Due to destructive, fibrotic, and remodeling mechanisms, we can find a varied constellation of aerated and cystic lung lesions in smoker patients with interstitial lung disease that pose a diagnostic challenge for both radiologists and pathologists. Radiologic terminology used for cystic lung lesions in smokers is varied and sometimes confusing, and the same applies to their pathologic correlation, with different names for similar findings. Moreover, there is substantial overlap among different cystic lesions in both radiology and pathology. Ultimately, the diagnosis of a given type of cyst may lead to a wrong diagnosis with important clinical implications. In this setting, the goals of this article are to present a diagnostic approach to these lesions by correlating radiologic findings with pathology and describing a series of radiologic characteristics of these lesions, which we have called "the four S of cystic lung lesions in smokers" for size, site, shape, and surrounding of the lesions. We will define the clue radiological findings of centrilobular emphysema, paraseptal emphysema, thin-walled cysts, traction emphysema, honeycombing, smoking-related diffuse cystic lung disease, cysts in Langerhans cell histiocytosis, and cystic lesions appearing in desquamative interstitial pneumonia and we will try to show a correlation of each of these lesions with pathology for a better understanding of radiological findings. Finally, we will deal with fibrosing lung diseases and cystic lung lesions in smokers, specifically with smoking-related interstitial fibrosis and its pathological variants, and with usual interstitial pneumonia, whose prognosis is strikingly different. CRITICAL RELEVANCE STATEMENT: Knowledge of the pathological correlation of the different cystic lesions that appear in smokers with interstitial lung disease permits a better understanding of their radiological manifestations. KEY POINTS: Interstitial lung disease in smokers is characterized by varied cystic lung lesions. Cystic lesions are characterized by their size, site, shape, and surroundings. Cystic lesions in smokers may help to characterize the underlying fibrosing disease.

Introduction: RET inhibitors with impressive overall response rates are now available for patients with NSCLC, yet the identification of RET fusions remains a difficult challenge. Most guidelines encourage the upfront use of next-generation sequencing (NGS), or alternatively, fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR) when NGS is not possible or available. Taken together, the suboptimal performance of single-analyte assays to detect RET fusions, although consistent with the notion of encouraging universal NGS, is currently widening some of the clinical practice gaps in the implementation of predictive biomarkers in patients with advanced NSCLC. Methods: This situation prompted us to evaluate several RET assays in a large multicenter cohort of RET fusion–positive NSCLC (n = 38) to obtain real-world data. In addition to RNA-based NGS (the criterion standard method), all positive specimens underwent break-apart RET FISH with two different assays and were also tested by an RT-PCR assay. Results: The most common RET partners were KIF5B (78.9%), followed by CCDC6 (15.8%). The two RET NGS-positive but FISH-negative samples contained a KIF5B(15)-RET(12) fusion. The three RET fusions not identified with RT-PCR were AKAP13(35)-RET(12), KIF5B(24)-RET(9) and KIF5B(24)-RET(11). All three false-negative RT-PCR cases were FISH-positive, exhibited a typical break-apart pattern, and contained a very high number of positive tumor cells with both FISH assays. Signet ring cells, psammoma bodies, and pleomorphic features were frequently observed (in 34.2%, 39.5%, and 39.5% of tumors, respectively). Conclusions: In-depth knowledge of the advantages and disadvantages of the different RET testing methodologies could help clinical and molecular tumor boards implement and maintain sensible algorithms for the rapid and effective detection of RET fusions in patients with NSCLC. The likelihood of RET false-negative results with both FISH and RT-PCR reinforces the need for upfront NGS in patients with NSCLC.

Objetivo: El objetivo de este estudio es describir una nueva técnica de localización de nódulos pulmonares previa a la cirugía mediante Onyx-34 y evaluar su utilidad y resultados posquirúrgicos. Material y métodos: Serie de casos con pacientes a los que se sometió a localización preoperatoria de uno o más nódulos pulmonares con Onyx-34 guiada por tomografía computarizada (TC) previo a la resección mediante toracoscopia asistida por vídeo (VATS). Se analizaron las características de los nódulos, el resultado posquirúrgico y las complicaciones. Resultados: La mediana del tamaño de los nódulos marcados fue de 10 mm (P25: 5,5-P75: 17,5) con una profundidad desde la pleura de 25 mm (P25: 6,5-P75: 30). La tasa de localización exitosa de los nódulos pulmonares guiada por TC fue del 100%. Todos los nódulos fueron resecados sin necesidad de conversión a toracotomía. No se registraron complicaciones importantes en el postoperatorio. La presencia de Onyx-34 en la muestra no interfirió en su análisis histológico. Conclusiones: Esta es la primera serie de casos de localización de nódulos pulmonares con Onyx-34 guiada por TC antes de la VATS. Esta técnica permitió una resección segura con una tasa de éxito absoluta y sin complicaciones postoperatorias graves.

Objective:The objective of this study is to describe a new technique for localizing pulmonary nodules before surgery using Onyx-34 and to evaluate its usefulness and post-operative results.Material and methods: A series of cases with patients who underwent pre-operative localization of one or more pulmonary nodules using computed tomography (CT)-guided Onyx-34, before resection by video-assisted thoracoscopy (VATS).The characteristics of the nodules, the post-operative outcome, and the complications were analyzed.Results: The median size of the marked nodules was 10 mm (P25: 5.5-P75: 17.5) with a depth from the pleura of 25 mm (P25: 6.5-P75: 30).The CT-guided successful localization rate of pulmonary nodules was 100%.All nodules were resected without the need of a thoracotomy.There were no major complications in the post-operative period.The presence of Onyx-34 in the specimen did not interfere in its histological analysis.Conclusion: This is the first series of cases of CT-guided Onyx-34 localization of lung nodules before VATS.This technique allowed safe resection with an absolute success rate and no serious post-operative complications.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

INTRODUCTION:Data on pathological changes in COVID-19 are scarce. The aim of this study was to describe the histopathological and virological findings of postmortem biopsies, and the existing clinical correlations, in people who died of COVID-19.MATERIALS AND METHODS:We performed postmortem needle core biopsies of the chest in 11 people who died of COVID-19 pneumonia. Tissue examination was done by light microscopy and real-time polymerase chain reaction (RTPCR).RESULTS:The age of the patients were between 61 to 94 years. Of the 11 postmortem chest biopsies, lung tissue was obtained in 8, myocardium tissue in 7, and liver tissue in 5. Histologically of lung, the main findings pertaining to the lung were diffuse alveolar damage in proliferative phase (n = 4, 50%), diffuse alveolar damage in exudative and proliferative phase (n = 3, 37.5%), diffuse alveolar damage in exudative (n=1; 12.5%) and acute pneumonia (n = 2, 25%). Necrotising pneumonia, acute fibrinous and organising pneumonia, and neutrophils were detected in one sample each (12.5%). Another case presented myocarditis. RT-PCR showed RNA of SARS-CoV-2 in 7 of the 8 lung samples (87.5%), 2 of the 7 myocardial tissue samples (28.6%), and 1 of the 5 liver tissue samples (20%).CONCLUSION:The postmortem examinations show diffuse alveolar damage, as well as acute or necrotising pneumonia. RT-PCR of SARS-CoV-2 was positive in most lung samples.

Although next-generation sequencing (NGS) is now the gold-standard for lung cancer biomarker testing, single-gene assays are still used for different reasons. Therefore, we were intrigued by the perfomance of commonly used fluorescence in situ hybridization (FISH) and real-time PCR assays in a cohort of RET fusion-positive non-small cell lung carcinoma (NSCLC) patients.

Background Autopsies can shed light on the pathogenesis of new and emerging diseases. Aim To describe needle core necropsy findings of the lung, heart, and liver in decedents with COVID-19. Material Cross-sectional study of needle core necropsies in patients who died with virologically confirmed COVID-19. Histopathological analyses were performed, and clinical data and patient course evaluated. Results Chest core necropsies were performed in 71 decedents with a median age of 81 years (range 52–97); 47 (65.3%) were men. The median interval from symptoms onset to death was 17.5 days (range 1–84). Samples of lung (n = 62, 87.3%), heart (n = 48, 67.6%) and liver (n = 39, 54.9%) were obtained. Fifty-one lung samples (82.3%) were abnormal: 19 (30.6%) showed proliferative diffuse alveolar damage (DAD), 12 (19.4%) presented exudative DAD, and 10 (16.1%) exhibited proliferative plus exudative DAD. Of the 46 lung samples tested for SARS-CoV-19 by RT-PCR, 39 (84.8%) were positive. DAD was associated with premortem values of lactate dehydrogenase of 400 U/L or higher [adjusted odds ratio (AOR) 21.73; 95% confidence interval (CI) 3.22–146] and treatment with tocilizumab (AOR 6.91; 95% CI 1.14–41.7). Proliferative DAD was associated with an onset-to-death interval of over 15 days (AOR 7.85, 95% CI 1.29–47.80). Twenty-three of the 48 (47.9%) heart samples were abnormal: all showed fiber hypertrophy, while 9 (18.8%) presented fibrosis. Of the liver samples, 29/39 (74.4%) were abnormal, due to steatosis (n = 12, 30.8%), cholestasis (n = 6, 15.4%) and lobular central necrosis (n = 5, 12.8%). Conclusion Proliferative DAD was the main finding on lung core needle necropsy in people who died from COVID-19; this finding was related to a longer disease course. Changes in the liver and heart were common.

Inhibitor of differentiation (ID) proteins are a family of transcription factors that contribute to maintaining proliferation during embryogenesis as they avoid cell differentiation. Afterward, their expression is mainly silenced, but their reactivation and contribution to tumor development have been suggested. In breast cancer (BC), the overexpression of ID1 has been previously described. However, whether the remaining ID genes have a specific role in this neoplasia is still unclear. We studied the mRNA expression of all ID genes by q RT-PCR in BC cell lines and 307 breast carcinomas, including all BC subtypes. Our results showed that ID genes are highly expressed in all cell lines tested. However, ID4 presented higher expression in BC cell lines compared to a healthy breast epithelium cell line. In accordance, ID1 and ID4 were predominantly overexpressed in Triple-Negative and HER2-enriched samples. Moreover, high levels of both genes were associated with larger tumor size, histological grade 3, necrosis and vascular invasion, and poorer patients' outcomes. In conclusion, ID1 and ID4 may act as biomarkers of tumor aggressiveness and worse prognosis in breast cancer, and they could be used as potential targets for new treatments discover.

INTRODUCTION:Tumors of the anterior pituitary gland (PTs) are mostly benign tumors with a low prevalence, which has nevertheless increased with advances in brain radiology techniques. Nearly half of PTs are not associated with a clinical endocrine syndrome. These tumors have been indistinctly named non-functioning pituitary adenomas (NFPAs) or silent pituitary tumors (SPTs) and the mechanisms of silencing are not fully known.AIM:To study the frequency and characterize the silent variant of PTs in a large local series, and to assess their pituitary adenohypophyseal gene expression.METHODS:This observational, cross-sectional study was performed in a Pituitary Tumor Center of Excellence and involved 268 PTs. After identifying the different subtypes according to the immunohistochemical (IHC) expression of adenohypophyseal hormones, we studied their gene expression by RT-qPCR.RESULTS:We found that silent tumors were larger and more invasive, but not more proliferative than their functional counterparts. The RT-qPCR complements the IHC typification of PTs, reducing the proportion of null-cell subtype. Finally, some silent PT subtype variants showed lower specific adenohypophyseal hormone gene expression than their functional counterparts, which may contribute to the absence of endocrine manifestations.CONCLUSIONS:This paper highlights the importance of identifying the silent variant of the PTs subtypes. As expected, silent tumors were larger and more invasive than their functioning counterparts. However, there was no difference in the proliferation activity between them. Finally, the lower specific gene expression in the silent than in the functioning counterparts of some PTs subtypes gives insights into the silencing mechanisms of PTs.

IntroductionRET inhibitors with impressive overall response rates are now available for patients with non-small cell lung carcinoma (NSCLC), yet the identification of RET fusions remains a difficult challenge. Most guidelines encourage the up-front use of next-generation sequencing (NGS), or alternatively fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR) if NGS is not possible or available. Taken together, the suboptimal performance of single-analyte assays to detect RET fusions, although consistent with the notion of encouraging universal NGS, is currently widening some of the clinical practice gaps on the implementation of predictive biomarkers in patients with advanced NSCLC.MethodsThis situation prompted us to evaluate several RET assays in a large multicentre cohort of RET fusion-positive NSCLC (n=38) to obtain real-world data. In addition to RNA-based NGS (the criterion standard method), all positive specimens underwent break-apart RET FISH with two different assays and were also tested by a RT-PCR assay.ResultsThe most common RET partners were KIF5B (78.9%), followed by CCDC6 (15.8%). The two RET NGS-positive but FISH-negative samples contained a KIF5B(15)-RET(12) fusion. The three RET fusions not identified with RT-PCR were AKAP13(35)-RET(12), KIF5B(24)-RET(9) and KIF5B(24)-RET(11). All three false-negative RT-PCR cases were FISH-positive, exhibited a typical break-apart pattern and contained a very high number of positive tumor cells with both FISH assays. Signet ring cells, psammoma bodies and pleomorphic features were frequently observed (in 34.2%, 39.5% and 39.5% of tumors, respectively).ConclusionsIn-depth knowledge of the advantages and disadvantages of the different RET testing methodologies could help clinical and molecular tumor boards implement and maintain sensible algorithms for a rapid and effective detection of RET fusions in patients with NSCLC. The likelihood of RET false negative results with both FISH and RT-PCR reinforces the need of up-front NGS in patients with NSCLC.

The onset of the lipoprotein secretory block provoked by CCl4 in the whole animal was monitored after purification of liver Golgi membranes. Both lipid transit through the apparatus the apparatus and hexosylation of the lipoprotein are markedly inhibited 5–15 min after poisoning. Pre‐treating the animal with alpha‐tocopherol, shown to prevent lipid peroxidation without modifying the covalent binding due to CCl4 metabolites, affords little protection against lipid accumulation in the Golgi, but total preservation of galactosyl transferase activity. While haloalkylation therefore appears to be the major mechanism of damage in the early phases of CCl4‐induced derangement of lipid secretion, lipid peroxidation is probably more involved later, this is indicated by the marked, though never complete, protection against fatty liver afforded at 24 h after CCl4 poisoning by supplementation of the membrane with alpha‐tocopherol.

El riesgo de tumores secundarios en los pacientes que han recibido radioterapia mediastínica es ampliamente conocido. La adenosis microglandular de la mama es una lesión poco frecuente considerada como benigna, aunque se plantea su papel precursor del carcinoma infiltrante de mama. Presentamos un caso de adenosis microglandular en una paciente que recibió radioterapia mediastínica en la infancia por linfoma de Hodgkin. Hasta la fecha este es el primer caso informado en la literatura de adenosis microglandular en paciente con radioterapia mediastínica, planteando un interrogante en la contribución en la patogénesis.

The risk of secondary tumors in patients who have received mediastinal radiation therapy is well-known. Microglandular adenosis of the breast is a rare lesion that is considered benign, although its possible role as a precursor of invasive breast carcinoma has been considered. We present a case of microglandular adenosis in a patient who received mediastinal radiation therapy in childhood for Hodgkin's lymphoma. To our knowledge, this is the first reported case of microglandular adenosis in a patient with mediastinal radiotherapy which may shed light on its pathogenesis.

miR-17-5p and E2F1 have been described as deregulated in cancer, but they have scarcely been studied in pituitary neuroendocrine tumours (PitNETs). This study evaluates the relationship of E2F1 and miR-17-5p with the invasiveness and proliferation of PitNETs. In this cross-sectional descriptive study, we evaluated the expression of E2F1, MYC, and miR-17-5p by quantitative real time PCR analysis in 60 PitNETs: 29 gonadotroph (GT), 15 functioning somatotroph (ST), and 16 corticotroph (CT) tumours, of which 8 were silent (sCT). The clinical data were collected from the Spanish Molecular Register of Pituitary Adenomas (REMAH) database. We defined invasiveness according to the Knosp classification and proliferation according to a molecular expression of Ki-67 ≥ 2.59. E2F1 was more expressed in invasive than in non-invasive tumours in the whole series (p = 0.004) and in STs (p = 0.01). In addition, it was overexpressed in the silent subtypes (GTs and sCTs; all macroadenomas) and normoexpressed in the functioning ones (fCTs and STs; some microadenomas). miR-17-5p was more expressed in proliferative than in non-proliferative tumours (p = 0.041) in the whole series but not by subtypes. Conclusions: Our study suggests that in PitNETs, E2F1 could be a good biomarker of invasiveness, and miR-17-5p of proliferation, helping the clinical management of these tumours.

The potential role of miRNAs in the silencing mechanisms of pituitary neuroendocrine tumors (PitNETs) has not been addressed. The aim of the present study was to evaluate the expression levels and the potential associated role of some miRNAs, pathways, and transcription factors in the silencing mechanisms of corticotroph tumors (CTs). Accordingly, the expression of miR-375, miR-383, miR-488, miR-200a and miR-103; of PKA, MAP3K8, MEK, MAPK3, NGFIB, NURR1, PITX1, and STAT3 were analyzed via qRT-PCR in 23 silent and 24 functioning CTs. miR-200a and miR-103 showed significantly higher expression in silent than in functioning CTs, even after eliminating the bias of tumor size, therefore enabling the differentiation between the two variants. Additionally, miR-383 correlated negatively with TBX19 in silent CTs, a transcription factor related with the processing of POMC that can participate in the silencing mechanisms of CTs. Finally, the gene expression levels of miR-488, miR-200a, and miR-103 were significantly higher in macroadenomas (functioning and silent) than in microadenomas. The evidence from this study indicates that miRNAs could be involved in the pathophysiology of CTs. The translational implications of these findings suggest that pharmacological treatments specifically targeting these miRNAs could become a promising therapeutic option for these patients.

Sclerosing pneumocytoma is an uncommon pulmonary tumor which generally behaves benignly and occurs predominately in women. Rarely, it is associated with neuroendocrine proliferations such as hyperplasia, tumorlets and carcinoid tumors, which may be observed in relation to the tumor or in the distant lung parenchyma; the mechanism underlying this neuroendocrine differentiation is not clear. We present a case of a 33 year-old male with sclerosing pnemocytoma with coexistent neuroendocrine hyperplasia and combined carcinoid tumorlets. Taking into account the pluripotentiality of the round cells present in the sclerosing pneumocytoma, with positive staining for stem cells markers, it is possible that the different components of this neoplasia share a common origin, in accordance with previously reported findings.

Background Medullary thyroid carcinoma very rarely metastasizes to the breast. Hematogenous spread to the liver, lungs, or mediastinum is more common. Case We describe the morphologic and immunohistochemical features of a 63-year-old woman who presented with a BIRADS-5 category nodule in the right breast and enlarged axillary lymph nodes. Core biopsy showed suggested breast cancer with neuroendocrine or apocrine differentiation. The immunohistochemical profile showed (RE-/RP-/HER-2-) and Ki67 10%. Chromogranin and synaptophysin were positive; AR and GCDFP-15 were negative. On reviewing the patient's clinical history, it was discovered that she had been treated for medullary thyroid carcinoma 15 years earlier. Additional stains showed positivity for TTF-1, CEA, and calcitonin. These findings were consistent with a diagnosis of breast metastasis from medullary thyroid carcinoma. We discuss briefly the morphologic features and the possible key features in order to make an accurate diagnosis. Conclusion This case highlights the importance of investigating a history of cancer in patients with discordant or unusual histologic or immunohistochemical findings, as this can help avoid misdiagnosis and inappropriate treatment.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)