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Andrew G Nicholson



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    ES08 - The Pathologist - An Essential Member of the Patient Care Team (ID 776)

    • Event: WCLC 2018
    • Type: Educational Session
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 206 AC
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      ES08.03 - Mesothelioma, Thymic Epithelial Tumors and Others (ID 11385)

      14:10 - 14:30  |  Presenting Author(s): Andrew G Nicholson

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA09 - Lung Cancer Surgical and Molecular Pathology (ID 908)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 202 BD
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      MA09.07 - Developing a Pathological Grading System in Predicting Prognosis for Invasive Mucinous Adenocarcinomas (ID 12124)

      15:55 - 16:00  |  Author(s): Andrew G Nicholson

      • Abstract
      • Presentation
      • Slides

      Background

      Invasive mucinous adenocarcinoma (IMA) is a variant of lung adenocarcinoma with a predominance of mucinous type neoplastic epithelial cells, often showing aerogenous spreading and multifocality. The correlation between histopathological features and prognosis has not been well studied due to its relatively rare incidence compared to non-mucinous adenocarcinoma. Our study aims to evaluate the significance of histopathological features in relation to clinical outcome.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed a series of 101 cases of IMAs resected between 2000 to 2012, comprised of stage I~IV tumours. Five pathological features were scored for each tumour: predominant histological pattern (lepidic: 1, acinar/papillary: 2, solid/micropapillary/cribriform: 3), nuclear atypia (mild:1, moderate: 2, severe: 3), mitotic activity per 2mm2 (<4: 0, ≥4: 1), necrosis (absent: 0, present: 1), lymphovascular invasion (absent: 0, present: 1), and pleural invasion (PL0: 0, PL1: 1, PL2: 2, PL3: 3). Each pathological feature was correlated with disease-free (DFS) and overall survival (OS). Cases were then divided into three grades based on the total pathological score (grade I: 2-4, grade II: 5-7, grade III: 8-11) and correlated with outcome.

      4c3880bb027f159e801041b1021e88e8 Result

      Nuclear atypia, mitotic activity, lymphovascular invasion, and pleural invasion showed significant correlation with OS (p < 0.05). Histological pattern and necrosis showed no significant correlation in relation to OS (p = 0.09). Pleural invasion and lymphovascular invasion were significantly correlated with DFS (p < 0.05), while a trend was noted for nuclear atypia (p = 0.086). No correlation with DFS was seen for histological pattern (p = 0.499), necrosis (p = 0.464), and mitotic activity (p = 0.931). There was an inverse correlation between OS and grade, with grade III tumours showing a significantly worse prognosis (p = 0.001). There was no significant difference in DFS between the three groups (p = 0.201).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our pathological scoring system was able to stratify IMAs into three separate groups with statistically significant differences in overall survival between grade III and grades I/II tumours.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA21 - Molecular Subtyping, CBL3, and Non Coding RNA (ID 924)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 205 BD
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      MA21.03 - Heterogeneity in MET Copy Number and Intratumoural Subsets in Pleomorphic Lung Carcinoma: Implications for MET Directed Therapy in NSCLC (ID 13061)

      15:25 - 15:30  |  Author(s): Andrew G Nicholson

      • Abstract
      • Presentation
      • Slides

      Background

      Pleomorphic Lung Carcinoma (PC) is a rare subtype of NSCLC poorly responsive to systemic therapy. Both epithelial and sarcomatoid phenotypes exist, suggesting an important role of epithelial-to-mesenchymal transition. We aimed to determine MET copy number (CN) within individual tumour components and establish its correlation with immunohistochemistry (IHC) expression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Histopathological assessment and diagnosis was confirmed for 57 cases of resected PCs from the Royal Brompton Hospital Biobank. DNA was isolated from multiple regions and MET copy number determined by digital droplet PCR (ddPCR). IHC using c-MET (EP1454Y) and H-scores were assigned independently by two histopathologists.

      4c3880bb027f159e801041b1021e88e8 Result

      Cases: median age 66 years, 36.2% T3, 41.4% T2 and 13.8% T1. In the epithelial areas, adenocarcinoma was the most common (45.6%) followed by undifferentiated NSCLC (22.8%) and squamous (17.5%): in pleomorphic areas, mixed giant/spindle cell (35%), spindle cell (31%) and giant cell (26%). MET-CN gain by ddPCR was seen in 25/58 (44%) of cases (CN>2.3). 3/58 (5%) had CN>5. There was a significantly higher MET-CN in pleomorphic compared to epithelial areas (2.7 versus 2.2 P = 0.046). While this did not correlate with c-MET IHC, an H-score of >223 had 75% sensitivity and 52.4% specificity for MET-CN >5.0 (Figure).

      met expression in pc2.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      There is intra-tumoral heterogeneity in MET-CN between tumoural subsets. This may account for the development of pleomorphic phenotypes in PC. Consequently MET-directed therapies such as crizotinib may be highly effective only against the MET-amplified component in PC and may not impact on overall tumoural control due to minimal efficacy in the non-amplified epithelial component. MET expression using IHC does not correlate with MET-CN determined by ddPCR, although may provide a screening tool for MET amplification. MET aberrations are potentially druggable and therefore this has implications for sampling and MET testing.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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      MA26.07 - ROS1 (SP384) Immunohistochemistry Inter-Reader Precision Between 12 Pathologists (ID 12387)

      14:10 - 14:15  |  Author(s): Andrew G Nicholson

      • Abstract
      • Presentation
      • Slides

      Background

      ROS1 positive non-small cell lung cancer (NSCLC) patients can be treated with specific tyrosine kinase inhibitors including crizotinib. ROS1 positivity is often clinically detected by fluorescence in situ hybridization (FISH), however ROS1 IHC can be used to screen samples prior to FISH confirmation of ROS1 status. The ROS1 (SP384) antibody detects ROS1 with high sensitivity, specificity, and consistency. Consistent interpretation of a ROS1 IHC assay between pathologists is important patient evaluation. Here we present inter-reader precision of 12 pathologists across 60 FFPE cases stained with ROS1 (SP384).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective cohort of 60 FFPE NSCLC cases stained with H&E, Rabbit Monoclonal Negative Control Ig, and ROS1 (SP384) were selected to represent positive, negative, and borderline ROS1 IHC status. Twelve practicing lung pathologists independently scored the cases as positive or negative around a cutoff of cytoplasm staining in > 30% tumor cells at a ≥2+ intensity level using Pathotrainer software (Pathomation bvba). Scoring was blinded to other readers and ROS1 status of the cases. Overall percent agreement (OPA), negative percent agreement (NPA), and positive percent agreement (PPA) were calculated in comparison to the group mode. Average overall percent agreement (AOPA), average positive agreement (APA), and average negative agreement (ANA) were calculated pairwise for each reader pair. Following independent assessment, participating pathologists conducted a discordant case review establishing consensus reads for all 60 cases and compared 44 cases to available FISH results.

      4c3880bb027f159e801041b1021e88e8 Result

      OPA of each of the 12 readers to the mode was 96.4% (95% CI 93.9-98.6) with PPA of 96.3% (95% CI 92.7-99.4) and NPA of 96.5% (95% CI 92.8-99.5). Pairwise AOPA between each of the 12 readers was 94.5% (95%CI 91.2-97.7) with APA 94.0% (95% CI 89.5-97.6) and ANA 95.0% (95%CI 91.2-97.9).

      Consensus IHC scores were concordant with FISH 90.0% (40/44 cases).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Inter-reader precision around a cutoff of >30% tumor cells with cytoplasmic staining at a ≥2+ intensity level was high in interpreting ROS1 (SP384) in NSCLC samples. Case review highlighted confirmation with FISH in questionable cases and staining patterns to be considered when interpreting ROS1 (SP384) IHC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    OA03 - Advances in Lung Cancer Pathology (ID 897)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 205 BD
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      OA03.03 - Phase 2B of Blueprint PD-L1 Immunohistochemistry Assay Comparability Study (ID 14530)

      10:50 - 11:00  |  Author(s): Andrew G Nicholson

      • Abstract
      • Presentation
      • Slides

      Background
      PD-L1 immunohistochemistry (IHC) has been established as companion or complementary diagnostic assays, each developed as predictive biomarker for specific anti PD1/PD-L1 immunotherapies. The Blueprint (BP) phase 1 comparability study demonstrated that three PD-L1 assays (28-8, 22C3, SP263) showed comparable analytical performance for assessment of PD-L1 expression on tumor cells (TPS), while the SP-142 PD-L1 assay appeared to stain a lower percentage of tumor cells when compared to the other assays. The first part of BP phase 2 (BP2A) re-affirmed these findings in a larger cohort of ‘real life’ specimens scored by 24 experienced pulmonary pathologists, and also showed that the 73-10 assay developed for avelumab showed greater sensitivity than all other assays to detect PD-L1 on tumour cells. BP2A also demonstrated generally excellent inter-observer agreement for tumor cell PD-L1 scoring using both glass slides and digital images, with slightly lesser agreement for the cytology samples included in the study cohort. Inter-observer agreement for immune cell scoring on glass or digital slides was poor. Phase 2B of Blueprint (BP2B) aimed to compare PD-L1 scoring on triplet samples representing large tumor resection blocks, small biopsy samples and fine needle aspirate cell blocks prepared from the same tumor. a9ded1e5ce5d75814730bb4caaf49419 Method
      Triplet samples of large resected tumor block, small biopsy sample and fine needle aspirate cell block (the latter two taken from the resected tumour specimen) were gathered from 31 resected primary lung cancers (17 adenocarcinomas, 12 squamous cell carcinomas, and 2 large cell carcinomas). Sections from all 93 blocks were stained with the pharmDx 28-8 and 22C3, the FDA-approved SP142 and SP263, or clinical trial associated 73-10 PD-L1 assays, in a CLIA-approved immunohistochemistry laboratory. All H&E and PD-L1 IHC slides were scanned and digital images were used to score all cases by the same 24 pathologists involved in BP2A. As before, tumor cells PD-L1 staining were scored as continuous variable and into 7 cut-off-defined categories, as used in various immune checkpoint inhibitor trials. Immune cells were not scored. 4c3880bb027f159e801041b1021e88e8 Result
      The data reaffirm the relative comparability of 28-8, 22C3 and SP263 assays across the range of scores; SP142 assay scores were lower, those for 73-10 higher. Inter-observer agreement between readers ranged from moderate to near perfect (Kappa-Fleiss (K-F) scores generally >0.7); best overall agreement was on aspirates. Overall, the agreement between scores on the different sample types from the same tumor was good (most K-F scores >0.7); aspirates showed no significant difference from biopsy samples or whole surgical blocks. In contrast to biopsies and surgical blocks, scores could, however, not be rendered in about 14% of aspirate sections. 8eea62084ca7e541d918e823422bd82e Conclusion
      The results of BP2B confirms earlier results and also demonstrate comparable performance for fine needle aspirates in those cases where TPS scores were possible. 6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.09 - Pathology (Not CME Accredited Session) (ID 941)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.09-25 - Invasive Size (Not Total Size) Predicts Overall Survival in Invasive Mucinous Adenocarcinomas (ID 12127)

      16:45 - 18:00  |  Author(s): Andrew G Nicholson

      • Abstract
      • Slides

      Background

      The 8th TNM pathological staging system advocates usage of the invasive size, rather than the total size, in the pT staging of pulmonary non-mucinous adenocarcinomas. However, few studies have addressed this issue regarding invasive mucinous adenocarcinomas (IMAs). Our study aimed to determine whether invasive size correlates with individual histological parameters and also whether it provides better prognostic stratification than overall tumour size.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed a series of 101 cases of IMAs resected between 2000 to 2012, comprised of stage I~IV tumours. In each IMA, the percentage of each growth pattern (lepidic, acinar, papillary, solid, micropapillary, and cribriform) was assessed in 5% increments. Due to the frequent multifocal nature of IMAs, the invasive size was calculated by multiplying the total tumour size with the total percentage of invasive (non-lepidic) components in all cases. The adjusted T (aT) stage, as determined by the cumulative size of invasive components, was correlated with disease-free (DFS) and overall survival (OS). Correlation with 7th and 8th T stage (using total tumour size) were also performed as comparison.

      4c3880bb027f159e801041b1021e88e8 Result

      The 7th aT stage was positively correlated with higher host response (tumour-associated inflammation), necrosis, pleural invasion, and nodal metastasis, while the 8th aT stage was significantly correlated with necrosis, vascular invasion, pleural invasion, and nodal metastasis. Using aT stage for risk stratification, we found a significant difference in OS in both 7th and 8th aT stage between the subgroups (p = 0.002 and 0.006, respectively), whereas DFS failed to reach statistical significance. There was a significant difference in DFS when using the 8th T stage (p = 0.002), whereas no significant difference was noted in OS. A trend was noted in DFS (p = 0.054) while OS failed to reach statistical significance when applying the 7th T staging.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study showed that invasive size may be a superior prognostic indicator compared to total size, which provides a rationale for prognostic stratification of IMAs based on the extent of invasive growth patterns (or invasive size) rather than total tumour size.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.06 - Mesothelioma (Not CME Accredited Session) (ID 955)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.06-41 - Differentiating Sarcomatoid Mesothelioma from Pleomorphic Carcinoma and Chest Wall Sarcoma Using GATA-3/MUC4/BAP1 IHC (ID 12694)

      16:45 - 18:00  |  Author(s): Andrew G Nicholson

      • Abstract
      • Slides

      Background

      Current immunohistochemistry (IHC) biomarkers, or so-called “mesothelial markers”, lack sensitivity and specificity in differentiating sarcomatoid mesothelioma from pleomorphic carcinoma of the lung, and poorly differentiated chest wall sarcoma. Hence it frequently poses a diagnostic challenge for pulmonary pathologists. In this pilot study we evaluated the diagnostic performance of two recently proposed IHC biomarkers, GATA-3 and MUC4, in conjunction with BAP1.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Sarcomatoid mesothelioma or sarcomatoid- predominant biphasic mesothelioma (10 cases), pleomorphic carcinoma of the lung (10 cases) and poorly differentiated primary or metastatic chest wall or pleural sarcoma (10 cases) were retrieved from our diagnostic archive. Resections or large biopsies were selected over small biopsies whenever possible. All the cases were diagnosed between 2009 and 2017 by a specialist pulmonary pathologist and discussed at the local multi-disciplinary team meeting in relation to final diagnosis. Whole slide GATA-3 (L50-823, pre-diluted), MUC4 (8G7, 1:50) and BAP1 (C-4, 1:50) immunohistochemistry was performed using Ventana Benchmark ULTRA system. Lymphocytes (GATA-3/BAP1) and bronchiolar epithelium (MUC4) were used as internal positive controls. Loss of GATA-3/BAP1 and MUC4 staining was defined as complete loss of nuclear or membrane & cytoplasmic signals, respectively. Any staining intensity above the external negative controls was accepted as positive. Extent of positive staining was grouped as <1%, 1-50% and >50%.

      4c3880bb027f159e801041b1021e88e8 Result

      GATA-3 was positive in 8/10 sarcomatoid mesothelioma, 6/10 chest wall/pleural sarcoma and 2/10 pleomorphic carcinoma of the lung. MUC4 positivity was observed exclusively in pleomorphic carcinoma of the lung (6/10), but only focally. BAP1 loss was infrequently observed in all three types of tumours.

      wclc figure 1 jpeg.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The combination of GATA-3 and MUC4 immunohistochemistry show promise as markers that would help in distinguishing these three tumours. The role of BAP1 is uncertain. These pilot results warrant an extended study that consists of a larger cohort to evaluate the utility of these biomarkers.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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