This study investigated the correlation of the matrix heterogeneity of tumors on 18F-fluorodeoxyglucose positron emission tomography–computed tomography (PET–CT) with gene-expression profiling in patients with pharyngeal cancer and determined the prognostic factors for radiotherapy-based treatment outcomes.
We retrospectively reviewed the records of 57 patients with stage III–IV oropharyngeal or hypopharyngeal cancer who had completed definitive therapy. Four groups of the textural features as well as 31 indices were studied in addition to maximum standard uptake value, metastatic tumor volume, and total lesion glycolysis. Immunohistochemical data from pretreatment biopsy specimens (Glut1, CAIX, VEGF, HIF-1α, EGFR, Ki-67, Bcl-2, CLAUDIN-4, YAP-1, c-Met, and p16) were analyzed. The relationships between the indices and genomic expression were studied, and the robustness of various textural features relative to cause-specific survival and primary relapse-free survival was analyzed.
The overexpression of VEGF was positively associated with the increased values of the matrix heterogeneity obtained using gray-level nonuniformity for zone (GLNUz) and run-length nonuniformity (RLNU). Advanced T stage (p = 0.01, hazard ratio [HR] = 3.38), a VEGF immunoreactive score of >2 (p = 0.03, HR = 2.79), and a higher GLNUz value (p = 0.04, HR = 2.51) were prognostic factors for low cause-specific survival, whereas advanced T stage, a HIF-1α staining percentage of ≥80%, and a higher GLNUz value were prognostic factors for low primary-relapse free survival.
The overexpression of VEGF was associated with the increased matrix index of GLNUz and RLNU. For patients with pharyngeal cancer requiring radiotherapy, the treatment outcome can be stratified according to the textural features, T stage, and biomarkers.
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Clinical target volumes
Gray-level nonuniformity for zone
Gross tumor volume
Head and neck squamous cell carcinoma
Human papilloma virus
Metastatic tumor volume
Positron emission tomography-computed tomography
Standardized uptake value
Total lesion glycolysis
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SW Chen, WC Shen, and CH Kao were responsible for design of the study. All authors collected the data. SW Chen, WC Shen, and CH Kao carried out statistical analysis, interpretation of data, and drafting the article. All authors provided some intellectual content. SW Chen, WC Shen, and CH Kao approved the version to be submitted. All authors read and approved the final manuscript.
This study was supported in part by China Medical University Hospital (DMR-104-041), Ministry of Science and Technology (NSC 100-2221-E-468-003 and MOST 105-5518-E-009-034), Taiwan; the Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW105-TDU-B-212-133019); China Medical University Hospital, Academia Sinica Taiwan Biobank Stroke Biosignature Project (BM10501010037); NRPB Stroke Clinical Trial Consortium (MOST 105-2325-B-039-003); Tseng-Lien Lin Foundation (Taichung, Taiwan), Taiwan Brain Disease Foundation (Taipei, Taiwan), and Katsuzo and Kiyo Aoshima Memorial Funds, Japan; CMU under the Aim for Top University Plan of the Ministry of Education, Taiwan; and the Welfare Surcharge of Tobacco Products, China Medical University Hospital Cancer Research Center of Excellence (MOHW105-TDU-B-212-134-003, Taiwan). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study.
Conflict of interest
Shang-Wen Chen declares that he/she has no conflict of interest. Wei-Chih Shen declares that he/she has no conflict of interest. Ying-Chun Lin declares that he/she has no conflict of interest. Rui-Yun Chen declares that he/she has no conflict of interest. Te-Chun Hsieh declares that he/she has no conflict of interest. Kuo-Yang Yen declares that he/she has no conflict of interest. Chia-Hung Kao declares that he/she has no conflict of interest.
This study was approved by a local institutional review board (CMUH103-REC2-093FR).
The IRB also specifically waived the consent requirement.
Shang-Wen Chen and Wei-Chih Shen contributed equally to this work.
Appendix 1. Representative images of immunohistochemistry for HIF-1α, VEGF, and Glut1
Appendix 4. Detailed data on the role of VEGF in pharyngeal cancer regarding to the textural features and treatment outcome
Primary relapse-free survival in patients who had tumors with a VEGF IRS of >2 and ≤2 (p = 0.002).
Cause-specific survival in oropharyngeal cancer patients who had tumors with a VEGF IRS of >2 and ≤2 (p = 0.005 and p = 0.006, respectively).
Indices calculated from the textural analysis and the area under the ROC curve for predicting the expression of VEGF using a cutoff of IRS >2 vs. ≤2.
Classification of matrix Index Area under the curve CT-based volume GTV 0.75 ± 0.07 Classical PET-related parameter SUVmax 0.57 ± 0.08 Gray-level co-occurrence matrix (GLCM) MTV2.5 0.71 ± 0.09 TLG40% 0.61 ± 0.10 Homogeneity 0.44 ± 0.08 Energy 0.31 ± 0.08 Correlation 0.55 ± 0.10 Contrast 0.61 ± 0.08 Entropy 0.67 ± 0.08 Dissimilarity 0.61 ± 0.08 Gray-level run length matrix (GLRLM) SRE 0.53 ± 0.09 LRE 0.49 ± 0.09 LGRE 0.37 ± 0.08 HGRE 0.61 ± 0.08 SRLGE 0.37 ± 0.08 SRHGE 0.60 ± 0.08 LRLGE 0.39 ± 0.08 LRHGE 0.64 ± 0.07 GLNUr 0.66 ± 0.09 RLNU 0.70 ± 0.09 RP 0.65 ± 0.09 Neighborhood gray-level different matrix (NGLDM) Coarseness 0.31 ± 0.09 Contrast 0.38 ± 0.09 Busyness 0.51 ± 0.09 Gray-level zone length matrix (GLSZM) SZE 0.51 ± 0.09 LZE 0.57 ± 0.09 LGZE 0.37 ± 0.08 HGZE 0.61 ± 0.08 SZLGE 0.34 ± 0.08 SZHGE 0.57 ± 0.08 LZLGE 0.53 ± 0.08 LZHGE 0.65 ± 0.10 GLNUz 0.72 ± 0.08 ZLNU 0.67 ± 0.08 ZP 0.48 ± 0.09
Appendix 5 The GLNUz value exhibited superior discrimination of local recurrence in patients with T3–T4 disease (n = 32). The 2-year PRFS for those with a GLNUz value in the >50th and ≤50th percentile was 10% and 84%, respectively (p < 0.001)
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Chen, S., Shen, W., Lin, Y. et al. Correlation of pretreatment 18F-FDG PET tumor textural features with gene expression in pharyngeal cancer and implications for radiotherapy-based treatment outcomes. Eur J Nucl Med Mol Imaging 44, 567–580 (2017). https://doi.org/10.1007/s00259-016-3580-5
- Head and neck cancer
- 18F-fluorodeoxyglucose positron emission
- Textural analysis
- Genomic expression