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Johan Botling

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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: 5
    • 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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      GR03.02 - Adenocarcinoma (Now Available) (ID 3310)

      15:45 - 17:15  |  Presenting Author(s): Andrew G Nicholson

      • Abstract
      • Presentation
      • Slides

      Abstract

      Many of the limitations in the WHO 2004 classification for adenocarcinomas (confusion over the term bronchioalveolar adenocarcinoma, usage of the term “mixed pattern” and no classification for small biopsy/cytology specimens) were addressed in the 2011 IASLC/ATS/ERS multidisciplinary classification,1 and this proposal was adopted by the 2015 WHO classification with minor changes.2

      Adenocarcinoma in situ, minimally invasive adenocarcinoma, lepidic predominant adenocarcinoma and invasive mucinous adenocarcinoma have now replaced the term “bronchioloalveolar adenocarcinoma”, with subsequent TNM staging changes to use invasive size for T factor size.3 However there remains significant interobserver variation between pathologists in relation to the point at which invasion starts, indicating that tighter definitions of distinguishing a lepidic pattern from other invasive patterns are needed, especially in areas where these disagreements have a clinical impact.

      Interobserver agreement between pathologists has been shown to be much better for distinction of invasive patterns (acinar, papillary, micropapillary, solid). Accumulating data supports the 2015 WHO proposal that the cribriform pattern be regarded as a pattern with adverse prognostic significance. It is also proposed that micropapillary be expanded to include a filigree, as well as classical, pattern. One of the most important needs is for pathologists to better recognize the morphologic spectrum of the micropapillary pattern which is often underestimated. Several publications suggest prognostic groupings as lepidic, acinar/papillary and solid/micropapillary as a stratification, and these have been shown to predict response to adjuvant therapy.4 This leads into the issue of grading of resected adenocarcinomas and the presence of more aggressive histological patterns as a minor component.

      The histological feature termed “spread through airspaces” or STAS has been shown to be a poor prognostic factor for all major histologic types of lung cancer, including adenocarcinoma where it is frequently seen. There is considerable evidence that the presence of STAS carries prognostic significance,5,6 in particular in relation to non-anatomic resections, but there remains a need to identify where STAS begins and artefactual dissemination of tumour due to handling and processing of specimens ends.7 A tighter definition and evidence of international reproducibility is needed.

      While subtyping of histological patterns is well established in non-mucinous adenocarcinomas, mucinous adenocarcinomas are less well characterised. Various patterns of mucinous differentiation have been proposed, as well as assignment of histologic patterns in similar fashion to non-mucinous ADCs although only invasive mucinous adenocarcinomas (IMA) and colloid adenocarcinomas currently have specific subgroupings.2 This proposal has proved to be well founded given the specific molecular features and behaviour pattern of IMAs,8 although again work is required to refine prognostication. More data is also required tumours with mixed mucinous and non-mucinous areas.

      Resections are increasingly occurring after neoadjuvant therapy, with there is already a need to assess these in a structured fashion.9,10 Work is ongoing within the IASLC Pathology Committee to propose a method for classification in this clinical scenario.

      The 2015 WHO classification saw a seminal change in its structure, in that a classification system was proposed for biopsies and cytology specimens, rather than solely resections. In addition, a major theme utilized in the 2015 WHO classification was a multidisciplinary approach incorporating surgery, imaging, oncologic respiratory medicine, molecular biology as well as pathology. which needs to be maintained into the discussions of future classifications.1 This approach must remain and will likely need to be enhanced, given the revolution in molecular and immunologic characterisation of tumours, especially adenocarcinomas, and all these new clinically relevant findings will need to be part of pathologic reporting for the ensuing decades. The relative importance and structure of morphologic, immunohistochemical, molecular and immunologic data will need to be incorporated into a system that is appropriate not just for the most advanced cancer centres where all data are available but for laboratories and diagnostic services in underserved countries where morphologic features may be the only ones available.

      REFERENCES

      1. Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society: international multidisciplinary classification of lung adenocarcinoma: executive summary. Proc Am Thorac Soc 2011;8:381-5.

      2. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyons, France.: International Agency for Research on Cancer (IARC); 2015.

      3. Travis WD, Asamura H, Bankier AA, et al. The IASLC Lung Cancer Staging Project: Proposals for Coding T Categories for Subsolid Nodules and Assessment of Tumor Size in Part-Solid Tumors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol 2016;11:1204-23.

      4. Tsao MS, Marguet S, Le Teuff G, et al. Subtype Classification of Lung Adenocarcinoma Predicts Benefit From Adjuvant Chemotherapy in Patients Undergoing Complete Resection. J Clin Oncol 2015;33:3439-46.

      5. Chen D, Mao Y, Wen J, et al. Tumor Spread Through Air Spaces in Non-Small Cell Lung Cancer: a systematic review and meta-analysis. Ann Thorac Surg 2019.

      6. Kadota K, Nitadori J, Sima CS, et al. Tumor Spread through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences after Limited Resection for Small Stage I Lung Adenocarcinomas. J Thorac Oncol 2015;10:806-14.

      7. Blaauwgeers H, Flieder D, Warth A, et al. A Prospective Study of Loose Tissue Fragments in Non-Small Cell Lung Cancer Resection Specimens: An Alternative View to "Spread Through Air Spaces". Am J Surg Pathol 2017;41:1226-30.

      8. Fernandez-Cuesta L, Plenker D, Osada H, et al. CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov 2014;4:415-22.

      9. Qu Y, Emoto K, Eguchi T, et al. Pathologic Assessment After Neoadjuvant Chemotherapy for NSCLC: Importance and Implications of Distinguishing Adenocarcinoma From Squamous Cell Carcinoma. J Thorac Oncol 2019;14:482-93.

      10. Blumenthal GM, Bunn PA, Jr., Chaft JE, et al. Current Status and Future Perspectives on Neoadjuvant Therapy in Lung Cancer. J Thorac Oncol 2018;13:1818-31.

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      GR03.03 - Pleomorphic Carcinomas (Now Available) (ID 3311)

      15:45 - 17:15  |  Presenting Author(s): Alain Borczuk

      • Abstract
      • Presentation
      • Slides

      Abstract

      The category of sarcomatoid carcinoma in lung cancer classification is composed of five tumor types - pleomorphic, spindle, giant cell, carcinosarcoma and blastoma. While these are all relatively rare tumors, the pleomorphic carcinoma category is the most common of this group. Pleomorphic carcinomas are defined as combinations of adenocarcinoma, squamous carcinoma or large cell carcinoma with a spindle or giant cell element. It may be that spindle or giant cell examples, while diagnostically more challenging, represent variants of similar histogenesis but with complete mesenchymal transformation. Small cell carcinoma in a pleomorphic carcinoma is exceedingly rare. These tumors are often bulky tumors at presentation, with a propensity for central necrosis. Historically, this tumor is highly aggressive and treatment refractory.

      The histology of this tumor type includes correct identification of a malignant spindle component morphologically, or a giant cell component. While nuclear pleomorphism is an aspect of the tumor, the degree of nuclear enlargement, multinucleation and the presence of emperipolesis all distinguish giant cells of pleomorphic carcinoma from nuclear enlargement in high grade tumors. Immunohistochemistry has be helpful in identifiable a cytokeratin positive spindle or giant cell component. The use of zinc finger E-box binding homeobox1 (ZEB1), a protein involved in epithelial-mesenchymal transition to identify spindle or giant cell component of these tumors, both in small samples and resections, is emerging.

      Molecular alterations have also been linked to pleomorphic carcinomas. The tumors harbor mutations in KRAS as well as a higher rate of MET exon 14 skipping mutations. This is generally confined to cases with an adenocarcinoma component. TP53 mutations are also frequent. The molecular mechanisms of pleomorphic carcinoma with a squamous only epithelial component remain to be characterized.

      It has been proposed that MET exon 14 mutations may be targetable using agents such as crizotinib. In addition, these tumors show an elevated rate of high positive PDL1 immunoreactivity which may offer immunotherapy option in these patients.

      The relationship between large cell carcinoma and new entities such as SMARCA4 deficient carcinoma/sarcoma and the category of sarcomatoid carcinoma remains unclear. Greater elucidation of the molecular underpinning of sarcomatoid carcinoma categories may help clarify the place for these entities within the classification of lung cancer.

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      GR03.04 - Molecularly-Defined Thoracic Malignancies (NUT, SMARCA4 and Others Sarcomas) (Now Available) (ID 3312)

      15:45 - 17:15  |  Presenting Author(s): Akihiko Yoshida

      • Abstract
      • Presentation
      • Slides

      Abstract

      Classification of tumors has been traditionally based on clinical and histological findings, with each entity often being characterized by molecular genetic changes. However, a few recently described tumor entities are defined by specific genetic abnormalities, and three such tumors are discussed here with a particular emphasis on their nosologic controversy. [NUT carcinoma] NUT carcinoma is a poorly-differentiated aggressive carcinoma with frequent squamous differentiation. NUT carcinoma harbors NUTM1 rearrangement by definition, with the most common fusion partner being BRD4 (~70%) and uncommon partners including NSD3 and BRD3. NUT carcinomas typically involve organs along the midline, such as the head, neck, and upper aerodigestive tract in young patients; however, a broader range of patient age and tumor sites exist. Recently, NUTM1 rearrangement has been reported in a small number of malignant tumors that lack epithelial differentiation, some of which show an undisputable phenotype of sarcoma. Tumors with CIC-NUTM1 fusion are the best known and their histological and transcriptomic similarities to CIC-DUX4 sarcomas suggest their relatedness with CIC sarcomas. Other NUTM1-rearranged sarcomas are highly heterogeneous, both histologically and genetically, including fusion partners such as BCORL1, MXD1, MXD4, and MGA. Interestingly, MGA-NUTM1 sarcomas have been repeatedly documented in the thoracic cavity of adults. More recently, NUTM1 rearrangement has been discovered in benign and malignant skin adnexal tumors. NUTM1 rearrangement is therefore no longer a signature of a single entity NUT carcinoma, and phenotypic correlation is critical for diagnosis. [SMARCA4-deficient thoracic sarcoma (DTS)] SMARCA4 is a core catalytic subunit of the SWI/SNF chromatin remodeling complex. SMARCA4 deficiency in thoracic tumors primarily occurs in association with carcinomas, accounting for 5–15% of lung adenocarcinomas and up to 30% of large cell and pleomorphic carcinomas. These carcinomas typically affect smoking men and are more common in poorly differentiated TTF1-negative tumors that are wild-type for EGFR and ALK. SMARCA4- DTS is a recently recognized sarcoma type with fewer than 60 cases reported to date. SMARCA4-DTS most commonly occurs in young to middle-aged adult men (median, 40 years old) with heavy smoking exposure and presents as large tumors in the thoracic cavity. SMARCA4-DTSs are aggressive, and the median survival is 4–7 months. Histologically, the tumors consist of diffusely infiltrating large dyscohesive epithelioid cells with relatively monotonous nuclei and prominent nucleoli, similar to proximal-type epithelioid sarcoma. Rhabdoid cells are seen in a subset of cases. By definition, all cases are deficient in SMARCA4 immunohistochemically because of inactivating SMARCA4 mutation. SMARCA4-DTS is different from SMARCA4-deficient lung carcinoma with respect to demographics (younger), clinical outcome (worse), histological features (more dyscohesive), immunophenotype (frequent positivity for CD34, SOX2, and/or SALL4, and negativity for claudin-4), and gene expression profiles. Interestingly, some SMARCA4-DTS tumors tested have frequent C:G/A:T transversion mutations and mutations in TP53, KRAS, KEAP1, and/or NF1, a shared profile with smoking-associated lung adenocarcinomas. The question has thus been raised whether these sarcomas might represent a dedifferentiated form of lung carcinoma. Nonetheless, an epithelial component has not been reported in any of the documented SMARCA4-DTS cases. Furthermore, most examples are not centered in the lung, and some entirely lack lung parenchymal involvement. [Primary pulmonary myxoid sarcoma (PPMS) with EWSR1-CREB1] PPMS is a rare low-grade lung sarcoma of young adults often presenting as an endobronchial mass. The tumor consists of multinodular myxoid growth that is populated by corded or reticular proliferation of spindle and/or epithelioid cells. These tumors often coexpress vimentin and epithelial membrane antigen and harbor EWSR1-CREB1 fusion. Tumors with a similar histological appearance have recently been reported in various soft tissue and visceral sites, including the brain, by the names of myxoid variant of angiomatoid fibrous histiocytoma (AFH) and intracranial myxoid mesenchymal tumors, which harbor EWSR1 fusions with genes encoding one of the CREB family transcription factors (ATF1, CREB1, or CREM). Primary pulmonary AFHs have been reported, with some showing myxoid features. Although PPMS is recognized in the WHO classification of the lung as a distinctive tumor, a significant overlap in histology and genetics, albeit several differences, may suggest a close relationship between PPMS and myxoid AFH.

      References:

      1. French CA. NUT Carcinoma: Clinicopathologic features, pathogenesis, and treatment. Pathol Int. 2018 Nov;68(11):583-595.

      2. Dickson BC, et al. NUTM1 Gene Fusions Characterize a Subset of Undifferentiated Soft Tissue and Visceral Tumors. Am J Surg Pathol. 2018 May;42(5):636-645.

      3. Le Loarer F, et al. Clinicopathologic Features of CIC-NUTM1 Sarcomas, a New Molecular Variant of the Family of CIC-Fused Sarcomas. Am J Surg Pathol. 2019 Feb;43(2):268-276.

      4. Stevens TM, et al. NUTM1-rearranged neoplasia: a multi-institution experienceyields novel fusion partners and expands the histologic spectrum. Mod Pathol.2019 Feb 5. [Epub]

      5. Sekine S, et al. Recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poroma and porocarcinoma. J Clin Invest. 2019 May 30;130. [Epub]

      6. Le Loarer F, et al. SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas. Nat Genet. 2015 Oct;47(10):1200-5.

      7. Yoshida A, et al. Clinicopathological and molecular characterization of SMARCA4-deficient thoracic sarcomas with comparison to potentially related entities. Mod Pathol. 2017 Jun;30(6):797-809.

      8. Thway K, et al. Primary pulmonary myxoid sarcoma with EWSR1-CREB1 fusion: a new tumor entity. Am J Surg Pathol. 2011 Nov;35(11):1722-32.

      9. Smith SC, et al. At the intersection of primary pulmonary myxoid sarcoma and pulmonary angiomatoid fibrous histiocytoma: observations from three new cases. Histopathology. 2014 Jul;65(1):144-6.

      10. Schaefer IM, et al. Myxoid variant of so-called angiomatoid "malignant fibrous histiocytoma": clinicopathologic characterization in a series of 21 cases. Am J Surg Pathol. 2014 Jun;38(6):816-23.

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      GR03.05 - Grading of NSCLCs - Problems and Solutions (Now Available) (ID 3313)

      15:45 - 17:15  |  Presenting Author(s): Andre Luis Moreira

      • Abstract
      • Presentation
      • Slides

      Abstract

      Background

      Tumor grading has been a traditional component of the pathologic evaluation and in many organ systems, tumor grading offers guideline to therapy and patient management. The latter has not been applied to NSCLC. However, considering the new advances in therapy modalities for NSCLC and advances in adenocarcinoma classification, it is now clear that there are different types of adenocarcinomas and these tumors should not be treated the same way. The 2015 WHO classification of pulmonary adenocarcinoma based on the predominant histological pattern has consistently been found to correlate with prognosis. There is broad agreement that the five histological patterns (lepidic, acinar, papillary, solid and micropapillary) are important prognostic indicators. Recent studies have proposed the inclusion of a number of additional pathologic features (the role of secondary patterns, non-traditional pattern such as cribriform and complex glandular patterns, nuclear grade, mitotic counts, presence of spread through alveolar space (STAS), and necrosis.) that also have prognostic value. The addition of these histological features to the predominant pattern could offer greater refinement of a grading scheme. Supplementing the classification of lung adenocarcinomas with an objective grading system will help define prognostic groups that could benefit from the changing landscape of emerging management and treatment options.

      Contrary to adenocarcinoma, there has been little advancements in the histological prognostic indicators in squamous cell carcinoma of the lung. Isolated reports have suggested that the presence of tumor budding into the stroma is the sole indicator of poor prognosis. Keratinization, which has been traditionally used to grade these tumors, does not appear to have prognostic value. However, a systematic evaluation of prognostic markers in these tumors have not been carried out. A summary of the current efforts in squamous cell carcinoma will be discussed.

      The IASLC pathology panel has proposed a systematic study to evaluate a set of histological criteria that have been described as prognostic indicators in adenocarcinoma aimed at establishing an objective grading system of invasive lung adenocarcinoma.

      Design

      A multi-institutional study involving well-annotated multiple cohorts of stage 1 adenocarcinomas with at least five years of follow up were evaluated. Annotation included an estimate of the percentage for each histological pattern present for each case; nuclear grade, cytology grade; and mitotic counts with pattern hot-spot association, presence of STAS, and necrosis. A cohort of 284 cases was used as a training set. Univariate analysis was performed to identify significant associations of histological features with recurrence-free survival and overall survival. ROC curve analysis was used to select the best model based on combinations of several features and its association with disease recurrence or death of disease. The results were validate on independent cohorts of 212 cases.

      Results

      Review of the literature showed that there are many variation in the classification and definitions on non-traditional patterns. In our cohorts, cribriform and complex glandular patterns followed similar curve as traditional high grade patterns (solid and micropapillary), therefore these non-traditional pattern were defined as patterns of high grade in the model. Another are of variation is the percentage of high grade pattern that can influence outcome. Therefore, the cut-off for a high grade pattern associated with recurrence or death of disease was also established in the training cohort and correspond to 20%. Therefore, amounts smaller than 20% of high grade pattern did not influence outcome.

      In the training cohort (n=284) all parameters tested, predominant patterns, mitotic count, nuclear grade, cytological grade, and STAS (but not necrosis) were found to have significant prognostic value on a univariate analysis. A Baseline Model composed of Age + Gender + Race + Type of surgery + Pathological Stage; showed an AUC of 0.673. In an attempt to improve this curve, histological parameters were added to the model.

      The addition of only the predominant pattern to the baseline increases the AUC to 0.698.

      A model based on the combination of predominant pattern paired with the second predominant pattern was found to have the highest AUC (0.765), followed by a combination of predominant pattern plus worse pattern (AUC=0.74). Addition of other histological features (nuclear grade, mitotic count, STAS etc.) did not significantly improve the model.

      Similar results were found in the validation set (N=212). The combination of the two most predominant patterns showed an AUC = 0.763, followed by a combination of predominant + worse pattern with AUC = 0.766. Addition of other histological features did not show improvement of the model.

      There was no statistical difference between the models using the two most predominant patterns and the predominant plus worse. There was good reproducibility scores for the 2 models

      Conclusion

      Our results suggest that an objective grading system for pulmonary adenocarcinoma is possible. Considering that there is no significant differences between a model that accounts for the 2 most predominant pattern and another composed of the predominant plus worse pattern. The IASLC pathology panel proposes the later to be used, because pathologists traditionally grade tumors by the worse component. Therefore, histologic assessment of the predominant pattern and worse pattern, would represent the most parsimonious and prognostic grading system for stage I lung adenocarcinomas.

      The use of the model in two other independent cohorts of adenocarcinomas (stages 1-3), as well as a reproducibility study will be discussed.

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Author of

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    EP1.01 - Advanced NSCLC (ID 150)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.01-15 - Systemic Hyperinflammation Is a Strong Independent Predictor of Early Mortality in Advanced NSCLC (Now Available) (ID 1143)

      08:00 - 18:00  |  Author(s): Johan Botling

      • Abstract
      • Slides

      Background

      Prognostic tools in NSCLC are important for treatment decisions and evaluation of new treatment options. Ample evidence support inflammation as a marker of outcome in NSCLC. Our study explores outcome for a population-based real-life cohort of patients in the highest stratum of inflammatory activity.

      Method

      The source cohort comprised all patients diagnosed with NSCLC between January 2016 – May 2017 at Gävle County Hospital, Sweden (n=155, inclusion rate 95%). Following exclusion of patients with active infection, the subgroup (n=77) in stage IIIB-IV with complete available laboratory parameters were studied further. Blood parameters were examined individually, and cut-offs (ESR>60 mm, CRP>20 mg/L, WBC>10 x10e9/L, PLT>400 x10e9/L) for high inflammation were set with an aim to pin-point the top echelon of hyperinflamed patients. A prognostic score was developed by assigning one point for each parameter above cut-off (0-4 points).

      Result

      One year survival of patients with an inflammation score of ≥2 (n=23) was 0% compared to 50% and 33% among patients with a score of 0 (n=36) and 1 (n=18), respectively (figure 1). The effect of a high inflammation score on overall survival remained significant in multi-variate analysis adjusted for confounding factors (stage, gender, age, smoking status, ECOG PS). The hazard ratio of an inflammation score ≥2 in multi-variate analysis (HR 3.45, CI 1.62-7.34) was on par with a change of ECOG PS from 0 to 2 (HR 3.67, CI 1.44-9.4).

      Conclusion

      Inflammation is a well established marker for treatment outcome in solid tumours. Our results show that high level inflammation is a strong independent marker for poor survival in patients with advanced stage NSCLC. This observation may indicate a need to stratify and subgroup patients in clinical studies with regard to systemic hyperinflammation and warrants further research on underlying mechanisms linked to tumour progression.

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    EP1.04 - Immuno-oncology (ID 194)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.04-18 - Real-World Treatment with Checkpoint Inhibitors: The Swedish Experience (Now Available) (ID 2590)

      08:00 - 18:00  |  Author(s): Johan Botling

      • Abstract
      • Slides

      Background

      The introduction of checkpoint inhibitors has fundamentally changed the treatment of advanced NSCLC patients.

      Method

      In order to evaluate if the encouraging results from clinical trials translates into the clinical routine and to confirm the value of biomarker testing we evaluated NSCLC patients that were treated with a checkpoint inhibitor in the Uppsala-Gävle health care region between Januari 2016 and October 2018. Latest patient follow up was done in March 2019. Patient information, including therapy, response rates and survival were obtained from patient records

      Result

      In total, 86 patients, were identified (44 female, median age 71 years; performance status 0=18, 1=45; 2-3=23). 28 patients were treated in the first line setting and 58 patients after previous chemotherapy. Checkpoint inhibitors that were given included pembrolizumab (31), nivolumab (36), atezolizumab (7). Two patients received a combination (durvalumab och tremelimumab).

      67 of 86 patients were evaluable for response and of these 23 patients showed progressive disease, 17 stable disease, 22 partial response and 5 complete response. However, most patients that were not evaluable for response either had only 1-2 cycles because of severe side effects or died early independent from treatment. Thus, for all patient treated with at least one course of checkpoint inhibitors response rate were lower (SD:20%; PR:26% and CR:6%). PD-L1 analysis was done for 69/86 patients (80%). The response (PR or CR) was numerically higher in the group with PD-L1 positivity ≥1% or ≥50% than with negative PD-L1 expression (54% vs 47% vs 13%), although not statistically significant (p=0.11). Median overall survival for patients with PD-L1 <1% was 2.3 years, for patients PD-L1 ≥1% 2.7 years and PD-L1≥50% 3.9 years (log rank-test, p=0.95).

      Conclusion

      In conclusion, the response rates to checkpoint inhibitors in the first and second line were comparable to those observed in clinical trials. We confirmed that patients with low PD-L1 expression are unlikely to respond to checkpoint inhibition.

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    MA18 - Advances in Diagnosis of Common Types of NSCLC (ID 145)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Pathology
    • Presentations: 1
    • Now Available
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      MA18.05 - Diagnostic Difference Between Neuroendocrine Markers in Pulmonary Cancers: A Comprehensive Study and Review of the Literature (Now Available) (ID 171)

      11:30 - 13:00  |  Author(s): Johan Botling

      • Abstract
      • Presentation
      • Slides

      Background

      The diagnostic distinction of pulmonary neuroendocrine (NE) tumors from non-small cell carcinomas (NSCC) is of high clinical relevance for prognosis and treatment. Diagnosis is based on morphology and immunohistochemical staining. The current WHO classification of lung tumors emphasizes synaptophysin and chromogranin A but also recommends CD56 as NE markers. The aim of the present study was to determine the diagnostic value of the insulinoma-associated protein 1 (INSM1) gene, in comparison with the established neuroendocrine markers, in pulmonary tumors.

      Method

      Tissue microarrays with tumor tissue from 54 resected pulmonary NE tumors and 632 NSCC were stained for INSM1, CD56, chromogranin A and synaptophysin. In a subset, gene expression data was available for analysis. Also, 419 metastases to the lungs were stained for INSM1. A literature search identified 37 additional studies with data on NE markers in lung cancers from the last 15 years, whereof six with data on INSM1.

      Result

      Depending on cut-off level (1%+ or 10%+ positive tumor cells), the sensitivity and specificity for INSM1 to separate NE tumors from NSCC were 72-91% and 98-99%, respectively. In comparison, the sensitivity and specificity for CD56 were 85-89% and 96-98%, for chromogranin A 56-67% and 98-99%, and for synaptophysin 85-93% and 86-92%, respectively. Analysis of literature data revealed that CD56 and INSM1 were the best markers for identification of high-grade NE pulmonary tumors when considering both sensitivity and specificity (see table). INSM1 gene expression was clearly associated with NE histology.

      ne markers.jpg

      Conclusion

      The solid data of our investigation and previous studies confirm the diagnostic value of INSM1 as a NE marker in pulmonary pathology. The combination of CD56 with INSM1 or synaptophysin should be the first-hand choice to confirm high-grade NE pulmonary tumors.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-37 - Lung Cancer in Never-Smokers: A Nationwide Population Based Mapping of Targetable Alterations (ID 2735)

      09:45 - 18:00  |  Author(s): Johan Botling

      • Abstract
      • Slides

      Background

      Lung cancer among never-smokers is common and increasing [1]. A smoking-independent subgroup of lung adenocarcinoma with certain molecular and clinical features exists [2-3]. In an ongoing project within the Swedish Molecular Initiative against Lung cancer (SMIL) we currently characterize lung cancer in never-smokers for etiological, diagnostic and therapeutic purposes.

      Method

      Through the Swedish National Lung Cancer Registry [1], we identified all individuals who underwent surgery for lung cancer in Sweden 2005-2014 and who were registered as never-smokers (n=540). At each study site, clinical data were reviewed by a thoracic oncologist or pulmonologist through patients’ medical charts and archived tumor tissues were retrieved and reviewed by a thoracic pathologist. For subsequent studies, we extracted DNA and RNA (using the Qiagen AllPrep kit for FFPE tissue) and constructed tissue microarrays. As first preplanned analyses, we performed fusion gene mapping using an RNA based NanoString nCounter Elements assay and mutational profiling by Next Generation Sequencing (NGS) using a 26-gene exon-focused panel, as previously described [4].

      Result

      Of the 540 never-smokers with surgically resected lung cancer, 69% were females and the majority of cases were adenocarcinomas. The median age at diagnosis was 69 years.

      In the first 310 analyzed tumor samples, we so far detected 24 fusions involving ALK (8%), 10 involving RET (3%) and 2 involving NRG1 (<1%). In addition, MET exon 14 skipping was found in 33 samples (11%).

      Furthermore, among the so far 147 cases where we have completed both the DNA and the RNA analyses, 59 tumors (40%) harbored EGFR mutations. In total, targetable alterations were revealed either by NanoString or NGS in 63% of tumors from never-smokers in our study.

      Conclusion

      SMIL is an ongoing nation-wide molecular research collaboration on lung cancer where we currently characterize one of the largest never-smoking lung tumor cohorts worldwide. From the first pre-planned analyses, we conclude that, in a population-based cohort of early stage lung cancer from never-smokers, targetable oncogenic fusions and mutations are frequent.

      References

      1. http://www.cancercentrum.se/vast/cancerdiagnoser/lunga-och-lungsack/kvalitetsregister

      2. Staaf J, Jönsson G, Jönsson M, Karlsson A, Isaksson S, Salomonsson A,Pettersson HM, Soller M, Ewers SB, Johansson L, Jönsson P, Planck M. Relation between smoking history and gene expression profiles in lung adenocarcinomas. BMC Med Genomics. 2012 Jun 7;5:22.

      3. Karlsson A, Ringnér M, Lauss M, Botling J, Micke P, Planck M, Staaf J. Genomic and transcriptional alterations in lung adenocarcinoma in relation to smoking history. Clin Cancer Res. 2014 Sep 15;20(18):4912-24.

      4. Lindquist KE, Karlsson A, Levéen P, Brunnström H, Reuterswärd C, Holm K, Jönsson M, Annersten K, Rosengren F, Jirström K, Kosieradzki J, Ek L, Borg Å, Planck M, Jönsson G, Staaf J. Clinical framework for next generation sequencing based analysis of treatment predictive mutations and multiplexed gene fusion detection in non-small cell lung cancer. Oncotarget. 2017 May 23;8(21):34796-34810.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-67 - Comparative Analysis of TMB and Mutations by Comprehensive Genomic Profiling (TSO500) in FFPE NSCLC Samples (ID 2106)

      10:15 - 18:15  |  Presenting Author(s): Johan Botling

      • Abstract

      Background

      Precision oncology for NSCLC involves an increasing number of targeted drugs and immunotherapy options. Comprehensive genetic profiling has been used in clinical studies to assess predictive biomarkers and mutation patterns, i.e. tumor mutation burden (TMB) associated with checkpoint therapy response. However, limited access to broader sequencing approaches, associated complex bioinformatic pipelines and issues with cross-platform reproducibility remain important hurdles for routine molecular pathology.

      Method

      Here we have used the novel TSO500 gene panel (523 genes, 1.95 Mb) on the NextSeq platform (Illumina) to analyze representative surgical FFPE NSCLC specimens (n=50). Detected mutations were evaluated in comparison to matched results from routine diagnostic sequencing based on a custom 18-gene HaloPlex panel (Agilent). Obtained TMB-scores will be compared to data from analysis with the FoundationOne CDx assay (work in progress).

      Result

      All 50 samples passed the pre-set QC filters. We found a wide range of TMB-values (0.79 to 610 non-synonymous mutations per Mb) with a median score of 5.6 mut/Mb (Figure 1). EGFR positive cases were found in the lower TMB range, while the remaining adenocarcinoma and squamous cell carcinomas were evenly distributed across the TMB spectrum. All known variants (n=105) from routine sequencing could be detected in the TSO500 data set (Illumina and in-house bioinformatic pipeline) with similar variant allele frequencies (r= 0.76).

      Conclusion

      Variant calling with regard to NSCLC hot-spot mutations seems to be robust, but the precision and performance of TSO500 outside clinical hot-spot regions remain to be established. The distribution of TMB scores in our series of NSCLC seems to be consistent with previously published data and concordance to results with FoundationOne CDx will be presented.

      tmb figure abstract.png

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    P2.09 - Pathology (ID 174)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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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): Johan Botling

      • 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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