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Prudence Russell
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MTE 06 - Lung Cancer Pathology Update (Sign Up Required) (ID 555)
- Event: WCLC 2017
- Type: Meet the Expert
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 07:00 - 08:00, Room 315
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MTE 06.01 - Lung Cancer Pathology Update (ID 7782)
07:00 - 08:00 | Presenting Author(s): Prudence Russell
- Abstract
- Presentation
Abstract:
This session will focus on some new definitions and concepts in the recently published 2015 WHO classification of lung tumors (1), some of which were showcased in the 2011 IASLC/ATS/ERS lung adenocarcinoma classification (2), while others are introduced for the first time. We will focus on resected lung adenocarcinoma as well resected squamous cell carcinoma, large cell carcinoma and the neuroendocrine tumor spectrum. Adenocarcinoma: In the 2015 WHO classification, the definition of adenocarcinoma has been expanded from a malignant epithelial tumor with glandular differentiation or mucin production to include tumors that also express pneumocyte immunomarkers (e.g. TTF1, Napsin A). This means that undifferentiated carcinomas formerly classified as large cell carcinoma that express pneumocyte immunomarkers, like undifferentiated carcinomas that show mucin expression, are now included in the solid adenocarcinoma category. Invasive adenocarcinomas account for >70% of all surgically resected cases and consist of a complex admixture of histologic subtypes. In an effort to represent this morphologic complexity, comprehensive histologic subtyping was introduced in the 2011 IASLC/ATS/ERS classification. A number of recent studies have demonstrated the utility of comprehensive histologic subtyping in identifying prognostically significant groups of tumors . Studies published both before and after the 2011 IASLC/ATS/ERS classification have highlighted the importance of the secondary patterns in addition to the predominant pattern in resected lung adenocarcinoma. Comprehensive histologic subtyping, its pitfalls and the emerging significance of secondary patterns in tumour recurrence and prognosis will be discussed further in this session. Grading: There is no well-established, internationally accepted grading system in resected lung adenocarcinoma. A simple grading system based on predominant histologic subtype has been proposed due to the prognostic significance of predominant histologic subtype. Other suggested grading schemes include different combinations of mitotic count, second predominant pattern and nuclear features with predominant histologic subtype. The emerging concept of an objective grading system for pulmonary adenocarcinomas will be briefly explored in this session. Another newly introduced concept in the 2015 WHO classification is that of tumour spread through alveolar spaces (STAS) which may occur with micropapillary clusters, solid nests or single cells. STAS was found to be associated with an increased recurrence rate in patients with stage I adenocarcinomas <2cm who underwent sublobar resections (3). Tumour size and staging: A recent study confirmed that in resected non-mucinous adenocarcinoma, the size of the invasive component, excluding the lepidic (equated with in situ) component of the tumor, correlates better with patient outcome than total tumour size (4). This finding has been supported by other studies and is expected to be included in the upcoming 8[th] edition TNM staging system for the T descriptor for pathologic staging in resected non-mucinous adenocarcinoma (5). Squamous cell carcinoma (SQCC) is the second most prevalent Non-small cell lung cancer (NSCLC), behind adenocarcinoma. Contrary to the latter where most changes in nomenclature, diagnosis and molecular pathology have occurred, SQCC has a strong association to smoking and remains a challenge for oncologists with few therapeutic advances. To reduce the risk of over diagnosing SQCC, the definition of SQCC became stricter in the 2015 WHO classification. For the diagnosis of this entity it is necessary to have evidence of keratinization and intercellular bridges. For non-keratinizing SQCC it is necessary to demonstrate evidence of squamous differentiation by immunohistochemical (IHC) stain (diffuse positivity for p40 or p63 and absence of adenocarcinoma markers such as TTF-1 and napsin-A). Non-keratinizing SQCC shares a solid pattern of growth with adenocarcinoma; in addition, solid type adenocarcinomas can have squamoid features such as glassy and abundant cytoplasm that can mimic SQCC (6), therefore it is recommended the use of IHC for any NSCLC with solid pattern of growth. Presence or absence of mucin is not a criterion for diagnosis of SQCC. Similar to adenocarcinoma, there is no grading system for SQCC. There is evidence that tumour budding is associated with worse prognosis (7). Basaloid carcinoma is now classified in the same group of SQCC and no longer part of large cell carcinoma. In contrast, Lymphoepithelioma-like carcinoma of the lung that share IHC profile with squamous cell carcinoma is grouped in the category of other undifferentiated tumours that also include NUT carcinoma. Large cell carcinoma: remains a separate category; however, the diagnosis of this entity is greatly reduced. Large cell carcinoma is an undifferentiated carcinoma (positive for cytokeratin markers), which lacks evidence of differentiation by morphology and lineage specific immunohistochemical profile (TTF-1/Napsin-A and p40 negative). This classification is supported by molecular profile (8). High Grade Neuroendocrine Carcinomas. This tumour category remains largely the same from previous classification with the exception that Large Cell Neuroendocrine Carcinoma (LCNC) is now grouped with neuroendocrine tumours. It is no longer part of a Large Cell Carcinoma category. Recent studies have suggested that LCNEC is a heterogeneous group ranging in the spectrum from NSCLC-like to small cell carcinoma-like tumours (9). LCNEC that resemble NSCLC have higher incidence of KRAS mutations, whereas those morphologically closer to small cell carcinoma have higher incidence of RB mutation. The significance of these findings for tumour classification and especially for therapeutic options are still unknown as more studies need to be done. There have been several studies on the genetic and epigenetic profile of small cell carcinoma that could lead to new therapeutic options (10). However, the diagnosis and classification of this tumour remains the same. Carcinoid Tumours: Typical and atypical carcinoid tumours maintained the same morphological criteria for diagnosis and classification. Recent molecular studies have showed however that these tumours have distinct molecular profiles from the high grade relatives (LCNC and small cell carcinoma) (10). References: Travis WD, Brambilla E, Nicholson A, Noguchi M, et al, (eds). (2015) WHO Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. 4[th] ed., Lyon: IARC. Travis WD, Brambilla E, Noguchi M, et al. (2011). International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 6: 244-85 Nitadori J, Bograd AJ, Kadota K, et al. (2013) Impact of micropapillary histologic subtype in selecting limited resection vs lobectomy for lung adenocarcinoma of 2cm of smaller. J Natl Cancer Inst. 105:1212-10. Yoshizawa A, Motoi N, Riely GJ, et al. (2011). Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Mod Pathol. 24: 653-64. Travis WD, Asamura H, BAnkier AA et al. (2016) The IASLC Lung cancer Staging Project: Proposal for coding T category 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. 11:1204-23. Rekhtman N, Paik P, Arcila M, et al (2012). Clarifying the spectrum of driver oncogene mutations in pure, biomarker-verified squamous cell carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations. Clin Cancer Res. 18:1167-76. KAdota K, Nitadori J, woo KM et al. (2014). Comprehensive pathological analyses in lung squamous cell carcinoma:single cell invasion, nuclear diameter, and tumor budding are independent prognostic gfactors for worse outcomes. J Thorac Oncol. 9:1126-39 Rekhtman N, Tafe LJ, Chaft JE et al. (2013) Distinct profile of driver mutations and clinical features in immunomarker-defined subsets of pulmonary large cell carcinoma. Modern Pathol. 26:511-22. Rekhtman N, Pietanza MC, Hellman M, et al. (2016) Next-Generation Sequencing of Pulmonary Large cell neuroendocrine Carcinoma Reveals Small Cell Carcinoma-like and Non-Small Cell Carcinoma-like subsets. Clin Cancer Res. 22:3618-29. Bunn PA, Minna J, Augustyn A et al. (2016). Small cell Lung Cancer: can recent advacnes in biology and molecular biology be translated into improved outcomes? J Thorac Oncol. 11:453-74
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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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P2.02-039 - Spatial Heterogeneity of Immunological Markers Between Cores and Complete NSCLC Sections Using Multispectral Fluorescent IHC (ID 9728)
09:30 - 09:30 | Author(s): Prudence Russell
- Abstract
Background:
Immunotherapy with immune checkpoint inhibitors have revolutionised the management of solid organ malignancy including melanoma and NSCLC. Direction has turned to the tumour immune microenvironment (TIM) to explore predictive biomarkers. The spatial arrangement of immune infiltrative cells has the potential to better explain the TIM. Vectra multispectral immunohistochemistry (IHC) allows accurate definition of the TIM and may help detect mechanisms of immune evasion.
Method:
Multispectral fluorescent immunohistochemistry with a panel including CKAE1/3, CD8, FOXP3 and PD-L1 (clone E1L3N, Cell Signalling Technology) was used to analyse the TIM in six patients (pts) with resected NSCLC (full face section from block). Respective tissue microarrays were collected in triplicate from each specimen and underwent conventional IHC scoring for PD-L1, tumour infiltrating lymphocytes (TILs), CD8, FOXP3 and scored (0,1,2,3). The spatial arrangement of lymphocytes relative to tumour cells, stroma and PD-L1 expression was examined.
Result:
All six pts had adenocarcinoma histology, with the following level of PD-L1 expression: low(0-5%;n=2), intermediate(5-50%;n=2) and high(>50%;n=2)Figure1. In PD-L1[hi] pts Vectra staining showed uniform staining of PD-L1 across the full face. CD8 lymphocytes were present mainly in tertiary lymphoid structures without evidence of clustering. In PD-L1[lo] pts, one had heterogenous staining of TILs with dense stromal clustering (3:1 ratio of stroma to intratumoural). Neither patient (PD-L1[lo]) demonstrated significant PD-L1 uptake on full section assessment. Of the PD-L1[int] pts, although heterogeneity in PD-L1 expression was evident across the full face, the majority of tumour rich areas stained positively and TILs were uniform in the stroma. FOXP3 had low expression across all 6 patients <1% almost uniformly in the stroma.Figure 1
Conclusion:
Although PD-L1 staining heterogeneity was limited in this small dataset, clear differences in immune-cell infiltrate were seen between full-face sections and limited cores. Multiplex Immunofluorescent IHC provides accurate quantification of immune infiltrates and spatial alterations within the TIM and may facilitate predictive biomarkers.
