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Appropriate management requires timely and accurate confirmation of non-small cell lung cancer (NSCLC) recurrence in patients who have had curative-intent surgical resection. We assessed the association between circulating tumor DNA (ctDNA) identified using amplicon sequencing and evidence of recurrence on CT surveillance. A prospective cohort study of NSCLC patients with early-stage disease undergoing curative-intent resection was conducted. Surveillance was performed post-operatively at pre-defined intervals with both liquid biopsy and chest CT imaging. Amplicon panel next-generation sequencing was performed on DNA and RNA from tumor tissue and on plasma cell-free DNA for tumor-informed ctDNA detection. Resected tumors from 78 NSCLC patients were analyzed. Alterations were detected on the DNA assay for 65 tumors and only on the RNA assay for 4 tumors. Of the 65 patients with alterations detected on the tumor DNA assay, 29 completed post-operative liquid biopsy testing. Four of those 29 patients had evidence of recurrence on imaging, of whom two had biopsy confirmation of recurrence and detectable ctDNA at the 12-month follow-up. Molecular confirmation of NSCLC recurrence can be provided through amplicon sequencing of plasma cell-free DNA in cases with imaging evidence of recurrence. Invasive tissue diagnosis may be avoidable in patients with ctDNA confirmation of recurrence that is suspected based on imaging. Further study of ctDNA assessment technologies in the setting of suspected recurrence is necessary to inform post-operative lung cancer surveillance guidelines.
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Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Neoplasias Pulmonares , Recurrencia Local de Neoplasia , Humanos , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/patología , Biopsia Líquida/métodos , Femenino , Masculino , Anciano , Persona de Mediana Edad , Carcinoma de Pulmón de Células no Pequeñas/cirugía , ADN Tumoral Circulante/sangre , Estudios Prospectivos , Anciano de 80 o más AñosRESUMEN
Prognostic stratification of pulmonary carcinoids into "typical" and "atypical" categories requires examination of large tissue volume. However, there is a need for tools that provide similar prognostic information on small biopsy samples. Ki-67 and OTP immunohistochemistry have shown promising prognostic value in studies of resected pulmonary carcinoids, but prognostic value when using biopsy/cytology specimens is unclear. Ki-67 immunohistochemistry was performed on small biopsy/cytology specimens from pulmonary carcinoid tumors (n=139), and labeling index was scored via automated image analysis of at least 500 cells. OTP immunohistochemistry was performed on 70 cases with sufficient tissue and scored as positive or negative (<20% tumor nuclei staining). Higher Ki-67 index was associated with worse disease-specific progression-free survival (ds-PFS), with 3% and 4% thresholds having similarly strong associations with ds-PFS ( P <0.001, hazard ratio ≥11). Three-year ds-PFS was 98% for patients with Ki-67 <3% and 89% for patients with Ki-67≥3% ( P =0.0006). The optimal Ki-67 threshold for prediction of typical versus atypical carcinoid histology on subsequent resection was 3.21 (AUC 0.68). Negative OTP staining approached significance with atypical carcinoid histology ( P =0.06) but not with ds-PFS ( P =0.24, hazard ratio=3.45), although sample size was limited. We propose that Ki-67 immunohistochemistry may contribute to risk stratification for carcinoid tumor patients based on small biopsy samples. Identification of a 3% hot-spot Ki-67 threshold as optimal for prediction of ds-PFS is notable as a 3% Ki-67 threshold is currently used for gastrointestinal neuroendocrine tumor stratification, allowing consideration of a unified classification system across organ systems.
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Biomarcadores de Tumor , Tumor Carcinoide , Antígeno Ki-67 , Neoplasias Pulmonares , Supervivencia sin Progresión , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Biomarcadores de Tumor/análisis , Biopsia , Tumor Carcinoide/patología , Tumor Carcinoide/mortalidad , Tumor Carcinoide/química , Tumor Carcinoide/cirugía , Inmunohistoquímica , Antígeno Ki-67/análisis , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/química , Neoplasias Pulmonares/cirugía , Valor Predictivo de las Pruebas , Factores de TiempoRESUMEN
Gangliocytic paragangliomas are rare neoplasms occurring almost exclusively in the ampullary region of the gastrointestinal tract. Although these tumors are not typically considered in the differential diagnosis of primary pulmonary neoplasia, 5 cases of primary pulmonary gangliocytic paragangliomas have been previously reported. Herein we report our experience with 3 additional examples, all referred to our Anatomic Pathology Consultation service. The patients (a 32-year-old man, a 69-year-old woman and a 55-year-old man) each presented with an endobronchial (2 cases) or upper lobe lung mass, ranging from 1.5 to 2.5 cm in maximum dimension. Biopsy and endobronchial debulking specimens demonstrated the classic triphasic morphology of gangliocytic paraganglioma, with epithelial, spindled and ganglion-like cells. By immunohistochemistry, the tumors were positive for keratin, synaptophysin and chromogranin A in the epithelial component, S100 protein and glial fibrillary acidic protein (GFAP) in the Schwannian spindled cells, and synaptophysin in ganglion cells. TTF1 expression was seen in the epithelial components of 2 cases. The Ki-67 labelling index was low (<2%). Primary pulmonary gangliocytic paragangliomas should be distinguished from carcinoid tumors, given the different natural histories and risk stratification approaches for these morphologically similar tumors. Awareness that gangliocytic paraganglioma may occur in the lung and appropriate immunohistochemical studies are key to correct diagnosis.
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Biomarcadores de Tumor , Tumor Carcinoide , Inmunohistoquímica , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Diagnóstico Diferencial , Biomarcadores de Tumor/análisis , Adulto , Tumor Carcinoide/patología , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/química , Paraganglioma/patología , Paraganglioma/diagnóstico , Biopsia , Valor Predictivo de las PruebasRESUMEN
Primary pulmonary salivary gland-type tumours are rare neoplasms that are thought to arise from seromucinous glands that are located in the submucosa of large airways. These neoplasms have clinical and pathologic features that are distinct from other pulmonary neoplasms. The majority of primary pulmonary salivary gland-type tumours are malignant, with the most common entities being mucoepidermoid carcinoma, adenoid cystic carcinoma, and epithelial-myoepithelial carcinoma. Less commonly seen are myoepithelial carcinoma, hyalinizing clear cell carcinoma, acinic cell carcinoma, secretory carcinoma, salivary duct carcinoma, intraductal carcinoma, and polymorphous adenocarcinoma. Benign salivary gland-type tumours of the lung include pleomorphic adenoma and sialadenoma papilliferum. Morphologic, immunophenotypic, and molecular features of these neoplasms are largely similar to salivary gland tumours elsewhere, and therefore the exclusion of metastatic disease requires clinical and radiologic correlation. However, the differential diagnostic considerations are different in the lung. The distinction of salivary gland-type tumours from their histologic mimics is important for both prognostication and treatment decisions. Overall, salivary gland type-tumours tend to have a more favourable outcome than other pulmonary carcinomas, although high-grade variants exist for many of these tumour types. Recent advances in our understanding of the spectrum of salivary gland-type tumours reported in the lung and their diversity of molecular and immunohistochemical features have helped to refine the classification of these tumours and have highlighted a few differences between salivary gland-type tumours of the lung and those primary to other sites.
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Adenoma Pleomórfico , Carcinoma de Células Acinares , Carcinoma Adenoide Quístico , Carcinoma Mucoepidermoide , Carcinoma , Neoplasias Pulmonares , Neoplasias de las Glándulas Salivales , Humanos , Neoplasias de las Glándulas Salivales/patología , Carcinoma Adenoide Quístico/patología , Adenoma Pleomórfico/patología , Carcinoma/patología , Carcinoma Mucoepidermoide/diagnóstico , Carcinoma Mucoepidermoide/patología , Carcinoma de Células Acinares/patología , Glándulas Salivales/patología , Pulmón/patología , Neoplasias Pulmonares/patología , Biomarcadores de Tumor/metabolismoRESUMEN
BACKGROUND: Obtaining a diagnosis and treating pulmonary malignancies during the same anesthesia requires either an on-site pathologist or a system for remotely evaluating microscopic images. Cytology specimens are challenging to remotely assess given the need to navigate through dispersed and three-dimensional cell clusters. Remote navigation is possible using robotic telepathology, but data are limited on the ease of use of current systems, particularly for pulmonary cytology. METHODS: Air dried modified Wright-Giemsa stained slides from 26 touch preparations of transbronchial biopsies and 27 smears of endobronchial ultrasound guided fine needle aspirations were scored for ease of adequacy assessment and ease of diagnosis on robotic (rmtConnect Microscope) and non-robotic telecytology platforms. Diagnostic classifications were compared between glass slides and the robotic and non-robotic telecytology assessments. RESULTS: Compared to non-robotic telecytology, robotic telecytology had a greater ease of adequacy assessment and non-inferior ease of diagnosis. The median time to diagnosis using robotic telecytology was 85 s (range 28-190 s). Diagnostic categories were concordant for 76% of cases in robotic versus non-robotic telecytology and 78% of cases in robotic telecytology versus glass slide diagnosis. Weighted Cohen's kappa scores for agreement in these comparisons were 0.84 and 0.72, respectively. CONCLUSIONS: Use of a remote-controlled robotic microscope improved the ease of adequacy assessment compared to non-robotic telecytology and enabled strongly concordant diagnoses to be expediently rendered. This study provides evidence that modern robotic telecytology is a feasible and user-friendly method of remotely and potentially intraoperatively rendering adequacy assessments and diagnoses on bronchoscopic cytology specimens.
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Microscopía , Telepatología , Humanos , Citodiagnóstico/métodos , Técnicas Citológicas/métodos , Biopsia con Aguja Fina/métodos , Telepatología/métodosRESUMEN
Thymic carcinoma is an aggressive malignancy that can be challenging to distinguish from thymoma using histomorphology. We assessed two emerging markers for these entities, EZH2 and POU2F3, and compared them with conventional immunostains. Whole slide sections of 37 thymic carcinomas, 23 type A thymomas, 13 type B3 thymomas, and 8 micronodular thymomas with lymphoid stroma (MNTLS) were immunostained for EZH2, POU2F3, CD117, CD5, TdT, BAP1, and MTAP. POU2F3 (≥10% hotspot staining), CD117, and CD5 showed 100% specificity for thymic carcinoma versus thymoma with 51%, 86%, and 35% sensitivity, respectively, for thymic carcinoma. All POU2F3 positive cases were also positive for CD117. All thymic carcinomas showed >10% EZH2 staining. EZH2 (≥80% staining) had a sensitivity of 81% for thymic carcinoma and a specificity of 100% for thymic carcinoma versus type A thymoma and MNTLS but had poor specificity (46%) for thymic carcinoma versus B3 thymoma. Adding EZH2 to a panel of CD117, TdT, BAP1, and MTAP increased cases with informative results from 67/81 (83%) to 77/81 (95%). Overall, absent EZH2 staining may be useful for excluding thymic carcinoma, diffuse EZH2 staining may help to exclude type A thymoma and MNTLS, and ≥10% POU2F3 staining has excellent specificity for thymic carcinoma versus thymoma.
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Separation of mesothelioma from metastatic carcinoma requires immunohistochemical support, with small batteries of stains recommended as a starting-point, but these numbers commonly expand to 10, 12 or more stains, a process that is not only expensive but frequently generates anomalous or confounding results, leading to even more stains. Here we review data on HEG1 clone SKM9-2, a new (now commercially available) mesothelioma marker and claudin-4, a broad-spectrum carcinoma marker, to ask whether these two stains are sufficient, by themselves, to separate mesotheliomas from non-small-cell lung (NSCLC) as well as other carcinomas. Data for HEG1, derived from four laboratories, showed membrane staining in 393 of 434 (91%) epithelioid/biphasic mesotheliomas and one of 360 (0.3%) NSCLC (sensitivity 91%, specificity 99.7%). Reports from seven laboratories evaluating claudin-4 in NSCLC showed positivity in 469 of 502 (93%) carcinomas and weak positivity in five of 463 (1.0%) epithelioid/biphasic mesotheliomas (sensitivity 93%, specificity 98.9%). Comparable results were found with carcinomas from other sites, except for serous and thyroid carcinomas, some of which react with HEG1 but are also positive for claudin-4. For sarcomatoid mesotheliomas, HEG1 sensitivity is modest and staining sometimes difficult to interpret. We hypothesise that the combination of HEG1 and claudin-4 immunostaining will potentially allow the separation of epithelioid/biphasic mesotheliomas from NSCLC carcinomas with high accuracy using only two immunostains in most cases. This combination will probably also work for carcinomas from most other sites, but more reports on HEG1 SKM9-2 staining of carcinomas other than NSCLC are needed. This approach would greatly simplify the diagnosis of mesothelioma.
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma , Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Humanos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/patología , Claudina-4 , Colorantes , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Inmunohistoquímica , Diagnóstico Diferencial , Biomarcadores de Tumor , Mesotelioma Maligno/diagnóstico , Mesotelioma/diagnóstico , Mesotelioma/patología , Carcinoma/diagnóstico , Coloración y Etiquetado , Proteínas de la MembranaRESUMEN
In this study, we evaluate the impact of whole genome and transcriptome analysis (WGTA) on predictive molecular profiling and histologic diagnosis in a cohort of advanced malignancies. WGTA was used to generate reports including molecular alterations and site/tissue of origin prediction. Two reviewers analyzed genomic reports, clinical history, and tumor pathology. We used National Comprehensive Cancer Network (NCCN) consensus guidelines, Food and Drug Administration (FDA) approvals, and provincially reimbursed treatments to define genomic biomarkers associated with approved targeted therapeutic options (TTOs). Tumor tissue/site of origin was reassessed for most cases using genomic analysis, including a machine learning algorithm (Supervised Cancer Origin Prediction Using Expression [SCOPE]) trained on The Cancer Genome Atlas data. WGTA was performed on 652 cases, including a range of primary tumor types/tumor sites and 15 malignant tumors of uncertain histogenesis (MTUH). At the time WGTA was performed, alterations associated with an approved TTO were identified in 39 (6%) cases; 3 of these were not identified through routine pathology workup. In seven (1%) cases, the pathology workup either failed, was not performed, or gave a different result from the WGTA. Approved TTOs identified by WGTA increased to 103 (16%) when applying 2021 guidelines. The histopathologic diagnosis was reviewed in 389 cases and agreed with the diagnostic consensus after WGTA in 94% of non-MTUH cases (n = 374). The remainder included situations where the morphologic diagnosis was changed based on WGTA and clinical data (0.5%), or where the WGTA was non-contributory (5%). The 15 MTUH were all diagnosed as specific tumor types by WGTA. Tumor board reviews including WGTA agreed with almost all initial predictive molecular profile and histopathologic diagnoses. WGTA was a powerful tool to assign site/tissue of origin in MTUH. Current efforts focus on improving therapeutic predictive power and decreasing cost to enhance use of WGTA data as a routine clinical test.
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Neoplasias , Algoritmos , Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica , Humanos , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
p53 immunohistochemistry has long been proposed for the separation of benign from malignant mesothelial proliferations, with the older literature suggesting that any degree of positivity supported a diagnosis of mesothelioma. However, using modern immunohistochemistry platforms in other organ systems, notably gynecologic tumors, it has become clear that p53 staining can represent wild-type protein, and only specific staining patterns (absent, overexpression, or cytoplasmic expression) are indicative of a TP53 mutation. We applied these principles to two tissue microarrays containing 94 mesotheliomas and 66 reactive mesothelial proliferations. Seven/65 (11%) epithelioid mesotheliomas showed aberrant staining (four absent and three overexpression patterns) as did 5/29 (17%) of sarcomatoid mesotheliomas (all overexpression patterns). We sequenced the TP53 gene (exons 2-11) in five of the epithelioid and three of the sarcomatoid cases with aberrant staining as well as 12 epithelioid and eight sarcomatoid mesotheliomas with wild-type staining. All three sarcomatoid cases with aberrant staining showed mutated TP53, as did three of the epithelioid cases; in two of the epithelioid cases no mutation was detected, most likely because of large deletions not detected by this assay. In contrast, none of the 20 mesotheliomas with wild-type staining contained mutated TP53. We conclude that absent or overexpression p53 staining patterns can be used as a marker of a malignant vs. a benign mesothelial proliferation. The sensitivity of p53 staining by itself is low, but here addition of p53 to BAP1/MTAP staining increased sensitivity from 72 to 81% for epithelioid and 38 to 50% for sarcomatoid mesotheliomas.
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Genes p53/genética , Mesotelioma/genética , Mesotelioma/patología , Mutación , Biomarcadores de Tumor , Estudios de Cohortes , Humanos , Inmunohistoquímica , Estudios Retrospectivos , Análisis de Matrices TisularesRESUMEN
The color variation of hematoxylin and eosin (H&E)-stained tissues has presented a challenge for applications of artificial intelligence (AI) in digital pathology. Many color normalization algorithms have been developed in recent years in order to reduce the color variation between H&E images. However, previous efforts in benchmarking these algorithms have produced conflicting results and none have sufficiently assessed the efficacy of the various color normalization methods for improving diagnostic performance of AI systems. In this study, we systematically investigated eight color normalization algorithms for AI-based classification of H&E-stained histopathology slides, in the context of using images both from one center and from multiple centers. Our results show that color normalization does not consistently improve classification performance when both training and testing data are from a single center. However, using four multi-center datasets of two cancer types (ovarian and pleural) and objective functions, we show that color normalization can significantly improve the classification accuracy of images from external datasets (ovarian cancer: 0.25 AUC increase, p = 1.6 e-05; pleural cancer: 0.21 AUC increase, p = 1.4 e-10). Furthermore, we introduce a novel augmentation strategy by mixing color-normalized images using three easily accessible algorithms that consistently improves the diagnosis of test images from external centers, even when the individual normalization methods had varied results. We anticipate our study to be a starting point for reliable use of color normalization to improve AI-based, digital pathology-empowered diagnosis of cancers sourced from multiple centers. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Inteligencia Artificial , Eosina Amarillenta-(YS) , Neoplasias/diagnóstico , Neoplasias/patología , Coloración y Etiquetado , Algoritmos , Hematoxilina , Humanos , Reino UnidoRESUMEN
PD-L1 expression in non-small cell lung cancer (NSCLC) is predictive of response to immunotherapy, but scoring of PD-L1 immunohistochemistry shows considerable interobserver variability. Automated methods may allow more consistent and expedient PD-L1 scoring. We aimed to assess the technical concordance of PD-L1 scores produced using free open source QuPath software with the manual scores of three pathologists. A classifier for PD-L1 scoring was trained using 30 NSCLC image patches. A separate test set of 207 image patches from 69 NSCLC resection cases was used for comparison of automated and manual scores. Automated and average manual scores showed excellent correlation (concordance correlation coeffecient = 0.925), though automated scoring resulted in significantly more 1-49% scores than manual scoring (p = 0.012). At both 1% and 50% thresholds, automated scores showed a level of concordance with our 'gold standard' (the average of three pathologists' manual scores) similar to that of individual pathologists. Automated scoring showed high sensitivity (95%) but lower specificity (84%) at a 1% threshold, and excellent specificity (100%) but lower sensitivity (71%) at a 50% threshold. We conclude that our automated PD-L1 scoring system for NSCLC has an accuracy similar to that of individual pathologists. The detailed protocol we provide for free open source scoring software and our discussion of the limitations of this technology may facilitate more effective integration of automated scoring into clinical workflows.
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Antígeno B7-H1/análisis , Biomarcadores de Tumor/análisis , Carcinoma de Pulmón de Células no Pequeñas , Procesamiento de Imagen Asistido por Computador/métodos , Neoplasias Pulmonares , Programas Informáticos , HumanosRESUMEN
Sarcomatoid mesothelioma is an aggressive malignancy that can be challenging to distinguish from benign spindle cell mesothelial proliferations based on biopsy, and this distinction is crucial to patient treatment and prognosis. A novel deep learning based classifier may be able to aid pathologists in making this critical diagnostic distinction. SpindleMesoNET was trained on cases of malignant sarcomatoid mesothelioma and benign spindle cell mesothelial proliferations. Performance was assessed through cross-validation on the training set, on an independent set of challenging cases referred for expert opinion ('referral' test set), and on an externally stained set from outside institutions ('externally stained' test set). SpindleMesoNET predicted the benign or malignant status of cases with AUC's of 0.932, 0.925, and 0.989 on the cross-validation, referral and external test sets, respectively. The accuracy of SpindleMesoNET on the referral set cases (92.5%) was comparable to the average accuracy of 3 experienced pathologists on the same slide set (91.7%). We conclude that SpindleMesoNET can accurately distinguish sarcomatoid mesothelioma from benign spindle cell mesothelial proliferations. A deep learning system of this type holds potential for future use as an ancillary test in diagnostic pathology.
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Aprendizaje Profundo/clasificación , Mesotelioma Maligno/diagnóstico , Mesotelioma/diagnóstico , Neoplasias Pleurales/diagnóstico , Área Bajo la Curva , Proliferación Celular , Diagnóstico Diferencial , Humanos , Procesamiento de Imagen Asistido por Computador , Mesotelioma/clasificación , Mesotelioma Maligno/clasificación , Redes Neurales de la Computación , Neoplasias Pleurales/clasificación , Pronóstico , Curva ROC , Sensibilidad y EspecificidadRESUMEN
The site of the gastrointestinal (GI) tract where biopsies are most likely to be diagnostic of graft-versus-host disease (GvHD) remains controversial. Recent reports have indicated that biopsies from the rectosigmoid have sufficient sensitivity and specificity for diagnosing GI GvHD and can be obtained via a less invasive flexible sigmoidoscopy procedure. While GvHD histologic grades 1-3 have little correlation with patients' symptoms and overall clinical grade, histologic grade 4 GvHD does correlate with severe clinical presentation and a poor prognosis. We examined cases of lower GI biopsies obtained via a complete colonoscopy with ileal intubation for the evaluation of GvHD within a 2-year period from patients who underwent stem cell transplantation. In our study cohort, grade 4 GvHD was significantly more likely to be identified in a terminal ileum biopsy than in a biopsy from another site in the lower GI tract. Significantly, 5 of 6 patients with histologic grade 4 GvHD diagnosed on ileal biopsies died from complication of severe GI GvHD. Given the poor prognosis of histologic grade 4 GvHD in the terminal ileum, the detection of this finding may serve to inform clinicians that escalation or modification of treatment may need to be considered. Furthermore, our findings suggest that terminal ileal biopsies may help to increase sensitivity for identifying patients at high risk for poor outcome of GvHD.
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Enfermedad Injerto contra Huésped/diagnóstico , Íleon/patología , Trasplante de Células Madre/efectos adversos , Adulto , Anciano , Biopsia , Colonoscopía , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/patología , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Trasplante de Células Madre/mortalidad , Resultado del Tratamiento , Adulto JovenRESUMEN
The separation of malignant mesothelioma from non-small cell lung carcinomas can be a difficult problem. Sex-determining region Y box 6 (SOX6) and disabled homolog 2 (DAB2) have recently been proposed as sensitive/specific markers of mesothelial lineage, but have not yet been independently tested for utility in mesothelioma diagnosis. Using tissue microarrays containing mesotheliomas (epithelioid: n=40, sarcomatoid: n=23) and non-small cell lung carcinomas (adenocarcinoma: n=52, squamous cell carcinoma: n=57, large cell carcinoma: n=12) we evaluated the performance of SOX6 and DAB2 by themselves, in conjunction with other established mesothelioma markers (calretinin, WT1, D2-40, CK5/6, HEG1) and combined with 3 broad-spectrum established carcinoma markers: claudin-4, MOC31, and BerEP4. For epithelioid mesothelioma, SOX6 and DAB2 had sensitivities of 85% and 98%, respectively. For sarcomatoid mesothelioma, SOX6 had a sensitivity of 13% and DAB2 could not be assessed due to background stromal staining. For SOX6 alone, specificity for mesothelioma versus adenocarcinoma, squamous cell carcinoma, and large cell carcinoma was 94%, 79%, and 92%, respectively, while for DAB2 specificity was 77%, 86%, and 67%. Combinations of SOX6 and established mesothelioma markers produced sensitivities of 95% or greater. A combination of SOX6 positive/claudin-4 negative staining was 95% to 100% specific for mesothelioma versus carcinoma with a sensitivity of 85%. SOX6 is a promising marker for the diagnosis of mesothelioma and potentially could be combined with other mesothelial markers or a broad-spectrum carcinoma marker to reach an accurate diagnosis with relatively few immunostains, The relatively low specificity and difficulty of interpreting DAB2 staining limits its utility for mesothelioma diagnosis.
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Proteínas Adaptadoras Transductoras de Señales/análisis , Proteínas Reguladoras de la Apoptosis/análisis , Biomarcadores de Tumor/análisis , Mesotelioma Maligno/diagnóstico , Factores de Transcripción SOXD/análisis , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Diagnóstico Diferencial , Humanos , Neoplasias Pulmonares/diagnóstico , Sensibilidad y EspecificidadRESUMEN
INTRODUCTION: PD-L1 expression may be used as a biomarker predictive of non-small cell lung carcinoma (NSCLC) response to PD-L1 inhibitor treatment. Spatial and temporal heterogeneity in PD-L1 expression and variation in PD-L1 test interpretation may contribute to differences in PD-L1 test results between samples of the same patient's disease. METHODS: Retrospective chart review identified 77 NSCLC patients with 22C3 PharmDx PD-L1 assays performed on two different tumor samples. Patients clinically suspected to have two separate primaries were excluded. PD-L1 test results in different score categories (<1%, 1-49% and ≥50%) were considered discordant. Clinical and pathologic factors associated with discordance were assessed. RESULTS: 28 (36%) of the 77 cases had discordant PD-L1 scores between samples. Patients with an initial test result of 1-49% were most likely to have a discordant second test result. Specimen type (cytology, small biopsy or resection), specimen site (lung, lymph node, pleura/pleural effusion or distant metastasis), time between specimen collection, and treatment between specimen collection were not significantly associated with the rate of discordance. CONCLUSIONS: Repeat PD-L1 testing of the same patient's NSCLC results frequently resulted in discordant test results, independent of whether the samples differed in clinical or pathologic factors. This discordance rate underscores the extent to which PD-L1 levels are heterogeneous and difficult to accurately represent with a single test value. Further study of the predictive value of PD-L1 scores in cases with discordant results is needed.
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Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/patología , Masculino , Estudios Retrospectivos , Manejo de EspecímenesRESUMEN
BACKGROUND: RNA-sequencing-based classifiers can stratify pancreatic ductal adenocarcinoma (PDAC) into prognostically significant subgroups but are not practical for use in clinical workflows. Here, we assess whether histomorphological features may be used as surrogate markers for predicting molecular subgroup and overall survival in PDAC. METHODS: Ninety-six tissue samples from 50 patients with non-resectable PDAC were scored for gland formation, stromal maturity, mucin, necrosis, and neutrophil infiltration. Prognostic PDAC gene expression classifiers were run on all tumors using whole transcriptome sequencing data from the POG trial (NCT02155621). Findings were validated using digital TCGA slides (n = 50). Survival analysis used multivariate Cox proportional-hazards tests and log-rank tests. RESULTS: The combination of low gland formation and low neutrophil infiltration was significantly associated with the poor prognosis PDAC molecular subgroup (basal-like or squamous) and was an independent predictor of shorter overall survival, in both frozen section (n = 47) and formalin-fixed paraffin-embedded (n = 49) tissue samples from POG patients, and in the TCGA samples. This finding held true in the subgroup analysis of primary (n = 17) and metastatic samples (n = 79). The combination of high gland formation and high neutrophils had low sensitivity but high specificity for favorable prognosis subgroups. CONCLUSIONS: The assessment of gland formation and neutrophil infiltration on routine histological sections can aid in prognostication and allow inferences to be made about molecular subtype, which may help guide patient management decisions and contribute to our understanding of heterogeneity in treatment response.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Carcinoma Ductal Pancreático/mortalidad , Neutrófilos/inmunología , Neoplasias Pancreáticas/mortalidad , Biomarcadores de Tumor/genética , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Pronóstico , Tasa de Supervivencia , Neoplasias PancreáticasRESUMEN
CONTEXT.: Serosal involvement (pT4a category) and lymphovascular invasion have prognostic significance in colorectal carcinoma, but are subject to interobserver variation in assessment. OBJECTIVES.: To provide the first large-scale assessment of interobserver variability in pT4a category and lymphovascular invasion reporting in real-world practice and to explore the impact of information from guidelines on variability in reporting these features. DESIGN.: Analysis of 1555 consecutive synoptic reports of colorectal carcinoma was performed using multivariate logistic regression. Interobserver variability before and after the presentation of guideline information was assessed using an image-based survey. RESULTS.: Significant differences in the odds of reporting pT4a versus pT3 category, detecting lymphovascular invasion of any type, and detecting large vessel invasion were identified among hospital sites and for individual pathologists compared with the median pathologist at the same site. Consistent with these results, interobserver agreement was only moderate in the image-based survey regarding T4a staging and lymphovascular invasion (all κ ≤ 0.57). The provision of information from guidelines did not tend to increase interobserver agreement in the survey, though responses in favor of using an elastic stain increased following recommendations for their use. However, when observers were provided with elastic-stained images, interobserver agreement remained only moderate (κ = 0.55). CONCLUSIONS.: Real-world reporting of pT4a category and lymphovascular invasion shows substantial variability at both local and regional levels. Our study underscores the need to address these features in quality initiatives, and provides a novel method through which existing synoptic data can be harnessed to monitor reporting patterns and provide individualized feedback.