Cytoplasmic p53 Immunostaining in Salivary Duct Carcinoma: A Poor Prognostic Factor Associated With Characteristic TP53 Variants

Salivary duct carcinoma (SDC) is an uncommon, high-grade malignancy. Identifying suitable prognostic factors is crucial for developing effective treatment strategies for SDC. p53 Immunohistochemistry (IHC) is a potential prognostic marker for SDC. Traditionally, only the nuclear expression has been considered when evaluating aberrant p53 IHC patterns. However, recent studies on other organ cancers have highlighted the significance of the cytoplasmic p53 expression. We aimed to investigate the prognostic implications of cytoplasmic p53 positivity and its association with TP53 variants in a large cohort of patients with SDC. p53 IHC was performed in 327 patients with SDC who had undergone primary curative resection. Based on the immunostaining patterns, patients were classified into 4 groups: wild-type (WT), overexpression (OE), complete absence (CA), and cytoplasmic (CY). Additionally, the TP53 gene status was analyzed in 239 cases by Sanger and/or next-generation sequencing. The p53 IHC patterns of 327 cases were as follows: WT (n = 125; 38.2%), OE (n = 100; 30.6%), CA (n = 75; 22.9%), and CY (n = 27; 8.3%). A TP53 genetic analysis of 239 cases revealed the following: WT status (n = 80; 33.5%), missense/inframe variants (n = 86; 36.0%), and truncating variants (n = 73; 30.5%). Notably, 24 of the 25 CY cases (96%) harbored TP53 variants, which were predominantly located in the domains responsible for nuclear translocation. Of these, 22 exhibited truncating variants. In a multivariate analysis, CY cases demonstrated significantly shorter disease-free survival (DFS) than WT cases (P = .01). Furthermore, patients with aberrant p53 expression patterns (OE+CA+CY) had significantly worse DFS and overall survival than those with WT (P = .003 and .002, respectively). The presence of TP53 variants was also associated with poorer DFS and overall survival (P = .003 and .02, respectively). Our findings suggest that the cytoplasmic expression of p53 in SDC represents a distinct aberrant pattern underlying characteristic genetic abnormalities and has significant prognostic implications.