation to include STAS as a histologic descriptor for the Ninth Edition of the TNM Classification of Lung Cancer. Hopefully, gathering these data in the coming years will facilitate a thorough analysis to better understand the relative impact of STAS, LVI, and VPI on lung cancer staging for the Tenth Edition TNM Stage Classification.

Sterile inflammation via TRPM8 RNA-dependent TLR3-NF-kB/IRF3 activation promotes antitumor immunity in prostate cancer.

Inflammation is a common condition of prostate tissue, whose impact on carcinogenesis is highly debated. Microbial colonization is a well-documented cause of a small percentage of prostatitis cases, but it remains unclear what underlies the majority of sterile inflammation reported. Here, androgen- independent fluctuations of PSA expression in prostate cells have lead us to identify a prominent function of the Transient Receptor Potential Cation Channel Subfamily M Member 8 (TRPM8) gene in sterile inflammation. Prostate cells secret TRPM8 RNA into extracellular vesicles (EVs), which primes TLR3/NF-kB-mediated inflammatory signaling after EV endocytosis by epithelial cancer cells. Furthermore, prostate cancer xenografts expressing a translation-defective form of TRPM8 RNA contain less collagen type I in the extracellular matrix, significantly more infiltrating NK cells, and larger necrotic areas as compared to control xenografts. These findings imply sustained, androgen-independent expression of TRPM8 constitutes as a promoter of anticancer innate immunity, which may constitute a clinically relevant condition affecting prostate cancer prognosis.

A neuroligin-2-YAP axis regulates progression of pancreatic intraepithelial neoplasia.

Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a dismal prognosis that arises from precursor lesions called pancreatic intraepithelial neoplasias (PanINs). Progression from low- to high-grade PanINs is considered as tumor initiation, and a deeper understanding of this switch is needed. Here, we show that synaptic molecule neuroligin-2 (NLGN2) is expressed by pancreatic exocrine cells and plays a crucial role in the regulation of contact inhibition and epithelial polarity, which characterize the switch from low- to high-grade PanIN. NLGN2 localizes to tight junctions in acinar cells, is diffusely distributed in the cytosol in low-grade PanINs and is lost in high-grade PanINs and in a high percentage of advanced PDACs. Mechanistically, NLGN2 is necessary for the formation of the PALS1/PATJ complex, which in turn induces contact inhibition by reducing YAP function. Our results provide novel insights into NLGN2 functions outside the nervous system and can be used to model PanIN progression.

An in-silico analysis reveals further evidence of an aggressive subset of lung carcinoids sharing molecular features of high-grade neuroendocrine neoplasms.

Little is known as to whether there may be any pathogenetic link between pulmonary carcinoids and neuroendocrine carcinomas (NECs). A gene signature we previously found to cluster pulmonary carcinoids, large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), and which encompassed MEN1, MYC, MYCL1, RICTOR, RB1, SDHA, SRC and TP53 mutations or copy number variations (CNVs), was used to reclassify an independent cohort of 54 neuroendocrine neoplasms (NENs) [31 typical carcinoids (TC), 11 atypical carcinoids (AC) and 12 SCLC], by means of transcriptome and mutation data. Unsupervised clustering analysis identified two histology-independent clusters, namely CL1 and CL2, where 17/42 (40.5%) carcinoids and all the SCLC samples fell into the latter. CL2 carcinoids affected survival adversely, were enriched in T to G transversions or T > C/C > T transitions in the context of specific mutational signatures, presented with at least 1.5-fold change (FC) increase of gene mutations including TSC2, SMARCA2, SMARCA4, ERBB4 and PTPRZ1, differed for gene expression and showed epigenetic changes in charge of MYC and MTORC1 pathways, cellular senescence, inflammation, high-plasticity cell state and immune system exhaustion. Similar results were also found in two other independent validation sets comprising 101 lung NENs (24 carcinoids, 21 SCLC and 56 LCNEC) and 30 carcinoids, respectively. We herein confirmed an unexpected sharing of molecular traits along the spectrum of lung NENs, with a subset of genomically distinct aggressive carcinoids sharing molecular features of high-grade neuroendocrine neoplasms.

Pulmonary Low Malignant Potential Adenocarcinoma: A Validation of the Proposed Criteria for This Novel Subtype.

Adenocarcinoma (ADC) is the most common histologic type of lung cancer, including in situ (lepidic), minimally invasive, and invasive forms. While the former 2 types are associated with a favorable outcome, the latter includes tumors with variable behavior, often tumor stage-related. A recent study proposed strict morphologic criteria defining a new subgroup of resected stage I invasive ADC (16% of cases) with favorable outcomes (100% disease-specific survival), named "ADC of low malignant potential (LMP-ADC)." The following criteria were met: ≤3 cm size, nonmucinous histotype, ≥15% lepidic growth, and the absence of the following: high-grade patterns, >1 mitosis/2 mm 2 , necrosis, and vascular/pleural invasion. The aim of the present study was to validate the performance of such criteria to identify LMP-ADC in a series of 274 stage IA resected lung ADCs from a single institution. Thirty-four tumors (12.4%) met the proposed criteria for LMP-ADC, as confirmed by additional stains for mitotic figures, Ki67 index, and elastic fibers (helpful to assess alveolar wall invasion). Minor differences between the lepidic and invasive components were observed regarding cell atypia and proliferation. p53 was normally expressed by invasive tumor cells. Mutations occurred in known lung cancer genes (mostly KRAS and EGFR). Five patients (14.7%) developed disease progression and 2 of them (5.9%) died of the disease. In our series, the disease-specific survival was 94.1%. In conclusion, in resected invasive lung ADC, a subgroup presenting low-grade morphologic features and associated with favorable prognosis does exist. Morphologic criteria for LMP-ADC supported by ancillary techniques represent a valid tool to better define this novel subgroup and to refine the stratification of invasive lung ADC, possibly suggesting modified follow-up protocols, based on the observed indolent behavior in most cases.

Improved assessment of donor liver steatosis using Banff consensus recommendations and deep learning algorithms.

BACKGROUND & AIMS: The Banff Liver Working Group recently published consensus recommendations for steatosis assessment in donor liver biopsy, but few studies reported their use and no automated deep-learning algorithms based on the proposed criteria have been developed so far. We evaluated Banff recommendations on a large monocentric series of donor liver needle biopsies by comparing pathologists' scores with those generated by convolutional neural networks (CNNs) we specifically developed for automated steatosis assessment. METHODS: We retrospectively retrieved 292 allograft liver needle biopsies collected between January 2016 and January 2020 and performed steatosis assessment using a former intra-institution method (pre-Banff method) and the newly introduced Banff recommendations. Scores provided by pathologists and CNN models were then compared, and the degree of agreement was measured with the intraclass correlation coefficient (ICC). RESULTS: Regarding the pre-Banff method, poor agreement was observed between the pathologist and CNN models for small droplet macrovesicular steatosis (ICC: 0.38), large droplet macrovesicular steatosis (ICC: 0.08), and the final combined score (ICC: 0.16) evaluation, but none of these reached statistically significance. Interestingly, significantly improved agreement was observed using the Banff approach: ICC was 0.93 for the low-power score (p <0.001), 0.89 for the high-power score (p <0.001), and 0.93 for the final score (p <0.001). Comparing the pre-Banff method with the Banff approach on the same biopsy, pathologist and CNN model assessment showed a mean (±SD) percentage of discrepancy of 26.89 (±22.16) and 1.20 (±5.58), respectively. CONCLUSIONS: Our findings support the use of Banff recommendations in daily practice and highlight the need for a granular analysis of their effect on liver transplantation outcomes. IMPACT AND IMPLICATIONS: We developed and validated the first automated deep-learning algorithms for standardized steatosis assessment based on the Banff Liver Working Group consensus recommendations. Our algorithm provides an unbiased automated evaluation of steatosis, which will lay the groundwork for granular analysis of steatosis's short- and long-term effects on organ viability, enabling the identification of clinically relevant steatosis cut-offs for donor organ acceptance. Implementing our algorithm in daily clinical practice will allow for a more efficient and safe allocation of donor organs, improving the post-transplant outcomes of patients.

Genomic Staging of Multifocal Lung Squamous Cell Carcinomas Is Independent of the Comprehensive Morphologic Assessment.

INTRODUCTION: Morphologic and molecular data for staging of multifocal lung squamous cell carcinomas (LSCCs) are limited. In this study, whole exome sequencing (WES) was used as the gold standard to determine whether multifocal LSCC represented separate primary lung cancers (SPLCs) or intrapulmonary metastases (IPMs). Genomic profiles were compared with the comprehensive morphologic assessment. METHODS: WES was performed on 20 tumor pairs of multifocal LSCC and matched normal lymph nodes using the Illumina NovaSeq6000 S4-Xp (Illumina, San Diego, CA). WES clonal and subclonal analysis data were compared with histologic assessment by 16 thoracic pathologists. In addition, the immune gene profiling of the study cases was characterized by the HTG EdgeSeq Precision Immuno-Oncology Panel. RESULTS: By WES data, 11 cases were classified as SPLC and seven cases as IPM. Two cases were technically suboptimal. Analysis revealed marked genomic and immunogenic heterogeneity, but immune gene expression profiles highly correlated with mutation profiles. Tumors classified as IPM have a large number of shared mutations (ranging from 33.5% to 80.7%). The agreement between individual morphologic assessments for each case and WES was 58.3%. One case was unanimously interpreted morphologically as IPM and was in agreement with WES. In a further 17 cases, the number of pathologists whose morphologic interpretation was in agreement with WES ranged from two (one case) to 15 pathologists (one case) per case. Pathologists showed a fair interobserver agreement in the morphologic staging of multiple LSCCs, with an overall kappa of 0.232. CONCLUSIONS: Staging of multifocal LSCC based on morphologic assessment is unreliable. Comprehensive genomic analyses should be adopted for the staging of multifocal LSCC.

Updates on lung neuroendocrine neoplasm classification.

Lung neuroendocrine neoplasms (NENs) are a heterogeneous group of pulmonary neoplasms showing different morphological patterns and clinical and biological characteristics. The World Health Organisation (WHO) classification of lung NENs has been recently updated as part of the broader attempt to uniform the classification of NENs. This much-needed update has come at a time when insights from seminal molecular characterisation studies revolutionised our understanding of the biological and pathological architecture of lung NENs, paving the way for the development of novel diagnostic techniques, prognostic factors and therapeutic approaches. In this challenging and rapidly evolving landscape, the relevance of the 2021 WHO classification has been recently questioned, particularly in terms of its morphology-orientated approach and its prognostic implications. Here, we provide a state-of-the-art review on the contemporary understanding of pulmonary NEN morphology and the potential contribution of artificial intelligence, the advances in NEN molecular profiling with their impact on the classification system and, finally, the key current and upcoming prognostic factors.

Diagnostic Utility of a Modified Reticulin Algorithm in Pediatric Adrenocortical Neoplasms.

Pediatric adrenocortical neoplasms (ACNs) are extremely rare tumors in contrast to their adult counterparts. Distinguishing benign from malignant is challenging based on pure morphologic grounds. Previously, 2 scoring systems were proposed in pediatric ACN, including the Wieneke criteria (WC) and its modified version (modified WC [mWC]). In adults, the reticulin algorithm (RA) has proven inexpensive, reliable, predictive, and reproducible; however, it has been validated only recently in children in a limited number of cases. This study aims to assess the RA utility compared with other scoring systems in a series of 92 pediatric ACNs. All cases were individually scored, and mitotic rate cutoffs were recorded. Reticulin alterations were classified as quantitative and qualitative. Outcome data were available in 59/92. The median age was 5 years (0.1 to 18 y) with an M:F of 0.6. Clinical presentation included virilization (39%), Cushing syndrome (21%), other symptoms (4%), and asymptomatic (36%). The reticulin framework was intact in 27% and altered in 73% of cases, showing qualitative (22%), quantitative (73%), and both (5%) alterations. In patients with favorable outcomes, 59% showed either intact reticulin or qualitative alteration compared with the unfavorable outcome group, where 90% showed quantitative alterations. All scoring systems WC ( P < 0.0001), mWC ( P = 0.0003), and the adult/pediatric RA ( P < 0.0001) had predictive value. The RA is comparable to WC and mWC, easier to apply, and is the most sensitive histopathological approach to identifying aggressive behavior in pediatric ACN. Its integration into the WC might be helpful in ACN of uncertain malignant potential and deserves further investigation.

ALK inhibitors increase ALK expression and sensitize neuroblastoma cells to ALK.CAR-T cells.

Selection of the best tumor antigen is critical for the therapeutic success of chimeric antigen receptor (CAR) T cells in hematologic malignancies and solid tumors. The anaplastic lymphoma kinase (ALK) receptor is expressed by most neuroblastomas while virtually absent in most normal tissues. ALK is an oncogenic driver in neuroblastoma and ALK inhibitors show promising clinical activity. Here, we describe the development of ALK.CAR-T cells that show potent efficacy in monotherapy against neuroblastoma with high ALK expression without toxicity. For neuroblastoma with low ALK expression, combination with ALK inhibitors specifically potentiates ALK.CAR-T cells but not GD2.CAR-T cells. Mechanistically, ALK inhibitors impair tumor growth and upregulate the expression of ALK, thereby facilitating the activity of ALK.CAR-T cells against neuroblastoma. Thus, while neither ALK inhibitors nor ALK.CAR-T cells will likely be sufficient as monotherapy in neuroblastoma with low ALK density, their combination specifically enhances therapeutic efficacy.

Circulating autoantibodies to alpha-enolase (ENO1) and far upstream element-binding protein 1 (FUBP1) are negative prognostic factors for pancreatic cancer patient survival.

Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis due to a lack of early diagnostic markers and effective therapy. In PDA patients, the glycolytic enzyme and plasminogen receptor alpha-enolase (ENO1) and the transcription factor far upstream element-binding protein 1 (FUBP1) are upregulated and elicit the production of autoantibodies (aAb) that discriminate healthy subjects from PDA patients, with the latter mostly directed to post-translational phosphorylated isoforms. Here, the correlation of prognosis with circulating ENO1 and FUBP1aAb, and their protein tissue expression was analyzed in PDA patients. Circulating ENO1 and FUBP1 aAb was analyzed in two cohorts of PDA patients by ELISA (n = 470), while tissues expression was observed by immunohistochemistry (n = 45). Overall survival (OS) was estimated using the Kaplan-Meier method, while the Cox model was used to estimate the hazard ratios (HR) adjusted for the main prognostic factors. Logistic models were applied to assess associations between death and its risk indicators. All statistical analyses were performed with Stata version 15. Unlike ENO1 aAb, there was a significant correlation between FUBP1 aAb and FUBP1 expression in tumors (p = 0.0268). In addition, we found that high ENO1 (p = 0.016) and intermediate FUBP1 aAb levels (p = 0.013) were unfavorable prognostic factors. Notably, it was found that high anti-FUBP1 aAb level is a good prognostic marker for tail-body PDA (p = 0.016). Our results suggest that different levels of circulating aAb to ENO1 and FUBP1 predict a poor outcome in PDA patients and can be used to improve therapeutic strategies.

Cohort profile: the Turin prostate cancer prognostication (TPCP) cohort.

Introduction: Prostate cancer (PCa) is the most frequent tumor among men in Europe and has both indolent and aggressive forms. There are several treatment options, the choice of which depends on multiple factors. To further improve current prognostication models, we established the Turin Prostate Cancer Prognostication (TPCP) cohort, an Italian retrospective biopsy cohort of patients with PCa and long-term follow-up. This work presents this new cohort with its main characteristics and the distributions of some of its core variables, along with its potential contributions to PCa research. Methods: The TPCP cohort includes consecutive non-metastatic patients with first positive biopsy for PCa performed between 2008 and 2013 at the main hospital in Turin, Italy. The follow-up ended on December 31st 2021. The primary outcome is the occurrence of metastasis; death from PCa and overall mortality are the secondary outcomes. In addition to numerous clinical variables, the study's prognostic variables include histopathologic information assigned by a centralized uropathology review using a digital pathology software system specialized for the study of PCa, tumor DNA methylation in candidate genes, and features extracted from digitized slide images via Deep Neural Networks. Results: The cohort includes 891 patients followed-up for a median time of 10 years. During this period, 97 patients had progression to metastatic disease and 301 died; of these, 56 died from PCa. In total, 65.3% of the cohort has a Gleason score less than or equal to 3 + 4, and 44.5% has a clinical stage cT1. Consistent with previous studies, age and clinical stage at diagnosis are important prognostic factors: the crude cumulative incidence of metastatic disease during the 14-years of follow-up increases from 9.1% among patients younger than 64 to 16.2% for patients in the age group of 75-84, and from 6.1% for cT1 stage to 27.9% in cT3 stage. Discussion: This study stands to be an important resource for updating existing prognostic models for PCa on an Italian cohort. In addition, the integrated collection of multi-modal data will allow development and/or validation of new models including new histopathological, digital, and molecular markers, with the goal of better directing clinical decisions to manage patients with PCa.

SS18-SSX Antibody: A Useful Tool to Save Time and Reduce Costs in Synovial Sarcoma Diagnosis. Proposal of a Novel Diagnostic Algorithm.

Synovial sarcoma is a rare malignant mesenchymal neoplasm mostly affecting young adults, characterized by a specific translocation which results in the fusion of the SS18 gene on chromosome 18 with one of the three highly homologous SSX genes on chromosome X. Its morphological diagnosis, especially in monophasic or poorly differentiated variants, can be challenging because histological features often overlap with other malignant mesenchymal tumors. Until recently, the differential diagnosis mostly relied on the use of cytogenetic or molecular analyses to detect the specific t(X;18)(p11;q11) translocation, thus virtually restricting its correct identification to referral centers with a high histological and molecular pathology workflow. The recently commercialized highly sensitive and fusion-specific SS18-SSX antibody has significantly improved the approach to these tumors, representing a relatively cheap and easy to access tool for synovial sarcoma diagnosis. Through a retrospective analysis of 79 synovial sarcomas and histological mimickers, this study confirms the usefulness of the SS18-SSX antibody in the diagnosis of synovial sarcoma, particularly focusing on its application in the pathological response evaluation after neoadjuvant treatment as well as its time- and cost-saving advantages. Finally, we here propose a new diagnostic algorithm to apply into the routine practice.

IgG4-infiltrate in post-intubation tracheal stenosis: a call to interventional pulmonologist and thoracic surgeons.

BACKGROUND: Since December 2019, Sars-CoV2 infection has become a pandemic health emergency. The most severe manifestation of COVID-19 is acute respiratory distress syndrome requiring intensive care unit admission and mechanical ventilation. The most serious, although rare, complication of prolonged MV is post-intubation tracheal stenosis. We hypothesized that, in addition to recognized risk factors in COVID-19 patients, additional factors may promote airways injury. METHODS: We analyzed data from 13 patients with PITS referred to our Thoracic Surgery Department from 2020 to 2022 divided in two groups: 8 ex-COVID-19 patients (in MV for ARDS during Sars-Cov2 positivity) and 5 non-COVID-19 patients (in MV for other reasons). Computer-tomography and bronchoscopy were performed to confirm diagnosis of PITS. Surgical treatment including tracheal resection and end-to-end anastomosis was performed in all patients. Tracheal samples were histologically analyzed to define the existence of any difference between the two groups. RESULTS: The presence of total immunoglobulin G (IgG) and immunoglobulin G4 (IgG4) were tested. IgG infiltrate was present in both groups. IgG4-infiltrate was significantly represented in the tracheal sample of ex-COVID-19 patients and absent in the non-COVID-19 cohort of patients. CONCLUSIONS: It is suggested that COVID-19 patients have almost double the risk of developing tracheal injuries. This work supports the idea of a major predisposition for such injuries in COVID-19 patients due to a possible immune-mediated mechanism leading to aberrant and fibrotic wound healing following a trigger insult (in this case MV with oro-tracheal tube). In the near future an increasing incidence of PITS is expected. Interventional pulmonologist and thoracic surgeons might be called to deal with this possibility. Clarification of the physiopathology of PITS is needed to prevent excessive tracheal scarring following prolonged endotracheal intubation and recurrence after endoscopic and/or surgical treatment. Careful prevention, early detection and effective management of this life-threatening condition are warranted.

Clinical and Pathological Features and Gene Expression Profiles of Clinically Aggressive Papillary Thyroid Carcinomas.

Papillary thyroid carcinoma (PTC) is considered an indolent neoplasm but it may demonstrate aggressive behavior. We aimed to identify clinical and pathological characteristics and molecular signatures associated with aggressive forms of PTCs. We selected 43 aggressive PTC cases based on the presence of metastases at the time of diagnosis, the development of distant metastasis during follow-up, and/or biochemical recurrence, and 43 PTC patients that were disease-free upon follow-up, matching them according to age, sex, pT, and pN parameters. Twenty-four pairs (a total of 48 cases) and 6 normal thyroid tissues were studied using targeted mRNA screening of cancer-associated genes employing NanoString nCounter® technology. In general, aggressive PTCs showed distinctive clinical and morphological features. Among adverse prognostic parameters, the presence of necrosis and an increased mitotic index were associated with shorter disease-free and overall survivals. Other parameters associated with shorter disease-free or overall survivals include a lack of tumor capsule, the presence of vascular invasion, tumor-infiltrating lymphocytes, fibrosclerotic changes, age > 55 years, and a high pTN stage. Various pathways were differentially regulated in non-aggressive as compared to aggressive PTC, including the DNA damage repair, the MAPK, and the RAS pathways. In particular, the hedgehog pathway was differentially de-regulated in aggressive PTC as compared to non-aggressive PTC cases, being WNT10A and GLI3 genes significantly up- and down-regulated in aggressive PTC and GSK3B up-regulated in non-aggressive PTC cases. In conclusion, our study revealed specific molecular signatures and morphological features in aggressive PTC that may be useful to predict more aggressive behavior in a subset of PTC patients. These findings may be useful when developing novel, tailored treatment options for these patients.

Correlation between high-resolution computed tomography appearance and histopathological features in the diagnosis of interstitial lung diseases. A real-life study.

BACKGROUND: According to current guidelines, a surgical biopsy is rarely required when a high-confidence radiologic interstitial lung disease (ILD) diagnosis is made on thin-section high-resolution computed tomography (HRCT). Nevertheless, disowning HRCT scans diagnosed by biopsy are more common than presumed. Our study aimed to describe the concordance rate between HRCT scans and pathological diagnoses of ILDs obtained by surgical biopsy. The current guideline suggests the use of surgical lung biopsy (SLB) in patients with newly detected ILD of unknown cause. METHODS: Patients who underwent mini-invasive surgical biopsies for interstitial lung diseases from January 2018 to August 2022 were analyzed. The HRCT scans were reviewed by an observer blinded to the patient's clinical information. The concordance between histological and HRCT-scan were assessed. RESULTS: Data from 104 patients with uncertain low confidence diagnosis of interstitial lung diseases at HRCT were analyzed. Most of the patients are male (65; 62.5%). The more frequent HRCT pattern were: alternative diagnoses (46; 44.23%), UIP probable (42; 40.38%), UIP indeterminate (7; 6.73%), and non-specific interstitial pneumonia (NSIP) (9, 8.65%). The more common histological diagnosis was UIP definite (30; 28.84%), hypersensitivity pneumonia [HP](19; 18.44%), NSIP (15; 14.42%), sarcoidosis (10; 9.60%). In 7 (20%) cases, the final pathological finding denies HRCT-scans diagnoses; indeed, a moderate agreement was observed between HRCT-scan findings and the definitive histological diagnosis (kappa index: 0.428). CONCLUSIONS: HRCT-scan has limitations if the objective is to define interstitial lung diseases accurately. Consequently, pathological assessment should be taken into account in order to provide more accurate tailored treatment strategies because the risk is to wait from 12 to 24 months to ascertain if the ILD will be treatable as progressive pulmonary fibrosis (PPF). Undeniably true, video-assisted surgical lung biopsy (VASLB) with endotracheal intubation and mechanical ventilation is associated with a risk of mortality and morbidity that is far from nil. Nevertheless, in recent years a VASLB approach performed in awake subjects under loco-regional anesthesia (awake-VASLB) has been suggested as an effective method to obtain a highly confident diagnosis in patients with diffuse pathologies of the lung parenchyma.

Solitary fibrous tumor of the thyroid: report of three cases with a focus on cytological features and histological clues for malignancy.

Solitary fibrous tumor is a mesenchymal tumor of intermediate malignant potential characterized by a recurrent NAB2::STAT6 fusion and STAT6 nuclear expression. Primary thyroid solitary fibrous tumor is relatively uncommon, with 45 cases described in the English literature to date. Although its histologic features are characteristic, its diagnosis in the thyroid can be problematic, especially in small biopsies or cytology specimens. We herein present three new cases of thyroid solitary fibrous tumor, one of which is malignant, with new insights on the morphological spectrum and malignant potential of this tumor. We additionally provide a review of the literature with a focus on the clues and challenges of a preoperative cytological diagnosis of this tumor, which can nowadays be supported by STAT6 nuclear expression, when appropriately suspected.

Recurrence-Free Survival in Early and Locally Advanced Large Cell Neuroendocrine Carcinoma of the Lung after Complete Tumor Resection.

BACKGROUND: Large Cell Neuroendocrine Carcinoma (LCNEC) is a rare subtype of lung cancer with poor clinical outcomes. Data on recurrence-free survival (RFS) in early and locally advanced pure LCNEC after complete resection (R0) are lacking. This study aims to evaluate clinical outcomes in this subgroup of patients and to identify potential prognostic markers. METHODS: Retrospective multicenter study including patients with pure LCNEC stage I-III and R0 resection. Clinicopathological characteristics, RFS, and disease-specific survival (DSS) were evaluated. Univariate and multivariate analyses were performed. RESULTS: 39 patients (M:F = 26:13), with a median age of 64 years (44-83), were included. Lobectomy (69.2%), bilobectomy (5.1%), pneumonectomy (18%), and wedge resection (7.7%) were performed mostly associated with lymphadenectomy. Adjuvant therapy included platinum-based chemotherapy and/or radiotherapy in 58.9% of cases. After a median follow-up of 44 (4-169) months, the median RFS was 39 months with 1-, 2- and 5-year RFS rates of 60.0%, 54.6%, and 44.9%, respectively. Median DSS was 72 months with a 1-, 2- and 5-year rate of 86.8, 75.9, and 57.4%, respectively. At multivariate analysis, age (cut-off 65 years old) and pN status were independent prognostic factors for both RFS (HR = 4.19, 95%CI = 1.46-12.07, p = 0.008 and HR = 13.56, 95%CI 2.45-74.89, p = 0.003, respectively) and DSS (HR = 9.30, 95%CI 2.23-38.83, p = 0.002 and HR = 11.88, 95%CI 2.28-61.84, p = 0.003, respectively). CONCLUSION: After R0 resection of LCNEC, half of the patients recurred mostly within the first two years of follow-up. Age and lymph node metastasis could help to stratify patients for adjuvant therapy.

Full cost of diagnostic pathology for lung carcinoma in Italy: results from four Pathology Units.

Objective: To calculate the full cost of diagnostic pathology tests for Non-Small Cell Lung Cancer (NSCLC) across four Italian Pathology Units. Methods: Pathology Units were located in private (2) and public (2) hospitals distributed across the Italian territory (North: 2; Centre: 1; South: 1). Pathologists provided via questionnaire data on tests on NSCLC samples along with the identification and quantification of the necessary healthcare resources (diagnostic technologies, laboratory instruments and personnel). Resources were valued according to hospital-specific unit, yearly and hourly costs (disposables; technologies; professional clusters). Results: The full cost per NSCLC tissue sample included histopathological immunophenotypic and required molecular analysis. Overall, it reached € 659.77 and it was mainly composed of direct costs (77.69%). The processing of a NSCLC tissue sample was labour intensive, as a relevant share of the full cost (44.98%) was actually due to personnel costs, with laboratory technicians, biologists and pathologist driving this finding (17.09%,12.43% and 10.81%, respectively). Conclusions: The results of this research can facilitate the negotiation of new dedicated tariffs for NSCLC sample processing with the national or local third party-payers.

Topography of Prostate Cancer Recurrence: A Single-centre Analysis of Salvage Radical Prostatectomy Specimens and Implications for Focal Salvage Treatments.

Background: Most prostate cancer (PCa) recurrences after nonsurgical first-line treatment are managed with androgen deprivation therapy (ADT). When local treatment is indicated, salvage focal treatment (FT) may achieve outcomes similar to those after salvage radical prostatectomy (sRP), with lower morbidity. However, descriptions of the topography of PCa recurrence are scarce. Objective: To describe the characteristics and topography of recurrent PCa at sRP. Design setting and participants: We performed a review of the final pathology for consecutive men undergoing sRP at a single centre between 2007 and 2021. Outcome measurements and statistical analysis: Clinical and pathological outcomes and recurrence localisation (standardised map) were recorded. Suitability for salvage FT was evaluated using criteria defined a priori. Results and limitations: We included 41 men who underwent sRP after whole-gland treatment (82.9% primary radiotherapy). Of these, 68.3% had grade group ≥3 and 46.3% had pT3 disease, including nine men (22%) with seminal vesicle involvement >1 cm. The pN+ rate was 29.3%. Surgical margins were positive in 39% (mostly at the apex, 21.9%). PCa was located at <3 mm from the apex in 68% of cases. The segment most frequently involved was the mid-gland (93%). The median prostate and index lesion (IL) volume was 31.4 cm3 (interquartile range [IQR] 23-37) and 2 cm3 (IQR 0.5-6), respectively. A solitary IL was present in 63.4% of cases, while 7.3% had whole-gland PCa involvement. Overall, 56% of the men (n = 23) were deemed suitable for salvage FT (although seven had pN+ disease). The sample size, single-centre retrospective design, and unavailability of magnetic resonance imaging data are the main limitations. Conclusions: According to sRP pathology, radiorecurrent PCa is an aggressive disease, frequently showing extraprostatic extension, positive margins, and apical involvement. The majority of cases still harbour a solitary index lesion and a consistent proportion may be suitable for a gland-preserving strategy. Patient summary: In this report we looked at the location of prostate cancer recurrence within the prostate gland after radiotherapy or ablation, in which energy (such as heat, cold, or laser energy) is used to kill cells. We found that although these recurrences are often high-grade locally advanced disease, around half of cases might be suitable for a gland-preserving salvage treatment.