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Erik Thunnissen
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MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
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MA 05.07 - Whole Body PD-1 and PD-L1 PET in Pts with NSCLC (ID 9219)
15:45 - 17:30 | Author(s): Erik Thunnissen
- Abstract
- Presentation
Background:
Tumor PD-L1 IHC relates moderately with treatment outcome following anti-PD1 therapy in pts with NSCLC and single biopsies do not account for tumor heterogeneity. Aim: 1. Assess safety of the PET procedures. 2. Quantify [89]Zirconium-labeled nivolumab ([89]Zr-nivo) and [18]F-labeled BMS-986192 ([18]F-PD-L1) uptake. 3. Assess tracer uptake heterogeneity. 4. Correlate tracer uptake with PD-1/PD-L1 IHC in tumor, stroma and with treatment outcome.
Method:
NSCLC pts eligible for treatment with nivolumab were included. Pts received whole body [18]F-PD-L1 and [89]Zr-nivo PET scans. Baseline tumor biopsy was required to assess PD-(L)1 IHC status (28.8 assay). SUV~peak~ was calculated for delineable lesions and correlated to PD-(L)1 IHC and response after 12 wks of nivolumab treatment.
Result:
10 pts (3 ≥50%, 5 ≥1%, 5 negative by PD-L1 IHC) were enrolled and 37 lesions analysed. No toxicity related to radiotracer was observed. Tumor uptake of both tracers was visualized in all pts, but not in all lesions. Tracer uptake varied among pts with mean [18]F-PD-L1 SUV~peak~ 4.6, range 0.5 - 14.4 and mean [89]Zr-nivo SUV~peak~ 5.0, range 1.6 – 11 (p=0.03) and within pts with mean SUV~peak~ difference 3.6-fold (±2.1) and 2.4-fold (±0.77) between lesions for [18]F-PD-L1 and [89]Zr-nivo, respectively. For lesions with ≥50% PD-L1 IHC, mean [18]F-PD-L1 SUV~peak~ was 8.0 (±4.7) as compared to 3.5 (±1.6) for lesions with <50% PD-L1 IHC (p=0.03). For tumors with high TIL/ stromal PD-1 expression, mean [89]Zr-nivo SUV~peak~ was 8.6 (±2.4) as compared to 6.1 (±2.1) for lesions with low PD-1 expression (p=0.1). Mean SUV~peak ~for [18]F-PD-L1 was 8.4 (±5.4) for pts with PR and 4.5 (±2.9) for pts with PD/SD (p=0.3). Mean SUV~peak~ for [89]Zr-nivo was 7.8 (±1.8) for pts with PR and 5.4 (±2.2) for pts with PD/SD (p=0.2).
Conclusion:
1. PET-imaging with both tracers is safe and feasible, with good tumor-to-normal tissue contrast. 2. Tumor uptake showed heterogeneity among pts and among tumors within pts. 3. Pts with ≥50% tumor PD-L1 expression showed higher [18]F-PD-L1 uptake. 4. Pts with high PD-1 expression showed higher [89]Zr-nivo uptake, and pts with PR demonstrated higher [18]F-PD-L1 and [89]Zr-nivo tracer uptake than pts with PD/SD, although these are without statistical significance which may be due to the small dataset.
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MA 06 - Lung Cancer Biology I (ID 660)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:N. Motoi, Keith M Kerr
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 501
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MA 06.06 - Assessment of RANK Prevalence and Clinical Significance in the NSCLC European Thoracic Oncology Platform Lungscape Cohort (ID 10006)
15:45 - 17:30 | Presenting Author(s): Erik Thunnissen
- Abstract
- Presentation
Background:
Receptor Activator of Nuclear Factor κappa-B (RANK) is a pathway involved in bone homeostasis. Recent evidence suggests that RANK signalling may also play a role in bone metastasis, and primary breast and lung cancers. The European Thoracic Oncology Platform (ETOP) Lungscape project allows evaluation of the prevalence of RANK expression and its clinical significance in a cohort of surgically-resected NSCLCs.
Method:
RANK expression was assessed on tissue microarrays (TMAs) using immunohistochemistry. Up to 4 cores per patient were analysed based on sample acceptance criteria. An H-Score (staining intensity + % cells stained) was used to assess RANK expression (positivity), as defined by at least 1 core with any degree of positive staining. Prevalence of RANK positivity and its association with clinicopathological characteristics, other cancer-related biomarkers (IHC ALK/MET/PTEN/PD-L1 expression and EGFR/KRAS/PIK3CA mutations) and patient outcome [Relapse-free Survival (RFS), Time-to-Relapse (TTR), Overall Survival (OS)] was explored in a subset of the ETOP Lungscape cohort. The prevalence of RANK overexpression (proportion of positive cancer cells ≥50%) was also investigated.
Result:
RANK expression was assessed in patients from 3 centers, a total of 402 from the 2709 patients of the Lungscape cohort, with median follow-up 44 months; 32.6% female, 40.8/54.2/5.0% adenocarcinomas (AC)/squamous cell carcinomas (SCC)/other, 44.8/28.4/26.9% with stage I/II/III, 20.6/57.7/18.9% current/former/never smokers (and 2.7% with unknown smoking status). Median was 74 months for both RFS and OS, while median TTR was not reached. Prevalence of RANK positivity was 26.6% (107 of the 402 cases), with 95% confidence interval (95%CI):22.4%-31.2%; significantly higher in AC: 48.2% (79 of 164 cases), 95%CI:40.3%-56.1%; vs SCC: 9.2% (20 of 218 cases), 95%CI:5.7%-13.8%; (p<0.001). RANK positivity was more frequent in females (38.9% vs 20.7% in males, p<0.001) and tumors≤4cm (30.7% vs 21.1% in tumors>4cm, p=0.031). Significant associations were also detected between RANK and PTEN expression in AC (RANK positivity 57.4% in PTEN expression vs 30.5% in PTEN loss; p=0.0011) and with MET status in SCC (RANK positivity 27.8% in MET+ vs 7.6% in MET-; p=0.016). No association with outcome was found. RANK overexpression was identified in 43 (10.7%; 95%CI: 7.9%-14.1%) cases.
Conclusion:
In this early-stage NSCLC cohort, RANK positivity (26.6% overall) is found to be significantly more common in adenocarcinomas (48.2%), females, patients with tumors of smaller size, with PTEN expression (in SCC) and MET positivity (in AC). No prognostic significance of RANK expression was found. Analysis of additional cases is ongoing and results will be presented.
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MTE 02 - Appropriate and Optimized Handling of Specimens (Sign Up Required) (ID 569)
- Event: WCLC 2017
- Type: Meet the Expert
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 07:00 - 08:00, Room 316
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MTE 02.01 - Appropriate and Optimized Handling of Surgically Resected Specimens (ID 7803)
07:00 - 08:00 | Presenting Author(s): Erik Thunnissen
- Abstract
- Presentation
Abstract:
Erik Thunnissen[1], Chris Dickhoff[2,3], Rutger Lely[4], MA (Rick) Paul[3] Departments of [1]Pathology, [2]Surgery, [3]Cardiothoracic Surgery and [4]Radiology, VU University Medical Center, Amsterdam, the Netherlands. Guidelines for gross handling are to our knowledge not formulated in the literature. However, the College of American Physicians (CAP) formulates "required elements" for synoptic reporting regarding gross handling of pulmonary resection specimen, mainly focusing at pathology staging, but does not include grossing requirements[1]. The current practice of handling resection specimen in Amsterdam involves interaction with surgeons for submission of specimen. This includes i) Information about pretreatment, type of surgery (including pneumonectomy, (sleeve) lobectomy, segmentectomy, and wedge resection), site of specimen, number of tumors; ii) eventual frozen section for diagnosis and/or resection margin; iii) eventual additional information of specimen e.g. adhesion from parietal pleura, additional wedge from adjacent lobe adhesion; iv) agreement on marking the ‘cold’ side from bronchial resection slice [see note A]; For the pathologist, the order of handling the fresh specimen is i) to maintain the 3 dimensional orientation of the resection specimen along the axial, coronal and sagital planes; ii) to describe outer surface of specimen; iii) to photograph overview from medial and lateral side; iv) to cut slice of bronchial resection margin; v) to cut tumor, preferably in axial plane for sampling of normal lung tissue and tumor for research (culture, freezing) [see notes B and C]; vi) to perform perfusion fixation of peripheral lung; vii) and to immerse whole specimen in large volume neutral buffered formalin. After 24 hours, fixation the specimen is handled in the following way: i) Intrapulmonary lymph nodes are separately embedded ii) the specimen is further cut in slices along the same plane as done for the fresh specimen; iii) the slices are positioned in order of cutting, numbered and photographs taken; iv) description of specimen with tumor characteristics: focality (size; vital, necrosis, fibrosis), distance from tumor to margins recorded (to bronchial resection, pleura). If tumor is present in sequential slices, cumulative tumor thickness is measured; v) other characteristics are described (mucus in dilated bronchi; post-obstruction pneumonia; emphysema etc.) vi) sample representative blocks from tumor, normal tissue, resection margin arteria pulmonalis, and nearest point(s) to pleura for embedding in paraffin; vii) annotate the location of sampled blocks on a copy of the gross slices. After a few days during first microscopy, the 3 dimensional orientation can be reconstructed and the pTNM parameters extracted from the gross and microscopic information. If needed, additional samples can be taken [see note C]. Classification is performed for most parts according to the WHO[2], except for not reproducible categories and immature concepts. Pathology reporting contains pTNMR [see note D]. The pathology report is usually made within 9 working days, except if bony structures are included, then the process will contain an additional week. If postoperative radiotherapy is indicated, the 3 dimensional approach also supports determination of the position(s) for radiation, especially if clips were not placed during surgery. Note A As for frozen section, the cold side of the bronchial resection margin [i.e. the side distant from the patient] is placed downwards on the frozen template, the first cut frozen section sections [representing the nearest to the patient tissue margins (warm side)] are sequentially placed on the microscope slide. In case of uneven surface maximally 6 sections, until complete circumference is achieved, are placed on two microscopic slides, and stained for H&E The bronchial resection margin is considered tumour-free, if the complete circumferential margin does not contain tumor. If needed, in this judgement sequential complementarity of the 6 sections may be taken into account. The sleeve lobectomy has two resection margins: one on the cold side and the other on the warm side (larger bronchial diameter). These are separately examined. If only tumor cells are found in lymph vessels (but no direct tumor spread), this will be reported, but not considered necessary for indication of additional bronchial margin, as lymphangitic distribution is associated with N2 disease[3,4]. Note B As it has been proven that loose tissue fragments are caused by gross cutting[5,6], the knife is rinsed and quickly wiped after each slice that happens to contain tumor. STAS is considered to be an artifact and in contrast to CAP and WHO classification, is not considered as part of the tumor. Note C In Pancoast tumor, the ‘en-bloc resection’ incorporates extrapulmonary structures directly invaded by tumor, usually ribs. During the fresh handling, the thoracic wall is cut from the lung. Subsequently, both cut surfaces are coloured to denote the artifical edges. Bone requires after fixation extra time for decalcification, extending reporting with one week. Note D The R = defined as follows: R0 = free resection margins; R1 = microscopic margins not free; R2 = margins not free during gross examination/surgery;. Peripheral wedge resections contain a parenchymal margin, which is represented by the tissue at the staple line(s). The staples are cut from the specimen, but not further examined. Adjacent tissue is sampled for microscopic examination. If this section does not contain tumor, the margin is free (R0). However, if this contains tumor, an educated guess is reasonable, encompassing the amount of tumor compared to the other sections, and the estimation of the staple thickness (±2mm). 1. College of American Pathologists. Cancer Protocol Templates. Lung cancer vs4. http://www.cap.org/web/oracle/webcenter/portalapp/pagehierarchy/cancer_protocol_templates.jspx?_afrLoop=445529225217710#!%40%40%3F_afrLoop%3D445529225217710%26_adf.ctrl-state%3Dxmm1doio_4. 2. Travis W., Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. (Travis W., Brambilla E, Burke AP, Marx A, Nicholson AG, eds.). Lyon: IARC; 2015. 3. Thunnissen FBJM, den Bakker MA. Implications of frozen section analyses from bronchial resection margins in NSCLC. Histopathology. 2005;47(6):638-640. doi:10.1111/j.1365-2559.2005.02263.x. 4. Vallières E, Van Houtte P, Travis WD, Rami-Porta R, Goldstraw P. Carcinoma in situ at the bronchial resection margin: a review. J Thorac Oncol. 2011;6(10):1617-1623. doi:10.1097/JTO.0b013e31822ae082. 5. Blaauwgeers H, Flieder D, Warth A, et al. A Prospective Study of Loose Tissue Fragments in Non–Small Cell Lung Cancer Resection Specimens. Am J Surg Pathol. June 2017:1. doi:10.1097/PAS.0000000000000889. 6. Thunnissen E, Blaauwgeers HJLG, de Cuba EM V, et al. Ex Vivo Artifacts and Histopathologic Pitfalls in the Lung. Arch Pathol Lab Med. 2016;140(3):212-220. doi:10.5858/arpa.2015-0292-OA.
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-024 - False Positivity Due to Polysomy in Fluorescence in Situ Hybridization (ID 10523)
09:30 - 16:00 | Presenting Author(s): Erik Thunnissen
- Abstract
Background:
Pathologists may recognize the phenomenon of polyploidy in FISH, which may be misleading in interpretation of break apart fluorescence in-situ hybridization (FISH). The chance for single or split probe signals is likely to increase with the degree of polysomy. The aim of this study was to explore whether false positivity due to polyploidy occurs in practice.
Method:
A cohort of cases referred for study or patient care was collected from the archives. From the cases where the ALK and/or ROS1 in-situ hybridization test was repeated in our hospital the outcome of testing was compared. Additionally tumor DNA of an occasional case was tested by an orthogonal method (Ion Torrent Oncomine Focus Assay) for translocations.
Result:
Three cases with ALK FISH rearrangement elsewhere were diagnosed with polyploidy in the referral center. One case was reported with rearrangements in both the ALK and the ROS1 gene detected by FISH analysis. In the repeated FISH analysis the average number of co-localization signals in the tumor cell nuclei was 7.6 for ALK and 9.5 for ROS1 respectively (range 1 - 30). Moreover, the morphology of this case was a giant cell carcinoma, variant of pleomorphic carcinoma of the lung. Examination with an orthogonal method (Ion Torrent Oncomine Assay) revealed no translocations and the tumor cells were negative for ALK and ROS1 by immunohistochemistry proving the original report as false positive, supported by absence of response on crizotinib. In break apart FISH the 15% threshold for positivity was obtained in cells emphasizing that in cross sections of normal nuclei occasionally split signals or 3’ probe signals may be present even in diploid nuclei. In the range of 15-20% the chance of false positive FISH is >1%.[1] However, in polyploid tumors the higher number of probe signals within one nucleus comes with an increased chance of split or 3’ signals and a higher rate of false-positive results when maintaining a uniform threshold 15% irrespective of ploidy. Moreover, this may in case of ALK be an additional reason for discordancy with ALK immunohistochemistry, explaining the lack of response on targeted therapy in these patients.[2] 1. vLaffert Lung cancer. 2015;90:465 2. vdWekken. Clin Cancer Res.epub.
Conclusion:
In case of polysomy there is a increased chance of false positive in break apart FISH results. An addition technique should be used to confirm a positive FISH status in tumors with highly increased gene copy number due to polysomy.
