RICTOR amplification is associated with Rictor membrane staining and does not correlate with PD-L1 expression in lung squamous cell carcinoma.

RICTOR gene, which encodes the scaffold protein of mTORC2, can be amplified in various tumor types, including squamous cell carcinoma (SCC) of the lung. RICTOR amplification can lead to hyperactivation of mTORC2 and may serve as a targetable genetic alteration, including in lung SCC patients with no PD-L1 expression who are not expected to benefit from immune checkpoint inhibitor therapy. This study aimed to compare RICTOR amplification detected by fluorescence in situ hybridization (FISH) with Rictor and PD-L1 protein expression detected by immunohistochemistry (IHC) in SCC of the lung. The study was complemented by analysis of the publicly available Lung Squamous Cell Carcinoma (TCGA, Firehose legacy) dataset. RICTOR amplification was observed in 20% of our cases and 16% of the lung SCC cases of the TCGA dataset. Rictor and PD-L1 expression was seen in 74% and 44% of the cases, respectively. Rictor IHC showed two staining patterns: membrane staining (16% of the cases) and cytoplasmic staining (58% of the cases). Rictor membrane staining predicted RICTOR amplification as detected by FISH with high specificity (95%) and sensitivity (70%). We did not find any correlation between RICTOR amplification and PD-L1 expression; RICTOR amplification was detected in 18% and 26% of PD-L1 positive and negative cases, respectively. The TCGA dataset analysis showed similar results; RICTOR copy number correlated with Rictor mRNA and protein expression but showed no association with PD-L1 mRNA and protein expression. In conclusion, the correlation between RICTOR amplification and Rictor membrane staining suggests that the latter can potentially be used as a surrogate marker to identify lung SCC cases with RICTOR amplification. Since a significant proportion of PD-L1 negative SCC cases harbor RICTOR amplification, analyzing PD-L1 negative tumors by RICTOR FISH or Rictor IHC can help select patients who may benefit from mTORC2 inhibitor therapy.

Guidelines for Pathologic Diagnosis of Mesothelioma.

CONTEXT.­: Mesothelioma is an uncommon tumor that can be difficult to diagnose. OBJECTIVE.­: To provide updated, practical guidelines for the pathologic diagnosis of mesothelioma. DATA SOURCES.­: Pathologists involved in the International Mesothelioma Interest Group and others with expertise in mesothelioma contributed to this update. Reference material includes peer-reviewed publications and textbooks. CONCLUSIONS.­: There was consensus opinion regarding guidelines for (1) histomorphologic diagnosis of mesothelial tumors, including distinction of epithelioid, biphasic, and sarcomatoid mesothelioma; recognition of morphologic variants and patterns; and recognition of common morphologic pitfalls; (2) molecular pathogenesis of mesothelioma; (3) application of immunohistochemical markers to establish mesothelial lineage and distinguish mesothelioma from common morphologic differentials; (4) application of ancillary studies to distinguish benign from malignant mesothelial proliferations, including BAP1 and MTAP immunostains; novel immunomarkers such as Merlin and p53; fluorescence in situ hybridization (FISH) for homozygous deletion of CDKN2A; and novel molecular assays; (5) practical recommendations for routine reporting of mesothelioma, including grading epithelioid mesothelioma and other prognostic parameters; (6) diagnosis of mesothelioma in situ; (7) cytologic diagnosis of mesothelioma, including use of immunostains and molecular assays; and (8) features of nonmalignant peritoneal mesothelial lesions.

Rictor-A Mediator of Progression and Metastasis in Lung Cancer.

Lung carcinoma is one of the most common cancer types for both men and women. Despite recent breakthroughs in targeted therapy and immunotherapy, it is characterized by a high metastatic rate, which can significantly affect quality of life and prognosis. Rictor (encoded by the RICTOR gene) is known as a scaffold protein for the multiprotein complex mTORC2. Among its diverse roles in regulating essential cellular functions, mTORC2 also facilitates epithelial-mesenchymal transition and metastasis formation. Amplification of the RICTOR gene and subsequent overexpression of the Rictor protein can result in the activation of mTORC2, which promotes cell survival and migration. Based on recent studies, RICTOR amplification or Rictor overexpression can serve as a marker for mTORC2 activation, which in turn provides a promising druggable target. Although selective inhibitors of Rictor and the Rictor-mTOR association are only in a preclinical phase, they seem to be potent novel approaches to reduce tumor cell migration and metastasis formation. Here, we summarize recent advances that support an important role for Rictor and mTORC2 as potential therapeutic targets in the treatment of lung cancer. This is a traditional (narrative) review based on Pubmed and Google Scholar searches for the following keywords: Rictor, RICTOR amplification, mTORC2, Rictor complexes, lung cancer, metastasis, progression, mTOR inhibitors.

The Role of Radiology in Multidisciplinary Discussion of Patients With Interstitial Lung Diseases.

Radiologists fulfill a vital role in the multidisciplinary care provided to patients with interstitial lung diseases and other diffuse parenchymal lung disorders. The diagnosis of interstitial lung diseases hinges on the consensus of clinical, radiology, and pathology medical subspecialists, but additional expertise from rheumatology, immunology, or hematology can be invaluable. The thin-section computed tomography (CT) features of lung involvement informs the diagnostic approach. Radiologists should be familiar with radiologic methods (including inspiratory/expiratory and prone imaging) and be well versed in the recognition of the CT features of fibrosis, assessment of the overall pattern of lung involvement, and classification according to the latest guidelines. We present a case-based review that highlights examples wherein CT features and subspecialist radiologist interpretation informed the multidisciplinary team consensus diagnosis and care pathways.

Diffuse pulmonary meningotheliomatosis.

Diffuse pulmonary meningotheliomatosis (DPM) is an ultra-rare pulmonary disease characterized by innumerable bilateral minute meningothelial-like nodules, sometimes presenting a characteristic 'cheerio-sign' on imaging. Most patients with DPM are asymptomatic and experience no disease progression. Although little is known about its nature, DPM may be associated with pulmonary malignancies, mostly lung adenocarcinoma.

Real-time visualization of lung malignancy with needle-based confocal laser endomicroscopy during shape-sensing robotic-assisted bronchoscopy.

Robotic-assisted bronchoscopy (RAB) improves endoscopic diagnostic yield of solitary pulmonary nodules (SPN). Needle-based confocal laser endomicroscopy (nCLE) is an emerging technology that allows high-resolution, in-vivo, real-time assessment of living tissues at a cellular and subcellular level. Their combined use has been scarcely reported. We used them simultaneously in three patients with SPNs. For each, the nodule was evaluated with nCLE and sampled for pathology, followed by mediastinal staging. Median age was 77 years (67% male). Median nodule minimum size was 1.8 cm and maximum was 2.1 cm. nCLE detected abnormal patterns suggestive of malignancy for all nodules and pathology confirmed primary lung adenocarcinomas in two patients and lung primary squamous cell carcinoma in the other. The combined use of RAB with nCLE may potentially enhance the differentiation of malignant cells in real-time and increase sample adequacy, accuracy, and diagnostic yield when biopsying a suspicious pulmonary lesion.

Lymphoid Interstitial Pneumonia (LIP) Revisited: A Critical Reappraisal of the Histologic Spectrum of "Radiologic" and "Pathologic" LIP in the Context of Diffuse Benign Lymphoid Proliferations of the Lung.

The use of lymphoid interstitial pneumonia (LIP) as a diagnostic term has changed considerably since its introduction. Utilizing a multi-institutional collection of 201 cases from the last 20 years that demonstrate features associated with the LIP rubric, we compared cases meeting strict histologic criteria of LIP per American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus ("pathologic LIP"; n=62) with cystic cases fulfilling radiologic ATS/ERS criteria ("radiologic LIP"; n=33) and with other diffuse benign lymphoid proliferations. "Pathologic LIP" was associated with immune dysregulation including autoimmune disorders and immune deficiency, whereas "radiologic LIP" was only seen with autoimmune disorders. No case of idiopathic LIP was found. On histology, "pathologic LIP" represented a subgroup of 70% (62/88) of cases with the distinctive pattern of diffuse expansile lymphoid infiltrates. In contrast, "radiologic LIP" demonstrated a broad spectrum of inflammatory patterns, airway-centered inflammation being most common (52%; 17/33). Only 5 cases with radiologic cysts also met consensus ATS/ERS criteria for "pathologic LIP." Overall, broad overlap was observed with the remaining study cases that failed to meet consensus criteria for "radiologic LIP" and/or "pathologic LIP." These data raise concerns about the practical use of the term LIP as currently defined. What radiologists and pathologist encounter as LIP differs remarkably, but neither "radiologic LIP" nor "pathologic LIP" present with sufficiently distinct findings to delineate such cases from other patterns of diffuse benign lymphoid proliferations. As a result of this study, we believe LIP should be abandoned as a pathologic and radiologic diagnosis.

Atypical Lung Carcinoid With EML4/ALK Fusion Detected With Circulating Tumor DNA.

Atypical carcinoids are a rare subset of neuroendocrine tumors that originate from cells within the bronchopulmonary tree. Compared to typical carcinoids, atypical carcinoids are associated with a worse prognosis. EML4-ALK fusions are reported in 5% of non-small cell lung carcinoma, but are rare in atypical carcinoids with only five previously reported cases. We report a case of a 70-year-old female with atypical carcinoid with metastasis to the liver and axial skeleton. She did not respond to standard of care chemotherapy with carboplatin and etoposide and was elected to enroll in hospice because of worsening clinical status. However, a circulating tumor DNA (ctDNA) sample was obtained the same day which revealed an EML4-ALK fusion gene. She immediately began therapy with the second-generation ALK inhibitor alectinib, with a remarkable symptomatic and radiographic response. Seven months later, the disease progression was demonstrated in the liver and the patient was switched to the third-generation ALK inhibitor lorlatinib. At the time of writing, the patient has continued to demonstrate sustained clinical, radiographic, and biochemical responses while on lorlatnib for two years. The dramatic treatment results highlighted in this case make the argument to consider ctDNA after the diagnosis of locally advanced or metastatic atypical carcinoid.

Late Complications of COVID-19.

CONTEXT.­: Studies of lungs in patients with COVID-19 have focused on early findings. OBJECTIVE.­: To systematically study histopathologic and imaging features and presence of SARS-CoV-2 RNA in lung tissue from patients in later stages of COVID-19. DESIGN.­: Autopsies, explants, surgical lung biopsies, transbronchial biopsies, cryobiopsies, and needle biopsies from patients with COVID-19 whose onset of symptoms/confirmed diagnosis was more than 28 days before the procedure were studied. Available images were reviewed. Reverse transcription droplet digital polymerase chain reaction for SARS-CoV-2 RNA was performed on lung tissue. RESULTS.­: Of 44 specimens (43 patients; median age, 59.3 years; 26 [60.5%] male) features of acute lung injury (ALI) were seen in 39 (88.6%), predominantly organizing pneumonia and diffuse alveolar damage, up to 298 days after onset of COVID-19. Fibrotic changes were found in 33 specimens (75%), most commonly fibrotic diffuse alveolar damage (n = 22) and cicatricial organizing pneumonia (n = 12). Time between acquiring COVID-19 and specimen was shorter in patients with diffuse ALI (median, 61.5 days) compared with patients with focal (140 days) or no ALI (130 days) (P = .009). Sixteen (of 20; 80%) SARS-CoV-2 reverse transcription droplet digital polymerase chain reaction tests were positive, up to 174 days after COVID-19 onset. Time between COVID-19 onset and most recent computed tomography in patients with consolidation on imaging was shorter (median, 43.0 days) versus in patients without consolidation (87.5 days; P = .02). Reticulations were associated with longer time to computed tomography after COVID-19 onset (median, 82 versus 23.5 days; P = .006). CONCLUSIONS.­: ALI and SARS-CoV-2 RNA can be detected in patients with COVID-19 for many months. ALI may evolve into fibrotic interstitial lung disease.

The 2021 WHO Classification of Tumors of the Pleura: Advances Since the 2015 Classification.

Substantial changes in the 2021 WHO Classification of Tumors of the Pleura and Pericardium since the 2015 WHO Classification include the following: (1) pleural and pericardial tumors have been combined in one chapter whereas in the 2015 WHO, pericardial tumors were classified with cardiac tumors; (2) well-differentiated papillary mesothelioma has been renamed well-differentiated papillary mesothelial tumor given growing evidence that these tumors exhibit relatively indolent behavior; (3) localized and diffuse mesothelioma no longer include the term "malignant" as a prefix; (4) mesothelioma in situ has been added to the 2021 classification because these lesions can now be recognized by loss of BAP1 and/or MTAP by immunohistochemistry and/or CDKN2A homozygous deletion by fluorescence in situ hybridization; (5) the three main histologic subtypes (i.e., epithelioid, biphasic, and sarcomatoid) remain the same but architectural patterns and cytologic and stromal features are more formally incorporated into the 2021 classification on the basis of their prognostic significance; (6) nuclear grading for epithelioid diffuse mesothelioma is introduced, and it is recommended to record this and other histologically prognostic features in pathology reports; (7) BAP1, EZH2, and MTAP immunohistochemistry have been found to be useful in separating benign mesothelial proliferations from mesothelioma; (8) biphasic mesothelioma can be diagnosed in small biopsies having both epithelioid and sarcomatoid components even if the amount of one component is less than 10%; and (9) the most frequently altered genes in diffuse pleural mesothelioma include BAP1, CDKN2A, NF2, TP53, SETD2, and SETDB1.

A Case of Full Recovery from Prolonged Cardiac Arrest after Infusion with Paclitaxel and Pembrolizumab.

Lung cancer is one of the most common cancers and has the highest risk of mortality in both genders. This devastating cancer is also a significant financial and emotional burden to patients and the healthcare system. Chemotherapy and immunotherapy have become the cornerstone for the treatment of lung cancer. However, treatment may come with severe and sometimes fatal side effects. In this report, we present the case of a 52-year-old Caucasian male who suffered two episodes of prolonged cardiac arrest after the infusion of paclitaxel and pembrolizumab.

Progression and metastasis of small cell lung carcinoma: the role of the PI3K/Akt/mTOR pathway and metabolic alterations.

Small cell lung carcinoma (SCLC) is characterized by high metastatic rate and poor prognosis. The platinum-based chemotherapy still represents the backbone of the therapy; however, acquired resistance develops almost in all patients. Although SCLC has been formerly considered a homogeneous disease, recent advances in SCLC research have highlighted the importance of inter- and intratumoral heterogeneity and have resulted in the subclassification of SCLC. The newly described SCLC subtypes are characterized by distinct biological behavior and vulnerabilities that can be therapeutically exploited. The PI3K/Akt/mTOR pathway is frequently affected in SCLC, and its activation represents a promising therapeutic target. Since the mTOR pathway is a master regulator of cellular metabolism, its alterations may also influence the bioenergetic processes of SCLC cells. Despite the encouraging preclinical results, both mTOR and metabolic inhibitors have met limited clinical success so far. Patient selection for personalized therapy, the development of rational drug combinations, and a better understanding of heterogeneity and spatiotemporal evolution of the tumor cells may improve efficacy and can help to overcome acquired resistance. Here we provide a summary of current investigations regarding the role of the mTOR pathway and metabolic alterations in the progression and metastasis formation of SCLC.

Endobronchial Extranodal Marginal Zone B-Cell Lymphoma with Plasmacytic Differentiation.

Endobronchial tumors (ET) are unusual and mostly malignant, presenting with non-specific symptoms that often delay appropriate diagnosis and treatment. Lymphomas in the airway represent less than 1% of pulmonary malignancies and require multidisciplinary approach for their management. We present a case of a 48-year-old male former smoker with a one-year history of recurrent respiratory infections and new-onset shortness of breath. Diagnostic tests included a chest computed tomography (CT) reporting the presence of an endobronchial mass and neck and cervical lymph node biopsies with inconclusive results. Bronchoscopy was successfully performed for tumor resection, improving the patient's respiratory symptoms. Histological analysis described an extranodal marginal zone B-cell lymphoma (ENMZL) with plasmacytic differentiation; a subtype of non-Hodgkin's lymphoma (NHL) in mucosa-associated lymphoid tissue (MALT), rarely found as an endobronchial growth. ET should be considered in the setting of persistent and worsening respiratory symptoms. ENMZL with plasmacytic differentiation is rarely found as an ET and diagnosis requires bronchoscopic intervention and extensive immunohistochemical analysis.

Characterization of mTOR Activity and Metabolic Profile in Pediatric Rhabdomyosarcoma.

mTOR activation has been observed in rhabdomyosarcoma (RMS); however, mTOR complex (mTORC) 1 inhibition has had limited success thus far. mTOR activation alters the metabolic pathways, which is linked to survival and metastasis. These pathways have not been thoroughly analyzed in RMSs. We performed immunohistochemistry on 65 samples to analyze the expression of mTOR complexes (pmTOR, pS6, Rictor), and several metabolic enzymes (phosphofructokinase, lactate dehydrogenase-A, ß-F1-ATPase, glucose-6-phosphate dehydrogenase, glutaminase). RICTOR amplification, as a potential mechanism of Rictor overexpression, was analyzed by FISH and digital droplet PCR. In total, 64% of the studied primary samples showed mTOR activity with an mTORC2 dominance (82%). Chemotherapy did not cause any relevant change in mTOR activity. Elevated mTOR activity was associated with a worse prognosis in relapsed cases. RICTOR amplification was not confirmed in any of the cases. Our findings suggest the importance of the Warburg effect and the pentose-phosphate pathway beside a glutamine demand in RMS cells. The expression pattern of the studied mTOR markers can explain the inefficacy of mTORC1 inhibitor therapy. Therefore, we suggest performing a detailed investigation of the mTOR profile before administering mTORC1 inhibitor therapy. Furthermore, our findings highlight that targeting the metabolic plasticity could be an alternative therapeutic approach.

Lung Transplantation in a Patient with COPA Syndrome.

COPA syndrome is a newly discovered, rare genetic autoimmune disorder, which can affect the lungs, joints, and kidneys. It is difficult to recognize, and the survival benefit of lung transplantation for these patients is not yet known. We present a case of a 24-year-old woman who received bilateral lung transplant for COPA syndrome. At 15 months posttransplant, her pulmonary function is stable with no episodes of acute cellular- or antibody-mediated rejection and no evidence of disease recurrence.

mTOR in Lung Neoplasms.

With the discovery of rapamycin 45 years ago, studies in the mechanistic target of rapamycin (mTOR) field started 2 decades before the identification of the mTOR kinase. Over the years, studies revealed that the mTOR signaling is a master regulator of homeostasis and integrates a variety of environmental signals to regulate cell growth, proliferation, and metabolism. Deregulation of mTOR signaling, particularly hyperactivation, frequently occurs in human tumors. Recent advances in molecular profiling have identified mutations or amplification of certain genes coding proteins involved in the mTOR pathway (eg, PIK3CA, PTEN, STK11, and RICTOR) as the most common reasons contributing to mTOR hyperactivation. These genetic alterations of the mTOR pathway are frequently observed in lung neoplasms and may serve as a target for personalized therapy. mTOR inhibitor monotherapy has met limited clinical success so far; however, rational drug combinations are promising to improve efficacy and overcome acquired resistance. A better understanding of mTOR signaling may have the potential to help translation of mTOR pathway inhibitors into the clinical setting.

Chromosome 3q26 Gain Is an Early Event Driving Coordinated Overexpression of the PRKCI, SOX2, and ECT2 Oncogenes in Lung Squamous Cell Carcinoma.

Lung squamous cell carcinoma (LSCC) is a prevalent form of lung cancer exhibiting distinctive histological and genetic characteristics. Chromosome 3q26 copy number gain (CNG) is a genetic hallmark of LSCC present in >90% of tumors. We report that 3q26 CNGs occur early in LSCC tumorigenesis, persist during tumor progression, and drive coordinate overexpression of PRKCI, SOX2, and ECT2. Overexpression of PRKCI, SOX2, and ECT2 in the context of Trp53 loss is sufficient to transform mouse lung basal stem cells into tumors with histological and genomic features of LSCC. Functionally, PRKCI and SOX2 collaborate to activate an extensive transcriptional program that enforces a lineage-restricted LSCC phenotype, whereas PRKCI and ECT2 collaborate to promote oncogenic growth. Gene signatures indicative of PKCι-SOX2 and PKCι-ECT2 signaling activity are enriched in the classical subtype of human LSCC and predict distinct therapeutic vulnerabilities. Thus, the PRKCI, SOX2, and ECT2 oncogenes represent a multigenic driver of LSCC.