Safety and Efficacy of Salvage Surgery after Treatment With Immune-Checkpoint Adjuvant Inhibitors for Advanced Non-Small Cell Lung Cancer: A Multicentric Study.

OBJECTIVE: In advanced non-small cell lung cancer (NSCLC), immune-checkpoint inhibitors (ICIs) can achieve significant clinical responses. This raises the question of whether to consider salvage surgery as a curative treatment option. Few case series reported encouraging results in terms of pathological response. However, intraoperative risk and postoperative morbidity have been highlighted. This study aims to assess the safety and feasibility of surgery after ICIs administration and to evaluate its effectiveness on the final pathological examination. METHODS: We retrospectively identified stages III-IVA NSCLC consecutive patients who underwent surgery with radical intent after ICIs at three National Centers (2016-2022). Before treatment, all patients were considered unresectable by a multidisciplinary discussion. After surgery, pathological response was evaluated according to the International Association for the Study of Lung Cancer (IASLC) recommendation. RESULTS: Thirty-one patients were included; pretreatment clinical stage was: IIIA in 4 patients (10%), IIIB in 13 (42%), IIIC in 3 (13%), and IVA in 11 (35%). Median treatment duration was four cycles. Only anatomical resections were performed, with lobectomy that represent the main type of resection (22 patients, 74%). A minimally invasive approach was performed in 10 patients (32%), with a conversion rate of 0%. Postoperative complications were observed in eight patients (25%). Complete pathologic response (CPR) and major pathologic response (MPR) were 48% and 16%, respectively. Two and 3-years survival were 88%. CONCLUSIONS: Based on our experience, salvage surgery of advanced NSCLC treated with ICIs confirm his feasibility and safety in responder patients. Moreover, it is associated with low morbidity, high CPR rate, and satisfying medium-term survival.

Real-world biomarker testing patterns: clinical-pathological portrait of early and late non-small cell lung cancer in hub and spoke North Italian centers.

Background: Lung cancer is still the main cause of cancer death. In the last decades, significant innovations were introduced in non-small cell lung cancer (NSCLC) treatment and management improving patient outcomes. The discovery of immune checkpoint inhibitors and the detection of an increasing list of actionable genetic alterations are enabling a tailored approach. Herein, we assessed in a pragmatic retrospective study the rate of biomarker tests within a large pulmonary pathology-based unit (PPU) network of the Veneto region (Northern Italy). Methods: Each PPU of 7 hubs and spoke centers implemented a biomarker database with pathologic and clinical data of patients with NSCLC diagnosis over 24 months. Results: Out of 1,817 NSCLC cases, 51% were advanced and 49% early stage, with 72% being adenocarcinomas. Programmed death ligand 1 expression and epidermal growth factor receptor mutations were available in most samples, 91% and 78%, respectively. Only 36% of advanced stages received all 5 biomarker tests with an increased rate over time. Co-occurring molecular alterations were detected in 42 cases (2%): the prevalence was (n=17) 41% and (n=25) 59% in early and late-stage adenocarcinomas, respectively. Conclusions: In this real-world study, while most patients received at least one biomarker test, less than 50% had all 5 biomarkers. The screening appeared to increase over time especially with the progressive use of next generation sequencing. Our results confirm the importance of systematic biomarker testing including all NSCLCs based on the evidence of several genomic alterations also in early-stage disease whose analysis may become relevant as neo-adjuvant targeted therapies are available. Keywords: Non-small cell lung cancer (NSCLC); biomarkers; actionable targets; lung cancer.

Is There a Link between Chronic Obstructive Pulmonary Disease and Lung Adenocarcinoma? A Clinico-Pathological and Molecular Study.

Chronic Obstructive Pulmonary Disease (COPD) and lung cancer are strictly related. To date, it is unknown if COPD-associated cancers are different from the tumors of non-COPD patients. The main goal of the study was to compare the morphological/molecular profiles of lung adenocarcinoma (LUAD) samples of COPD, non-COPD/smokers and non-COPD/non-smokers, and to investigate if a genetic instability also characterized non-pathological areas. This study included 110 patients undergoing surgery for a LUAD, divided into three groups: COPD/smoker LUAD (38), non-COPD/smoker LUAD (54) and non-COPD/non-smoker LUAD (18). The tissue samples were systemically evaluated by pathologists and analyzed using a 30-gene Next Generation Sequencing (NGS) panel. In a subset of patients, tissues taken far from the neoplasia were also included. The non-COPD/smoker LUAD were characterized by a higher proliferative index (p = 0.001), while the non-COPD/non-smoker LUAD showed higher percentages of lepidic pattern (p = 0.008), lower necrosis, higher fibrosis, and a significantly lower mutation rate in the KRAS and PIK3CA genes. Interestingly, the same gene mutations were found in pathological and normal areas exclusively in the COPD/smokers and non-COPD/smokers. COPD/smoker LUAD seem to be similar to non-COPD/smoker LUAD, particularly for the genetic background. A less aggressive cancer phenotype was confirmed in non-COPD/non-smokers. The genetic alterations detected in normal lungs from smokers with and without COPD reinforce the importance of screening to detect early neoplastic lesions.

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

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

The role of pathologists in the diagnosis of occupational lung diseases: an expert opinion of the European Society of Pathology Pulmonary Pathology Working Group.

Occupational lung/thoracic diseases are a major global public health issue. They comprise a diverse spectrum of health conditions with complex pathology, most of which arise following chronic heavy workplace exposures to various mineral dusts, metal fumes, or following inhaled organic particulate reactions. Many occupational lung diseases could become irreversible; thus accurate diagnosis is mandatory to minimize dust exposure and consequently reduce damage to the respiratory system. Lung biopsy is usually required when exposure history is inconsistent with imaging, in case of unusual or new exposures, in case of unexpected malignancy, and in cases in which there are claims for personal injury and legal compensation. In this paper, we provide an overview of the most frequent occupational lung diseases with a focus on pathological diagnosis. This is a paper that summarizes the expert opinion from a group of European pathologists, together with contributions from other specialists who are crucial for the diagnosis and management of these diseases. Indeed, tight collaboration of all specialists involved in the workup is mandatory as many occupational lung diseases are misdiagnosed or go unrecognized. This document provides a guide for pathologists in practice to facilitate the accurate diagnosis of occupational lung disease. The review article reports relevant topics discussed during an educational course held by expert pathologists, active members of the Pulmonary Pathology Working Group of the European Society of Pathology. The course was endorsed by the University of Padova as a "winter school" (selected project in the call for "Shaping a World-class University" 2022).

Tongue Metastasis From Pleural Mesothelioma.

This case report describes a 62-year-old nonsmoking man with multiple pleural thickenings and a marked effusion.

Pathological complete response in a patient with pleural mesothelioma treated with immunotherapy: a case report.

The role of immunotherapy in the multimodal treatment for pleural mesothelioma (PM) is still under investigation, particularly in the preoperative setting. Pathological complete response (pCR) has been previously described after chemotherapy and immunotherapy; however, there is no prior experience reported with immunotherapy alone before surgery. We report the case of a 58-year-old male with biphasic PM treated with immunotherapy, resulting in a major clinical partial response. Following a multidisciplinary evaluation between thoracic surgeons, medical oncologists, pathologists, radiologists and radiation oncologists, the patient underwent surgery with radical intent through a right extended pleurectomy/decortication (eP/D). Histopathological examination of the specimen confirmed a pathological Complete Response (pCR). This case supports the feasibility and potential efficacy of combining preoperative immunotherapy with surgery in the management of advanced PM.

Significance of Spread Through Air Spaces and Vascular Invasion in Early-stage Adenocarcinoma Survival: A Comprehensive Clinicopathologic Study of 427 Patients for Precision Management.

Spread through air spaces (STAS) is a novel invasive pattern of lung cancer associated with poor prognosis in non-small cell cancer (NSCLC). We aimed to investigate the incidence of STAS in a surgical series of adenocarcinomas (ADCs) resected in our thoracic surgery unit and to identify the association of STAS with other clinicopathological characteristics. We retrospectively enrolled patients with stage cT1a-cT2b who underwent resection between 2016 and 2022. For each case, a comprehensive pathologic report was accessible which included histotype, mitoses, pleural invasion, fibrosis, tumor infiltrating lymphocytes, necrosis, inflammation, vascular and perineural invasion, as well as STAS. PD-L1 expression was also investigated. A total of 427 patients with ADCs underwent surgery. Regarding overall survival (OS), no significant difference was observed between the STAS positive (STAS+) and STAS negative (STAS-) groups ( P =0.44). However, vascular invasion (VI) was associated with a poorer survival probability ( P =0.018). STAS+/VI+ patients had tendentially worse survival compared with STAS+/VI- ( P =0.089). ADCs with pathologic evidence of immune system (IS) activation (TILs>10% and PD-L1≥1) demonstrated significantly increased OS compared with ADCs with no IS and VI. In terms of recurrence rate, no statistical differences were found between the STAS+ and STAS- samples ( P =0.2). VI was also linked to a significantly elevated risk of recurrence ( P =0.0048). Our study suggests that in resected early-stage ADCs, STAS+ does not seem to influence recurrence or mortality. VI was instead an adverse pathologic prognostic factor for both survival and recurrence, whereas IS seemed to be protective.

Endobronchial solitary fibrous tumors: An enigma for diagnosis.

Solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms constituting less than 2% of all soft tissue tumors. They typically originate in the thoracic cavity, mainly in the pleura, but can also occur in other various sites such as lung parenchyma, pericardium, and bronchus. In this study, a 49-year-old non-smoking female with a history of allergies presented to our pulmonary clinic with a chronic cough. An explorative bronchoscopy revealed an intrabronchial mass in the left superior bronchi, and a 68 Ga-DOTATOC positron emission computed tomography suggested a carcinoid tumor. Subsequent pulmonary segmentectomy unveiled a well-circumscribed polypoid lesion diagnosed as a low-grade bronchus SFT through histopathological and immunohistochemical assessments. The patient was asymptomatic after surgical excision and showed no other lesion during the 6-month follow-up. The endobronchial location of SFT is uncommon, with only a few reported cases in the literature, underscoring the necessity of considering various differential diagnoses, including carcinoid, mucoepidermoid carcinoma, endobronchial pleomorphic adenoma, hamartoma, leiomyoma, and metastasis, depending on location and imaging features. This report underscores the importance of careful histological and immunohistochemical evaluation in understanding and appropriately stratifying the risk associated with polypoid lesions.

Assessing the role of phosphorylated S6 ribosomal protein in the pathological diagnosis of pulmonary antibody-mediated rejection.

BACKGROUND: Pulmonary antibody-mediated rejection is still a challenging diagnosis as C4d immunostaining has poor sensitivity. Previous studies have indicated that the phosphorylated S6 ribosomal protein, a component of the mammalian target of rapamycin (mTOR) pathway, is correlated with de novo donor-specific antibodies in lung transplantation. The objective of this study was to evaluate the phosphorylation of S6 ribosomal protein as a surrogate for antibody-mediated rejection diagnosis in lung transplant patients. METHODS: This multicentre retrospective study analyzed transbronchial biopsies from 216 lung transplanted patients, 114 with antibody-mediated rejection and 102 without (19 with acute cellular rejection, 17 with ischemia/reperfusion injury, 18 with infection, and 48 without post-transplant complications). Immunohistochemistry was used to quantify phosphorylated S6 ribosomal protein expression in macrophages, endothelium, epithelium, and inter-pathologist agreement was assessed. RESULTS: Median phosphorylated S6 ribosomal protein expression values were higher in antibody-mediated rejection cases than in controls for all cell components, with the highest sensitivity in macrophages (0.9) and the highest specificity in endothelial expression (0.8). The difference was mainly significant in macrophages compared to other post-lung transplantation complications. Inter-pathologist agreement was moderate for macrophages and endothelium, with higher agreement when phosphorylated S6 ribosomal protein expression was dichotomized into positive/negative. The inclusion of phosphorylated S6 ribosomal protein in the diagnostic algorithm could have increased antibody-mediated rejection certainty levels by 25%. CONCLUSIONS: The study supports the role of the mTOR pathway in antibody-mediated rejection-related graft injury and suggests that tissue phosphorylation of S6 ribosomal protein could be a useful surrogate for a more accurate pathological diagnosis of lung antibody-mediated rejection.

Exploring the pathologist's role in understanding COVID-19: from pneumonia to long-COVID lung sequelae.

The crucial role of pathologists in enhancing our understanding of SARS-CoV-2-related disease, from initial pneumonia manifestations to persistent long COVID lung symptoms, is the focus of this review. Pathological explorations have offered unprecedented insights into the early stages of severe COVID-19, shedding light on the interplay between the virus and subsequent complications, thereby shaping clinical approaches. Growing interest is directed to residual lung abnormalities of COVID-19 survivors. Although various radiological studies reported long-lasting pulmonary changes (e.g., ground glass opacities, reticulations, and bronchiectasis), the true incidence of pulmonary fibrosis and corresponding pathological findings in these patients remains largely unknown. There are a few high-impact and knowledgeable works on late complications in COVID-19 survivors, several coming from explant or autopsy cases, and rare cases from in vivo sampling. The study of biopsy samples has further deepened our knowledge of the aftermath of COVID-19 on lung tissue, uncovering alterations at the cellular level and shifts in vascular and epithelial dynamics. Despite the substantial progress made, future research is needed to devise a uniform strategy for interpreting lung biopsies, with a focus on leveraging advanced tools such as molecular and digital pathology techniques, along with artificial intelligence.

A Complex Case of Pulmonary Silico-Tuberculosis and Review of Literature.

Silicosis caused by the inhalation/deposition of free silica particles is characterized by pulmonary inflammation/fibrosis. Among the clinical disorders associated with silicosis, tuberculosis is by far the most prominent. A 66-year-old male non-smoker, originally from North Africa, reported a dry cough and significant weight loss. He was a foundry worker. He had a medical history of bladder carcinoma associated with schistosomiasis. Computed tomography (CT) and positron emission tomography (PET)/CT showed bilateral multiple hypermetabolic lung nodules, some with cavitation. The patient underwent surgical resection of the largest nodule, which was highly suspicious of lung metastasis. The histological examination revealed multiple nodular formations. Several lesions showed the characteristic features of silicotic nodules. There were also adjacent well-formed granulomas, some with central caseous necrosis. A real-time polymerase chain reaction, performed for the identification and quantification of the DNA of the Mycobacterium tuberculosis complex, was positive. Pulmonary silico-tuberculosis is often encountered in patients with a history of silica exposure in tuberculosis-endemic areas. This case serves as a reminder to never underestimate patient occupational exposure and geographic origin. A careful histological diagnosis and molecular investigation are mandatory when approaching difficult cases, especially patients with a prior cancer history and clinical/radiological features suggestive of tumour recurrence/metastasis.

Microscopical Variables and Tumor Inflammatory Microenvironment Do Not Modify Survival or Recurrence in Stage I-IIA Lung Adenocarcinomas.

Microscopical predictors and Tumor Immune Microenvironment (TIME) have been studied less in early-stage NSCLC due to the curative intent of resection and the satisfactory survival rate achievable. Despite this, the emerging literature enforces the role of the immune system and microscopical predictors as prognostic variables in NSCLC and in adenocarcinomas (ADCs) as well. Here, we investigated whether cancer-related microscopical variables and TIME influence survival and recurrence in I-IIA ADCs. We retrospectively collected I-IIA ADCs treated (lobectomy or segmentectomy) at the University Hospital (Padova) between 2016 and 2022. We assigned to pathological variables a cumulative pathological score (PS) resulting as the sum of them. TIME was investigated as tumor-infiltrating lymphocytes (TILs < 11% or ≥11%) and PD-L1 considering its expression (<1% or ≥1%). Then, we compared survival and recurrence according to PS, histology, TILs and PD-L1. A total of 358 I-IIA ADCs met the inclusion criteria. The median PS grew from IA1 to IIA, indicating an increasing microscopical cancer activity. Except for the T-SUVmax, any pathological predictor seemed to be different between PD-L1 < 1% and ≥1%. Histology, PS, TILs and PD-L1 were unable to indicate a survival difference according to the Log-rank test (p = 0.37, p = 0.25, p = 0.41 and p = 0.23). Even the recurrence was non-significant (p = 0.90, p = 0.62, p = 0.97, p = 0.74). According to our findings, resection remains the best upfront treatment in I-IIA ADCs. Microscopical cancer activity grows from IA1 to IIA tumors, but it does not affect outcomes. These outcomes are also unmodified by TIME. Probably, microscopical cancer development and immune reaction against cancer are overwhelmed by an adequate R0-N0 resection.

Intrathymic Localization of Melanoma: A Brief Report of Two Cases and a Review of the Literature.

Intrathymic localizations of melanoma represent a very rare entity, with fewer than ten cases of intrathymic melanoma described in the literature. Herein, we describe two cases of patients who underwent surgical removal of a thymic mass at our thoracic surgery department between 2015 and 2022. The final pathological examination revealed a malignant melanoma in both cases; we therefore carried out a literature review to identify such rare and similar cases. In the first case, the intrathymic localization of melanoma was the first manifestation of the disease, posing a dilemma regarding the metastatic and primitive nature of the neoplasm. The second case described a thymic metastasis from a known previous cutaneous melanoma, for which the patient had successfully been treated six years earlier. After carefully reviewing the literature, we identified only six cases of verified primary intrathymic melanomas and one case of intrathymic metastasis resulting from melanoma previously described. Pathologists should be aware of the occurrence of this rare entity and mindful of the differential diagnoses. Several tools, including immunostaining of melanocytic markers and molecular investigations, are mandatory for final pathological diagnosis.

Comprehensive bronchoalveolar lavage characterization in COVID-19 associated acute respiratory distress syndrome patients: a prospective cohort study.

COVID-19-related acute respiratory distress syndrome (CARDS) is associated with high mortality rates. We still have limited knowledge of the complex alterations developing in the lung microenvironment. The goal of the present study was to comprehensively analyze the cellular components, inflammatory signature, and respiratory pathogens in bronchoalveolar lavage (BAL) of CARDS patients (16) in comparison to those of other invasively mechanically ventilated patients (24). In CARDS patients, BAL analysis revealed: SARS-CoV-2 infection frequently associated with other respiratory pathogens, significantly higher neutrophil granulocyte percentage, remarkably low interferon-gamma expression, and high levels of interleukins (IL)-1ß and IL-9. The most important predictive variables for worse outcomes were age, IL-18 expression, and BAL neutrophilia. To the best of our knowledge, this is the first study that was able to identify, through a comprehensive analysis of BAL, several aspects relevant to the complex pathophysiology of CARDS.

An unexpected guest: Pulmonary echinococcosis diagnosed by intraoperative frozen section examination. A case report and literature review.

Echinococcosis is caused by tapeworms belonging to the Echinococcus genus. The most common site of infection is the liver although it may involve almost any organ. Symptoms of pulmonary echinococcosis vary depending on the location and structure of the cyst. While uncomplicated cysts usually appear at imaging as well-defined homogeneous lesions with fluid content and smooth walls of variable thickness, complicated lesions may have a more heterogeneous content with higher density making more difficult the distinction from malignancies or other infections. Hereby we describe the case of a 61-year-old Northern African male admitted to our tertiary center for left upper chest pain who then underwent a chest computed tomography (CT) scan which demonstrated a large hypodense lesion, with smooth and thick walls, in the upper left lobe. The following magnetic resonance confirmed the homogeneous fluid content, and the 18 F- fluorodeoxyglucose-positron emission tomography/CT demonstrated a mild uptake of the walls. According to these findings, the main differential diagnoses at imaging included bronchogenic cyst, synovial sarcoma, and pulmonary hematoma although the patient denied any recent trauma. Given the large size and clinical symptoms he underwent surgery. Intra-operative frozen section, supported by imprint cytology, excluded the presence of malignancy while suggested an echinococcal laminar exocyst. The final pathological examination confirmed the diagnosis of echinococcosis (i.e., Echinococcus Granulosus protoscolex). After surgery he was treated with albendazole and at the six-month follow-up he was in good clinical conditions. Our case highlights the importance of considering rare infections, particularly in individuals from endemic areas. Frozen tissue analyses can be a diagnostic challenge and often require ancillary tools such as imprint cytology and serial sections for more sensitive and accurate diagnosis.

Macrophages-derived Factor XIII links coagulation to inflammation in COPD.

Background: The local, extravascular, activation of the coagulation system in response to injury is a key factor mediating the resulting inflammatory response. Coagulation Factor XIIIA (FXIIIA) found in alveolar macrophages (AM) and dendritic cells (DC), by influencing fibrin stability, might be an inflammatory modifier in COPD. Aims: To study the expression of FXIIIA in AM and Langerin+DC (DC-1) and their relation to the inflammatory response and disease progression in COPD. Methods: In 47 surgical lungs, 36 from smokers (22 COPD and 14 no-COPD) and 11 from non-smokers we quantified by immunohistochemistry FXIIIA expression in AM and DC-1 along with numbers of CD8+Tcells and CXCR3 expression in lung parenchyma and airways. Lung function was measured prior to surgery. Results: The percentage of AM expressing FXIII (%FXIII+AM) was higher in COPD than no-COPD and non-smokers. DC-1 expressed FXIIIA and their numbers were higher in COPD than no-COPD and non-smokers. DC-1 positively correlated with %FXIII+AM (r=0.43; p<0.018). CD8+Tcells, which were higher in COPD than in no-COPD, were correlated with DC-1 (p<0.01) and %FXIII+AM. CXCR3+ cells were increased in COPD and correlated with %FXIII+AM (p<0.05). Both %FXIII+AM (r=-0.6; p=0.001) and DC-1 (r=-0.7; p=0.001) correlated inversely with FEV1. Conclusion: FXIIIA, an important link between the extravascular coagulation cascade and inflammatory response, is significantly expressed in alveolar macrophages and dendritic cells of smokers with COPD, suggesting that it could play an important role in the adaptive inflammatory reaction characteristic of the disease.

The significance of co-mutations in EGFR-mutated non-small cell lung cancer: Optimizing the efficacy of targeted therapies?

Non-small cell lung cancer (NSCLC) is the most common cause of cancer death worldwide. In non-squamous NSCLC, the identification of oncogenic drivers and the development of target-specific molecules led to remarkable progress in therapeutic strategies and overall survival over the last decade. Nevertheless, responses are limited by systematically acquired mechanisms of resistance early on after starting a targeted therapy. Moreover, mounting evidence has demonstrated that each oncogenic-driven cluster is actually heterogeneous in terms of molecular features, clinical behaviour, and sensitivity to targeted therapy. In this review, we aimed to examine the prognostic and predictive significance of oncogene-driven co-mutations, focusing mainly on EGFR and TP53. A narrative review was performed by searching MEDLINE databases for English articles published over the last decade (from January 2012 until November 2022). The bibliographies of key references were manually reviewed to select those eligible for the topic. The genetic landscape of EGFR-mutated NSCLC is more complicated than what is known so far. In particular, the occurrence of TP53 co-mutations stratify patients carrying EGFR mutations in terms of treatment response. The study provides a deeper understanding of the mechanisms underlying the variability of the genetic landscape of EGFR-mutated NSCLC and summarizes notably the clinical importance of TP53 co-mutations for an open avenue to more properly addressing the clinical decision-making in the near future.

Vascular/epithelial changes as late sequelae after recovery from SARS-COV-2 infection: an in-vivo comparative study.

AIMS: While there is partial evidence of lung lesions in patients suffering from long COVID there are substantial concerns about lung remodelling sequelae after COVID-19 pneumonia. The aim of the present retrospective comparative study was to ascertain morphological features in lung samples from patients undergoing tumour resection several months after SARS-CoV-2 infection. METHODS AND RESULTS: The severity of several lesions with a major focus on the vascular bed was analysed in 2 tumour-distant lung fragments of 41 cases: 21 SARS-CoV-2 (+) lung tumour (LT) patients and 20 SARS-CoV-2 (-) LT patients. A systematic evaluation of several lesions was carried out by combining their scores into a grade of I-III. Tissue SARS-CoV-2 genomic/subgenomic transcripts were also investigated. Morphological findings were compared with clinical, laboratory and radiological data. SARS-CoV-2 (+) LT patients with previous pneumonia showed more severe parenchymal and vascular lesions than those found in SARS-CoV-2 (+) LT patients without pneumonia and SARS-CoV-2 (-) LT patients, mainly when combined scores were used. SARS-CoV-2 viral transcripts were not detected in any sample. SARS-CoV-2 (+) LT patients with pneumonia showed a significantly higher radiological global injury score. No other associations were found between morphological lesions and clinical data. CONCLUSIONS: To our knowledge, this is the first study that, after a granular evaluation of tissue parameters, detected several changes in lungs from patients undergoing tumour resection after SARS-CoV-2 infection. These lesions, in particular vascular remodelling, could have an important impact overall on the future management of these frail patients.

Hepatoid Adenocarcinoma of the Lung: A Review of the Most Updated Literature and a Presentation of Three Cases.

In a Surgical Thoracic Center, two females and a man were unexpectedly diagnosed with hepatoid adenocarcinoma of the lung (HAL) in a single year. HAL is a rare lung cancer with pathological features of hepatocellular carcinoma with no evidence of liver tumor or other primitive sites of neoplasms. As of today, a comprehensive treatment is still not written. We reviewed the most updated literature on HAL, aiming to highlight the proposed treatments available, and comparing them in terms of survival. General hallmarks of HAL are confirmed: it typically affects middle-aged, heavy-smoker males with a median of 5 cm bulky right upper lobe mass. Overall survival remains poor (13 months), with a longer but non-significant survival in females. Treatments are still unsatisfactory today: surgery guarantees a small benefit compared to non-operated HALs, and only N0 patients demonstrated improved survival (p = 0.04) compared to N1, N2, and N3. Even though the histology is fearsome, these are probably the patients who will benefit from upfront surgery. Chemotherapy seemed to behave as surgery, and there is no statistical difference between chemotherapy only, surgery, or adjuvant treatments, even though adjuvant treatments tend to be more successful. New chemotherapies have been reported with notable results in recent years, such as Tyrosine Kinase Inhibitors and monoclonal antibodies. In this complicated picture, new cases are needed to further build shared evidence in terms of diagnosis, treatments, and survival opportunities.