Interobserver Reliability of Programmed Cell Death Ligand-1 Scoring Using the VENTANA PD-L1 (SP263) Assay in NSCLC.

INTRODUCTION: The VENTANA PD-L1 (SP263) Assay is approved for use with anti-programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) therapies in NSCLC and urothelial carcinoma. Here, we investigate interobserver reliability of the SP263 assay, applied to PD-L1 scoring of tumor cells (TCs) in NSCLC. METHODS: Six practicing European pulmonary pathologists independently scored the proportion of TCs expressing PD-L1 (TC score) from 200 archival, commercially sourced, formalin-fixed paraffin-embedded NSCLC resections stained using the SP263 assay. Agreement in scores was analyzed using the intraclass correlation coefficient and concordance in patient's classification using Fleiss' kappa. RESULTS: Results from 172 samples showed strong pair-wise correlations between pathologists (R2 >0.89) for TC scoring with an intraclass correlation coefficient of 0.96. Overall agreement was greater than 90% for TC of 1% and above, and greater than 94% for TCs of at least 25% and at least 50%. Fleiss' kappa showed substantial agreement for TC of 1% and above, and almost perfect agreement for TCs of at least 25% and at least 50%. CONCLUSIONS: Assessment of TC score in NSCLC was highly reproducible using the SP263 assay, building confidence in the accuracy of this assay in selection of patients for anti-PD-1/PD-L1 therapy.

British Thoracic Society quality standards for the investigation and management of pulmonary nodules.

INTRODUCTION: The purpose of the quality standards document is to provide healthcare professionals, commissioners, service providers and patients with a guide to standards of care that should be met for the investigation and management of pulmonary nodules in the UK, together with measurable markers of good practice. METHODS: Development of British Thoracic Society (BTS) Quality Standards follows the BTS process of quality standard production based on the National Institute for Health and Care Excellence process manual for the development of quality standards. RESULTS: 7 quality statements have been developed, each describing a key marker of high-quality, cost-effective care for the investigation and management of pulmonary nodules, and each statement is supported by quality measures that aim to improve the structure, process and outcomes of healthcare. DISCUSSION: BTS Quality Standards for the investigation and management of pulmonary nodules form a key part of the range of supporting materials that the Society produces to assist in the dissemination and implementation of guideline recommendations.

A case of pulmonary placental transmogrification.

Pulmonary placental transmogrification is a rare lung lesion that microscopically resembles placenta with cystic spaces filled with papillary structures. Considered a histological variant of bullous emphysema, only 30 reported cases have been published in the world's literature. We report a rare case of pulmonary placental transmogrification in a 72-year-old man, in whom the clinical presentation of the disease mimicked lung carcinoma. Histopathology of the surgically resected segment showed a complex bulla with squamous metaplasia and placental transmogrification. Whilst rare, pulmonary placental transmogrification must be ruled out in all patients presenting with unilateral bullous emphysema, without known risk factors.

PD-L1 testing for lung cancer in the UK: recognizing the challenges for implementation.

A new approach to the management of non-small-cell lung cancer (NSCLC) has recently emerged that works by manipulating the immune checkpoint controlled by programmed death receptor 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1). Several drugs targeting PD-1 (pembrolizumab and nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved or are in the late stages of development. Inevitably, the introduction of these drugs will put pressure on healthcare systems, and there is a need to stratify patients to identify those who are most likely to benefit from such treatment. There is evidence that responsiveness to PD-1 inhibitors may be predicted by expression of PD-L1 on neoplastic cells. Hence, there is considerable interest in using PD-L1 immunohistochemical staining to guide the use of PD-1-targeted treatments in patients with NSCLC. This article reviews the current knowledge about PD-L1 testing, and identifies current research requirements. Key factors to consider include the source and timing of sample collection, pre-analytical steps (sample tracking, fixation, tissue processing, sectioning, and tissue prioritization), analytical decisions (choice of biomarker assay/kit and automated staining platform, with verification of standardized assays or validation of laboratory-devised techniques, internal and external quality assurance, and audit), and reporting and interpretation of the results. This review addresses the need for integration of PD-L1 immunohistochemistry with other tests as part of locally agreed pathways and protocols. There remain areas of uncertainty, and guidance should be updated regularly as new information becomes available.

Does the Clearance of Inhaled (99m)Tc-Sestamibi Correlate with Multidrug Resistance Protein 1 Expression in the Human Lung?

Purpose To examine the relation between the lung elimination rate of inhaled technetium 99m ((99m)Tc)-sestamibi and immunohistochemical expression of bronchopulmonary multidrug resistance protein 1 (MRP1) and permeability glycoprotein (P-gp) and assess the repeatability of the inhaled (99m)Tc-sestamibi clearance technique. Materials and Methods (99m)Tc-sestamibi is a known substrate for P-gp and MRP1, which are established cellular drug efflux transporters. The elimination rate of (99m)Tc-sestamibi from the lungs after inhalation as an aerosol has been hypothesized to be regulated by expression of these transporters. Institutional ethics committee approval was received for this prospective study. Written informed consent was obtained from all participants. The clearance of inhaled (99m)Tc-sestamibi from the lungs of 13 patients due to undergo surgery for primary lung cancer (five of 13) or spontaneous pneumothorax (eight of 13) was estimated after dynamic imaging of the lungs during a period of 40 minutes. The time taken to clear 50% of inhaled sestamibi (T1/2) was compared with a semiquantitative immunohistochemical assessment (grade 0-3) of MRP1 and P-gp expression in the lung by using parametric and nonparametric tests. The study was repeated in five participants to assess the repeatability of the technique by using a Bland Altman analysis method. Results MRP1 expression was seen in 12 of 13 patients, while P-gp expression was seen in only two. The mean (99m)Tc-sestamibi elimination rate was faster in patients (n = 6) with low levels of MRP1 expression (grade 0-1) and mean T1/2 of 105 minutes ± 20 (standard deviation), compared with those with higher levels of MRP1 expression (grade 2-3, n = 7) and mean T1/2 of 149 minutes ± 28 (P = .008). Bland-Altman analysis revealed excellent agreement between test and retest values. Conclusion Inhaled (99m)Tc-sestamibi clearance study is a repeatable technique demonstrating significant correlation with MRP1 expression in the lungs. (©) RSNA, 2016.

The LungPath study: variation in the diagnostic and staging pathway for patients with lung cancer in England.

The LungPath project investigated differences in lung cancer diagnostic practice by following the diagnostic pathways of 1507 patients from 19 representative English lung cancer centres. We found large variation in the proportion of patients receiving positron emission tomography-CT scan (range 13%-64%) and endobronchial ultrasound (range 2%-31%). There was also wide variation in the proportion of patients with good performance status who had their tumours histologically confirmed (range 61%-100%). The variation is discussed with reference to current national guidelines and implications for patient care.

Microdroplet digital PCR: detection and quantitation of biomarkers in archived tissue and serial plasma samples in patients with lung cancer.

INTRODUCTION: There is much interest in the use of noninvasive biomarkers in the management of lung cancer, particularly with respect to early diagnosis and monitoring the response to intervention. Cell-free tumor DNA in patients with cancer has been shown to hold potential as a noninvasive biomarker, in which the response to treatment may be evaluated using a blood test only. Multiple technologies have been suggested as being appropriate to measure cell-free tumor DNA. Microdroplet digital polymerase chain reaction (mdPCR) has a number of attributes that suggest it may be a useful tool for detecting clinically relevant genetic events. It offers precise and accurate quantitation of mutant alleles, including rare variants. METHODS: We evaluate the performance of mdPCR in the analysis of DNA extracted from reference standards, tumor biopsies, and patient plasma. RESULTS: The potential of mdPCR to detect clinically relevant mutations is demonstrated, in both formalin-fixed paraffin-embedded material and plasma. Furthermore, we show that mdPCR can be used to track changes in peripheral blood biomarkers in response to treatment and to detect the emergence of drug-resistant clones. CONCLUSIONS: MdPCR has potential as a tool to detect and quantify tumor-derived mutational events in cell-free DNA from patients with lung cancer.

Morphological and genetic classification of lung cancer: variation in practice and implications for tailored treatment.

AIMS: Tailored therapy of lung cancer requires high-quality pathology. Tumours must be subtyped accurately and material preserved for genetic analysis upon which treatment is increasingly based. There is a presumption that pathologists have risen to this challenge, but the nature and degree of variation in practice and quality are unknown. METHODS AND RESULTS: We collected detailed information on 1507 consecutive, newly diagnosed patients referred to 19 UK lung cancer units, ranging from district general hospitals to specialist cardiothoracic units. In only four centres were pathologists handling thoracic biopsies enrolled in the thoracic external quality assessment (EQA) scheme. Achievement of a positive diagnosis of malignancy ranged from 53 to 88%. Variation in tumour subtypes was wide, and the proportion of biopsies classified as merely 'non-small-cell lung cancer, not otherwise specified' varied from 3 to 20%, despite almost universal use of immunochemistry. The proportion of tumours tested for epidermal growth factor receptor (EGFR) gene mutation ranged from 12 to 92%. CONCLUSIONS: There is considerable variation in practice among UK pathologists and arguably in the quality of pathology, raising questions about expertise, adherence to guidelines, rigour of EQA and, ultimately, the reliability of the pathology that underpins the management of lung cancer.

EGFR-mutated lung cancer in Li-Fraumeni syndrome.

This is a revised case report of a 52 year old Caucasian female with Li-Fraumeni syndrome with a rare TP53 mutation, who was treated for breast cancer and later developed epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer.

Phase 2 study of sorafenib in malignant mesothelioma previously treated with platinum-containing chemotherapy.

INTRODUCTION: The incidence of mesothelioma is rising. First-line cisplatin and pemetrexed confers a survival benefit, with a median progression-free survival (PFS) of 5.7 months. Sorafenib inhibits tyrosine kinases, including receptors for vascular endothelial growth factor, which are implicated in mesothelioma pathogenesis by preclinical and clinical data. METHODS: Sorafenib, at 400 mg twice daily, was assessed in a single-arm multicenter phase 2 study, using Simon's two-stage design. Eligible patients had received platinum combination chemotherapy earlier. The primary endpoint was PFS at 6 months, with secondary endpoints, including response rate and metabolic response, assessed using fluorodeoxyglucose positron emission tomography. Published reference values for PFS in mesothelioma provide a benchmark for the null hypothesis of 28% progression-free at 6 months, and for moderate or significant clinical activity of 35% or 43% progression-free at 6 months, respectively. RESULTS: Fifty-three patients (72%) were treated. Most had epithelioid histology. Ninety-three percent of patients had a performance status 0 or 1. Treatment was well tolerated with few grade 3 or 4 toxicities. Median PFS was 5.1 months, with 36% of patients being progression-free at 6 months. Nine percent of patients remained on study beyond 1 year. Changes in fluorodeoxyglucose positron emission tomography parameters did not predict clinical outcome. CONCLUSIONS: Sorafenib is well tolerated in patients with mesothelioma after completion of platinum-containing chemotherapy. PFS of sorafenib compares favorably with that reported for other targeted agents, and suggests moderate activity in this disease.

Synchronous ductal carcinoma in situ of the breast and within epithelial inclusions in an ipsilateral sentinel lymph node.

Epithelial inclusions in the axillary lymph nodes are very rare and have even less commonly been reported with either benign or malignant changes. We present a case of synchronous high-grade micropapillary ductal carcinoma in situ arising in the breast and in an epithelial inclusion in an ipsilateral sentinel lymph node. Despite extensive sampling, no focus of invasive carcinoma was identified. This unique case highlights the difficulty in diagnosis of metastatic disease when there is a malignant change in an epithelial inclusion in a sentinel lymph node and highlights the need for very careful histologic assessment of such lesions.

Glomus tumour: a rare differential diagnosis of bronchial obstruction in a smoker.

Tracheo-bronchial glomus tumours are rare, usually benign tumours of modified smooth muscle cells. They commonly present as non-specific respiratory symptoms of cough, dyspnoea or haemoptysis. Generally, glomus tumours are benign, but extension beyond the bronchial wall into surrounding soft tissues has been described. Surgical treatment remains the treatment of choice for tracheo-bronchial glomus tumours. Endobronchial therapy should be considered in patients unfit for surgical excision. We describe a patient with a glomus tumour of the left main bronchus, who presented with mediastinal shift and lung atelectasis, treated by left upper sleeve lobectomy. The resection was complete and the patient was discharged home after 8 days from surgery.

Pleurectomy/decortication is superior to extrapleural pneumonectomy in the multimodality management of patients with malignant pleural mesothelioma.

INTRODUCTION: To compare the outcomes of two different multimodality regimens involving neoadjuvant chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant radiotherapy versus pleurectomy/decortication (P/D), hyperthermic pleural lavage with povidone-iodine, and adjuvant chemotherapy in patients with malignant pleural mesothelioma. METHODS: Nonrandomized prospective study of patients treated by multimodality therapy and operated on between January 2004 and June 2011. Second-line treatments were administered when appropriate. Survival and prognostic factors were analyzed by the Kaplan Meier method, log rank test, and Cox regression analysis. RESULTS: Twenty-five consecutive patients received neoadjuvant chemotherapy, 22 underwent EPP, and 17 received adjuvant radiotherapy. Over the same period, 54 consecutive patients underwent P/D and hyperthermic pleural lavage and received prophylactic radiotherapy and adjuvant chemotherapy. The 30-day mortality rate was 4.5%in the EPP group and nil in the P/D group. Fifteen patients (68%) in the EPP group and 15 (27.7%) in the P/D group experienced complications. There were no differences between the EPP and P/D groups for age, sex, histology, pathologic stage, and nodal status. Trimodality therapy was completed by 68%of the patients in the EPP group and 100%in the P/D group. Survival was significantly better in the P/D group: median survival was 23 months versus 12.8 months, 2-year survival was 49%versus 18.2 %, and 5-year survival was 30.1%versus 9%, respectively (p = 0.004). At multivariate analysis, epithelioid histology, P/D, and completeness of resection were independent prognostic factors. CONCLUSIONS: In our experience, P/D, hyperthermic pleural lavage with povidone-iodine, and adjuvant chemotherapy were superior to neoadjuvant chemotherapy, EPP, and adjuvant radiotherapy.

Induction chemotherapy, extrapleural pneumonectomy, and adjuvant radiotherapy for malignant pleural mesothelioma: experience of Guy's and St Thomas' hospitals.

PURPOSE: The treatment of malignant pleural mesothelioma (MPM) remains controversial. We present a prospective study of patients treated at our institution with neoadjuvant chemotherapy, extrapleural pneumonectomy (EPP), and radical radiotherapy. METHODS: Patients with MPM who were eligible for EPP and multimodality therapy were included in this study. Staging was through computed tomography and positron emission tomography and computed tomography (PET/CT) scanning, video-assisted thoracoscopic surgery (VATS), and mediastinoscopy. Our protocol involved three cycles of cisplatin-based neoadjuvant chemotherapy followed by extrapleural pneumonectomy and adjuvant radiotherapy (54 Gy). All patients were followed up every 3-6 months until death. RESULTS: From March 2004 through October 2008, 25 patients were referred for EPP following neoadjuvant chemotherapy. EPP was performed in all but three patients, who were found to have T4 disease at surgery. Surgical complications included arrhythmias (28%), bronchopleural fistulas (12 %), reoperations for bleeding (8%), acute respiratory distress syndrome (4%), pneumonia (4%), septicemia (4%), vocal cord palsy (4%), and Horner's syndrome (4%). The 30-day mortality was 4%. Adjuvant radiotherapy was administered to 81% of patients after EPP. Radiotherapy toxicities included thrombocytopenia, radiation pneumonitis, pulmonary embolus, radiation hepatitis, herpes zoster, transverse myelitis, and late constrictive pericarditis. Median survival from diagnosis was 12.8 months (95% confidence interval 7.8-17.7 months). One-year survival was 54.5%; 2-year survival was 18.2%. Disease progression occurred in 77.3% of patients. Nodal status (N0 disease versus N1-N2) or histology (epithelioid versus biphasic) had no significant impact on survival. CONCLUSION: Despite recent advances in chemotherapy, surgery, and radiotherapy, survival rates remain low for patients with MPM completing multimodality therapy including EPP.

Risk factors for regional nodal relapse in breast cancer patients with one to three positive axillary nodes.

PURPOSE: In many centers, supraclavicular fossa radiotherapy (SCF RT) is not routinely offered to breast cancer patients with one to three positive lymph nodes. We aimed to identify a subgroup of these patients who are at high risk of supra or infraclavicular fossa relapse (SCFR) such that they can be offered SCFRT at the time of diagnosis to improve long term locoregional control. METHODS AND MATERIALS: We performed a retrospective analysis of the pathological features of 1,065 cases of invasive breast cancer with one to three positive axillary lymph nodes. Patients underwent radical breast conserving surgery or mastectomy. A total of 45% of patients received adjuvant chest wall/breast RT. No patients received adjuvant SCFRT. The primary outcome was SCFR. Secondary outcomes were chest wall/breast recurrence, distant metastasis, all death, and breast-cancer specific death. Kaplan-Meier estimates were used to calculate actuarial event rates and survival functions compared using log-rank tests. Multivariate analyses (MVA) of factors associated with outcome were conducted using Cox proportional hazards models. RESULTS: Median follow-up was 9.7 years. SCFR rate was 9.2%. Median time from primary diagnosis to SCFR was 3.4 years (range, 0.7-14.4 years). SCFR was associated with significantly lower 10-year survival (18% vs. 65%; p < 0.001). Higher grade and number of positive lymph nodes were the most significant predictors of SCFR on MVA (p < 0.001). 10 year SCFR rates were less than 1% in all patients with Grade 1 cancers compared with 30% in those having Grade 3 cancers with three positive lymph nodes. Additional factors associated with SCFR on univariate analysis but not on MVA included larger nodal deposits (p = 0.002) and proportion of positive nodes (p = 0.003). CONCLUSIONS: Breast cancer patients with one to three positive lymph nodes have a heterogenous risk of SCFR. Patients with two to three positive axillary nodes and/or high-grade disease may warrant consideration of SCFRT.

Screening for EGFR and KRAS mutations in endobronchial ultrasound derived transbronchial needle aspirates in non-small cell lung cancer using COLD-PCR.

EGFR mutations correlate with improved clinical outcome whereas KRAS mutations are associated with lack of response to tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). Endobronchial ultrasound (EBUS)-transbronchial needle aspiration (TBNA) is being increasingly used in the management of NSCLC. Co-amplification at lower denaturation temperature (COLD)-polymerase chain reaction (PCR) (COLD-PCR) is a sensitive assay for the detection of genetic mutations in solid tumours. This study assessed the feasibility of using COLD-PCR to screen for EGFR and KRAS mutations in cytology samples obtained by EBUS-TBNA in routine clinical practice. Samples obtained from NSCLC patients undergoing EBUS-TBNA were evaluated according to our standard clinical protocols. DNA extracted from these samples was subjected to COLD-PCR to amplify exons 18-21 of EGFR and exons two and three of KRAS followed by direct sequencing. Mutation analysis was performed in 131 of 132 (99.3%) NSCLC patients (70F/62M) with confirmed lymph node metastases (94/132 (71.2%) adenocarcinoma; 17/132 (12.8%) squamous cell; 2/132 (0.15%) large cell neuroendocrine; 1/132 (0.07%) large cell carcinoma; 18/132 (13.6%) NSCL-not otherwise specified (NOS)). Molecular analysis of all EGFR and KRAS target sequences was achieved in 126 of 132 (95.5%) and 130 of 132 (98.4%) of cases respectively. EGFR mutations were identified in 13 (10.5%) of fully evaluated cases (11 in adenocarcinoma and two in NSCLC-NOS) including two novel mutations. KRAS mutations were identified in 23 (17.5%) of fully analysed patient samples (18 adenocarcinoma and five NSCLC-NOS). We conclude that EBUS-TBNA of lymph nodes infiltrated by NSCLC can provide sufficient tumour material for EGFR and KRAS mutation analysis in most patients, and that COLD-PCR and sequencing is a robust screening assay for EGFR and KRAS mutation analysis in this clinical context.

Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine followed by adjuvant chemotherapy in patients with malignant pleural mesothelioma.

INTRODUCTION: Malignant pleural mesothelioma is a fatal neoplasm related to asbestos exposure. We investigated the effects of pleurectomy/decortication (P/D), hyperthermic pleural lavage with povidone-iodine and adjuvant chemotherapy in patients with malignant pleural mesothelioma. PATIENTS AND METHODS: Observational prospective study of patients referred for multimodality therapy and operated on at our institution between October 2004 and May 2010. Thirty-six selected patients underwent P/D and hyperthermic pleural lavage, prophylactic radiotherapy, and adjuvant chemotherapy. All patients were reviewed at 4 weeks and then 6 monthly in the outpatient clinic, with positron-emission tomography-computed tomography. Second-line treatments were administered when appropriate. RESULTS: Thirty-day mortality was nil. Nine patients experienced postoperative complications: persistent air leak (n = 5, 13.9%), chylothorax requiring surgical intervention (n = 4, 11%), and adult respiratory distress syndrome (n = 1, 3.9%). Fourteen of 36 patients were alive at last follow-up (median follow-up: 33 months, range: 12-63 months). Ten patients were alive with no evidence of disease recurrence, four patients were alive with disease recurrence, and 22 patients had died of disease progression. Overall median survival (Kaplan-Meier) was 24 months (95% confidence interval: 18.5-29.4 months). One-year survival was 91.7%, and 2-year survival was 61%. Patients undergoing complete macroscopical resection (R0-R1) had a significantly better survival than those undergoing an incomplete macroscopical resection (R2) (median overall survival: 32 months versus 18.9 months, p = 0.012). CONCLUSION: In our experience, P/D combined with hyperthermic pleural lavage with povidone-iodine and adjuvant chemotherapy is a well-tolerated multimodality treatment associated with low morbidity and mortality. This multimodality treatment compares favorably with classical trimodality regimens involving chemotherapy, extrapleural pneumonectomy, and adjuvant radiotherapy, in our experience. Study limitations include small sample size, nonrandomization, and patient selection bias.

Role of integrated 18-fluorodeoxyglucose position emission tomography-computed tomography in patients surveillance after multimodality therapy of malignant pleural mesothelioma.

INTRODUCTION: To investigate the role of 18-fluorodeoxyglucose positron emission tomography-computed tomography (18-FDG-PET-CT) in the surveillance of patients after multimodality treatment of malignant pleural mesothelioma. METHODS: Retrospective study of patients who had chemotherapy, radical surgery, extrapleural pneumonectomy or pleurectomy/decortication, and radiotherapy for mesothelioma in our unit. PET-CT was performed after multimodality therapy to evaluate response to treatment or when disease recurrence was suspected. 18-FDG-PET scans were acquired from skull base to upper thigh with low-dose CT scans for attenuation correction and image fusion. RESULTS: Forty-four patients had extrapleural pneumonectomy (21) or pleurectomy/decortication (23) between January 2004 and July 2008. Twenty-five patients had PET-CT performed after multimodality therapy. This was performed in 11 patients in whom disease recurrence was suspected at a median of 9 (range, 6-16) months after treatment. PET-CT correctly diagnosed recurrent disease in eight patients and missed microscopic recurrence in one. Surveillance PET-CT was performed in 14 asymptomatic patients at a median of 11 (range, 7-13) months after treatment. It showed unsuspected recurrences in four patients. The standard uptake value max of recurrent mesothelioma was 8.9 +/- 4.0 (4-18.4). PET-CT had a sensitivity of 94%, a specificity of 100%, and the positive and negative predictive values of 100 and 88%, respectively. CONCLUSIONS: 18-FDG-PET-CT is useful in diagnosing disease recurrence after multimodality therapy for malignant pleural mesothelioma. We propose a prospective study to fully assess its value in this group of patients.