Primary pulmonary myxoid sarcoma (PPMS) and thoracic angiomatoid fibrous histiocytoma (AFH) are rare neoplasms with EWSR1 fusions and overlapping morphology. Both tumor types often show epithelial ...membrane antigen expression, but AFH characteristically co-expresses desmin. We encountered a case of PPMS with the unexpected finding of patchy, strong anaplastic lymphoma kinase (ALK) (previously reported in AFH) and synaptophysin expression. We evaluated a cohort of PPMS and thoracic AFH with systematic morphologic comparison and surveyed for aberrant expression of ALK and synaptophysin. Medical records and slides were reviewed for 16 molecularly confirmed cases of PPMS (n=5) and thoracic AFH (n=11). Each case was scored for morphologic characteristics typical of PPMS and/or AFH. ALK, synaptophysin, chromogranin, desmin, and epithelial membrane antigen immunostains were performed on cases with available tissue. AFH and PPMS cases showed similar age at presentation and long-term tumor behavior. Almost all cases of PPMS and AFH had a fibrous pseudocapsule and lymphoid rim. All PPMS had myxoid stroma and reticular growth pattern, but these features were also present in a subset of AFH. Synaptophysin expression was present in 6 of 11 AFH and 1 of 5 PPMS; all tested cases were negative for chromogranin (n=15). One case of AFH and 1 case of PPMS showed focally strong coexpression of synaptophysin and ALK. AFH and PPMS show considerable clinicopathologic overlap. When supportive, the immunohistochemical findings described may aid in diagnosis before molecular confirmation. PPMS and AFH may be morphologic variants of the same clinicopathologic entity, which can show more immunophenotypic variability than previously reported.
In advanced non-small cell lung cancer (NSCLC), small biopsy specimens from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are often the only available material from ...cancer tissue for the analysis of programmed death ligand-1 (PD-L1) expression. We aim to assess the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PD-L1 expression at ≥ 1% and ≥ 50% on EBUS-TBNA samples compared with their corresponding surgically resected tumor.
We retrospectively reviewed all patients who underwent EBUS-TBNA followed by surgical resection of NSCLC between July 2006 and September 2016. Demographic information and periprocedural/surgical data were collected. The archived specimens were retrieved and assessed for PD-L1. A positive PD-L1 stain was defined using two separate cutoff points: ≥ 1% and ≥ 50% of tumor cell positivity. EBUS-TBNA aspirates were compared with the surgically resected specimen to calculate the sensitivity, specificity, PPV, and NPV.
Sixty-one patients were included. For PD-L1 ≥ 1%, the sensitivity, specificity, PPV, and NPV were 72%, 100%, 100%, and 80%, respectively. For PD-L1 ≥ 50%, the sensitivity, specificity, PPV, and NPV were 47%, 93%, 70%, and 84%, respectively. The concordance rates for PD-L1 ≥ 1% and ≥ 50% were 87% and 82%, respectively.
A PD-L1 cutoff of ≥ 1% on EBUS-TBNA has a strong correlation with resected tumor specimen. For PD-L1 ≥ 50%, there is a significant decrease in the sensitivity and PPV of EBUS-TBNA specimen when compared with resected tumor. When analyzing for PD-L1 expression using a cutoff of ≥ 50%, EBUS-TBNA specimens may misclassify the status of PD-L1.
Diffuse alveolar damage (DAD) is a relatively common histopathologic finding at autopsy, particularly in patients dying with ARDS, and can result from a variety of causes. The spectrum of causes and ...associated prognostic implications for DAD diagnosed by surgical lung biopsy are unclear.
We identified 58 consecutive patients with DAD diagnosed by surgical lung biopsy over a 7-year period, January 1996 through December 2002. The presenting clinicoradiologic features, causes, and clinical course of these patients were studied.
The median age was 61 years, 48% were women, and 60% were immunocompromised. Ninety percent of patients fulfilled the criteria for ARDS at the time of surgical lung biopsy. Chest radiography demonstrated bilateral parenchymal infiltrates, while CT revealed predominantly ground-glass and consolidative opacities. Infections were the most common cause of DAD (22%). Other causes were noninfectious pulmonary complications of hematopoietic stem-cell or solid-organ transplantation (17%), connective tissue diseases (16%), acute exacerbation of idiopathic pulmonary fibrosis (12%), drugs (10%), and radiation therapy (2%). Twelve patients (21%) had acute interstitial pneumonia (ie, no identifiable cause or predisposing condition for DAD). Overall hospital mortality was 53%, with the highest mortality (86%) occurring among patients for whom DAD represented acute exacerbation of idiopathic pulmonary fibrosis.
Our study showed that infections and acute interstitial pneumonia are the most common causes of DAD diagnosed by surgical lung biopsy. Hospital mortality rate associated with DAD may vary depending on the underlying cause.
The significance of Complement 4d (C4d) deposition in the diagnosis of antibody-mediated rejection (AMR) in lung allografts is controversial. A potential cause may be the problematic reproducibility. ...We studied the reproducibility of C4d by immunofluorescence (IF) and immunohistochemistry (IHC) in lung allograft transbronchial biopsies (TBBx), correlated C4d by IF with IHC, and compared the results with clinical findings.
TBBx obtained between 2009 and 2012 were stained with C4d by IHC and available corresponding frozen tissue was stained with C4d by IF. Capillary C4d staining was scored as 0, 1+ (<10% of capillaries), 2+ (10% to 50%) or 3+ (>50%). Four lung transplant pathologists independently scored all slides. Serum donor-specific antibodies (DSA) from within 2 months of the TBBx were noted.
Of 228 consecutive TBBx, C4d by IHC (n = 221) and IF (n = 60) revealed agreement of 46.6% (95% CI 40.4% to 53.0%; κ = 0.13) and 81.4% (95% CI 68.7% to 89.7%; κ = 0.18), respectively. Correlations between IF and IHC varied among reviewers (0.10 to 0.36) (agreement 59.7% to 86.8%). Three patients were clinically diagnosed as having AMR or "possible" AMR.
Agreement of IF-based C4d staining in lung allografts appears superior to that of IHC. However, overall agreement for IF and IHC among pathologists is sub-optimal and correlation between IF and IHC is low, although this may be influenced in part by the low variability of the results given the mostly negative biopsies. C4d 3+ may be specific for AMR, although rare. A multidisciplinary approach seems to be the best way to diagnose AMR in lung allograft biopsies.
Genomic technologies present a promising mechanism of resolving the clinical dilemma of distinguishing independent primary tumors from intrapulmonary metastases in NSCLC. We evaluated the utility of ...discordant mapping somatic junctions from chromosomal rearrangements in diagnosing metastatic disease compared to the current standard histologic review.
Mate-pair sequencing was performed on DNA extracted from 76 distinct tumors from 37 cases of multiple lung cancers. Discordant mapping junctions and chromosomal copy levels were assessed for each tumor. Blood-derived DNA was available on 22 of these cases for germline assessments. A lung cancer next-generation sequencing panel was additionally performed on tumor pairs from 17 patients.
Whereas mate-pair sequencing was able to classify lineage in all tumor pairs, histologic review appeared to misclassify lineage in 9 of 33 (27%) same-histology tumor pair comparisons. Based on disagreement between the reviewing pathologists, histopathologic lineage was classified as indeterminate in seven cases. In two cases where pathologists agreed on a metastatic call, no shared junctions were found suggesting independent primaries. Although germline junctions passing algorithmic filters were common, on average less than three were present and all had predictable structures of small focal rearrangements or transposons. Evaluation of shared chromosomal copy changes and driver mutations through a lung cancer next-generation sequencing panel, while informative, were nondefinitive in calling lineage in all cases.
The highly unique nature and prevalence of chromosomal rearrangement in lung cancers provide a useful and definitive technique for calling lineage in multifocal lung cancer.
Malignant pleural mesothelioma is a disease primarily associated with exposure to the carcinogen asbestos. Whereas other carcinogen-related tumors are associated with a high tumor mutation burden, ...mesothelioma is not. We sought to resolve this discrepancy.
We used mate-pair (n = 22), RNA (n = 28), and T cell receptor sequencing along with in silico predictions and immunologic assays to understand how structural variants of chromosomes affect the transcriptome.
We observed that inter- or intrachromosomal rearrangements were present in every specimen and were frequently in a pattern of chromoanagenesis such as chromoplexy or chromothripsis. Transcription of rearrangement-related junctions was predicted to result in many potential neoantigens, some of which were proven to bind patient-specific major histocompatibility complex molecules and to expand intratumoral T cell clones. T cells responsive to these predicted neoantigens were also present in a patient’s circulating T cell repertoire. Analysis of genomic array data from the mesothelioma cohort in The Cancer Genome Atlas suggested that multiple chromothriptic-like events negatively impact survival.
Our findings represent the discovery of potential neoantigen expression driven by structural chromosomal rearrangements. These results may have implications for the development of novel immunotherapeutic strategies and the selection of patients to receive immunotherapies.
Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults, comprise 30% of all carcinoid malignancies, and are defined histologically as typical carcinoid (TC) and atypical ...carcinoid (AC) tumors. The role of specific genomic alterations in the pathogenesis of pulmonary carcinoid tumors remains poorly understood. We sought to identify genomic alterations and pathways that are deregulated in these tumors to find novel therapeutic targets for pulmonary carcinoid tumors.
We performed integrated genomic analysis of carcinoid tumors comprising whole genome and exome sequencing, mRNA expression profiling and SNP genotyping of specimens from normal lung, TC and AC, and small cell lung carcinoma (SCLC) to fully represent the lung neuroendocrine tumor spectrum.
Analysis of sequencing data found recurrent mutations in cancer genes including
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The mutated genes are involved in biological processes including cellular metabolism, cell division cycle, cell death, apoptosis, and immune regulation. The top most significantly mutated genes were
and
Pathway analysis of significantly mutated and cancer driver genes implicated MAPK/ERK and amyloid beta precursor protein (APP) pathways whereas analysis of CNV and gene expression data suggested deregulation of the NF-κB and MAPK/ERK pathways. The mutation signature was predominantly C>T and T>C transitions with a minor contribution of T>G transversions.
This study identified mutated genes affecting cancer relevant pathways and biological processes that could provide opportunities for developing targeted therapies for pulmonary carcinoid tumors.
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The question of withdrawing artificial nutrition and hydration from people in a permanent vegetative state sparks considerable ethical and legal debate. Therefore, understanding the elements that ...influence such a decision is crucial. However, exploring perceptions of artificial nutrition and hydration is methodologically challenging for several reasons. First, because of the emotional state of the professionals and family members, who are facing an extremely distressing situation; second, because this question mirrors representations linked to a deep-rooted fear of dying of hunger and thirst; and third, because of taboos surrounding death. We sought to determine the best method to explore such complex situations in depth. This article aims to assess the relevance of the photo-elicitation interview method to analyze the perceptions and attitudes of health professionals and families of people in a permanent vegetative state regarding artificial nutrition and hydration. The photo-elicitation interview method consists in inserting one or more photographs into a research interview. An original set of 60 photos was built using Google Images and participants were asked to choose photos (10 maximum) and talk about them. The situations of 32 patients were explored in 23 dedicated centers for people in permanent vegetative state across France. In total, 138 interviews were conducted with health professionals and family members. We found that the photo-elicitation interview method 1) was well accepted by the participants and allowed them to express their emotions constructively, 2) fostered narration, reflexivity and introspection, 3) offered a sufficient "unusual angle" to allow participants to go beyond stereotypes and habits of thinking, and 4) can be replicated in other research areas. The use of visual methods currently constitutes an expanding area of research and this study stressed that this is of special interest to enhance research among populations facing end-of-life and ethical issues.
•Non-small cell lung cancer (NSCLC) diagnosed at a younger age have patterns of care, responses to treatment, and outcomes that not entirely clear. Previous reports highlighted features of this ...population, including more advanced stages at diagnosis, characterizing a pattern of more aggressive disease.•Analyzing young patients with stage IV NSCLC in current study, we confirmed that they constitute a group with specific characteristics, like predominance of female, never-smokers, and adenocarcinomas.•Our study also found that responses to treatment in this group with stage-IV NSCLC are different: they benefit more when treated with surgery and targeted therapy. Molecular testing seems to play a critical in this population, where improved survival was identified.•Our study reveals a real-world patient cohort with long-term follow-up and comprehensive clinical data that characterized the treatment and prognosis of young patients with metastatic NSCLC. Testing for targeted therapies is critical and a more aggressive approach to this population needs to be considered.
Non-Small Cell Lung Cancer (NSCLC) diagnosed at a younger age have patterns of care, responses to treatment, and outcomes not entirely clear. A particular feature includes more advanced stages at diagnosis. Our objective was to characterize these young patients with advanced disease and evaluate the impact of targeted therapies.
Analyzing our cohort of 18,252 newly diagnosed NSCLC patients, we defined Young-age versus Norm-age based on the age distribution at the time of diagnosis. Stage-IV patients were investigated on their clinical information and outcomes; deaths were considered lung cancer-related. Primary outcome was overall survival (OS). Multivariate Cox models were built to evaluate independent prognostic factors in comparative age groups.
We found 4,267 patients with stage-IV NSCLC (359 Young-age; 3,908 Norm-age). Young patients had predominance of females (52.6% vs. 43.3%, P = 0.001), never-smokers (43.2% vs. 14.8%, P < 0.001), and adenocarcinoma (73.5% vs. 62.5%, P < 0.001). Mean OS was 21.1 months in the Young and 15.1 months in Norm, respectively (P < 0.001). Young patients were more often treated with surgery (6.7% vs. 5.0%), chemotherapy (53.2% vs. 44.1%), and targeted therapy (10.6% vs. 5.7%). Molecular studies were assessed in patients when the mutation tests became clinically available (93 Young, 875 Norm) and revealed a critical role of targeted therapy in the improved survival of both age groups.
Young patients with stage-IV NSCLC have a specific profile and benefit more when treated with surgery and targeted therapy. Molecular testing is critical in this population, where improved survival was identified. A more aggressive approach to this population needs to be considered.
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