Diversity within: a systematic review of intratumor heterogeneity in head and neck squamous cell carcinoma.

Objective

Head and neck squamous cell carcinoma (HNSCC), is a common, morbid, and frequently lethal malignancy with complex molecular landscapes that influence treatment outcomes and resistance. This systematic review aimed to evaluate the frequency and nature of intratumor heterogeneity (ITH) across multiple tumor regions.

Design

We systematically reviewed and screened studies on HNSCC intratumor heterogeneity. Mutation and heterogeneity rates were extracted, quality-assessed, and analyzed to classify genes by heterogeneity levels.

Results

We identified five eligible studies, analyzing 59 reported cases; after correcting for a partially overlapping patient cohort shared between 2 of the included studies, 57 unique cases were analyzed. Among them, 51 cases (89.5%) exhibited significant spatial heterogeneity, while only 6 cases (10.5%) showed mutational homogeneity. The most frequently mutated gene was TP53 (85.96%), which also showed the lowest ITH (34.69%), suggesting clonal origin. Other commonly mutated genes included TGFBR2, NOTCH1, CDKN2A, and EGFR. Notably, KRAS, NRAS, and BRAF genes associated with the MAPK and PI3K pathways exhibited 100% heterogeneity, implying subclonal and late-arising mutations. EGFR mutations, which are commonly targeted in several other malignancies, were observed in 30.43% of cases, with a heterogeneity rate of 64.29%.

Conclusion

Understanding ITH is key to precision oncology, improving personalized treatment and outcomes in HNSCC, though larger studies are needed to confirm its prognostic and therapeutic relevance.