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Akihiko Yoshida

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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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      GR03.04 - 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


      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.


      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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    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): Akihiko Yoshida

      • Abstract
      • Slides


      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.


      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).


      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.


      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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