Over half of carcinoma ex pleomorphic adenoma cases harbored pathogenic mutations—most commonly in TP53 and HRAS—while none were found in pleomorphic adenomas, according to a recent study published in Modern Pathology.
A prospective study evaluated the use of DNA methylation profiling and targeted next-generation sequencing (NGS) to distinguish pleomorphic adenoma (PA) from carcinoma ex pleomorphic adenoma (CXPA). The analysis included 140 salivary gland tumors—66 identified as PA and 74 as CXPA—collected through the French Rare Head and Neck Cancer Expert Network and the tumor bank of Toulouse University Hospital.
Methylation profiling was performed on 66 formalin-fixed paraffin-embedded tissue samples (33 PAs and 33 CXPAs) covering over 850,000 CpG sites. Hierarchical clustering categorized tumors into three groups based on methylation patterns: benign (n = 16), intermediate (n = 25), and malignant (n = 24). All ten invasive CXPAs were included in the malignant cluster, which had a median patient age of 65 years and a median Ki67 index of 25 percent. Three PAs were also grouped with malignant cases, though they showed no pathogenic mutations and had either flat or minimal copy number alterations.
Targeted NGS was performed on 130 tumors using a 48- to 50-gene panel. No pathogenic mutations were detected in any of the 63 PA cases. In contrast, 37 of 67 CXPA cases (55 percent) harbored pathogenic or likely pathogenic variants. The most frequently affected genes were TP53 and HRAS, with the HRAS p.Q61R variant found in 7 of 11 HRAS-mutated tumors. TERT promoter mutations (c.-124C>T and c.146C>T) were present in 2 of 13 myoepithelial CXPA cases. PD-L1 expression was observed in one of these two cases.
Copy number alterations (CNAs) were derived from methylation array data. The malignant cluster exhibited a median of 3.5 chromosomal alterations, with frequent gains in chromosomes 5 and 8. The benign cluster showed fewer genomic alterations, with 56 percent of cases exhibiting flat CNA profiles and a median Ki67 index of 10 percent.
Pathogenic alterations in TP53, HRAS, PTEN, and TERT, as well as HER2 amplification, were observed only in CXPA cases. The findings indicate that molecular data may support histologic assessment in the classification of tumors within the PA–CXPA spectrum.
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