Large Cell Carcinoma Research Articles

PD-L1 Expression in Non-Small-Cell Lung Cancer Including Various Adenocarcinoma Subtypes.

Purpose: Knowledge regarding programmed death-ligand 1 (PD-L1) expression in lung cancer is limited. We aim to clarify PD-L1-positive expression in non-small-cell lung cancer (NSCLC), including adenocarcinoma subtypes.Methods: In all, 90 NSCLC specimens containing various adenocarcinoma subtypes, in addition to squamous cell carcinoma and large-cell carcinoma were selected. PD-L1 was immunohistochemically stained by murine monoclonal antibody clone 22C3.Results: When PD-L1-positive expression was defined by tumor proportion score (TPS) ≥1%, the positive cases were 0/11 in adenocarcinoma in situ, 0/12 in minimally invasive adenocarcinoma, 1/10 in lepidic predominant adenocarcinoma, 1/13 in papillary predominant adenocarcinoma, 8/14 in acinar predominant adenocarcinoma, 6/11 in solid predominant adenocarcinoma, 0/3 in micropapillary predominant adenocarcinoma, 0/4 in invasive mucinous adenocarcinoma, 4/9 in squamous cell carcinoma, and 2/3 in large-cell carcinoma. PD-L1 positivity was higher in males, smokers, advanced pathologic stages, positive vessel invasion, and positive lymphatic invasion. Postoperative survival analysis revealed that PD-L1-positive expression was a significantly worse prognostic factor in univariate analysis for recurrence-free survival (RFS).Conclusion: PD-L1-positive tumors were frequent in acinar predominant adenocarcinoma and solid predominant adenocarcinoma than other adenocarcinoma subtypes. PD-L1 expression seemed to increase according to pathologic tumor progression, suggesting a worse postoperative prognosis in NSCLC patients.

MTE02.01 Update on WHO Classification and Staging of Lung Cancer

The most significant changes in the 2015 WHO classification of the lung tumors include classification criteria for small biopsy and cytology specimens, use of immunohistochemistry, integration of molecular testing, adoption of the IASLC/ATS/ERS adenocarcinoma classification and a strict definition of large cell carcinoma limited to surgical resection specimens only. 1,2 Tumors that show unequivocal morphology of adenocarcinoma or squamous cell carcinoma on a small specimen should be diagnosed without immunohistochemistry. Immunohistochemical work up of poorly differentiated tumors should be limited to TTF-1and p40/p63, while neuroendocrine markers should be used only if morphologically indicated. This approach should reduce the diagnosis of NSCC, NOS to less than 5% and preserve tissue for molecular testing. 1,2 Major changes in the adenocarcinoma classification for resected specimens include addition of adenocarcinoma in situ (AIS) to preinvasive group that already includes atypical adenomatous hyperplasia. Minimally invasive adenocarcinoma (MIA) defined as a solitary, lepidic predominant adenocarcinoma presenting measuring in gross size 3 cm or less and with invasion of ≤ 5 mm was added as a new category. These tumors are also recognized by the 8th edition of the AJCC staging of lung cancer and include Tis(adenocarcinoma) and T1a-mi. T stage of non-mucinous lepidic predominant adenocarcinomas is based on the microscopic size of invasion, but gross size should be recorded in the pathology reports. Multifocal ground glass opacities/lung nodules most frequently present as MIAs and should be classified by the T category of the lesion with the highest T along with the number of lesions (#) or simply (m) for multiple indicated in parentheses, and with a single N and M category that applies to all of the multiple tumor foci. This approach should be applied to grossly or microscopically identified lesions occurring in the same or in different ipsilateral or contralateral lobes.3 For non-lepidic adenocarcinoma T stage is determined by gross size in 1.0 cm increments as each size subgroup carries prognostic significance. Former mucinous BAC are reclassified as invasive mucinous adenocarcinoma, excluding tumors that meet criteria for AIS or MIA. Signet ring and clear cell carcinomas are considered to represent cytologic variants rather than specific subtypes. Invasive adenocarcinomas should be subtyped by semi-quantitatively estimating the percentage of the various subtypes in 5% increments. 1,2 Reproducibility for lung adenocarcinoma predominant subtypes among pulmonary pathologists was good to moderate (κ-values 0.44 to 0.72).4 For untrained pathologists, κ-values were lower ranging from 0.38 to 0.47, but these improved after a training session and particularly for individual reviewer. 5 The 2015 WHO classification defines large cell carcinomas based on morphology, as carcinomas without morphologic evidence of glandular, squamous or neuroendocrine differentiation, and also based on null immunophenotype and genotype. 1This change in definition reflect what was already happening in the pathology practice. According to National Cancer Institute (NCI) Surveillance Epidemiology and End Results registry the diagnosis of large cell carcinoma started to decline about the time that TTF-1 was introduced into clinical diagnosis. 6 Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: International Agency for Research on Cancer, 2015. Travis WD. Et al. The 2015 World Health Organization Classification of Lung Tumors Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol 2015; 10 (9); 1243-1260 Frank C. Detterbeck, MD et al. The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification . J Thorac Oncol 2016;11(5): 639-650 Thunnissen E, Beasley MB, Borczuk AC, et al. Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study. Mod Pathol 2012;25:1574–1583. Warth A, Cortis J, Fink L, et al.; Pulmonary Pathology Working Group of the German Society of Pathology. Training increases concordance in classifying pulmonary adenocarcinomas according to the novel IASLC/ ATS/ERS classification. Virchows Arch 2012;461:185–193. Lewis DR, Check DP, Caporaso NE, Travis WD, Devesa SS. US lung cancer trends by histologic type. Cancer 2014;120:2883–2892. lung carcinoma- WHO classification- staging

903P - Neuroendocrine carcinoma of the urinary bladder: A large analysis of the French GETUG consortium

Background: Neuroendocrine carcinoma of the urinary bladder (NCUB) is a rare malignancy, accounting for <1% of bladder cancers. Despite high sensitivity to platinum-based chemotherapy (CT), prognosis remains poor. Methods: We retrospectively reviewed patients treated for NCUB in 18 French institutions to determine clinical/biologic characteristics, treatment efficacy and outcomes. Patient characteristics, treatment, follow-up and histological data were obtained from medical records. Tissue samples were pooled for further biological analyses. Results: From 1992 to 2017, we reviewed 234 NCUB cases (84% male, age 31–93 [median 67] years, ECOG PS 0–3 [median 1]). Small cell carcinoma was found in 47% of patients and large cell carcinoma in 9%; urothelial carcinoma was present in 51% of patients. Hematuria (71%) and pain (19%) were the main symptoms. Main metastatic sites at diagnosis of metastatic disease were lymph node (76%), liver (42%), bone (42%), pelvic recurrence (33%), lung (19%) or brain (12%). Of 230 patients evaluable for staging at diagnosis, 168 had stage I–III disease: stage I (3%), II (20%), III (34%), not evaluable (16%). They were treated with neoadjuvant CT (49%; mainly based on a platinum-based agent + etoposide [85%]), surgery (74%), radiotherapy (24%), and/or adjuvant CT (24%). Ninety-nine patients (59%) had metastatic recurrence. Median time to relapse was 4 months, disease-free survival was 14 months (95% confidence interval [CI] 12–18]), and median overall survival (mOS) was 28 months (95% CI 20–32). Of 62 patients (27%) with metastases at diagnosis, first-line CT was based on platinum + etoposide (81%), platinum + other drug (15%), or taxanes (4%). For these patients, median progression-free survival (mPFS) was 7 months (95% CI 4–9). Only 28 patients had second-line CT with mPFS of 5.2 months and mOS of 11 months (95% CI 8–15). Conclusions: This is, to our knowledge, the largest cohort of NCUB patients studied to date. Data emphasize the heterogeneity and aggressiveness of this disease. Future studies should investigate disease biology and the activity of targeted therapies in NCUB. Molecular characteristics based on tumor tissue analysis are underway. Legal entity responsible for the study: HEGP (European Georges Pompidou Hopsital). Funding: Pierre Fabre. Disclosure: All authors have declared no conflicts of interest.

1866P - Association of the rs1883832 variant of CD40 with NSCLC risk and overall survival

Background: During the last few years a growing number of studies has attempted to shed light on the role of CD40 (Tumor Necrosis Factor Receptor Superfamily Member 5) in non-small-cell lung cancer (NSCLC), which remains the leading cause of cancer-related deaths worldwide. The aim of the current study was to investigate the clinical relevance of CD40 functional single nucleotide polymorphism (SNP) rs1883832 (-1C/T) with susceptibility to NSCLC, the clinicopathological parameters, relapse and survival rates of NSCLC patients, as well as with the protein expression of CD40. Methods: CD40 SNP rs1883832 was genotyped in 268 randomly selected NSCLC patients and 279 age- and gender-matched healthy donors. Patients were under observation during a five-year period. Immunohistochemical analysis for CD40 was performed on 106 NSCLC tumor tissue samples. All the participants were Greeks with Caucasian origin. Results: Genotype frequencies of rs1883832 (CC, CT, and TT) were significantly different between healthy controls and patients. CC homozygotes had higher risk for NSCLC compared to T allele carriers in univariate (P < 0.001), as well as in multivariate analysis (P = 0.006). In addition, rs1883832 was related to overall survival. More specifically, CT heterozygotes had worse clinical outcome after two-, three- and five-year observation compared to TT and CC homozygotes (P = 0.015, P = 0.005 and P = 0.017, respectively). Stratifying according to histological subtype, this association was observed only in patients with adenocarcinomas (P = 0.028) and not in patients with squamous- and large-cell carcinomas. Furthermore, taking into consideration disease stage, worse survival for CT heterozygotes was observed in stage II patients and not in patients of other stages (P = 0.016). Moreover, the variant had also strong association with brain metastases, with T allele carriers developing more often metastatic disease in CNS (P = 0.018). Interestingly, rs1883832 was related to CD40 protein expression in malignant cells (P < 0.001) as well as in stromal cells (P = 0.004). Conclusions: The present findings suggest that investigated SNP rs1883832 may be a useful and independent biomarker in NSCLC. However, more studies are needed in order to further demonstrate their role in NSCLC. Legal entity responsible for the study: University of Patras. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Predictors of Postoperative Stricture After Endoscopic Submucosal Dissection for Large Superficial Esophageal Squamous Cell Neoplasms

Introduction: Endoscopic submucosal dissection (ESD) has been widely accepted for resecting superficial esophageal squamous cell neoplasms (ESCNs). The aim of this study was to evaluate the predictors for postoperative stricture after ESD for large ESCNs (>3/4 circumferential mucosal defect). Methods: We consecutively enrolled 63 patients with large ESCNs(Histologic depth<sm1) who underwent ESD at the Chinese PLA General Hospital were enrolled. Patients were grouped as post-ESD stricture group and no post-ESD stricture group according to stricture occurrence or not after ESD. The demographic characteristics of the patients and the tumor and technical factors were analyzed for investigating predictive factors of postoperative stricture. Results: All the ESD procedures were successfully performed for 63 patients of which 25(39.4%) taking prophylactic methods for preventing post-ESD stricture. The rates of postoperative stricture for different circumferential defects of ≥3/4 to <7/8, ≥7/8 to <4/4 and 4/4 were 38.2%(13/34), 50.0%(6/12) and 76.5%(13/17) respectively. The total stricture rate was 50.8%(32/63). Patients with post-ESD stricture had a significantly higher degree of circumferential mucosal defect(P=0.036), larger longitudinal tumor size ((5.72±2.16) versus (4.24±1.61) cm, P = 0.003) and more patients with presence of muscle injury(9 vs 2, P = 0.023).There was no significant differences in age, sex, tumor location, macroscopic type, procedure time, the longitudinal diameter of specimens, the circumferential diameter of specimens, en bloc resection, histological depth and taking prophylactic measures (P>0.05). After multivariate analysis, circumferential mucosal defect (≥ 7/8) and not taking prophylactic measures are predictors for stricture development in patients with large ESCNs after ESD. Conclusion: Circumferential mucosa defect >7/8 is the main factor leading to the stricture of the esophagus after ESD for large early ESCNs. For patients with post- operative circumferential mucosa defect >3/4, appropriate preventive measures can effectively reduce the incidence of postoperative stricture after ESD.354_A Figure 1. Groups according to circumferential mucosal defect. Patients who underwent ESD or ESTD for large superficial esophageal squamous cell carcinoma(ESCC):Group A, ≥3/4 and <7/8; Group B, ≥7/8 and <4/4; Group C, entire circumferential mucosal defect(4/4)354_B Figure 2. Stricture was encountered after submucosal dissection (ESD) involving total circumferential resection. A. Chromoendoscopy with iodine staining revealed a discolored area in the lower esophagus. B. Entire (4/4) circumferential mucosal defect after ESD. C. Resected sleeved specimen with the lesion in an en bloc resection, the length of which was approximately 4.5 cm. D. A fully covered esophageal stent was implanted for prevention of stricture. E. Endoscopy displayed stricture 63 days after ESD. F. Endoscopic balloon dilatation is performed against the postoperative stricture. G. The stricture site was dilated after balloon dilatation, a 9.8-mm-diameter esophagogastroduodenoscopy (EGD) could be passed through this lumen. H. The lumen 7 months after ten EBD treatments.354_C Figure 3. The detailed data of the 63 patients enrolled in the study.

PRIMARY PULMONARY COLLISION TUMOR WITH ADENOCARCINOMA AND SCLC

SESSION TITLE: Lung Cancer 3 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: A collision tumor is defined as two histologically independent malignant neoplasms within the same organ. Our case presents a 78 year-old man with heavy smoking history that presented with 1 week long history of productive cough and shortness of breath. Imaging revealed a large pleural effusion; a spiculated left lung mass, fluid analysis positive for mixed adenocarcinoma and small lung cell carcinoma and pleural histology showed small lung cell carcinoma. CASE PRESENTATION: A 78-year-old man was brought to the emergency department with 1 week history of productive cough and shortness of breath. He reported unintentional 60 lbs weight loss over the 2 months, and reported heavy smoking history since he was 7 years-old. Physical exam and imaging were consistent with large left pleural effusion and consolidation of the left upper and left lower lobes. Pleural fluid chemistry suggested exudative effusion, and cytology revealed metastatic mixed adenocarcinoma and small cell carcinoma consistent with lung primary tumor. He underwent pleural biopsy, talc pleurodesis and partial decortication. Pleural histology was positive for small lung cell carcinoma. DISCUSSION: Collision tumors are rare entities, defined as two or more histologically distinct malignant neoplasms developing in the same organ [1]. There are 3 main tumorigenesis theories that explain the pathophysiology. The first one considers the accidental meeting of coexisting malignancies developing in the same organ, the second one considers a single carcinogen that precipitates two distinct neoplasms that collide, and the third theory is the tumor-to-tumor carcinogenesis, in which one neoplasm induces the second primary [2]. Clinical data has suggested that some of these collision tumors are developing from a single cell that eventually differentiates into distinct types and on the other hand our patient does have a strong smoking history and would likely be the carcinogenic stimulus [2, 3]. The relative risk of lung cancer in smokers of 20 or more cigarettes a day is 20 to 30 times higher than in nonsmokers [3]. Small Cell Lung Carcinoma is the histopathological subtype most commonly associated with smoking and adenocarcinoma most commonly seen in nonsmokers [3].Prognosis is dependent on the cytological grading of each neoplasm, and staging, which is highly undifferentiated and advanced in our patient [3]. When brain metastases are present, without treatment, the median survival is about 1-2 months. Whole brain radiotherapy (WBRT) is the mainstay of treatment with median survival between 3-6 months. CONCLUSIONS: Collision tumor of the lung with multiple primary lung neoplasms is a rare occurrence. It is mostly diagnosed port operatively after histological diagnosis and classification. Due to its very low incidence, this case is meant to bring awareness of cancer behavior, tumorigenesis, differentiation, and adhesion. Reference #1: Suzuki, Shigeki, T. Ohtsuka, T. Hato, et al., “Primary pulmonary collision tumor with three components in the underlying interstitial lung disease,” Thoracic Cancer, vol. 5, no. 5, pp 460-462, 2015. Reference #2: Michalinos, Adamantios, A. Constantinidou, M. Kontos, “Gastric collision tumors: An insight into their origin and clinical significance,” Gastroenterology Research and Practice, vol. 2015, Article ID 314158, 8 pages, 2015. https://doi.org/10.1155/2015/314158 Reference #3: Nakata, Shoji, Y. Nagata, M. Sugaya, et al., “Primary pulmonary collision cancer consisting of large cell carcinoma and adenocarcinoma,” Annals of Thoracic Surgery, vo. 2008, no. 80, pp 340-2. DISCLOSURES: No relevant relationships by Sandra Donahue, source=Web Response No relevant relationships by Anoopa Gollapudi, source=Web Response

Automated Lung Segmentation on Computed Tomography Image for the Diagnosis of Lung Cancer.

Image processing techniques are widely used in several medical areas for early detection and treatment especially in the detection of various cancer tumors such as Squamous, Adenocarcinoma, Large Cell Carcinomas and Small Cell Lung Cancer. Segmentation of lung tissues from Computed Tomography (CT) image is considered as a pre-processing step in Lung Imaging. However, during Lung Segmentation, the Juxta-Pleural nodules (nodules attach to parenchymal walls) are missed out as they have similar appearance (intensity) to that of other non-pulmonary structures, which leads to a challenge to segment lung region along with Juxta-Pleural nodules. The complexity to segment lung region is mainly due to its inhomogeneity (different structures and intensity values of lungs). Thus, the existing segmentation algorithms like image thresholding algorithm, region-growing algorithm, active contour, level sets, etc. fail to segment lung tissues including Juxta-Pleural nodules. So, in this paper, a new fully-automated lung segmentation method with Juxta-Pleural nodules inclusion, is proposed.

Presence and activity of HPV in primary lung cancer.

Evaluate the presence of human papillomavirus (HPV) in biopsies of Brazilian patients with lung cancer and also the expression of the E6 and E7 oncoproteins. HPV is widely known as an important condition for cervical cancer although evidence today shows it is associated with several other types of cancer and may also be involved in lung cancer development. However, there are some divergences regarding the presence and activity of HPV in lung carcinogenesis. The detection of HPV was performed by PCR, followed by genotype and immunohistochemical evaluation of E6 and E7 HPV type specific, from 63 patients. HPV was found to be present in 33 of the 63 samples, and types 16 and 18 were detected with frequencies of 81% (27/33) and 19% (6/33), respectively. About the presence of the virus in different histological types of tumors, HPV was detected in squamous cell carcinoma (39.39%), followed by adenocarcinoma (33.33%) and small cell carcinoma (18.18%) and large cell carcinoma (9.1%). The presence of the E6 (antibody anti-HPV 16 and anti-HPV 18) and E7 (antibody anti-HPV 16 and anti-HPV 18) oncoproteins was detected by immunohistochemical stain technique in 28/33 samples and 25/33 samples, respectively. Our results suggest that the lung tumor patients have high prevalence of HPV and the virus is not only present but also active in tumor cells. Therefore, the HPV is probably playing a role in lung carcinogenesis.

Usefulness of complementary next-generation sequencing and quantitative immunohistochemistry panels for predicting brain metastases and selecting treatment outcomes of non–small cell lung cancer

To demonstrate the usefulness of complementary next-generation sequencing (NGS) and immunohistochemistry (IHC) counting, we analyzed 196 patients with non-small cell lung cancer who underwent surgical resection and adjuvant chemotherapy. Formalin-fixed, paraffin-embedded samples of adenocarcinoma (ADC), squamous cell carcinoma, and large cell carcinoma were used to prepare tissue microarrays and were examined by protein H-score IHC image analysis and NGS for oncogenes and proto-oncogenes and genes of tumor suppressors, immune checkpoints, epithelial-mesenchymal transition factors, tyrosine kinase receptors, and vascular endothelial growth factors. In patients with brain metastases, primary tumors expressed lower PIK3CA protein levels. Overexpression of p53 and a higher PD-L1 protein H-score were detected in patients who underwent surgical treatment followed by chemotherapy as compared with those who underwent only surgical treatment The absence of brain metastases was associated with wild-type sequences of genes EGFR, CD267, CTLA-4, and ZEB1. The combination of protein overexpression according to IHC and mutation according to NGS was rare (ie, represented by a very low percentage of concordant cases), except for p53 and vascular endothelial growth factor. Our data suggest that protein levels detected by IHC may be a useful complementary tool when mutations are not detected by NGS and also support the idea to expand this approach beyond ADC to include squamous cell carcinoma and even large cell carcinoma, particularly for patients with unusual clinical characteristics. Conversely, well-pronounced immunogenotypic features seemed to predict the clinical outcome after univariate and multivariate analyses. Patients with a solid ADC subtype and mutated genes EGFR, CTLA4, PDCD1LG2, or ZEB1 complemented with PD-L1 or p53 protein lower expression that only underwent surgical treatment who develop brain metastases may have the worst prognosis.

Expression of HMB45, MelanA and SOX10 is rare in non-small cell lung cancer

BackgroundNon-small cell lung cancer (NSCLC) and melanoma are frequent entities in routine diagnostics. Whereas the differential diagnosis is usually straight forward based on histomorphology, it can be challenging in poorly differentiated tumors as melanoma may mimic various histological patterns. Distinction of the two entities is of outmost importance as both are treated differently. HMB45 and MelanA are recommended immunohistological markers for melanoma in this scenario. SOX10 has been described as an additional marker for melanoma. However, comprehensive large-scale data about the expression of melanoma markers in NSCLC tumor tissue specimen are lacking so far.MethodsTherefore, we analyzed the expression of these markers in 1085 NSCLC tumor tissue samples. Tissue microarrays of NSCLC cases were immunohistochemically stained for HMB45, MelanA, and SOX10. Positivity of a marker was defined as ≥1% positive tumor cells.ResultsIn 1027 NSCLC tumor tissue samples all melanoma as well as conventional immunohistochemical markers for NSCLC could be evaluated. HMB45, MelanA, and SOX10 were positive in 1 (< 1%), 0 (0%) and 5 (< 1%) cases. The HMB45 positive case showed co-expression of SOX10 and was classified as large cell carcinoma. Three out of five SOX10 positive cases were SqCC and one case was an adenosquamous carcinoma.ConclusionsExpression of HMB45, MelanA and SOX10 is evident but exceedingly rare in NSCLC cases. Together with conventional immunomarkers a respective marker panel allows a clear-cut differential diagnosis even in poorly differentiated tumors.

A Case of Large Breast Spindle Cell Carcinoma Which Resected Pulmonary Metastasis 3 Years after the Primary Surgery

A Case of Large Breast Spindle Cell Carcinoma Which Resected Pulmonary Metastasis 3 Years after the Primary Surgery

Assessment of programmed cell death ligand-1 expression by 4 diagnostic assays and its clinicopathological correlation in a large cohort of surgical resected non-small cell lung carcinoma

Immune checkpoint blockade targeting the PD-1/PD-L1 axis has recently demonstrated efficacy and promise in cancer treatment. Appropriate biomarker selection is therefore essential for improving treatment efficacy. However, the establishment of PD-L1 assay in pathology laboratories is complicated by the presence of multiple testing platforms using different scoring systems. Here we assessed the PD-L1 expression in 713 consecutive non-small cell lung carcinomas by four commercially available PD-L1 immunohistochemical assays, namely, 22C3, 28-8, SP142 and SP263. The analytical performances of the four assays and diagnostic performances across clinically relevant cutoffs were evaluated. The prevalence of PD-L1 (22C3) expression was 21% with a ≥50% cutoff and 56% with a ≥1% cutoff. High PD-L1 expression (using a ≥50% cutoff) was significantly associated with male sex (P = 0.001), ever smoking history (P < 0.001), squamous cell carcinoma (P = 0.001), large cell carcinoma (P < 0.001), lymphoepithelioma-like carcinoma (P = 0.006), sarcomatoid carcinoma (P < 0.001), mutant KRAS (P = 0.005) and wild-type EGFR (P = 0.003). Elevated PD-L1 expression was also significantly associated with shorter survival in patients with adenocarcinoma (log-rank P = 0.026) and remained an independent prognostic factor by multivariable analysis. Among the four assays, 22C3, 28-8 and SP263 were highly concordant for tumor cell scoring. With a cutoff of ≥50% (i.e., the threshold for first-line patient selection), inter-rater agreement was high among the three assays with percentage agreement >97%. In conclusion, three PD-L1 assays showed good analytical performance and a high agreement with each other, but not all cases were correctly classified using the same clinical cutoff. Further studies comparing the predictive value of these assays are required to address the interchangeability of these assays for clinical use.

Abstract A36: Establishment of patient-derived xenograft models of lung adenocarcinoma with two different EGFR mutations, L858R and exon19 deletion

Abstract Preclinical tumor models that resemble the characteristics of patients’ tumors are essential for development of novel therapy. Patient-derived tumor xenograft (PDX) models are considered to be interesting candidates. However, success rate of PDX models of lung cancer, especially adenocarcinoma, is much lower than that of other types of tumors, including colon cancer. This study was conducted to establish clinically relevant PDX models of lung cancer. We obtained fresh surgically resected specimens from 20 NSCLC patients (10 squamous cell carcinomas, 9 adenocarcinomas, and 1 large cell carcinoma) who had submitted the written informed consent for this study, which was performed in accordance with protocols approved by the IRB of Kanazawa University. We inoculated the tumor fragments subcutaneously into immunodeficient mice, NOG mice or SCID hairless outbred (SHO) mice. The tumor take rate was 40% (8/20), with higher rates for squamous cell carcinoma (60%, 6/10) than for adenocarcinoma (22%, 2/9). Interestingly, both of two adenocarcinomas that successfully developed PDX tumors had EGFR mutations, L858R and exon 19 deletion, respectively. These PDX tumors maintained histology of adenocarcinoma and EGFR mutation even after repeated in vivo passages. Furthermore, the third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) osimertinib dramatically regressed tumors in these EGFR mutated PDX models. Osimertinib treatment is ongoing in these EGFR-mutated PDX models to obtain tumors that acquired resistance to osimertinib. Our PDX models of lung adenocarcinoma with different EGFR mutations may be useful for investigating the mechanisms of resistance to EGFR-TKIs, including third-generation inhibitor osimertinib. Citation Format: Kenji Kita, Koji Fukuda, Akihiro Nishiyama, Sachiko Arai, Shinji Takeuchi, Koushiro Ohtsubo, Kaname Yamashita, Masaya Tamura, Isao Matsumoto, Seiji Yano. Establishment of patient-derived xenograft models of lung adenocarcinoma with two different EGFR mutations, L858R and exon19 deletion [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A36.

Surgical intervention may be a therapeutic option for NSCLC patients with AJCC stage IV: a large population-based study

BackgroundFew studies have focused on the role of surgery in the treatment of stage IV non-small cell lung cancer (NSCLC). In our study, we mainly focused on the surgical therapeutic option for NSCLC patients with American Joint Committee on Cancer stage IV.Patients and methodsUsing the Surveillance Epidemiology and End Results database, we screened out an appropriate patient population with stage IV NSCLC treated between 2004 and 2013. Kaplan–Meier curve analysis was used to compare the survival between patients receiving surgery and standard of care. The effect of surgery on primary and regional/distant sites on overall survival (OS) was further evaluated by Cox proportional hazard model. Finally, subgroup analysis based on patient and disease variables was conducted by Cox proportional hazard and presented as a forest plot.ResultsA total of 61,418 stage IV NSCLC patients were enrolled. However, only 11.6% received local surgical treatment. Surgery to primary and regional/distant sites were both independent prognostic factors of OS (P<0.001). Survival advantage was identified in those patients who received surgery to primary sites for all subgroup variables (P<0.001). However, survival benefit was not demonstrated for patients with surgery to regional/distant sites in some subgroup variables, including black racial background, squamous cell carcinoma, large cell carcinoma, and N1 staging (all, P>0.1). Importantly, we observed that surgery of primary tumor sites at stage N0 showed the maximum OS benefit (P<0.001).ConclusionThese findings about N staging and primary tumor site treatment should be taken into consideration by surgeons when determining the suitability of surgery for stage IV NSCLC patients.

The impact of histology and ground-glass opacity component on volume doubling time in primary lung cancer.

Correlations between volume doubling time (VDT) of primary lung cancer (PLC), histology, and ground glass opacity (GGO) components remain unclear. The purpose of this study was to evaluate and compare VDT of PLC in terms of histology and presence or absence of GGO components. A total of 371 surgically resected PLCs from 2003 to 2015 in our institute were retrospectively reviewed. The VDT was calculated both from the diameters of the entire tumor and of consolidation by using the approximation formula of Schwartz. The median VDTs of adenocarcinoma, squamous cell carcinoma, and others (large cell neuroendocrine carcinomas, small cell lung carcinomas, pulmonary pleomorphic carcinomas, and large cell carcinomas combined) were 261, 70, and 70 days, respectively; these differ significantly (P<0.001). All PLCs with GGO were adenocarcinomas. The VDT of adenocarcinomas with GGO was significantly longer than that of those without GGO (median VDT: 725 and 177 days, respectively), squamous cell carcinomas, and others. When the VDT calculated from the maximum diameter of consolidation component was compared, adenocarcinomas with GGO also showed significantly slower growth than those without GGO (median VDT: 248 versus 177 days, respectively, P=0.040). The VDT of PLCs is longest for adenocarcinomas. VDT was significantly longer in adenocarcinomas with GGO components than in those without such components, irrespective of VDT calculated on the basis of either the entire tumor diameter or consolidation diameter.

Metabolic signatures of four major histological types of lung cancer cells.

Histologically lung cancer is classified into four major types: adenocarcinoma (Ad), squamous cell carcinoma (SqCC), large cell carcinoma (LCC), and small cell lung cancer (SCLC). Presently, our understanding of cellular metabolism among them is still not clear. The goal of this study was to assess the cellular metabolic profiles across these four types of lung cancer using an untargeted metabolomics approach. Six lung cancer cell lines, viz., Ad (A549 and HCC827), SqCC (NCl-H226 and NCl-H520), LCC (NCl-H460), and SCLC (NCl-H526), were analyzed using liquid chromatography quadrupole time-of-flight mass spectrometry, with normal human small airway epithelial cells (SAEC) as the control group. The principal component analysis (PCA) was performed to identify the metabolic signatures that had characteristic alterations in each histological type. Further, a metabolite set enrichment analysis was performed for pathway analysis. Compared to the SAEC, 31, 27, 34, 34, 32, and 39 differential metabolites mainly in relation to nucleotides, amino acid, and fatty acid metabolism were identified in A549, HCC827, NCl-H226, NCl-H520, NCl-H460, and NCl-H526 cells, respectively. The metabolic signatures allowed the six cancerous cell lines to be clearly separated in a PCA score plot. The metabolic signatures are unique to each histological type, and appeared to be related to their cell-of-origin and mutation status. The changes are useful for assessing the metabolic characteristics of lung cancer, and offer potential for the establishment of novel diagnostic tools for different origin and oncogenic mutation of lung cancer.

Evaluation of asymptomatic skeletal metastasis by 99mTc MDP bone scans in NSCLC patients attending INMAS, Rajshahi

&lt;p&gt;&lt;strong&gt;&lt;em&gt;Background: &lt;/em&gt;&lt;/strong&gt;Lung cancer is the leading cause of cancer deaths worldwide. Lung cancer is often insidious, producing no symptoms until the disease is well advanced. In approximately 7-10% of cases, lung cancer is diagnosed in asymptomatic patients. Some patients are asymptomatic for skeletal metastasis and a recent prospective study showed that in staging of non-small cell lung cancer (NSCLC), failure to perform a bone scan could miss asymptomatic bone metastasis in 14–22% of patients. Radionuclide bone scintigraphy with &lt;sup&gt;99m&lt;/sup&gt; Tc MDP (Technetium-99mmethylene diphosphonate) is very useful nuclear imaging tool to detect skeletal metastasis with a sensitivity of 98.2% and a specificity of 95.2%. The aim of this study was to detect the asymptomatic skeletal metastasis of non-small cell lung cancer patients by &lt;sup&gt;99m&lt;/sup&gt;Tc MDP bone scan.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;&lt;em&gt;Patients and methods:&lt;/em&gt;&lt;/strong&gt; It is a retrospective study, carried out from January 2015 to December 2016 in Institute of Nuclear Medicine and Allied Sciences, Rajshahi. Bone scan was performed by an intravenous bolus injection of 20 m Ci &lt;sup&gt;99m&lt;/sup&gt;Tc MDP. Bone phase images were taken at three hours after injection of the radiotracer.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;&lt;em&gt;Results:&lt;/em&gt;&lt;/strong&gt; A total of 52 patients were enrolled in the study. The mean age of the patients was 57.6 ± 14.5 years (mean ± SD) with range from 36 to 75 years and 42 (80.77%) were male and 10 (19.23%) were female. Out of 52 patients, only 06 (11.54%) patients were diagnosed as positive and 46 (88.46%) were negative for bone metastasis. Out of 06 patients with positive skeletal metastasis 04 (66.67%) patients had multiple sites (two or more) and 02 (33.33%) patients had solitary site of bone involvement. Common sites of metastasis were in thoracic (83.33%) and lumbar spine (83.33%), ribs (50%), pelvic bones (33.33%), long bones (16.66%), skull (16.66%) and other bony sites including clavicle, sternum, scapula, sacrum (16.66%). Regarding staging prior to bone scan, out of 06 bone scan positive patients 03 (50%) patients were in stage III, 02 (33.33%) patients were in stage IV and 01(16.67%) patient was in stage II. On the basis of histopathology, out of 06 skeletal metastatic patients 04 (66.67%) patients had adenocarcinoma, 01 (16.67%) patient had squamous cell carcinoma and 01 (16.67%) had large cell carcinoma. The exclusion of bone metastasis is important in the initial staging of non-small cell lung cancer.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;&lt;em&gt;Conclusion:&lt;/em&gt;&lt;/strong&gt; There is debate about whether bone scans should be performed routinely or restricted to patients who present with clinical or laboratory indicators suggesting skeletal metastasis. The present study indicates that if bone scans were done only in patients reporting skeletal symptoms an important number of patients (11.54%) would have been miss-staged due to asymptomatic bone metastasis. As bone scan is very cost effective in comparison to other imaging modalities (MRI / PET-CT), it can play a vital role in detecting asymptomatic skeletal metastasis in NSCLC patients.&lt;/p&gt;&lt;p&gt;Bangladesh J. Nuclear Med. 20(2): 110-114, July 2017&lt;/p&gt;

The Expression Levels of IL-4/IL-13/STAT6 Signaling Pathway Genes and SOCS3 Could Help to Differentiate the Histopathological Subtypes of Non-Small Cell Lung Carcinoma.

BackgroundThe interleukin (IL)-4/IL-13/signal transducer and activator of transcription (STAT) 6 signaling pathway and the SOCS3 gene, one of its main regulators, constitute an important link between the inflammation process in the epithelial cells and inflammatory-related tumorigenesis. The present study is the first to evaluate IL-4, IL-13, STAT6, and SOCS3 mRNA expression in non-small cell lung carcinoma (NSCLC) histopathological subtypes.MethodsGene expression levels were assessed using TaqMan® probes by quantitative reverse transcription PCR (qRT-PCR) in lung tumor samples and unchanged lung tissue samples.ResultsIncreased expression of IL-4, IL-13, and STAT6 was observed in all histopathological NSCLC subtypes (squamous cell carcinoma [SCC], adenocarcinoma [AC], and large cell carcinoma [LCC]). Significantly higher expression of IL-13 and STAT6 (p = 0.019 and p = 0.008, respectively) was found in SCC than in LCC. No statistically significant differences were found for IL-4. Significantly higher SOCS3 expression was found in LCC than in AC (p = 0.027). A negative correlation (rho = –0.519) was observed for the STAT6 and SOCS3 genes in SCC (p = 0.005). No associations were found between gene expression and tumor staging (post-operative Tumor Node Metastasis [pTNM], American Joint Committee on Cancer [AJCC]), patients’ age, sex, or history of smoking.ConclusionsAs the number of LCC cases in our study was quite low, the statistically significant results obtained should be confirmed in a larger group of patients, particularly as the relationships identified between increased IL-4, IL-13, and STAT6 mRNA expression and decreased SOCS3 expression suggest that these genes may serve as potential diagnostic markers for differentiating between NSCLC histopathological subtypes.

Surgical significance and efficacy of epidermal growth factor receptor tyrosine kinase inhibitors in patients with primary lung adenosquamous carcinoma.

BackgroundPrimary adenosquamous carcinoma (ASC) of the lung is a rare and aggressive disease. The accurate diagnosis of ASC based on small biopsies is challenging because of the mixed components within the tumor, and this may lead to suboptimal treatment. Furthermore, information about the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in lung ASC is limited.Patients and methodsData on a cohort of patients with lung ASC who underwent surgery between October 2008 and December 2016 at a single institution were retrospectively reviewed.ResultsThis study analyzed 148 patients. Differences between the pre- and post-resection diagnosis were observed. Based on the results of preoperative biopsy, patients were diagnosed as having squamous cell carcinoma (n=26), adenocarcinoma (n=20), poorly differentiated carcinoma (n=20), and large cell carcinoma (n=1), and finally diagnosed as having ASC based on histopathological examination of the surgical specimens. Thirty patients (20.3%) with EGFR-sensitizing mutations (TKI group) were treated with EGFR-TKIs after surgery, whereas the remaining patients (79.7%) with unknown EGFR-mutation status received chemotherapy or chemoradiotherapy alone (non-TKI group). TKI treatment was associated with better median overall survival (OS) (HR=0.619; p=0.034). Multivariate analysis identified the presence of EGFR-TKI treatment as an independent prognostic factor for OS (HR=0.471; p=0.003).ConclusionDiscrepancies between the pre- and post-operative diagnosis reflect the inadequacy of non-resection approaches to the diagnosis of ASC. ASC patients harboring EGFR-sensitizing mutations who were treated with EGFR-TKIs showed a significantly better prognosis than those receiving chemotherapy or chemoradiotherapy alone.

Concordance levels of PD-L1 expression by immunohistochemistry, mRNA in situ hybridization, and outcome in lung carcinomas

Targeted inhibition of programmed cell death-1 (PD-1) and its ligand (PD-L1) has emerged as first-line therapy for advanced non-small cell lung cancer. Although patients with high PD-L1 expression have improved outcomes with anti-PD-1/PD-L1-directed therapies, use as a predictive biomarker is complicated by robust responses in some patients with low-level expression. Furthermore, reported PD-L1 levels in lung cancers vary widely, and discrepancies exist with different antibodies. PD-L1 expression was thus compared by immunohistochemistry (IHC) versus RNA in situ hybridization (ISH) in 112 lung cancers by tissue microarray: 51 adenocarcinoma, 42 squamous cell carcinoma, 9 adenosquamous carcinoma, 5 carcinoid, 3 undifferentiated large cell carcinoma, 1 large cell neuroendocrine carcinoma, and 1 small cell carcinoma. At least 1% tumor cell staining was considered positive in each modality. A positive concordance of only 60% (67/112) was found between IHC and ISH. Fifty percent (56/112) were positive by IHC and 50% (56/112) by ISH; however, 20% (22/112) were ISH positive but IHC negative. Conversely, 21% (23/112) were IHC positive but ISH negative. There was no significant stratification of PD-L1 positivity by histologic subtype. A trend of more PD-L1-positive stage I cancers identified by ISH versus IHC was observed but was not statistically significant (50% [27/54] by IHC and 64% [35/55] by ISH, P = .18). No significant difference in survival was identified, with an average of 5.3 months in IHC versus 5.2 months in ISH-positive cases. The results demonstrate discordance between PD-L1 RNA levels and protein expression in non-small cell lung cancers, warranting comparison as predictive biomarkers.