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Elisabeth Brambilla

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    ES04 - Multimodality Management of Small Cell and Neuroendocrine Cancers (ID 7)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
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      ES04.02 - Pathology Overview for Carcinoid and NE Spectrum (Now Available) (ID 3169)

      10:30 - 12:00  |  Presenting Author(s): Elisabeth Brambilla

      • Abstract
      • Presentation
      • Slides


      Pathology Overview for carcinoid and Neuroendocrine Spectrum

      The spectrum of neuroendocrine (NE) tumors ranges from low grade typical carcinoid (TC) to intermediate grade Atypical carcinoids to high grade small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) Although very different from high grade tumors in their molecular genetics and expression profiling, carcinoid are included in the spectrum of NE tumors since WHO 2015 (1) on the basis of their common NE epithelial differentiation.Carcinoids display many clinical differences with high grade NE tumors being not strongly associated with smoking (only 20-40% smokers), their specific association with Multiple Endocrine Neoplasia type 1 (MEN1 ) not seen in High grade tumors and their occurrence on the background of NE cell hyperplasia and tumorlets in 60% of TC and AC, very rare in high grade tumors . Whereas carcinoid are never combined with conventional lung cancer , 20 to 25% of SCLC and LCNEC are combined. Since the NE markers are common in the full spectrum , morphology , mitoses and KI 67 (proliferations markers) are useful to differentiate carcinoids from SCLC and LCNEC . The accurate diagnosis of each is critical in view of their eminently different therapeutic management .

      Small cell lung carcinoma (SCLC

      SCLC is the most frequent NE lung tumor (15-20% of lung cancer) and has the worse prognosis in the spectrum. Most are proximal,70% perihilar forming peribronchial growth involving lymph nodes .Less than 5% are solitary primary nodules stage I. SCLC is a high grade malignant epithelial NE tumor with characteristic cytopathologic features recognizable in routine microscopy without use of immunohistochemistry (IHC) in optimal cell preservation. IHC may be used in suboptimal condition (crush artifact) to confirm the diagnosis.

      SCLC is made of sheets of small cells ,round/oval or spindle shaped forming whorls, with little cytoplasm , nuclei with unconspicuous nucleoli , finely granular dispersed chromatin , and nuclear molding . Mitotic rate is very high more than 50 reaching 100 for 2mm2 and KI67 exceeds 50% (50-100%).Extensive necrosis is frequent .Most SCLC express NE markers Chromogranine A, Synaptophysin and CD56 . 75% express TTF1 (recommended clone 8G7G3 1) . Less than 10% remain negative for all 3 NE markers and TTF1 . In these cases a P40 staining is mandatory to eliminate a basaloid carcinoma (P40 Positive) with which it may be confused in suboptimal preparations .

      SCLC can present as pure or combined. Any association of small cells with another NSCLC (Adenocarcinoma, Squamous cell carcinoma , large cell or large cell NE carcinoma , sarcomatoid giant and spindle cells ) is diagnosed as combined SCLC (20%) .

      Several studies of their molecular characteristics were recently published and compared with other tumors of the NE spectrum . Theses are specific , closer from a part of LCNEC but distinct from theses of carcinoids (Georges 2016 , Georges 2018 ) . Small cell carcinoma in non-smokers should be looked for EGFR mutation (acquired after TKI therapy of an Adenocarcinoma or spontaneous ).

      Large cell neuro endocrine carcinoma (LCNEC)

      LCNEC is a high grade NE lung tumor accounting for 3% of lung cancers .The diagnosis is based on the necessary association of NE morphology (organoid nesting ,rosettes ,palisading) and expression of NE markers (at least one) : chromogranine A, synaptophysin and CD56. Seventy-nine % develop in the lung periphery , 5% show endobronchial growth .They form circonscribed nodular mass intensely necrotic .They lack typical cytology in contrast with SCLC .The mitotic rate is more than 10 per 2mm2to distinguish them from atypical carcinoid (2 -10/2mm 2) ,ranging from 20 to 80-100 with KI67 very high exceeding 50% usually 80-100%. They are composed of large cells with low nuclear to cytoplasmic ratio , a conspicuous nucleoli and vesicular chromatin .A spectrum of morphologies range from SCLC (small cell –like) to non small cell-like or to a few atypical carcinoids-like , showing the need for an accurate diagnosis using objective criteria (proliferation). A constellation of multiple criteria should be used to distinguish them fro SCLC or AC .Combined LCNEC is the association of any LCNEC component with a conventional component ( 25% ). Due to spatial heterogeneity of NE morphology and NE expression the diagnostic may be difficult on small biopsies .However a NSCLC without NE morphology but 1 or 2 NE markers is diagnosed as a NSCLC (with unclear phenotype ) since 15 % of NSCLC also express 1 or 2 NE markers.TTF1 is expressed in 41 % of LCNEC specially when combined with adenocarcinoma.Molecular genomics and expression profiling classify in 2 categories one simiilar to SCLC with biallelic inactivation of P53 and RB genes and another with KEAP 1 or LKB1 mutations looking like NSCLC .LCNEC are very different from Carcinoids (Georges 2018 )

      Carcinoids tumors : Typical and Atypical Carcinoids

      Carcinoids account for 1-2 % of lung tumors of which 10% are Atypical carcinoid .Typical ( low grade) and atypical carcinoids(intermediate grade) are distinquished on objective criteria (mitoses index (table I) and necrosis, but KI67 has no defined cut- off to separate them.

      They develop centrally as endobronchial growth or in the lung periphery (16-40 %) Cytology allows accurate recognition . NE morphology is well achieved with organoid patterns( glandular, follicular ,trabecular , angiomatoid…) most often multiple .Spindle cell pattern is more frequent in the peripheral carcinoids.

      All express the 3 NE markers and TTF1 is usually negative (except in a few peripheral carcinoids )


      Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO classification of tumours of the lung, pleura, thymus and heart, 4th ed. Lyon: IARC; 2015. 

      Travis WD ,Nicholson AG ,Geisinger KR, Brambilla E.Tumors of the lower respiratory tract AFIP Atlas of Tumor pathology series 4 ed. AFIP Press Bethesda 2019

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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): Elisabeth Brambilla

      • 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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