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A.G. Nicholson

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    MINI 01 - Pathology (ID 93)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 14
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      MINI01.01 - Immunohistochemical Distinction between Primary Lung Squamous Cell Carcinoma and Pulmonary Metastasis of Head and Neck Squamous Cell Carcinoma (ID 1525)

      10:45 - 12:15  |  Author(s): J. Ichinose, A. Shinozaki-Ushiku, K. Nagayama, J. Nitadori, M. Anraku, M. Fukayama, J. Nakajima, D. Takai

      • Abstract
      • Presentation
      • Slides

      Background:
      It is extremely difficult to distinguish between primary lung squamous cell carcinoma (LUSq) and pulmonary metastasis of head and neck squamous cell carcinoma (HNSq) in patients with a past history of HNSq, even by histological examination of the resected specimen. This study aimed to establish an immunohistochemical scoring system for discrimination between LUSq and pulmonary metastasis of HNSq.

      Methods:
      We selected genes that were expressed in a markedly different manner in LUSq and HNSq using the results of expression microarrays and chose the antibodies for four proteins (CK19, MMP3, ZNF830, PI3) that had immunohistochemical results shown in the Human Protein Atlas (http://www.proteinatlas.org) that were distinguishable between LUSq and HNSq. We constructed the tissue microarrays using the resected specimens of 39 LUSqs and 48 HNSqs as the training set and evaluated the tendency of HNSq using the 16-grade system according to the positive staining of the four antibodies. Twenty-seven of the patients with pulmonary tumors that were resected and pathologically diagnosed as squamous cell carcinoma between 1999 and 2014 had a past history of HNSq. Their pulmonary tumors and primary HNSqs were analyzed immunohistochemically as the test set. We defined LU-associated recurrence as postoperative recurrence in the thoracic cavity, mediastinum, brain, bone, and liver and defined HN-associated recurrence as recurrence in the other sites. We compared the diagnosis of our immunohistochemical scoring system to the preoperative clinical diagnosis and the pathological diagnosis according to the predictive power of HN-associated recurrence.

      Results:
      The sensitivity, specificity, and accuracy of our immunohistochemical scoring system were 90%, 67%, and 79%, respectively in the training set, and our system correctly diagnosed 96% of HNSq specimens in the test set. Twenty-three out of 27 pulmonary tumors in the test set were diagnosed as pulmonary metastasis of HNSq, and four were diagnosed as LUSq. Eleven of 23 patients (48%) with pulmonary metastasis of HNSq developed HN-associated recurrence (3-year HN-associated recurrence-free probability was 46%), and 10 died because of HNSq, while none of the four patients with LUSq had HN-associated recurrence. Compared with the clinical diagnosis (five LUSq, 14 pulmonary metastasis of HNSq, eight uncertain) and the pathological diagnosis (two LUSq, 17 pulmonary metastasis of HNSq, eight uncertain), our immunohistochemical scoring system could predict the risk of HN-associated recurrence more accurately. Figure 1



      Conclusion:
      Immunohistochemical analysis of four proteins (CK19, MMP3, ZNF830, PI3) was clinically useful for discrimination between LUSq and pulmonary metastasis of HNSq.

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      MINI01.02 - Is It Possible to Distinguish between Second Primary vs Metastasis in Resectable Synchronous Nodules with the Same Histotype of Lung Cancer? (ID 2122)

      10:45 - 12:15  |  Author(s): G. Luciano, P. Viola, M. Al Sahaf, Z. Niwaz, H. Raubenheimer, M.E. Cufari, H. Chavan, C. Proli, M. Leung, V. Anikin, N. McGonigle, E. Beddow, G. Ladas, S. Jordan, M. Dusmet, A.G. Nicholson, E. Lim

      • Abstract
      • Presentation
      • Slides

      Background:
      The prognostic significance of additional lung nodules in the setting of lung cancer is important as the impact on survival is often considered for the justification of surgical selection in the management of patients with synchronous nodules. TNM 7 down staged the impact on T category but did not distinguish between second primary versus metastasis. Traditional distinctions such as the Martini criteria do not take the same histological type into account and classification continues to improve (e.g. IASLC classification of adenocarcinoma). The aim of our study is to determine if it is possible to distinguish between second primary versus metastases in patients with the same histological type and quantity any difference in survival.

      Methods:
      We retrospectively analysed data from a prospectively collated database at our institution. We collected all the records which included two resected nodules. The detailed pathology reports of these patients were retrieved and the histology, subtype and pTNM of tumours documented. Slides were re-reviewed to determine the histological subtypes according to the current IASLC adenocarcinoma classification. Survival was calculated using Kaplan Meier methods and adjusted survival compared using Cox regression on R (statistical software).

      Results:
      From April 1999 to February 2013, a total of 2925 lung cancer resection were performed. Of these, 379 (14%) operations fulfilled the inclusion criteria of multiple nodules with 316 having synchronous tumours (83.3%) and 63 having metachronous tumours (16.6%). The tumours were ipsilateral in 87.3% and the vast majority were in the same lobe (70.9%). For synchronous tumours, patients with the same histological type had a poorer 5-years survival rate compared to tumours with different histology (p=0.041). The pathologist’s designation between second primary versus intra-pulmonary metastasis distinguished between overall survival (p= 0.001) and this remained statistically significant in the tumours of the same cell type (p= 0.035). Figure 1. Survival outcomes between patients with multiple nodules classified as second primary versus intra-pulmonary metastasis Figure 1



      Conclusion:
      Our results suggest that distinction between second primary and intra-pulmonary metastasis remains important for staging as appreciable differences in survival were observed in patients with synchronous nodules. Survival was poorer in patients with multiple nodules of the same histologic type (compared to different histology) and within the same histological subtype it is possible for pathologists to distinguish between second primary and intra-pulmonary metastasis. As this is currently confirmed only on pathologic stage in the majority, it presently does not influence the selection for surgery.

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      MINI01.03 - Pathology-Imaging Agreement in Distinguishing Separate Primary Tumours and Intrapulmonary Metastasis in Staging of Multiple Lung Cancers (ID 2659)

      10:45 - 12:15  |  Author(s): P. Viola, A. Devaraj, E. Lim, G. Luciano, S. Popat, A.G. Nicholson

      • Abstract
      • Presentation
      • Slides

      Background:
      The 7[th] TNM staging system for lung cancer recommended staging for cases with multiple nodules viewed as intrapulmonary metastases (IM) as T3 (same lobe), T4 (ipsilateral different lobe) and M1a (contralateral lobe), whilst those classified as separate primary tumours (SPTs) as T(x)NM where “x” is the number of primary tumours, either as a number or “m” for multiple. With an increase in patients presenting with multiple nodules, we sought to develop a set of criteria for c-staging on imaging and to determine the agreement between clinical and pathological staging in a cohort of resected lung cancers who had multiple nodules.

      Methods:
      In 2013 and 2014, there were a total of 48 consecutive cases with available imaging resected with multiple tumours, ranging from 2 to 5 nodules. Of these, one case was excluded as it was a carcinoid with background DIPNECH. These cases were classified as SPT or IM based on previously published criteria (Girard et al. Am J Surg Pathol 2009;33:1752-64). Imaging criteria were generated based on clinical experience in similar fashion with indicators of SPT being 1) Lesions of equivalent size (one not more than 100% of the other) 2) Smaller lesion is spiculated , 3) At least one lesion is subsolid, 4) Presence of field change. (For signs 1 and 2, if the lesions were in different lungs, an absence of mediastinal disease on imaging was required). Cases with at least one positive sign were classified as SPTs. The interobserver agreement between radiologists and pathologist were then generated.

      Results:
      Of the 47 cases, the additional nodules were not identifiable on CT in 7 cases. In the remaining 40 cases, there was agreement in 28 cases, of which 16 were SPTs and 12 were IM. Of 12 cases where there was disagreement, only 3 were SPTS and the majority were cases classified on pathology as IM. There was 70% agreement, greater than that expected by chance (p = 0.002) with a kappa value of 0.41.

      Conclusion:
      Moderate agreement can be achieved in terms of clinical and pathological staging of lung cancers presenting with multiple nodules using imaging and pathologic criteria. Using pathology as the gold standard, there was greater agreement in categorisation of SPTs (84% (16/19)) than IM (57% (12/21)).

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      MINI01.04 - Discussant for MINI01.01, MINI01.02, MINI01.03 (ID 3296)

      10:45 - 12:15  |  Author(s): N. Rekhtman

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI01.05 - Local Diagnostic Practices for Advanced Non-Small-Cell Lung Cancer in Europe and Japan: ASSESS Study (ID 2629)

      10:45 - 12:15  |  Author(s): N. Normanno, K. Hagiwara, B. Han, S. Tjulandin, C. Grohé, T. Yokoi, A. Morabito, S. Novello, E. Arriola, O. Molinier, R. McCormack, M. Ratcliffe, M. Reck

      • Abstract
      • Presentation
      • Slides

      Background:
      ASSESS (a large, multicentre, non-interventional, diagnostic study; NCT01785888) evaluated local diagnostic practices for patients with advanced non-small-cell lung cancer (aNSCLC) in Europe/Japan.

      Methods:
      Eligible patients: local/metastatic aNSCLC; chemotherapy-naïve, newly diagnosed/recurrent disease after resection; ineligible for curative treatment. We report diagnostic assessments and epidermal growth factor receptor (EGFR) mutation test turnaround times (secondary endpoints) associated with tissue/cytology samples from patients in Europe/Japan.

      Results:
      1311 patients enrolled (300 Japan). Immunohistochemistry (IHC) was used to confirm pathological diagnosis in 727/960 (76%) and 142/146 (97%) patients in Europe and Japan, respectively (where data were available); the following markers were assessed using IHC: TTF-1 (Europe 96% and Japan 79%); p65 (4% and 8%); and p40 (9% and 24%). EGFR mutation tests were not performed on samples from 110 patients and tested samples from 17 patients did not yield results. The most common reason for not testing was insufficient material provided (Europe 60% [47/78 responses]; Japan 56% [5/9 responses]). The percentages of neoplastic cells in samples (data available: Europe n=281; Japan n=20) were: <20% tumour cells: Europe 15% vs Japan 35%; 20–50% tumour cells: 23% vs 45%; >50% tumour cells: 61% vs 20%. Considering sampling methodologies, the most common sampling sites (data available: Europe n=996; Japan n=291) were the lung parenchyma (Europe 73%; Japan 79%) or lymph nodes (Europe 9%; Japan 9%); the most common sample collection method was bronchoscopy (Europe 39%; Japan 68%; Table 1). Median EGFR mutation test turnaround time was longer in Europe (11 days) versus Japan (8 days; Table 2). Mutation test success rates for Europe and Japan were 98.3% and 99.6%, respectively.

      Conclusion:
      Diagnostic assessments, sampling methodologies and EGFR mutation testing practices vary between and within Europe and Japan; further understanding of local practices will drive improvements and enable more patients to receive appropriate personalised treatment. Figure 1 Figure 2





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      MINI01.06 - Pathological Second-Predominant Component Predicts Recurrence in Lung Adenocarcinoma (ID 1070)

      10:45 - 12:15  |  Author(s): M. Ito, Y. Miyata, Y. Tsutani, T. Mimura, S. Murakami, H. Ito, H. Nakayama, M. Okada

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung adenocarcinoma is pathologically subdivided according to its predominant component. Approximately 50–70% of invasive adenocarcinomas are diagnosed as adenocarcinomas of either papillary or acinar predominant subtype. The prognostic difference between these subtypes has not been revealed, and these 2 similar subtypes may further be classified. This study aimed to investigate whether the pathological second-predominant component that follows the most predominant component predict recurrence in adenocarcinoma.

      Methods:
      We retrospectively reviewed 347 consecutive cN0 lung adenocarcinoma cases resected between April 2006 and December 2010 at Hiroshima University Hospital and Kanagawa Cancer Center. We further classified papillary and acinar predominant adenocarcinomas into either the papillary/acinar-lepidic type (Pap/Aci-Lep type) or the papillary/acinar-nonlepidic type (Pap/Aci-NonLep type). Tumor recurrence and the frequency of each invasion status such as lymphatic, vascular, and pleural invasion were compared between Pap/Aci-Lep type and Pap/Aci-NonLep type adenocarcinomas. In addition, we estimated the correlation between the radiological and pathological characteristics of these subtypes. Whole-tumor size, ground-glass opacity (GGO) ratio, solid size, and tumor disappearance ratio (TDR) on high-resolution computed tomography and maximum standardized uptake value (SUVmax) on positron emission tomography (CT) were measured as radiological parameters.

      Results:
      Papillary (n = 70) and acinar predominant adenocarcinomas (n = 61) were subdivided into the Pap/Aci-Lep type (n = 72) and Pp/Aci-NonLep type (n = 59). Compared with the Pap/Aci-NonLep type, the Pap/Aci-Lep type showed a significantly higher disease-free survival rate (5-year DFS: 89.4% vs 70.6%, p = 0.0374) and fewer cases of lymphatic invasion (15.3% vs 30.5%, p = 0.037), vascular invasion (15.3% vs 33.9%, p = 0.013), and pleural invasion (9.72% vs 25.4%, p = 0.031). Furthermore, radiological findings significantly differ between the Pap/Aci-Lep and Pap/Aci-NonLep types as follows: GGO ratio (μ ± 1 ´ SD: 34.4% ± 25.2% vs 3.81% ± 18.0%, p < 0.01), CT solid size (μ ± 1 ´ SD: 1.35 ± 0.65 cm vs 1.73 ± 0.55 cm, p = 0.015), TDR (μ ± 1 ´ SD: 41.8% ± 26.7% vs 17.5% ± 22.6%, p < 0.01), and SUVmax (μ ± 1 ´ SD: 2.37 ± 2.15 vs 3.96 ± 3.06, p < 0.01). Significant recurrence-free survival and prevalences of lymphatic and vascular invasion were observed between the lepidic predominant type (n = 109) and Pap/Aci-Lep type.

      Conclusion:
      The pathological second-predominant component allows for subclassification of papillary and acinar predominant adenocarcinomas with prognostic significance. Pathological features of these subtypes can be represented on clinical imaging. Not only the most predominant component but also the second-predominant component should be given clinical and pathological attention in order to predict malignant potential or decide indication for adjuvant therapy.

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      MINI01.07 - Comparison of Grading Systems Based on Histologic Patterns and Mitotic Activity to Predict Recurrence in Stage I Lung Adenocarcinoma (ADC) (ID 3030)

      10:45 - 12:15  |  Author(s): K.S. Tan, K. Kadota, A. Moreira, P.S. Adusumilli, W.D. Travis

      • Abstract
      • Presentation
      • Slides

      Background:
      An established grading system for lung adenocarcinoma does not exist but is greatly needed. The histologic classification proposed by the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS) and the European Respiratory Society (ERS) has been shown to define prognostically significant subgroups of lung adenocarcinoma (ADC). Since then, various grading systems based on histologic patterns have emerged as promising methods to further discriminate patient risk of clinical outcomes. The aim of this work is to quantitatively assess the discrimination properties of a set of grading systems proposed in recent years to identify the best grading scale(s) independent of other clinical factors to predict recurrence.

      Methods:
      We considered five grading systems: (1) single predominant pattern as six subtypes; (2) as three grades of low (lepidic), intermediate (acinar, papillary) and high (micropapillary, solid); (3) two most predominant grades; (4) predominant grade with mitotic grade; and (5) predominant grade with cribriform pattern and mitotic activity criteria. We evaluated the performance of each grading system with the concordance predictive estimate (CPE). The CPE represents the probability that for any pair of patients, the patient with the better predicted outcome from the Cox model had the longer survival time. CPE > 0.80 demonstrates strong performance. To compare the performance of the grading systems, we determined the significance of the differences between the CPEs. Five-year recurrence-free probability (RFP) was derived using the Kaplan-Meier method.

      Results:
      We applied the grading systems to a uniform large cohort of stage I lung ADC (N=909). The scale based on the single predominant pattern as five subtypes yielded a CPE of 0.63 (95% CI, 0.59-0.67), indicating moderate discrimination. Our analysis showed that grading systems (1), (2), and (3) were not significantly different from each other, suggesting that identifying finer subtypes and second predominant pattern may not improve discrimination. Grading system (4) [CPE, 0.67; 95% CI, 0.63-0.71] yielded a significantly higher CPE than (1), (2) and (3) [p<0.01]. Grading system (5) [CPE, 0.67; 95% CI, 0.63-0.71] was significantly better than (1), (2) and (3) but not (4) [p=0.776]. The lack of improvement in discrimination with the inclusion of cribriform between (4) and (5) can be attributed to the significant relationship between cribriform pattern and mitoses. As the proportion of cribriform pattern increased, the amount of mitotic activity also increased (p<0.001). Under (2), the 5-year RFP of the intermediate grade was 0.81. The addition of cribriform and mitotic counts further classified the intermediate (acinar, papillary) grade such that those with <10% cribriform and low mitotic count had 5-year RFP of 0.89, while the 5-year RFP for the other combinations are between 0.73-0.75.

      Conclusion:
      Grading systems based on histologic patterns and mitotic activity out-perform those with only histologic pattern. This comparison study suggests that proposed grading systems (4) or (5) provide valuable information in discriminating patients with different risks of disease-recurrence in patients with lung ADC.

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      MINI01.08 - Survival Differences of Adenocarcinoma Lung Tumors with Squamous Cell Carcinoma or Neuroendocrine Profiles by Gene Expression Subtyping (ID 384)

      10:45 - 12:15  |  Author(s): G. Mayhew, N. Hayes, C. Perou, M. Lai-Goldman, H. Faruki

      • Abstract
      • Presentation
      • Slides

      Background:
      Gene expression profiling can provide valuable information beyond the morphologic diagnosis. A previously validated 52-gene Lung Subtype Panel (LSP) for differentiating lung tumors into Adenocarcinoma (AD), Squamous Cell Carcinoma(SQ), and Neuroendocrine (NE) was explored in several publically available lung tumor datasets, including the TCGA RNAseq dataset.

      Methods:
      The LSP 3-class nearest centroid predictor developed in array data was applied to AD and SQ samples in TCGA (RNAseq, n=1,160), the Director’s Challenge (Affy array, n=442), and Tomida et al. (Agilent array, n=117) datasets. Each sample was predicted as AD, SQ, or NE. Kaplan Meier plots and log rank tests were used to assess and compare 5-year overall survival in two gene expression groups, AD predicted AD (AD-AD) and AD predicted SQ or NE (AD-notAD). Cox models were used to assess survival differences while controlling for T stage, N stage, and proliferation (as measured by the PAM50 score). The distribution of samples among the AD subtypes (Terminal Respiratory Unit(TRU), Proximal Proliferative(PP), and Proximal Inflammatory(PI)) was investigated.

      Results:
      The predictor confirmed AD in 80% of the AD samples. AD samples were called SQ and NE by the LSP in 8% and 12% of cases, respectively. The AD-notAD group (AD by histology and SQ or NE by gene expression LSP) had worse survival than the AD-AD group (AD by both histology and LSP) in each data set (logrank p-value in TCGA, Director’s Challenge, and Tomida were 1.17e-06, 0.0009, and 0.0001, respectively). Pooling the 3 data sets and using a stratified cox model that allowed for different baseline hazards in each study, the hazard ratio comparing AD-notAD to AD-AD was 2.14 (95% CI 1.70-2.70). When we fit the model adjusting for T stage, N stage, and proliferation score, the HR was 1.70 (95% CI 1.31-2.20). Adenosubtype profiling of AD-notAD samples indicated that tumors were overwhelmingly of the PP or PI gene expression subtypes (209/213).

      Conclusion:
      Gene expression tumor subtyping may provide valuable clinical information identifying a subset of AD samples with poor prognosis. Poor prognosis adenocarcinoma samples belong to the PI and PP expression subtypes, and demonstrate elevated proliferation scores. This subset of AD tumors may be less responsive to standard adenocarcinoma management.

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      MINI01.09 - Discussant for MINI01.05, MINI01.06, MINI01.07, MINI01.08 (ID 3297)

      10:45 - 12:15  |  Author(s): E. Thunnissen

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI01.10 - Analysis of the Status of Lymphocyte Infiltration in Patients with NSCLC (ID 2292)

      10:45 - 12:15  |  Author(s): E.A. Richardet, M.E. Richardet, P.A. Hernandez, E. Pets, M. Cortes, M. Molina, A.A. Riso, C. Di Tada, L.P. Acosta, P. Companys, M. Paradelo

      • Abstract
      • Presentation
      • Slides

      Background:
      Current evidence highlights the potential role of tumor-infiltrating lymphocytes (TILS) as a prognostic factor in many types of tumors; in non-small cell lung cancer (NSCLC), this relationship is not well determined. TILs are being studied with different methods such as immunohistochemistry and optical microscopy. The primary endpoint is to identify TILS in patients with NSCLC, classified as present or absent, and its relation to progression-free survival (PFS) and overall survival (OS). Our secondary endpoint is to establish the relationship between the TILS and treatment received.

      Methods:
      Retrospective and analytical case study of Instituto Oncológico de Córdoba, from 2004 to 2014. 166 patients with stage IIIB and IV NSCLC were analyzed. TILS are descriptively classified as present or absent. Survival curves were calculated using the Kaplan-Meier method.

      Results:
      59% of patients had adenocarcinoma and 41% squamous cell carcinoma. 70% were men. 82% were smokers. 58% of patients with squamous histology and 65% with adenocarcinoma, showed TILS. In relation to first-line chemotherapy, 63,8% of patients received carboplatin-paclitaxel (CP) and 36,2% gemcitabine-cisplatin (GC). Patients with adenocarcinom with TILS present had higher PFS and OS; 8.86 and 13.43 months respectively, compared to patients with absent, 3.78 and 7.9 months. These differences were statistically significant (PFS: p = 0.000002 and OS: p = 0.003). The patients with squamous cell carcinoma with TILS had 6.78 and 12 months PFS and OS respectively. Those who had infiltrated absent had a PFS of 3.96 months and OS of 6.37 months. These differences were also statistically significant (PFS: p = 0.003 OS p = 0.001).

      Conclusion:
      Our study shows that patients whose pathological samples presented inflammatory infiltrate had higher OS and PFS. The presence of TILS could be used as an important prognostic factor in this patient population.

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      MINI01.11 - Transcriptome Sequencing of Tumor vs. Surrounding Non-Malignant Lung Tissue in Non-Small Cell Lung Cancer (ID 1765)

      10:45 - 12:15  |  Author(s): K. Reynders, E. Wauters, J. Vansteenkiste, H. Decaluwé, P. De Leyn, K. Nackaerts, S. Peeters, C. Dooms, W. Janssens, D. Lambrechts, D. De Ruysscher

      • Abstract
      • Slides

      Background:
      Both the response and the therapeutic ratio of targeted agents in NSCLC may depend on the expression of the target molecules in the tumor and the surrounding non-malignant lung tissue. We therefore performed transcriptome analysis and investigated correlations with histology, gender, age, CRP level and smoking status as well as evaluated the differential pathway expression in primary resected NSCLC and the surrounding non-malignant lung of the same patient.

      Methods:
      Transcriptome sequencing was performed on the primary tumor and distant lung tissue of the same patient from resection specimens of NSCLC patients. Differential gene expression between different conditions was identified using the statistical algorithms Cufflinks, EdgeR and DeSeq. Differential expression with P-values <0.05 after Benjamini-Hochberg correction was considered significant. Pathway analysis for overall tumor versus distant lung tissue was performed with the PANTHER gene classification platform using the Cufflinks, DeSeq and EdgeR differentially expressed gene sets as input.

      Results:
      Twenty-five patients were studied, 19 males and 6 females, with a median age of 69 years. Ten were current smokers, 14 former smokers (>4 weeks before surgery) and 1 non-smoker. Eleven patients had squamous cell carcinoma, 14 adenocarcinoma. A heat map with the results for the most commonly targeted genes in NSCLC is represented in figure 1. When compared to distant lung tissue, PD-L1 was downregulated in tumor tissue of adenocarcinoma and active smokers, but not in squamous cell carcinoma or ex-smokers. Internal control of tumor tissue of squamous vs. adenocarcinoma and ex-smokers vs. active smokers shows an important trend towards a higher expression of PD-L1 in squamous cell carcinoma and ex-smokers in both Cufflinks and EdgeR algorithms. Additional pathway analysis revealed 188 differentially regulated pathways. The most notable were downregulation of VEGF signaling, angiogenesis and B and T cell activation in tumor tissue when compared to distant lung tissue. Figure 1



      Conclusion:
      Our first results show a higher expression of PD-L1 in squamous tumors than in adenocarcinoma and a higher expression in tumors of ex-smokers than in those of active smokers. This may have consequences for the therapeutic ratio with anti-PD-L1 treatment. Downregulation of VEGFR-genes in tumor tissue was observed across almost all conditions. We will make this data more complete by adding methylation data as well as immunohistochemistry for protein localization.

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      MINI01.12 - Implementation of a Molecular Tumor Board: The Impact on Treatment Decisions for NSCLC Patients Evaluated at Dartmouth-Hitchcock in One Year (ID 2719)

      10:45 - 12:15  |  Author(s): L.J. Tafe, I.P. Gorlov, F. De Abreu, J.A. Lefferts, X. Liu, J.R. Pettus, J.D. Marotti, K.J. Bloch, V.A. Memoli, A.A. Suriawinata, C.E. Fadul, G.N. Schwartz, C.R. Morgan, B.M. Holderness, J.D. Peterson, G.J. Tsongalis, T.W. Miller, M.D. Chamberlin, K.H. Dragnev

      • Abstract
      • Presentation
      • Slides

      Background:
      Genetic profiling of tumors is a powerful approach to predict drug sensitivity and resistance. Definitive interpretation of the clinical significance of somatic mutations is possible for only a few well studied mutations. For the majority, prediction of clinical significance is challenging. We established a Molecular Tumor Board (MTB) at our Cancer Center to interpret individual patients’ tumor genetic profiles and provide treatment recommendations.

      Methods:
      DNA from tumor specimens was sequenced in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory to identify coding mutations in a 50-gene panel. Cases were evaluated by a MTB composed of molecular and anatomic pathologists, medical oncologists, basic research scientists, and genetic counselors.

      Results:
      35 cases were evaluated in 1 year by the MTB including 8 metastatic NSCLC cases. The most common reason for MTB referral was for recommendations on targeted therapies (91.9%), and for potential germline mutations. Tumors exhibited genetic heterogeneity: 71 different mutations were found across 300 genes (for NSCLC 18 mutations across 10 genes). In 18/32 of advanced/metastatic cases, MTB recommended non-standard therapy with a specific targeted agent (11 clinical trials; 7 off-label use), 4 of the 18 patients were subsequently treated with a MTB-recommended targeted therapy. The remaining 14 patients continued on current therapy because disease was stable (n=4), were treated with non-MTB-recommended standard therapy (n=4), declined conventional therapy (n=5), or died prior to receiving further therapy (n=1). For 4 out of the 8 NSCLC cases MTB recommended a BRAF inhibitor (1), RET inhibitor (1), or MET inhibitor (2). One patient received a BRAF inhibitor, 6 continued on current standard of care therapy, one declined therapy.

      Conclusion:
      Case evaluation by a multidisciplinary group of individuals in the context of a MTB frequently shapes treatment options and decisions. Importantly, anticipated obstacles to capitalizing on the benefits of a MTB such as access to drugs were rarely encountered in the entire cohort and in the NSCLC patients. Instead, the most commonly encountered reasons that MTB-recommended therapy was not administered stemmed from patient preferences, and genetic profiling at a very late stage of disease.

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      MINI01.13 - Biologically Driven Sub-Classification of Early Lung Adenocarcinomas (ID 2418)

      10:45 - 12:15  |  Author(s): D.A. Moore, E. Al Dujaily, J. Le Quesne

      • Abstract
      • Presentation
      • Slides

      Background:
      Early lung adenocarcinomas have previously been successfully sub-classified by Noguchi et al on the basis of histopathological characteristics, in particular the pattern of growth exhibited by the tumour and the response of the adjacent stroma. A wholly in situ pattern of growth characterises preinvasive lung lesions, namely atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS). It is not uncommon for large areas of an invasive tumour to show this in situ pattern of growth. Metastases to the lung from other organs can also show areas of in situ spread, and this shows that truly invasive malignant clones of cells can grow along the alveolar surface. This study aimed to identify whether the characteristics of in situ growth in an individual tumour may give an indication of the underlying tumour biology, and be of prognostic value.

      Methods:
      We reviewed all small (sub 35 mm) lung adenocarcinomas resected with curative intent over a 4 year period from our thoracic surgical centre. Nodal metastasis data was also collected, which the reviewing pathologists were blinded to. All tumour sections were reviewed by 2 thoracic histopathologists, who separated these into 4 categories, based on the patterns of growth, stromal changes, cytological changes between in situ and invasive components and overall symmetry of the lepidic growth. On the basis of these appearances early lung adenocarcinomas were divided into 4 groups. Type 1 showed minimal stromal reaction analogous to Noguchi A/B tumours. Types 2 and 3 are subdivisions of mixed in situ/invasive adenocarcinomas (equivalent to the Noguchi C group). Type 2 showed marked stromal changes in the invasive component and a cytologically lower grade asymmetrical lepidic component. Type 3 showed a concentric rim of lepidic growth cytologically similar to the invasive disease. Type 4 were wholly invasive tumours. Tumour type was subsequently correlated to pathological lymph node staging.

      Results:
      156 tumours were included and sub-classified. Of these 12 were type 1, 30 were type 2, 46 were type 3 and 68 were type 4. The rate of nodal metastasis was increased across the tumour types from 1 to 4, at 0%, 7%, 24% and 29% respectively.

      Conclusion:
      We find that partly invasive lung adenocarcinomas fall into two histologically and biologically distinct groups with different potential toward nodal metastasis. We suggest the type 2 tumours represent the emergence of an invasive subclone in an in situ adenocarcinoma lacking this property. The type 3 tumours have a lepidic region at their edge which represents infiltration of normal structures by migratory malignant cells but may have no truly biologically ‘in situ’ disease. This group also shows more tendency toward metastasis. Type 4 lesions without any kind of lepidic growth have the highest rate of nodal involvement, and their destructive pattern of growth represents the most aggressive form of early tumours. Future molecular characterisation of these lesions and their various components may further inform our understanding of the pathways of tumorigenesis in lung adenocarcinoma.

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      MINI01.14 - Discussant for MINI01.10, MINI01.11, MINI01.12, MINI01.13 (ID 3298)

      10:45 - 12:15  |  Author(s): K. Politi

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS 05 - Tumor Heterogeneity (ID 23)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 4
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      MS05.01 - Overview of Tumor Heterogeneity (ID 1864)

      14:15 - 15:45  |  Author(s): C. Swanton

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Despite advances in genomic technologies, most advanced solid tumors remain incurable and drug resistance is almost inevitable with limited biomarkers available to personalize therapy. Two important lessons have emerged from the comprehensive genomic analyses of cancers, which may provide an explanation for difficulties that have been encountered in biomarker development. First, each tumor contains an individual assortment of multiple genomic aberrations, few of which are shared between patients with the same histopathological tumor subtype. Second, emerging evidence suggests that these anomalies appear to vary both spatially and temporally within the tumor, indicating substantial intratumor heterogeneity. Increasingly, molecular evidence suggests that intratumor heterogeneity may contribute to tumor growth through a branched (polytypic) rather than a linear pattern of tumor evolution. Branched evolutionary growth and intratumor heterogeneity results in coexisting cancer cell subclones with variegated genotypes and associated functional phenotypes that may be regionally separated within the same tumor or distinct within one biopsy and alter in dominance over time. Variegated phenotypes, resulting from intratumoral genetic heterogeneity and the emergence of new subclones at relapse, are likely to have important implications for developing novel targeted therapies and for preventing the emergence of drug resistance. Intratumor heterogeneity and tumour sampling bias, resulting from single biopsy-driven biomarker discovery and validation approaches, may also contribute to the recently reported failures in implementation of robust biomarkers in the clinical setting. Clinical trial efforts taking into account tumour heterogeneity and its relevance to lung cancer will be addressed.

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      MS05.02 - How Does Tumor Heterogeneity Affect Molecular Testing on Biopsy Samples - Diagnostic vs. Rebiopsy (Resistance) (ID 1865)

      14:15 - 15:45  |  Author(s): K. Kerr

      • Abstract
      • Presentation
      • Slides

      Abstract:
      There are many different manifestations of heterogeneity within lung tumours. The three main considerations are: Morphologically, all of the neoplastic cells in a tumour are not identical. These structural differences may be due to differential protein expression and cellular differentiation, in turn the result of either differential expression of wild type genes, post-transcriptional modification or expression of altered genes (mutation, fusion genes etc). Nuclear morphology varies at least in part due to alteration in chromosome structure and number. Genetically, tumour cell populations are heterogeneous, as mentioned above but also it can be demonstrated that there may be heterogeneity related to driver mutations and other functionally important changes which may not necessarily be deterministic of cell morphology. Compositely speaking, tumours are made up of more than just neoplastic cells; stromal cells, immune cells and vasculature for example may account for much of the tumour bulk. Potentially, all three of these may impact upon molecular testing practice in the initial diagnostic phase and at re-biopsy. Molecular testing may be executed in many different ways and may seek many different molecular changes, such that the potential for heterogeneity making an impact on testing is considerable. Some molecular tests involve the morphological examination of a histological or cytological slide for the presence or absence of a particular factor. Proteins are normally assessed at a morphological level using immunohistochemistry. In situ hybridisation can be used to visualise and assess the presence of specific mRNAs. The same technique is used to assess DNA; specific gene copy numbers (gene amplification, polysomy), the creation of new ‘fusion genes’ during rearrangement using break-apart probes etc. These techniques require the molecular signal to be visualised in the cells of interest (usually the tumour cells); morphological and compositional tumour heterogeneity greatly impact the ease with which these techniques are executed. In lung cancer molecular testing, most current interest is in mutation testing. Compositional heterogeneity is a significant practical issue and drives recommendations that samples are pathologically assessed before extraction and mandates steps be taken to maximize the proportion of the sample for extraction that is tumour (macro- or microdissection techniques are often used). The dilution of mutant alleles by wild type alleles from non-neoplastic tissue may lower the mutation allele frequency below the threshold for detection. Are therapeutically important mutations such as those in exons 18-21 of EGFR heterogeneously expressed in tumour cells? This remains a matter of some controversy. Some have argued that since these are addictive driver mutations, they are present from the start of tumourigenesis and therefore present in every tumour cell, as determined by clonal expansion of the neoplastic cell population. Studies which demonstrate mutations in some areas of extracted tumour but not in others, are criticized by failing to use sufficiently sensitive techniques to detect mutations which are over-diluted by non-neoplastic DNA. It is known that selective amplification of mutant alleles (MASI) is heterogeneous in tumours and this may lead to apparent heterogeneity of mutation (detectable in some areas and not in others) when the number of mutant alleles per tumour cell varies in different parts of the tumour, and those areas with fewer mutant alleles are not detected due to poor test sensitivity. This explanation for apparent mutational heterogeneity has been challenged by some studies, however, which have appeared to demonstrate heterogeneity, even when highly sensitive techniques are used. Heterogeneity appears to be associated with lower response rates to EGFR TKIs in EGFR mutant tumours. Discrepancy has been reported in mutational findings between synchronous primary tumour and metastatic deposits. These findings are not universal for EGFR mutations, but when present, tend to involve a mutated primary with wild type metastases more often than the reverse. Data are few but could influence biopsy strategies. More than one mutation may be present in a lung cancer. In the context of molecular aberrations commonly tested for (EGFR, KRAS mutation; ALK rearrangement), double mutations are described but are rare. It is rather more common, for example for double or even triple EGFR mutations to be found in the same tumour sample. For example, in the author’s laboratory, double EGFR mutations are found in 13.8% of EGFR-mutated cases; triple mutations in 0.6%. KRAS double mutations are exceptionally rare (0.8%). The presence of more than one mutation, often at different allelic frequencies (such as can be estimated in many studies), implies different clones of cells bearing different mutations, and from this comes the concept of minor clones of therapeutically resistant cells which are responsible for some, though probably not all disease recurrences on TKI therapy. The best known scenario fitting this ‘minor clone’ hypothesis is the emergence of tumour bearing the EGFR T790M resistance mutation, as well as the original sensitizing mutation, for which an EGFR TKI was given. Resistant minor clones of MET amplified cells may be an alternative source of recurrent, EGFR TKI resistant disease. Similarly with ALK mutated or KRAS mutated recurrences during ALK TKI therapy for ALK rearranged tumours. This increasingly recognised outcome in patients treated with EGFR or ALK TKIs is now driving re-biopsy of recurrent disease into standard of care. Testing approaches and strategy for recurrent disease are still evolving and are driven by this concept of minor clone heterogeneity. Another finding in the re-biopsy setting is histological subtype transformation. Whilst the initial EGFR or ALK altered tumour is almost always adenocarcinoma, recurrent disease may be small cell, sarcomatoid or even squamous cell carcinoma. Little is known about the mechanism of this transformation; emergent clones of different histology or differential stem cell differentiation? There are also emergent data demonstrating that where recurrence occurs at multiple sites, detectable resistance mechanisms may vary. In a broader sense, heterogeneity of sensitivity to particular therapies, amongst tumour cells, is a major driver of treatment resistance and/or relapse, and effectively why there are so very few instances of true cure of lung cancer as a consequence of systemic therapy. The development of effective treatment strategies to overcome recurrence will require a better understanding of how tumour heterogeneity influences this process.

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      MS05.03 - Genomic Evolution and Tumor Heterogeneity (ID 1866)

      14:15 - 15:45  |  Author(s): D. Sidransky, E. Izumchenko, M. Brait, W. Westra

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Adenocarcinomas represent the most frequent subtype of lung cancer[1], and they are usually discovered late in the course of the disease even in the setting of vigilant radiographic and cytologic screening[2]. Despite improvements in molecular diagnosis and targeted therapies, the average 5 year-survival rate for lung adenocarcinoma remains only 15%[3]. Novel strategies based on the detection of genetic markers offer new hope for improved risk assessment, early cancer detection, therapeutic intervention and tumor surveillance, but the impact of these strategies has been limited by an incomplete understanding of the biology of lung cancer, particularly in its early developmental stages. Disappointingly, relatively few genetic alterations critical to the development of lung adenocarcinomas are currently recognized, and the timing and manner by which these alterations initiate and drive glandular neoplasia remains to be delineated. Recent refinements in the histologic classification of lung adenocarcinomas provide greater resolution of the sequential steps of glandular lung neoplasia[4]. Atypical adenomatous hyperplasia (AAH) is a microscopic discrete focus of cytologically atypical type II pneumocytes and/or Clara cells[5-6]. Once dismissed as a reactive change, AAH is now regarded as the first histologic step in a morphologic continuum culminating in the fully malignant adenocarcinoma. The link between AAH and invasive adenocarcinoma is strong and compelling: 5-20% of lungs resected for primary adenocarcinomas also harbor AAH, and AAH harbors some of the same genetic and epigenetic alterations found in adenocarcinomas including KRAS mutations, EGFR mutations, loss of heterozygosity at 9q and 16p, TP53 mutations, and epigenetic alterations in the WNT pathway. Like AAH, adenocarcinoma in situ (AIS) (formerly known as bronchioloalveolar carcinoma, BAC) is recognized as a non-invasive form of glandular neoplasia, but one that exhibits increased size, cellularity and morphologic atypia. In effect, it represents a next step in the continuum towards malignant adenocarcinoma. Minimally-invasive adenocarcinoma (MIA) is defined as a small adenocarcinoma (≤ 3cm) with a predominantly lepidic pattern and invasion of 5 mm or less in any one focus[4]. Invasive growth is present, albeit so limited that these carcinomas have been associated with 100% disease free survival[7,8]. This enhanced delineation of early glandular neoplasia provides a rational histologic framework for studying the timing of genetic alterations driving the early stages of lung tumorigenesis. “Branched evolutionary tumor growth” is the concept that cancers evolve by a repetitive process of clonal expansion, genetic diversification and clonal selection within the adaptive landscapes of tissue ecosystems[9]. In this study, to determine whether this phenomenon is operational during early stages of tumor progression, we evaluated lung glandular neoplasms spanning the full spectrum of early histologic progression using next generation sequencing (NGS) of coding regions from 125 well-characterized cancer-driving genes. We specifically targeted multifocal AAHs and advancing zones of histologic progression within individual AISs and MIAs. This multi-region sequencing revealed that clonal expansion is an early event that can be confirmed even in the earliest recognized step in glandular neoplasia. Moreover, the identification of significant genetic alterations such as KRAS mutations, loss of P53 activity and EGFR activation points to the presence of functionally relevant “drivers” that empower territorial expansion of subclones en route to malignancy. Importantly, these driver alterations are potentially measurable in clinical samples. Using ultra-sensitive droplet digital PCR (ddPCR), mutant DNA associated with early lesions was detected in a patient’s plasma and sputum providing proof of principle that even the earliest stages of glandular neoplasia can be detected via analysis of circulating DNA (circDNA). Our study provides the unique insight into the genetic alterations that initiate and drive the progression of lung glandular neoplasia and underlines the need for precise definition of these events to improve proper diagnosis and early detection of tumors. Identification of mutational features which characterize relevant lesions that actually progress to cancers will allow to better predict the fate of these early lesions and tailor the right therapy to prevent the progression. 1. Colby T. V., Koss M. N. & W., T. in Tumors of the Lower Respiratory Tract (eds Colby T. V., Koss M. N., & Travis W. D.) 91-106 (Armed Forces Institute of Pathology Washington DC, 1994). 2. Frost, J. K. et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Johns Hopkins study. The American review of respiratory disease 130, 549-554 (1984). 3. Imielinski, M. et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107-1120, doi:10.1016/j.cell.2012.08.029 (2012). 4. Travis, W. D. et al. Diagnosis of lung adenocarcinoma in resected specimens: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Archives of pathology & laboratory medicine 137, 685-705, doi:10.5858/arpa.2012-0264-RA (2013). 5. Weng, S. Y., Tsuchiya, E., Kasuga, T. & Sugano, H. Incidence of atypical bronchioloalveolar cell hyperplasia of the lung: relation to histological subtypes of lung cancer. Virchows Archiv. A, Pathological anatomy and histopathology 420, 463-471 (1992). 6. Chapman, A. D. & Kerr, K. M. The association between atypical adenomatous hyperplasia and primary lung cancer. British journal of cancer 83, 632-636, doi:10.1054/bjoc.2000.1317 (2000). 7. Borczuk, A. C. et al. Invasive size is an independent predictor of survival in pulmonary adenocarcinoma. The American journal of surgical pathology 33, 462-469, doi:10.1097/PAS.0b013e318190157c (2009). 8. Yim, J. et al. Histologic features are important prognostic indicators in early stages lung adenocarcinomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20, 233-241, doi:10.1038/modpathol.3800734 (2007). 9. Greaves, M. & Maley, C. C. Clonal evolution in cancer. Nature 481, 306-313, doi:10.1038/nature10762 (2012).

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      MS05.04 - Hetergeneity and Drug Resistance (ID 1867)

      14:15 - 15:45  |  Author(s): S. Peters

      • Abstract
      • Presentation

      Abstract not provided

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Author of

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    MINI 01 - Pathology (ID 93)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 2
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      MINI01.02 - Is It Possible to Distinguish between Second Primary vs Metastasis in Resectable Synchronous Nodules with the Same Histotype of Lung Cancer? (ID 2122)

      10:45 - 12:15  |  Author(s): A.G. Nicholson

      • Abstract
      • Presentation
      • Slides

      Background:
      The prognostic significance of additional lung nodules in the setting of lung cancer is important as the impact on survival is often considered for the justification of surgical selection in the management of patients with synchronous nodules. TNM 7 down staged the impact on T category but did not distinguish between second primary versus metastasis. Traditional distinctions such as the Martini criteria do not take the same histological type into account and classification continues to improve (e.g. IASLC classification of adenocarcinoma). The aim of our study is to determine if it is possible to distinguish between second primary versus metastases in patients with the same histological type and quantity any difference in survival.

      Methods:
      We retrospectively analysed data from a prospectively collated database at our institution. We collected all the records which included two resected nodules. The detailed pathology reports of these patients were retrieved and the histology, subtype and pTNM of tumours documented. Slides were re-reviewed to determine the histological subtypes according to the current IASLC adenocarcinoma classification. Survival was calculated using Kaplan Meier methods and adjusted survival compared using Cox regression on R (statistical software).

      Results:
      From April 1999 to February 2013, a total of 2925 lung cancer resection were performed. Of these, 379 (14%) operations fulfilled the inclusion criteria of multiple nodules with 316 having synchronous tumours (83.3%) and 63 having metachronous tumours (16.6%). The tumours were ipsilateral in 87.3% and the vast majority were in the same lobe (70.9%). For synchronous tumours, patients with the same histological type had a poorer 5-years survival rate compared to tumours with different histology (p=0.041). The pathologist’s designation between second primary versus intra-pulmonary metastasis distinguished between overall survival (p= 0.001) and this remained statistically significant in the tumours of the same cell type (p= 0.035). Figure 1. Survival outcomes between patients with multiple nodules classified as second primary versus intra-pulmonary metastasis Figure 1



      Conclusion:
      Our results suggest that distinction between second primary and intra-pulmonary metastasis remains important for staging as appreciable differences in survival were observed in patients with synchronous nodules. Survival was poorer in patients with multiple nodules of the same histologic type (compared to different histology) and within the same histological subtype it is possible for pathologists to distinguish between second primary and intra-pulmonary metastasis. As this is currently confirmed only on pathologic stage in the majority, it presently does not influence the selection for surgery.

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      MINI01.03 - Pathology-Imaging Agreement in Distinguishing Separate Primary Tumours and Intrapulmonary Metastasis in Staging of Multiple Lung Cancers (ID 2659)

      10:45 - 12:15  |  Author(s): A.G. Nicholson

      • Abstract
      • Presentation
      • Slides

      Background:
      The 7[th] TNM staging system for lung cancer recommended staging for cases with multiple nodules viewed as intrapulmonary metastases (IM) as T3 (same lobe), T4 (ipsilateral different lobe) and M1a (contralateral lobe), whilst those classified as separate primary tumours (SPTs) as T(x)NM where “x” is the number of primary tumours, either as a number or “m” for multiple. With an increase in patients presenting with multiple nodules, we sought to develop a set of criteria for c-staging on imaging and to determine the agreement between clinical and pathological staging in a cohort of resected lung cancers who had multiple nodules.

      Methods:
      In 2013 and 2014, there were a total of 48 consecutive cases with available imaging resected with multiple tumours, ranging from 2 to 5 nodules. Of these, one case was excluded as it was a carcinoid with background DIPNECH. These cases were classified as SPT or IM based on previously published criteria (Girard et al. Am J Surg Pathol 2009;33:1752-64). Imaging criteria were generated based on clinical experience in similar fashion with indicators of SPT being 1) Lesions of equivalent size (one not more than 100% of the other) 2) Smaller lesion is spiculated , 3) At least one lesion is subsolid, 4) Presence of field change. (For signs 1 and 2, if the lesions were in different lungs, an absence of mediastinal disease on imaging was required). Cases with at least one positive sign were classified as SPTs. The interobserver agreement between radiologists and pathologist were then generated.

      Results:
      Of the 47 cases, the additional nodules were not identifiable on CT in 7 cases. In the remaining 40 cases, there was agreement in 28 cases, of which 16 were SPTs and 12 were IM. Of 12 cases where there was disagreement, only 3 were SPTS and the majority were cases classified on pathology as IM. There was 70% agreement, greater than that expected by chance (p = 0.002) with a kappa value of 0.41.

      Conclusion:
      Moderate agreement can be achieved in terms of clinical and pathological staging of lung cancers presenting with multiple nodules using imaging and pathologic criteria. Using pathology as the gold standard, there was greater agreement in categorisation of SPTs (84% (16/19)) than IM (57% (12/21)).

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    MINI 23 - Lung Cancer Risk: Genetic Susceptibility and Airway Biology (ID 135)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Screening and Early Detection
    • Presentations: 1
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      MINI23.12 - HAases and HAS in Lung/Bronchial Pre-Neoplastic Lesions: Impact on Prognosis (ID 395)

      16:45 - 18:15  |  Author(s): A.G. Nicholson

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is the result of a multi-step accumulation of genetic and/or epigenetic alterations; therefore, a better understanding of the molecular mechanism, by which these alterations affect lung cancer pathogenesis, would provide new diagnostic procedures and prognostic factors for early detection of recurrence. In this regard, many have studied molecular or other markers in pre-neoplastic and neoplastic lesions to discover what might relate to tumor recurrence and shortened survival.

      Methods:
      A series of 136 lung/bronchial and lung parenchyma tissue samples from 136 patients consisting of basal cell hyperplasia, squamous metaplasia, moderate dysplasia, adenomatous hyperplasia, severe dysplasia, squamous cell carcinoma and adenocarcinoma were analyzed for the distribution of hyaluronidase 1 (HYAL1) and 3 (HYAL3), and hyaluronan synthases 1 (HAS1), 2 (HAS2) and 3 (HAS3) by immunohistochemistry.

      Results:
      HYAL 1 was significantly more expressed in basal cell hyperplasia compared to moderate dysplasia (p=0.01), atypical adenomatous hyperplasia (p=0.0001) and severe dysplasia (p=0.03). A lower expression of HYAL 3 was found in atypical adenomatous hyperplasia compared to basal cell hyperplasia (p=0.01) and moderate dysplasia (p=0.02). HAS 2 was significantly higher in severe dysplasia compared to basal cell hyperplasia (p=0.002), and equally higher in squamous metaplasia compared to basal cell hyperplasia (p=0.04). HAS 3 was significantly expressed in basal cell hyperplasia compared to atypical adenomatous hyperplasia (p=0.05) and severe dysplasia (p=0.02). A lower expression of HAS 3 was found in severe dysplasia compared to squamous metaplasia (p=0.01) and moderate dysplasia (p=0.01). Epithelial HYAL 1 and 3 and HAS 1, 2 and 3 expressions were significantly increased in pre neoplastic lesions compared to neoplastic lesions. Comparative Cox multivariate analysis controlled by N stage and histologic types of tumors showed a significant association between poor survival and high pre neoplastic cell associated to HAS3 (HR=1.19; p=0.04).

      Conclusion:
      We concluded that localization of HYALs and HASs in lung/bronchial pre-neoplastic and neoplastic lesions was inversely related to malignancy, these factors emerging as potentially important diagnostic markers in patients with suspicion of lung cancer.

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    MINI 38 - Biology and Prognosis (ID 167)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      MINI38.03 - Validation of a Specific Missense GTF2I Mutation in More Indolent Thymic Epithelial Tumours (ID 3017)

      18:30 - 20:00  |  Author(s): A.G. Nicholson

      • Abstract
      • Presentation
      • Slides

      Background:
      Thymic epithelial tumours (TETs) are rare intrathoracic cancers that can be invasive and very difficult to treat. There is currently a huge gap in the understanding of the basic science behind their development as well as great clinical need for development of effective treatments. Recently a missense mutation (T>A, at the same position on chromosome 7, 74146970) was identified in GTF2I at high frequency (78%) in the more indolent type A and AB thymomas. We examined the frequency of this alteration in an independent cohort of well clinically characterized patients from the UK.

      Methods:
      Tumour samples were collected from 94 patients from a single tertiary cardiothoracic centre in the UK, the Royal Brompton & Harefield NHS Foundation Trust (London). These were subject to histological assessment by expert Consultant Histopathologists to confirm the diagnosis and determine tumour abundance. DNA was extracted with Quiagen’s QIAamp DNA FFPE Tissue Kit (Catalogue No. 56404). PCR and Sanger sequencing was performed with semi-nested primers.

      Results:
      We assessed the frequency of the GTF2I mutation in a total of 94 TETs with a tumour abundance of at least 70%. The mean age for all patients was 57 and the male: female ratio was 1:1.25 The GTF2I mutation was seen in 25 of 87 evaluable TETs (29%) and was present more commonly in type A (85%) and AB (46%) thymomas. The frequency decreased to 9% in type B1 (1/11) and 5% in type B2 thymomas (1/19). In our cohort the mutation was not detected in any B3 thymomas or carcinomas, including neuroendocrine tumours or two cases of thymic hyperplasia. Interestingly all AB thymomas with the mutation had a much lower percentage of mutant alleles compared to the majority of the A thymomas. Twenty-three of the 25 patients (92%) with the mutation had Stage I – II disease at presentation and had complete resection of their thymoma.

      Conclusion:
      Our results confirm the presence of the GTF2I mutation at a high frequency in type A and AB thymomas in an entirely different patient cohort. Although the frequency of the mutation in type A thymomas in our cohort is very similar to what was reported originally (85% and 82% respectively) it was lower in the AB thymomas (46% and 74% respectively). Explanations for this include the smaller sample number in our cohort and a higher percentage of the lymphocytic component in our samples than that in the original series. The lower mutation frequency in the B subtypes and carcinomas compared to the original series could be due to the smaller numbers in our cohort. We aim to address these issues by expanding our validation series to over 200 samples. Whole exome and RNA sequencing of TETs is ongoing and will allow us to further confirm and extend this finding.

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    ORAL 24 - CT Detected Nodules - Predicting Biological Outcome (ID 122)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Screening and Early Detection
    • Presentations: 1
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      ORAL24.03 - Increasing Incidence of Non-Smoking Lung Cancer: Presentation of Patients with Early Disease to a Tertiary Institution in the UK (ID 2717)

      10:45 - 12:15  |  Author(s): A.G. Nicholson

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer in never-smokers is recognised as a distinct entity. Many are expected to present late. As there are no established aetiological factors, identification of patients at risk is challenging. The aim of the study is to define the incidence and clinical features of never-smokers presenting sufficiently early for surgery to determine if it is possible to identify patients at risk.

      Methods:
      We retrospectively analysed data from a prospectively collected database of patients who underwent surgery at our institution. The incidence was defined as number of never-smokers versus current and ex-smokers by year. Clinical features at presentation were obtained and collated as frequency (percentage).

      Results:
      A total of 2170 patients underwent surgical resection for lung cancer from March 2008 to November 2014. The annual incidence of developing lung cancer in never-smokers increased from 13, 15, 18, 19, 20, 20 to 28 percent respectively, attributable to an absolute increase in number and not a change in the ratio of never smokers to current and ex-smokers. A total of 436 (20%) patients were never smokers. The mean age at presentation was 60 (16 SD) years and 295 (67%) were female. Good lung function was observed with mean predicted FEV1 of 90% (23 SD) and FVC of 97% (25 SD). The majority histological types were adenocarcinoma 54% and carcinoid 27%. The main presenting features were non-specific consisting of cough in 142 (34%), chest infections in 75 (18%) and haemoptysis in 46 (11%). Recurrent chest infections were predominantly a symptom of central carcinoid tumours (30 versus 15 percent; P=0.004). A total of 59 (14%) were detected on incidental chest film, 127 (30%) on incidental CT, 32 (7%) on incidental PET/CT and 4(1%) on incidental MRI.

      Conclusion:
      We observed more than double the annual incidence of never smokers presenting with non small cell lung cancer, in the last 7 years, increasing from 13 to 28 percent, and hypothesise that this is representative of the UK, as we are one of the highest surgical volume centres in our country. Patients present with non-specific symptoms and the majority were detected on incidental imaging. We conclude that imaging is likely to play a more important role and further efforts need to be expended on early detection of lung cancer in this increasing cohort without any observable risk factors.

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    ORAL 40 - Biology 1 (ID 154)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      ORAL40.02 - Molecular Landscape of Malignant Mesothelioma from Whole Exome Sequencing (ID 2439)

      16:45 - 18:15  |  Author(s): A.G. Nicholson

      • Abstract
      • Presentation
      • Slides

      Background:
      Whole exome sequencing has revealed key genetic events in several cancer types that have been successfully translated into clinical benefits. These advances are still lacking in malignant mesothelioma (MM), a highly aggressive malignancy with limited effective therapy. Frequent BAP1 mutations occur in a subset of this disease but the full molecular landscape of MM is still poorly characterized.

      Methods:
      We have therefore conducted whole exome sequencing of tumours from the pleura for 36 cases of MM. DNA from matched blood was available for 7 of the cases and was also sequenced. The variants were identified with GATK tools and annotated with ANNOVAR. Variants were filtered with the following criteria: quality score ≤ 50, present in dbSNP138, 1000 genomes variants and NHLBI ESP 6500 variants. Mutations with deleterious functional consequences predicted by Polyphen-2, SIFT and Mutation Taster tools were confirmed by Sanger sequencing.

      Results:
      A total of 9,064 variants (3,256 somatic) were identified. We confirmed mutations in genes previously described to be mutated in MM in 5 cases: BAP1 (R227C, Q684X, H141P), NF2 (76_76del, R221X) and TP53 (I195N). In BAP1 wt tumours (6 of the 7 cases with matched blood), we confirmed somatic mutations in 5 genes encoding components of either MAPK or WNT signaling pathways. In addition, we validated somatic mutations in 12 genes across 4 of the 6 cases, many of which are novel in MM and are involved in chromatin modification. We also observed these genes to be mutated in BAP1 wt tumours in the 29 additional unmatched MM cases.

      Conclusion:
      Thus our data suggests that in addition to BAP1, mutations in genes associated with MAPK, WNT signaling and the chromatin remodeling complex may represent a consistent pattern of molecular alterations in MM.

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    P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P1.04-010 - Pilot Internet Survey of Interobserver Variability in Pathology Diagnoses of Multiple Tumor Nodules (ID 2851)

      09:30 - 17:00  |  Author(s): A.G. Nicholson

      • Abstract
      • Slides

      Background:
      The distinction between separate primary lung cancers (SPLC) or intrapulmonary metastases (IM) is of great clinical importance because of the substantial staging and prognostic implications. With the broad implementation of CT screening for lung cancer, the recognition of multiple tumor nodules is increasingly common. Currently, similarities and differences in histology between two tumors provide the most definitive distinction between SPT and IM. However, the level of agreement among pathologists regarding this question has not been tested. The IASLC Pathology Committee and the Multidisciplinary SPT Working Group has addressed this issue through a pilot online survey. This study assesses the feasibility and reports preliminary results of a web-based survey to determine interobserver variation in distinguishing SPT and IM.

      Methods:
      A pilot study was conducted to test whether multiple observers could assess a collection of 50 cases of multiple tumors through a digital web-based system. Five pairs of resected nodules were assembled from the University of Colorado and scanned into an image database using an Aperio AT2 slide scanner (Leica Biosystems) with a 40X objective. Reviewers were asked to review slide images, to provide a histological diagnosis according to WHO criteria, to answer questions regarding specific histological details related to each nodule and to determine whether the multiple nodules were SPT and IM. Combined results were evaluated for level of concordance on the central question of primary or metastatic status. Results were also correlated with EGFR, KRAS, ALK and TP53 mutational status.

      Results:
      A total 21 pulmonary pathology subspecialists completed the survey, evaluating 10 nodules from 5 patients. Ten of the reviewers were from the US, 3 from Japan, 2 from the UK, and one each from Canada, France, Germany, the Netherlands, Korea and Sweden. On the question of SPLC vs IM, 10 reviewers agreed on all cases and these determinations were regarded the histological consensus. There was 85% overall concordance with the consensus diagnosis. Most of dissenting opinions related to a single case. In all but one instance, tumors from the same individual with different histological diagnoses were designated SPLC. However, in 30% of the cases, tumors from the same individual with identical histological diagnoses were determined to be SPLC. The histological attributes regardless of WHO diagnostic category that significantly (each p>0.0001) contributed to this conclusion included lepidic growth, cell size, nuclear pleomorphism and nucleolar prominence. The mutational status of these cases was in complete agreement with the histological consensus. Mutations that distinguished SPT included KRAS, EGFR or TP53 mutation in only one member of a tumor pair or different EGFR mutations in each member of a pair. In IM, identical KRAS mutation was found in both members of a tumor pair.

      Conclusion:
      In this pilot study a high level of consensus was achieved in separating SPLC vs or IM. A large minority (30%) of tumor pairs with identical histological diagnoses were determined to be SPLC suggesting that histological features beyond those used for WHO classification are taken into account when determining SPT status.

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    P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P3.04-011 - A Validation Study for the Use of ROS-1 Immunohistochemistry in Screening for ROS-1 Translocations in Lung Cancer (ID 2826)

      09:30 - 17:00  |  Author(s): A.G. Nicholson

      • Abstract
      • Slides

      Background:
      ROS-1 translocations are a rare genetic abnormality in lung cancers that, when identified, are a target for personalised therapy. The current test of choice is FISH, although with a rate of no more than 1-2%, screening using FISH is an expensive proposition. A further possibility is using immunohistochemistry (IHC) as a screening tool and commercial antibodies are now available that identify the ROS-1 protein in tumour cells. We present our data in undertaking a validation study for potential diagnostic usage.

      Methods:
      Given the relative rarity of the translocation and the fact the most driver mutations occur in isolation, a test cohort of cases was selected from patients recruited to phase 1 of the Cancer Research UK-Stratified Medicine Project (CRUK-SMP), who were identified as negative for EGFR, KRAS and/or BRAF mutations, as well as ALK translocations. Negative cases were then screened with an antibody for ROS-1 (D4D6, Cell Signalling, 1 in 300 dilution) and scored as negative, weakly positive or moderately positive, along with the percentage of positive cells. Cases were then sent for FISH analysis for the ROS-1 translocation, with a cut-off of > or = to15%, and the sensitivity and specificity of positive staining for ROS-1 was generated.

      Results:
      From 170 patients recruited from our institution into CRUK-SMP phase 1, a total of 103 patients were wild type for the above mutations (90 for all 4 genetic abnormalities. 9 further cases had failed tests for one and 4 for two mutations (6 carcinoids, 38 squamous cell carcinomas, 5 small cell carcinoma, 2 adenosquamous carcinoma, 1 pleomorphic carcinoma, 3 large cell carcinoma, 2 large cell neuroendocrine cell carcinoma, 7 non-small cell carcinoma (on biopsy) and 39 adenocarcinomas). 39 cases were tested (adenocarcinoma = 37, adenosquamous carcinoma = 2) with FISH, and one case was positive (78% positive cells). FISH testing was negative in 35 cases with scores of 1-8%, and three cases failed. The one positive case was positive on IHC (>90% of cells, moderate staining). In the 35 cases negative for FISH, four cases showed variable positivity on IHC (20, 40,50, 90%, moderate staining) and five cases showed weak focal staining (<5, <5, 10, 20, 30%, weak staining). The remainder were negative on IHC. All non-adenocarcinomas were negative on IHC. Several cases show positive staining of entrapped background pneumocytes and alveolar macrophages, making scoring problematic in some adenocarcinomas.

      Conclusion:
      Moderate staining for ROS-1 using IHC, independent of percentage positive cells, showed high sensitivity (100%) for tumours that contained a high level of translocated cells. However, specificity was at best 50%, even if a cut-off of 50% positive cells was applied. Pathologists also need to be aware of background staining so cases are not interpreted as false positives.

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    P3.06 - Poster Session/ Screening and Early Detection (ID 220)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Screening and Early Detection
    • Presentations: 1
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      P3.06-015 - Is the Development of Primary Lung Adenocarcinoma Simply Due To 'Bad Luck'? (ID 2825)

      09:30 - 17:00  |  Author(s): A.G. Nicholson

      • Abstract
      • Slides

      Background:
      Recently, Tomasetti and Vogelstein proposed that the variation in cancer risk among tissue is explained by the number of stem cell division, and this was widely interpreted as “bad luck” due to random mutations arising during DNA replication in normal non-cancerous stem cells. Smoking is widely considered as the main aetiological risk factor for the lung cancer and the aim of our study is to evaluate the hypothesis comparing the differences in proportions of the two main histological subtypes in smokers and never smokers in a patients with early stage primary lung cancer to determine the impact of smoking on the development of squamous and adenocarcinoma.

      Methods:
      Data were retrospectively analysed from a prospectively collated database at our institution over a 7 year period. Histological data were extracted and compared for the two main historical subtypes of squamous and adenocarcinoma (subtyped according to the new IASLC adenocarcinoma classification). Frequencies were compared using Fishers exact or Chi square tests as appropriate to the data.

      Results:
      A total of 2170 patients underwent surgical resection for lung cancer at our institution from March 2008 to November 2014 of which 436 (20%) patients were never smokers. The mean age (SD) was 66 (12) years and 48% were female. The relative proportion of patients with squamous carcinoma was significantly different between smokers 323 (27.0%) and never-smokers 16 (5.7%) with P <0.001 with a risk ratio of 4.70 (95% CI 2.9 to 7.6). However the relative proportions between patients with adenocarcinoma were similar between smokers 578 (48.3%) and never-smokers (54.4%) P=0.06 with a risk ratio of 0.89 (0.79 to 1.00).

      Conclusion:
      Our results suggest that smoking remains an important aetiological risk factor for the development of primary lung squamous cell carcinoma. For adenocarcinoma, the relative proportions between smokers and never-smokers were similar (in fact lower for smokers) supporting Tomasetti and Vogelstein hypothesis of random mutations arising during DNA replication in normal non-cancerous stem cells– or simply put as “bad luck”.

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    P3.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 226)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      P3.08-020 - Clinicopathological Features of Primary Intra-Thoracic Follicular Dendritic Cell Sarcomas (ID 2869)

      09:30 - 17:00  |  Author(s): A.G. Nicholson

      • Abstract
      • Slides

      Background:
      Follicular dendritic cell sarcoma (FDCS) is defined in the WHO as a neoplastic proliferation of spindle/ovoid cells with morphological and immunohistochemical features of follicular dendritic cells. It is a rare tumour with no clear aetiology, often misdiagnosed and difficult to characterise. Occasionally it occurs in association with the hyaline-vascular type of Castleman disease which, in such cases, is considered its precursor lesion. Most cases are reported in lymph nodes, however several cases with extranodal presentation have been described. Despite the fact that metastasis are common in the lung, only 7 cases have been reported as primary pulmonary FDCS. Surgical excision with chemotherapy is the treatment of choice giving transient, partial response in some cases. We report our experience within the last 15 years of 6 cases of FDCS arising in the mediastinum and in the lung.

      Methods:
      The study included 7 patients referred to Royal Brompton Hospital between 2001 and 2014 with a diagnosis of FDCS. Criteria for inclusion were morphological and immunohistochemical: fascicles/whorls of spindle to ovid cells with features resambling follicular dendritic cells and the expression of one or more specific markers (CD21, CD23 and CD35). We performed a broad immunohistochemical panel and we looked for the presence of Castleman’s disease and the type of inflammatory infiltrate in the background. Clinical information were obtained from hospital records and clinicians.

      Results:
      After review, we identified 6 cases consistent with the diagnosis of FDCS, four males and two females between 25 and 61 years old. One case was excluded because of equivocal expression of specific markers. Three patients presented with a mediastinal mass and one having two recurrences within the study period. Two patients presented with a lung mass and one with a radiological pleurally based mass infiltrating the lung and chest wall. Clinical presentation was mainly with cough and chest pain due to the location of the tumour.Histologically all cases showed an atypical spindle cell proliferation with storiform pattern within a mixed inflammatory stroma. Mitotic rate was generally low except in case of recurrences. In three cases Castleman’s features were present in the background.Five out 6 cases (83.3%) expressed CD21, CD35, p53 and cyclin D1, 3 cases (50%) expressed CD35, S100, lysozyme and bcl2 and 2 cases (33.3%) expressed KP1, PGM1, CD45, CD4, CD30 and bcl6. All were negative for keratins. Four cases (66.7%) were initially misdiagnosed as pleomorphic malignant tumour.Background showed a variably amount of B and T cells, with T cells expressing CD4 and PD1. Follow up data were available for 4 patients: one died after 5 years, 2 were alive with no recurrence after one year and one is alive after 8 years and two recurrences.

      Conclusion:
      FDCS is a rare tumour and should be considered in cases with a malingant spindle cells proliferation negative for the most common markers. Our series also showed Cyclin D1 expression in this tumour which has not previously been reported. This may raise the possibility for a new more effective therapeutic approach but further studies are needed.

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