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MAURO GIULIO PAPOTTI



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    GR03 - Problem Areas for the Next WHO Classification of Lung Cancers (ID 31)

    • Event: WCLC 2019
    • Type: Grand Rounds Session
    • Track: Pathology
    • Presentations: 1
    • Now Available
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      GR03.01 - High Grade Neuroendocrine Tumors (Now Available) (ID 3309)

      15:45 - 17:15  |  Presenting Author(s): MAURO GIULIO PAPOTTI

      • Abstract
      • Presentation
      • Slides

      Abstract

      The four-tier WHO 2015 classification scheme of lung neuroendocrine neoplasms (NEN) includes morphologically and clinically heterogeneous conditions (1). High grade tumors typically encompass large and small cell neuroendocrine carcinomas (LCNEC and SCLC, respectively). The survival of these two types of poorly differentiated NENs is similar and significantly different from that of the well differentiated carcinoid tumors. Thus their appropriate classification is a clinically relevant exercise. While the morphological features of classical SCLC and those of low grade carcinoids allow to easily take these two tumors apart, the correct classification of some atypical carcinoids and of LCNEC is less straightforward.

      In fact, morphology alone may not be sufficient to identify the various histotypes (that still represent the most relevant prognostic parameter in NENs), and to specifically classify aggressive forms into the group of high grade carcinomas. Even immunophenotype profiling may fail to some extent and only the more recent genetic data have been able to better stratify variations within each single histological type (as recognized by the current WHO criteria). According to such criteria (1), high grade neuroendocrine (NE) carcinomas are defined as malignant tumors made of large or small cells having a solid, diffuse (or more rarely irregularly organoid) growth patterns, with extensive necrosis and a mitotic index exceeding 10 per 10 high power fields. This definition fits for a relatively wide group of tumors, whose clinical behavior is not perfectly overlapping. In particular, while SCLC are invariably associated to a high mitotic rate and high grade cytological features including classical salt&pepper chromatin pattern, LCNEC belong to a grey area that merges with atypical carcinoids on the one side (having intermediate values of mitotic index), and with SCLC on the other (with the occurrence of combined small and large cell NE carcinoma variants).

      Immunophenotypic markers are not always useful for accurately stratifying NENs. In fact, chromogranin A, synaptophysin and CD56 are generally expressed by the majority of NENs, though with a different intensity and distribution (for example, SCLC may be negative or only focally reactive for chromogranin, but invariably expresses synaptophysin) (2,3). Some transcription factors such as TTF1 and hASH1 are usually intensely positive in high grade tumors, both LCNEC and SCLC, as opposed to carcinoid tumors, that are generally not reactive (with the possible exception of some peripherally located spindle cell carcinoids).

      The proliferation index, as defined by Ki-67 immunohistochemistry, was proposed as an effective complementary tool to identify different prognostic subgroups, although its use is not officially accepted by the WHO classification with the exception of a differential diagnostic role in small biopsy specimens (1). Indeed, high grade tumors have a much higher mean Ki67 index compared to carcinoids (mean values of 60-80% versus 2-8%). For this reason, the integration of Ki67 data with the two official morphological parameters (necrosis and mitoses) proved effective in a proposed grading system (4).

      The spectrum of aggressive NENs is unfortunately complicated by the existence of combined NENs, having areas of brisk proliferation admixed with a relatively quiescent tumor cell population. In addition, rare cases have been demonstrated to progress from well differentiated carcinoid to high grade NE carcinomas. The relationship between low and high grade NENs is further supported by the observed heterogeneous genetic profile of high grade tumors, namely LCNEC. Apart from the original detection of the carcinoid-specific MEN1 mutations in a small fraction of “morphological” LCNECs, and of two other different groups of LCNEC, one related to SCLC and the other associated to a genetic signature of non small cell lung carcinomas (5,6), recent comprehensive genomic and transcriptomic analyses of 75 LCNEC identified two molecular subgroups, labeled "type I LCNEC" (having bi-allelic TP53 and STK11/KEAP1 gene alterations, and a NE profile with ASCL1 high / DLL3 high / NOTCH low), and "type II LCNEC" (enriched for bi-allelic inactivation of TP53 and RB1 genes, reduced NE markers, ASCL1 low / DLL3 low / NOTCH high, upregulation of immune-related pathways) (7). In this latter study, some genomic alterations were shared with pulmonary adenocarcinomas and squamous cell carcinomas.

      In a more recent study (8), the reverse approach was used, starting from a series of carcinoid tumors. With the aim of a full molecular NEN characterization by integrative analyses of genomic, transcriptomic, and methylome data, three molecular groups were identified: clusters A through C were enriched by typical carcinoids (TC), atypical carcinoids (AC) and LCNEC, respectively. Interestingly, the latter cluster also included a subgroup of six “morphological” ACs, here designated “supra-AC” that were molecularly similar to LCNEC, thus supporting the postulated link between the low and high grade lung NENs. Therefore, misclassification is common between AC and LCNEC, due to the existence of “carcinoid-like” LCNEC (5,7), possibly resulting from the evolution of a well- into a poorly differentiated NEN (9), as also reported in thymic LCNEC (10).

      In conclusion, the correct classification of high grade lung NENs is in general easily obtained in conventional forms of oat cell SCLC and of highly atypical and proliferating LCNEC. Conversely, the separation is more subtle in the presence of the rare intermediate (grey zone) cases, standing between AC and LCNEC, that probably correspond to the recently proposed category of “G3 NE Tumor” in the pancreas (11) and the gastrointestinal tract (expected in the next WHO classification of digestive system NENs).

      References

      1 Travis et al. WHO classification of tumors of the lung. IARC press, Lyon, 2015

      2 Thunissen E et al. J Thorac Oncol 2017;12:334-346

      3 Yatabe et al. J Thorac Oncol 2019;14:377-407

      4 Rindi G et al. Endocr Rel Cancer 2013;21:1-16

      5 Rekthman N et al. Clin Cancer Res 2016; 22, 3618-3629

      6 Simbolo M et al. J Pathol 2017; 241: 488–500

      7 George J et al. Nat Commun 2018; 9: 1048 (1-13)

      8 Alcala N et al. Nat Commun 2019 (in press)

      9 Pelosi G et al. Virchows Arch 2018;472:567-577

      10 Fabbri A et al. Virchows Arch 471, 31-47

      11 Lloyd RV et al. WHO classification of endocrine tumors. IARC press, Lyon, 2017

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-45 - Immune-Oncology Gene Expression Profiles Allow Lung Cancer Patients’ Stratification and Identification of Responders to Immunotherapy (ID 2339)

      09:45 - 18:00  |  Author(s): MAURO GIULIO PAPOTTI

      • Abstract
      • Slides

      Background

      Immune-checkpoint inhibitors (ICI) represent a new standard of care for Non-Small Cell Lung Cancer (NSCLC) patients. Beyond tumor PD-L1 protein expression, other biological parameters are emerging as potential predictive biomarkers. We evaluated high-throughput immune-related Gene Expression Profiles (GEP) in tumor tissue from ICI-treated patients, correlating immune activation data with clinical response to immunotherapy.

      Method

      RNA was isolated from tumor tissues of 44 metastatic NSCLC patients treated with Nivolumab (as 2nd or 3rd line therapy) and collected from different Italian centers. The nCounter® PanCancer IO360™ Panel was applied on NanoString platform to analyze 770 genes involved in key immuno-oncology pathways. Clinical-pathological data, as well as best response to ICI treatment, have been collected.

      Result

      Patients were dichotomized as responders (7 Partial Response and 19 Stable Disease) and non-responders (18 Progressive Disease). A pre-identified T-cell inflamed signature was evaluated at single gene level and the expression of CCL5, CD27, CD276, CMKLR1, CXCL9, CXCR6, LAG3, NKG7, PDCD1LG2, PSMB10, TIGIT was higher in the responder group, although not reaching statistical significance. Moreover, higher STING, CGAS and IRF3 genes expression level appeared to be more commonly associated with non-responder patients.

      Considering the disease stage at the time of diagnosis, a different gene panel (CCL5, CD27, CD274, CD8A, CXCL9, CXCR6, HLA-DQA1, HLA-DRB1, HLA-E, IDO1, LAG3, NKG7, PSMB10, TIGIT) resulted to be more expressed in early and locally advanced (16 from stage I to IIIA) compared to metastatic (28 stage IV) tissue samples.

      Conclusion

      A trend in differential expression patterns was observed between responders and non-responders NSCLC patients treated with Nivolumab and additional analyses on this cohort could reveal specific pathways able to predict unresponsiveness to ICI treatment. Different disease stage seems also to influence immune-related GEPs.

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    P2.06 - Mesothelioma (ID 170)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.06-23 - The Accuracy of Video-Assisted Thoracic Surgery Pleural Biopsy in Patients with Suspected Malignant Pleural Mesothelioma: A Real-Life Study (Now Available) (ID 1690)

      10:15 - 18:15  |  Author(s): MAURO GIULIO PAPOTTI

      • Abstract
      • Slides

      Background

      The heritage of occupational and environmental asbestos exposure in Piedmont, Italy, is an enduring epidemic of malignant pleural mesothelioma (MPM). Pleural biopsy (PB) performed via thoracoscopy (or video-assisted thoracic surgery (VATS)) remains the diagnostic gold standard for patients with suspected mesothelioma. The aim of our study was to investigate the accuracy of PB via VATS and to analyze the diagnostic path of the patients who experienced an initial MPM misdiagnosis.

      Method

      Patients who underwent PB by VATS for suspected MPM from 2004 to 2013 were analyzed . The Registry of Malignant Mesothelioma (RMM) records were examined to crosscheck incident cases and to recognize misdiagnosed MPM. Sensitivity and specificity of the initial PB assessment versus the final classification of cases by RMM were evaluated. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using log-rank test.

      Result

      km_mpm.png

      Data of 552 patients were analyzed. Of those, MPM was diagnosed in 178 cases (32%) and no false-positive PBs were observed. Sensitivity and specificity were 93% and 100%, respectively. The number of false-negative PBs was 14 (2%). Of those, 10 (71%) had an initial diagnosis of chronic pleuritis, 3 (28.5%) of atypical mesothelial proliferation and 1 had reactive mesothelial proliferation. All of them reported a history of asbestos exposure and the correct diagnosis was reached after a median of 160 days (interquartile range 86-243) as follow: 9 (64%) after a further PB by VATS, 3 (22%) by cytology examination of a pleural effusion, 1 (7%) by fine-needle biopsy and 1 (7%) by open surgery . The median survival time of the patients with eventual MPM diagnosis was 13.8 months (CI 95%: 10.3-16.6). ). One- and 4-year survival were 52% and 10% in MPM PB positive cases and 50% and 19% in false-negative cases (P=0.66) (Figure 1).

      Conclusion

      When a history of asbestos exposure is reported and a strong clinical suspicion persists after a negative PB, iterative biopsy attempts should be considered. In high-volume centers, MPM misdiagnosis rate remains small and future advancement in diagnostic technologies could further increase the accuracy of diagnosis.

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    P2.09 - Pathology (ID 174)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.09-18 - Lymphocyte Infiltration Pattern and STING Expression Identify Different Prognostic Groups in Early Stage NSCLC (ID 2536)

      10:15 - 18:15  |  Author(s): MAURO GIULIO PAPOTTI

      • Abstract
      • Slides

      Background

      Lymphocyte infiltration has been described has a potential biomarker of lung cancer patients’ survival. Different studies de-convoluted immune cell compartment (i.e. stromal CD8 density) trying to identify clinically relevant immune patterns.

      Method

      A series of 178 early-stage (IB-IIIA) NSCLC has been retrospectively collected at Department of Oncology, San Luigi Hospital (Orbassano, Italy). From Formalin-Fixed and Paraffine-Embedeed (FFPE) tumor blocks, Tissue Microarrays (TMA) were constructed (4 cores were selected for each case). Lymphocyte infiltration pattern was determined by light-microscopy on Hemathoxylin-Eosin (HE) whole slides. Immunohistochemistry was performed as follow: CD8 (SP57) and STING (D2P2F) antibodies were tested with Ventana Benchmark and PD-L1 (22C3) with Dako Autostainer. Infiltration pattern has been clustered in 4 different categories: brisk-diffuse, non-brisk multifocal, non-brisk focal and none. CD8 was quantified as positivity percentage, PD-L1 through TPS (<1%, 1-49% and ≥50%) and STING taking advantage of H-score. Overall survival (OS) and Progression Free Survival (PFS) were estimated using the Kaplan-Meier method and compared using log-rank test.

      Result

      Most represented patients had following features: male (119-71%), current or previous smokers (145-82%), stage II (94-53%) and adenocarcinoma histology (119-67%). Distribution of lymphocyte infiltration pattern was: 110 cases with brisk-diffuse (62%), 56 with non-brisk (multi-focal and focal) (31%) and 12 with none pattern (7%). CD8 positivity was distributed in 3 categories: high (66 - 37%), intermediate (75 - 42%) and low (37 -21%) density. For PD-L1 TPS analyses 111 cases (62%) had <1%, 39 cases (22%) 1-49% and 28 cases (16%) >50%. STING high-expressors were 88 (49%) and low-expressors 90 cases (51%). Lastly, were identified 81 samples (45%) with STING positivity at high-density on immune cells (IC) and 97 samples (55%) with low-density. As expected, Brisk-infiltrated samples presented an higher CD8 density (p=0.015). At PFS analyses, STING IC resulted associated (p=0.05) with a worse PFS for high-density patients. At OS analyses, brisk lymphocyte infiltration pattern appeared to have a negative impact (p=0.05) and STING higher-expressors on tumor cells had a worse prognosis (p=0.04).

      Conclusion

      NSCLC with wider lymphocyte infiltration and expression of immune activation markers (as STING) appeared to be associated with a worse prognosis (PFS and OS). These date need further validation at multivariate analyses.

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      P2.09-24 - IASLC Global Survey for Pathologists on PD-L1 Testing for Non-Small Cell Lung Cancer (ID 906)

      10:15 - 18:15  |  Author(s): MAURO GIULIO PAPOTTI

      • Abstract
      • Slides

      Background

      PD-L1 immunohistochemistry (IHC) is now performed for advanced non-small cell lung cancer (NSCLC) patients to examine their eligibility for pembrolizumab treatment, as well as in Europe for durvalumab therapy after chemoradiation for stage III NSCLC patients. Four PD-L1 clinical trial validated assays (commercial assays) have been FDA/EMA approved or are in vitro diagnostic tests in multiple countries, but high running costs have limited their use; thus, many laboratories utilize laboratory-developed tests (LDTs). Overall, the PD-L1 testing seems to be diversely implemented across different countries as well as across different laboratories.

      Method

      The Immune biomarker working group of the IASLC international pathology panel conducted an international online survey for pathologists on PD-L1 IHC testing for NSCLC patients from 2/1/2019 to 5/31/2019. The goal of the survey was to assess the current prevalence and practice of the PD-L1 testing and to identify issues to improve the practice globally. The survey included more than 20 questions on pre-analytical, analytical and post-analytical aspects of the PDL1 IHC testing, including the availability/type of PD-L1 IHC assay(s) as well as the attendance at a training course(s) and participation in a quality assurance program(s).

      Result

      344 pathologists from 310 institutions in 64 countries participated in the survey. Of those, 38% were from Europe (France 13%), 23% from North America (US 17%) and 17% from Asia. 53% practice thoracic pathology and 36%, cytopathology. 11 pathologists from 10 countries do not perform PD-L1 IHC and 7.6% send out to outside facility. Cell blocks are used by 75% of the participants and cytology smear by 9.9% along with biopsies and surgical specimens. Pre-analytical conditions are not recorded in 45% of the institutions. Clone 22C3 is the most frequently used (61.5%) (59% with the commercial assay; 41% with LDT) followed by clone SP263 (45%) (71% with the commercial assay; 29% with LDT). Overall, one or several LDTs are used by 57% of the participants. A half of the participants reported turnaround time as 2 days or less, while 13% reported it as 5 days or more. Importantly, 20% of the participants reported no quality assessment, 15%, no formal training session for PD-L1interpretation and 14%, no standardized reporting system.

      Conclusion

      There is marked heterogeneity in PD-L1 testing practice across individual laboratories. In addition, the significant minority reported a lack of quality assurance, formal training and/or standardized reporting system that need to be established to improve the PD-L1 testing practice globally.

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