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Distinguishing mesothelioma from non-small cell lung carcinoma often requires a battery of immunohistochemical stains, as many traditional markers used in mesothelioma lack sufficient specificity to allow them to be used alone. A recent large-scale TMA screen identified uroplakin-IIIb (UpIIIb; clone MSVA-736M) as a potentially specific marker for mesothelioma. We examined the performance of this antibody using tissue microarrays containing a panel of 48 epithelioid mesotheliomas, 26 sarcomatoid mesotheliomas, and 144 non-small cell lung carcinomas (NSCLCs). Here we show that UpIIIb has good sensitivity (37/47 evaluable cases positive, 79%) and excellent specificity for distinguishing epithelioid mesothelioma from NSCLC (0/140 evaluable cases positive). UPIIIb sensitivity for epithelioid mesotheliomas was only slightly inferior to the established highly specific mesothelioma marker HEG1 (41/46 evaluable cases positive on the same TMA, 89%). However, UpIIIb did not stain any sarcomatoid mesotheliomas (0/24 evaluable cases positive). We also found that UpIIIb stained a proportion of high-grade serous ovarian carcinomas, a perennial diagnostic confounder in the context of mesotheliomas. Taken together, our data suggest that UpIIIb can be used as a highly specific and sensitive mesothelial marker when the diagnostic question is epithelioid mesothelioma versus NSCLC; in particular, UpIIIb staining will pick up some number of epithelioid mesotheliomas that are HEG1 negative. Since UpIIIb is known to stain some proportion of urothelial carcinomas as well as gynecologic and a few pancreatic tumors, it should be used with caution in the peritoneal cavity or when the differential diagnosis includes carcinomas from these locations.
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Carcinoma Pulmonar de Células não Pequenas , Carcinoma , Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Feminino , Humanos , Imuno-Histoquímica , Biomarcadores Tumorais , Mesotelioma/diagnóstico , Mesotelioma/patologia , Mesotelioma Maligno/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Carcinoma/diagnóstico , Uroplaquinas , Diagnóstico DiferencialRESUMO
Large cell neuroendocrine carcinoma of the lung (LCNEC) is currently classified as a rare lung cancer subtype, but given the high incidence of lung cancer, the overall number of cases is considerable. The pathologic diagnosis of LCNEC is mainly based on the microscopic appearance of the tumor cells, the mitotic rate, the amount of intra-tumoral necrosis, and the presence of positive neuroendocrine markers identified by immunohistochemistry. Recently, a subdivision into two main categories was proposed based on mutation signatures involving the RB1, TP53, KRAS, and STK11/LKB1 genes, into SCLC-like (small cell lung cancer-like) and NSCLC-like (non-small cell lung cancer-like) LCNEC. In terms of treatment, surgery is still the best option for resectable, stage I-IIIA cases. Chemotherapy and radiotherapy have conflicting evidence. Etoposide/platinum remains the standard chemotherapy regimen. However, based on the newly proposed LCNEC subtypes, some retrospective series report better outcomes using a pathology-driven chemotherapy approach. Encouraging outcomes have also been reported for immunotherapy and targeted therapy, but the real impact of these strategies is still being determined in the absence of adequate prospective clinical trials. The current paper scrutinized the epidemiology, reviewed the reliability of pathologic diagnosis, discussed the need for molecular subtyping, and reviewed the heterogeneity of treatment algorithms in LCNEC.
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Carcinoma Neuroendócrino , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Estudos Prospectivos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/terapia , PulmãoRESUMO
Small-cell lung cancer (SCLC) is an aggressive, neuroendocrine tumour with high relapse rates, and significant morbidity and mortality. Apart from advances in radiation therapy, progress in the systemic treatment of SCLC had been stagnant for over three decades despite multiple attempts to develop alternative therapeutic options that could improve responses and survival. Recent promising developments in first-line and subsequent therapeutic approaches prompted a Canadian Expert Panel to convene to review evidence, discuss practice patterns, and reach a consensus on the treatment of extensive-stage SCLC (ES-SCLC). The literature search included guidelines, systematic reviews, and randomized controlled trials. Regular meetings were held from September 2022 to March 2023 to discuss the available evidence to propose and agree upon specific recommendations. The panel addressed biomarkers and histological features that distinguish SCLC from non-SCLC and other neuroendocrine tumours. Evidence for initial and subsequent systemic therapies was reviewed with consideration for patient performance status, comorbidities, and the involvement and function of other organs. The resulting consensus recommendations herein will help clarify evidence-based management of ES-SCLC in routine practice, help clinician decision-making, and facilitate the best patient outcomes.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Canadá , Terapia Combinada , Consenso , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológicoRESUMO
Non-small cell lung cancer (NSCLC) has historically been associated with a poor prognosis and low 5-year survival, but the use of targeted therapies in NSCLC has improved patient outcomes over the past 10 years. The pace of development of new targeted therapies is accelerating, with the associated need for molecular testing of new targetable alterations. As the complexity of biomarker testing in NSCLC increases, there is a need for guidance on how to manage the fluid standard-of-care in NSCLC, identify pragmatic molecular testing requirements, and optimize result reporting. An expert multidisciplinary working group with representation from medical oncology, pathology, and clinical genetics convened via virtual meetings to create consensus recommendations for testing of new targetable alterations in NSCLC. The importance of accurate and timely testing of all targetable alterations to optimize disease management using targeted therapies was emphasized by the working group. Therefore, the panel of experts recommends that all targetable alterations be tested reflexively at NSCLC diagnosis as part of a comprehensive panel, using methods that can detect all relevant targetable alterations. In addition, comprehensive biomarker testing should be performed at the request of the treating clinician upon development of resistance to targeted therapy. The expert multidisciplinary working group also made recommendations for reporting to improve clarity and ease of interpretation of results by treating clinicians and to accommodate the rapid evolution in clinical actionability of these alterations. Molecular testing of all targetable alterations in NSCLC is the key for treatment decision-making and access to new therapies. These consensus recommendations are intended as a guide to further optimize molecular testing of new targetable alterations.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Consenso , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologiaRESUMO
We report a rare case of stage IV pulmonary combined large-cell neuroendocrine carcinoma (LCNEC) and adenocarcinoma (ACA), both demonstrating anaplastic lymphoma kinase (ALK) rearrangement by IHC and FISH. This 61-year-old lifelong nonsmoking Asian woman presented with a cough, and after diagnosis and surgical treatment, completed four cycles of adjuvant cisplatin and etoposide chemotherapy. She subsequently developed recurrence with bony metastases of exclusively ALK-positive LCNEC. Alectinib was started, and the patient experienced a partial response.
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Adenocarcinoma de Pulmão , Carcinoma Neuroendócrino , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Quinase do Linfoma Anaplásico , Carbazóis , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Piperidinas , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
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/análise , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas , Processamento de Imagem Assistida por Computador/métodos , Neoplasias Pulmonares , Software , HumanosRESUMO
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 de Transdução de Sinal/análise , Proteínas Reguladoras de Apoptose/análise , Biomarcadores Tumorais/análise , Mesotelioma Maligno/diagnóstico , Fatores de Transcrição SOXD/análise , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Diagnóstico Diferencial , Humanos , Neoplasias Pulmonares/diagnóstico , Sensibilidade e EspecificidadeRESUMO
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 Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/patologia , Masculino , Estudos Retrospectivos , Manejo de EspécimesRESUMO
PD-L1 expression in non-small cell lung cancer (NSCLC) is predictive of response to treatment with PD-1 and PD-L1 inhibitors. Different inhibitors have been developed with different PD-L1 assays, which use different PD-1 antibody clones on different immunohistochemistry platforms. Depending on instrument and reagent availability, laboratory-developed tests with cross-platform use of PD-L1 antibodies may have practical benefits over commercial assays. The 22C3 pharmDx Assay (referred to as 22C3 DAKO), the VENTANA PD-L1 SP263 Assay (referred to as SP263 VENTANA) and a lab-developed test using the 22C3 antibody on the VENTANA BenchMark ULTRA IHC/ISH system (referred to as 22C3 VENTANA) were performed on whole sections of 85 NSCLC surgical resections. All sections were independently scored by three pathologists using tumor proportion scores. Correlation coefficients for continuous scores in pairwise comparisons between assays ranged from 0.976 to 0.978. When using a 1% positivity threshold (dichotomous scores), the 22C3 DAKO assay and 22C3 VENTANA assays showed the greatest agreement (93% agreement, κ = 0.86, 95% CI 0.75-0.97), and the 22C3 DAKO and SP263 VENTANA assays tended to show slightly less agreement (84% agreement, κ = 0.66, 95% CI 0.50-0.82). When using a 50% positivity threshold (dichotomous scores), all pairwise comparisons showed similar agreement (96-99% agreement, κ = 0.89-0.97). Overall, there was no significant difference between assays at 1% or 50% thresholds (P = .77). These data are consistent with potential interchangeability of these assays, which may widen the scope of PD-L1 assays available to laboratories and reduce logistical barriers to testing.
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Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Laboratórios/estatística & dados numéricos , Neoplasias Pulmonares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imuno-Histoquímica/métodos , Indicadores e Reagentes/provisão & distribuição , Laboratórios/provisão & distribuição , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Patologistas , Valor Preditivo dos TestesRESUMO
There have been 4 reported cases of squamous cell carcinoma (SCC) of the neovagina in transgender women. In this report, we present another case of neovaginal SCC in a transgender woman, which was HPV-related, with lung metastasis as the initial presentation, and which was also complicated by her previous history of metastatic renal cell carcinoma. This unique case highlights the diagnostic challenges in these unusual scenarios. Through this report, we hope to address the benefits of multidisciplinary tumor board rounds, provision of detailed clinical information, and familiarization of the transgender anatomy within the pelvis in this group of patients. We also propose that transgender women undergo a continuous annual follow-up after postoperative follow-up is completed.
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BACKGROUND: Transbronchial needle aspiration (TBNA) of peripheral lung nodules can be difficult with conventional devices due to their limited flexibility. A promising new technology for accessing these lesions is the PeriView FLEX TBNA device, which has a flexible spiral-grooved needle. The present study reports the unique cytologic features, diagnostic value, and potential pitfalls of PeriView FLEX TBNA specimens. METHODS: This study retrospectively evaluates 113 consecutive cases of lung nodules sampled using the PeriView FLEX device with radial endobronchial ultrasound guidance. RESULTS: PeriView FLEX specimens were satisfactory for evaluation in 111 of 113 cases (98%). A diagnosis of malignancy was made on 64 specimens (57%), with 100% specificity and 70% sensitivity for malignancy. In 4 cases, the PeriView FLEX sample was the only specimen from bronchoscopy that was diagnostic of malignancy. Of the 64 PeriView FLEX specimens with malignant cells, 58 (91%) were adequate for immunohistochemistry and 44 (69%) were adequate for molecular genetic testing. Potential pitfalls were largely ameliorated through education regarding the unique features of PeriView FLEX samples, such as the expected abundance of anthracotic pigment and the paucity of lymphocytes. CONCLUSIONS: TBNA using the PeriView FLEX device to sample pulmonary nodules contributed to the diagnostic value of bronchoscopy and tended to provide sufficient tissue for ancillary studies. Many of the possible pitfalls may be avoided through consideration of the unique cytologic features associated with this novel sampling method.
Assuntos
Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Neoplasias Pulmonares/diagnóstico , Nódulos Pulmonares Múltiplos/diagnóstico , Nódulo Pulmonar Solitário/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Prognóstico , Estudos Retrospectivos , Nódulo Pulmonar Solitário/diagnóstico por imagemRESUMO
AIMS: Accurate assessment of programmed death-ligand 1 (PD-L1) levels in non-small cell lung carcinoma (NSCLC) samples is complicated by intratumoral heterogeneity. We aimed to: (i) establish whether intratumoral PD-L1 variation is associated with differences in local histotype; (ii) identify histotypes associated with a tendency for there to be higher or lower PD-L1 scores; and (iii) estimate the frequency of clinically significant discordance in PD-L1 levels between intratumoral histotype areas. METHODS AND RESULTS: We reviewed 166 NSCLC resection specimens clinically tested for PD-L1 with the 22C3 pharmDx assay. Multiple histotypes were present in 55% (68/123) of non-mucinous adenocarcinoma samples. Solid histotypes had significantly higher PD-L1 levels than other histotypes, both when samples were grouped by predominant histotype, and when histotype areas within a tumour were compared (P < 0.02). Lepidic areas had significantly lower PD-L1 levels than other histotype areas within the same tumour (P < 0.02). Discordance between intratumoral histotype areas at a clinically relevant threshold (PD-L1 tumour proportion score of 1% or 50%) was present in 32% (22/68) of non-mucinous adenocarcinoma specimens with multiple histotype areas. The lepidic histotype was most frequently involved in discordance. CONCLUSIONS: Intratumoral heterogeneity in PD-L1 is associated with variation in histotype. Over-representation of solid areas may increase the PD-L1 score assigned to a tumour, whereas over-representation of lepidic areas may decrease the PD-L1 score. Evaluation of how histotype representation impacts on the predictive value of PD-L1 testing is warranted.
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Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/classificação , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/classificação , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
OBJECTIVES: The FDA approved PD-L1 tests for anti-PD-L1 immunotherapy are for surgical or histology specimens. It is not clear if cytology specimens could be used for PD-L1 testing to guide immunotherapy. In this study, we assess the suitability of EBUS-FNA cytology specimens for the testing of PD-L1. MATERIALS AND METHODS: Consecutive patients with Non-small cell lung cancer (NSCLC) underwent EBUS procedure between January 1, 2017 and March 31, 2018 for PD-L1 testing were included. The cell blocks of EBUS-FNA cytology specimens were used for PD-L1 testing using Dako 22C3 phamDx antibody according to the Dako protocol. PD-L1 protein expression in tumor cells is determined by using Tumor Proportion Score (TPS). RESULTS AND CONCLUSION: Of the 265 EBUS-FNA specimens from 262 patients sent for testing, 230 (86.8%) were adequate for PD-L1 testing. Of the 34 NSCLC patients with both histology and EBUS-FNA cytology specimens tested for PD-L1, the results from different specimen types had a concordance of 91.3%. The PD-L1 results from 16 paired specimens from the same anatomic site had 100% agreement. The rates of PD-L1 TPSâ¯≥â¯50% were significantly higher in the metastatic tumors in the lymph nodes than in the lung primary lesions. Therefore, EBUS-FNA cytology specimen is suitable for PD-L1 testing in patients with advanced NSCLC. The metastatic tumors in mediastinal lymph nodes appear to have higher PD-L1 expression than primary lesions.
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Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Biópsia por Agulha Fina , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Biópsia Guiada por Imagem , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Adulto , Idoso , Antígeno B7-H1/genética , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , UltrassonografiaRESUMO
SOX10 immunohistochemistry is used to identify tumors of neural crest origin, including melanocytic neoplasms. SOX10 expression has also been identified in myoepithelial cells of the breast and in a subset of invasive mammary carcinomas. In order to characterize SOX10 expression in ductal carcinomas of the breast, the aim of this study was to characterize the SOX10 in invasive ductal carcinomas according to molecular subtype, DCIS, and benign breast tissue. Forty cases of invasive ductal carcinoma of the breast were retrieved, with ten cases with immunohistochemical profile compatible with luminal A-like, luminal B-HER2-positive, non-luminal HER2-positive, and triple-negative subtypes. Whole tissue sections from each case were stained with SOX10. Six (60%) of ten triple-negative tumors were SOX10+ compared with 1 (3%) of 30 carcinomas of other molecular subtypes. All but one of the positive tumors showed at least moderate expression in at least 40% of tumor cells. All seven cases SOX10+ carcinomas were grade 3 tumors. Of the 13 cases with DCIS available for assessment, one (8%) showed positive SOX10 expression (a case associated with triple-negative carcinoma). Twenty-two cases contained normal breast tissue that showed SOX10 expression in both myoepithelial and luminal cells, predominantly patchy with variable intensity. SOX10 showed incomplete myoepithelial staining compared to other myoepithelial markers. In conclusion, SOX10 IHC cannot reliably differentiate between high-grade triple-negative carcinomas, melanomas, and myoepithelial tumors in the breast. SOX10 is not as robust a myoepithelial marker compared with other established markers.
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Neoplasias da Mama/patologia , Mama/patologia , Carcinoma Ductal de Mama/patologia , Fatores de Transcrição SOXE/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Células Epiteliais/patologia , Humanos , Imuno-Histoquímica , Melanoma/patologiaRESUMO
The Personalized Onco-Genomics (POG) program at BC Cancer integrates whole-genome (DNA) and RNA sequencing into practice for metastatic malignancies. We examined the subgroup of patients with metastatic non-small-cell lung cancer (NSCLC) and report the prevalence of actionable targets, treatments, and outcomes. We identified patients who were enrolled in the POG program between 2012 and 2016 who had a tumor biopsy and blood samples with comprehensive DNA (80×, 40× normal) and RNA sequencing followed by in-depth bioinformatics to identify potential cancer drivers and actionable targets. In NSCLC cases, we compared the progression-free survival (PFS) of "POG-informed therapies" with the PFS of the last regimen prior to POG (PFS ratio). In 29 NSCLC cases, 11 were male (38%), the median age was 60.2 yr (range: 39.4-72.6), and histologies included were adenocarcinoma (93%) and squamous cell carcinoma (7%). Potential molecular targets (i.e., cancer drivers including TP53 mutations) were identified in 26 (90%), and 21 (72%) had actionable targets. Therapies based on standard-of-care mutation analysis, such as EGFR mutations, were not considered POG-informed therapies. Thirteen received POG-informed therapies, of which three had no therapy before POG; therefore a comparator PFS could not be obtained. Of 10 patients with POG-informed therapy, median PFS ratio was 0.94 (IQR 0.2-3.4). Three (30%) had a PFS ratio ≥1.3, and three (30%) had a PFS ratio ≥0.8 and <1.3. In this small cohort of NSCLC, 30% demonstrated longer PFS with POG-informed therapies. Larger studies will help clarify the role of whole-genome analysis in clinical practice.
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Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Mutação , Adenocarcinoma/diagnóstico , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Sequenciamento Completo do GenomaRESUMO
Metastatic tumors to the breast are rare but constitute a major diagnostic dilemma. Of these, non-mammary carcinomatous metastases to the breast are particularly challenging and, without a clinical history, may be extremely difficult to distinguish from primary breast carcinoma (PBC). We specifically studied metastatic tumors of pulmonary origin, as the lung is one of the major primary sites for carcinomatous metastasis to breast. Sixteen metastatic lung tumors to the breast were identified in our archives between 1996 and 2017 including 12 non-small cell lung carcinomas (NSCLC), one large-cell neuroendocrine, one atypical carcinoid, and two small-cell carcinomas. Adenocarcinoma was the most frequent amongst the NSCLCs (11/14). We retrieved the clinical information of these cases and reviewed the pathological characteristics to provide practical tools for pathologists to aid in their identification. Even in the absence of a clinical history of lung cancer, metastatic pulmonary adenocarcinoma to the breast should be considered in at least one of the following scenarios: (1) single or multiple well-circumscribed lesions of the breast that lack an in situ component and that are accompanied by distant metastases but negative axillary lymph nodes, (2) breast tumors that are triple negative yet not high-grade, or (3) breast tumors presenting as stage 4 disease and/or having an unusually aggressive clinical course on standard breast therapy. Accurate and timely diagnosis of these tumors is mandatory because of treatment and prognostic implications.
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Neoplasias da Mama/secundário , Carcinoma Pulmonar de Células não Pequenas/secundário , Neoplasias Pulmonares/patologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Lung cancer risk prediction models have the potential to make programs more affordable; however, the economic evidence is limited. METHODS: Participants in the National Lung Cancer Screening Trial (NLST) were retrospectively identified with the risk prediction tool developed from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. The high-risk subgroup was assessed for lung cancer incidence and demographic characteristics compared with those in the low-risk subgroup and the Pan-Canadian Early Detection of Lung Cancer Study (PanCan), which is an observational study that was high-risk-selected in Canada. A comparison of high-risk screening versus standard care was made with a decision-analytic model using data from the NLST with Canadian cost data from screening and treatment in the PanCan study. Probabilistic and deterministic sensitivity analyses were undertaken to assess uncertainty and identify drivers of program efficiency. RESULTS: Use of the risk prediction tool developed from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial with a threshold set at 2% over 6 years would have reduced the number of individuals who needed to be screened in the NLST by 81%. High-risk screening participants in the NLST had more adverse demographic characteristics than their counterparts in the PanCan study. High-risk screening would cost $20,724 (in 2015 Canadian dollars) per quality-adjusted life-year gained and would be considered cost-effective at a willingness-to-pay threshold of $100,000 in Canadian dollars per quality-adjusted life-year gained with a probability of 0.62. Cost-effectiveness was driven primarily by non-lung cancer outcomes. Higher noncurative drug costs or current costs for immunotherapy and targeted therapies in the United States would render lung cancer screening a cost-saving intervention. CONCLUSIONS: Non-lung cancer outcomes drive screening efficiency in diverse, tobacco-exposed populations. Use of risk selection can reduce the budget impact, and screening may even offer cost savings if noncurative treatment costs continue to rise.
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Detecção Precoce de Câncer/economia , Neoplasias Pulmonares/economia , Programas de Rastreamento/economia , Idoso , Análise Custo-Benefício , Feminino , Humanos , Incidência , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Currently the most sensitive method for localizing lung cancers in central airways is autofluorescence bronchoscopy (AFB) in combination with white light bronchoscopy (WLB). The diagnostic accuracy of WLB + AFB for high grade dysplasia (HGD) and carcinoma in situ is variable depending on physician's experience. When WLB + AFB are operated at high diagnostic sensitivity, the associated diagnostic specificity is low. Raman spectroscopy probes molecular vibrations and gives highly specific, fingerprint-like spectral features and has high accuracy for tissue pathology classification. In this study we present the use of a real-time endoscopy Raman spectroscopy system to improve the specificity. A spectrum is acquired within 1 second and clinical data are obtained from 280 tissue sites (72 HGDs/malignant lesions, 208 benign lesions/normal sites) in 80 patients. Using multivariate analyses and waveband selection methods on the Raman spectra, we have demonstrated that HGD and malignant lung lesions can be detected with high sensitivity (90%) and good specificity (65%).
Assuntos
Detecção Precoce de Câncer/métodos , Neoplasias Pulmonares/diagnóstico , Análise Espectral Raman , Broncoscopia , Humanos , Pulmão , Sensibilidade e EspecificidadeRESUMO
Inhibitors of the programmed cell death 1 (PD-1) signaling axis have recently demonstrated efficacy and are rapidly being incorporated into the treatment of non-small cell lung cancers (NSCLCs). Despite clear benefits to certain patients, the association of these responses with a predictive biomarker remains uncertain. Several different biomarkers have been proposed, with differing results and conclusions. This study compares multiple methods of biomarker testing for treatment of NSCLCs with PD1-axis inhibitors. Tissue microarrays of matched primary and metastatic NSCLCs were used to compare four different PD-1 ligand (PD-L1) IHC techniques, as well as RNA ISH. Additional cases with whole genome and transcriptome data were assessed for molecular correlates of PD-L1 overexpression. Eighty cases were included in the IHC study. Multiple IHC methodologies showed a high rate of agreement (Kappa = 0.67). When calibrated to RNA expression, agreement improved significantly (Kappa = 0.90, p=0.0049). PD-L1 status of primary and metastatic tumors was discordant in 17 (22%) cases. This study suggests that different IHC methodologies for PD-L1 assessment provide slightly different results. There is significant discordance between the PD-L1 status of primary tumors and lymph node metastases. RNA ISH may be a useful adjunct to complement PD-L1 IHC testing.