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Published on: January 22, 2018
Receptor tyrosine kinase amplified gastric cancer: Clinicopathologic characteristics and proposed screening algorithm
Cheol Keun Park1, Ji Soo Park2, Hyo Song Kim2
1Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
Abstract:
Although targeted therapy for receptor tyrosine kinases (RTKs) of advanced gastric cancers (AGCs) has been in the spotlight, guidelines for the identification of RTK-amplified gastric cancers (RA-GCs) have not been established. In this study, we investigate clinicopathologic characteristics of RA-GCs and propose a screening algorithm for their identification. We performed immunohistochemistry (IHC) for MLH1, MSH2, PMS2, MSH6, key RTKs (EGFR, HER2, MET), and p53, in situ hybridization for Epstein-Barr virus encoding RNA, and silver in situ hybridization (SISH) for EGFR, HER2, and MET using tissue microarrays of 993 AGCs. On IHC, 157 (15.8%) 61, (6.15%), and 85 (8.56%) out of 993 cases scored 2+ or 3+ for EGFR, HER2, and MET, respectively. On SISH, 31.2% (49/157), 80.3% (49/61), and 30.6% (26/85) of 2+ or 3+ cases on IHC showed amplification of the corresponding genes. Of the 993 cases, 104 were classified as RA-GCs. RA-GC status correlated with older age (P < 0.001), differentiated histology (P = 0.001), intestinal or mixed type by Lauren classification (P < 0.001), lymphovascular invasion (P = 0.026), and mutant-pattern of p53 (P < 0.001). The cases were divided into four subgroups using two classification systems, putative molecular classification and histologic-molecular classification, based on Lauren classification, IHC, and SISH results. The histologic-molecular classification showed higher sensitivity for identification of RA-GCs and predicted patient prognosis better than the putative molecular classification. In conclusion, RA-GCs show unique clinicopathologic features. The proposed algorithm based on histologic-molecular classification can be applied to select candidates for genetic examination and targeted therapy.
Insights
This study identifies unique features of receptor tyrosine kinase-amplified gastric cancers (RA-GCs) and proposes a new screening algorithm. The histologic-molecular classification method improves identification and prognosis prediction for targeted therapy selection.
Area of Science:
- Oncology
- Molecular Diagnostics
- Cancer Genomics
Background:
- Targeted therapy for advanced gastric cancers (AGCs) focuses on receptor tyrosine kinases (RTKs), but identification guidelines for RTK-amplified gastric cancers (RA-GCs) are lacking.
- Understanding the clinicopathologic characteristics of RA-GCs is crucial for developing effective diagnostic and therapeutic strategies.
Purpose of the Study:
- To investigate the clinicopathologic characteristics of RA-GCs.
- To propose a screening algorithm for identifying RA-GCs using immunohistochemistry (IHC) and silver in situ hybridization (SISH).
Main Methods:
- Analyzed 993 AGC tissue microarrays using IHC for key RTKs (EGFR, HER2, MET) and p53, and SISH for EGFR, HER2, and MET amplification.
- Classified RA-GCs and evaluated two classification systems: putative molecular and histologic-molecular.
Main Results:
- 104 out of 993 cases (10.5%) were classified as RA-GCs.
- RA-GC status correlated with older age, differentiated histology, intestinal/mixed Lauren type, lymphovascular invasion, and mutant p53.
- The proposed histologic-molecular classification demonstrated higher sensitivity for RA-GC identification and better patient prognosis prediction.
Conclusions:
- RA-GCs exhibit distinct clinicopathologic features.
- The developed algorithm based on histologic-molecular classification aids in selecting candidates for genetic testing and targeted therapy in AGCs.
