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Venkata Manem
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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
- Moderators:Yuko Minami, Mary Beth Beasley
- Coordinates: 9/10/2019, 11:30 - 13:00, Tokyo (1982)
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MA18.06 - Gene Expression and Clustering of Pulmonary Neuroendocrine Tumors at the Border of Low/Intermediate and High Grade Morphology (Now Available) (ID 1096)
11:30 - 13:00 | Author(s): Venkata Manem
- Abstract
- Presentation
Background
The WHO classification of lung tumors is based on several features such as cell morphology, cell size, growth patterns, mitotic rate and presence of necrosis. Pulmonary neuroendocrine tumors are stratified into two categories, namely, low/intermediate grade (pulmonary carcinoid tumors) and high grade (pulmonary neuroendocrine carcinomas). Mitotic rate assessment on H&E stained slides play a crucial role in morphological classification of pulmonary carcinoids and high grade neuroendocrine carcinomas. Neuroendocrine tumors with 0-10 mitoses/ 2 mm² are classified as carcinoids and those with mitotic rate higher than 10 mitoses/ 2 mm² as neuroendocrine carcinomas. However, rare tumors which lie on the border of the spectrum with mitotic rates exceeding 10 mitoses/ 2 mm² but falling far below the average mitotic rates of high grade neuroendocrine carcinomas may actually share more molecular characteristics with carcinoids than high grade neuroendocrine carcinomas. The objective of the project was to explore gene expression of those tumors and a potential utility of molecular features in their classification. The study was based on the next generation RNA-sequencing.
Method
Five borderline tumors that exceeded the threshold of 10 mitoses/ 2 mm² in 3 hot-spot areas but remained on the lowest end of the spectrum of malignity for large cell neuroendocrine carcinomas (LCNECs) were selected from institutional archives. These tumors were defined by mitotic counts of 11 to 30 mitoses/ 2 mm². Besides, one case with higher mitotic rate in hot-spot zone (42 mitoses/ 2 mm²) but lower than 30 mitoses/ 2 mm² in the other areas was included in a group of borderline tumors. Seven pulmonary carcinoids and 6 LCNECs were selected for control groups. Ki-67 proliferation index and expression of p53 and pRB proteins were assessed by immunohistochemistry. Next generation RNA-sequencing was performed on fresh frozen tissues from all 18 samples on Illumina platform. Then, unsupervised hierarchical clustering was used to stratify the cases.
Result
Pulmonary carcinoids and LCNECs clustered into 2 different groups with no overlap. Borderline tumors presented as a heterogenous group where 3 tumors clustered with carcinoids and the other two with LCNECs. Tumors that clustered with LCNECs expressed higher mitotic rate and presented more prominent necrosis. One of 2 cases that clustered with LCNECs had abnormal p53 expression. There were no cases with pRB loss among borderline tumors. For comparison, p53 and pRB expression was preserved in all carcinoid tumors. A subset of tumors in LCNEC group had abnormal p53 expression (strong diffuse expression or complete loss) and pRB loss.
Conclusion
Next generation RNA-sequencing coupled with hierarchical clustering analysis allowed to demonstrate that a subset of borderline tumors classified as LCNEC by the current morphology-based WHO classification shows gene expression that is more compatible with pulmonary carcinoids. The data add to the evidence that molecular classification would prove to be a useful tool in stratification of low/intermediate and high grade pulmonary neuroendocrine tumors. However, immunohistochemistry for p53 and pRB is not sufficient for differentiation between pulmonary carcinoid and LCNEC.
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