Fibroblast Activation Protein Alpha (FAP) Expression Is Associated with Disease Recurrence and Poor Response to Tyrosine Kinase Inhibitors in Advanced Clear Cell Renal Cell Carcinoma

Abstract

Despite advances in the management of advanced clear cell renal cell carcinoma (ccRCC), robust biomarkers for prognosis and therapeutic response prediction remain elusive. Fibroblast activation protein-α (FAP), a marker of activated cancer-associated fibroblasts (CAFs), has emerged as a potential indicator of tumor aggressiveness and resistance to systemic therapies in various solid tumors. This study evaluated the clinical relevance of stromal FAP expression in a cohort of 137 patients with advanced ccRCC and long-term follow-up. FAP immunohistochemistry (IHC) was performed on primary tumor specimens and correlated with key clinicopathological features, disease-free survival (DFS), overall survival (OS), and radiological response to first-line tyrosine kinase inhibitors (TKIs). A significantly higher percentage of FAP-positive CAFs was observed in primary tumors with high histological grade, extensive local invasion (pT3-4), and advanced clinical stage (NCCN stage III-IV). Stromal FAP expression was associated with shorter DFS and OS. Moreover, tumors lacking FAP expression were more likely to achieve complete response to TKI therapy as defined by RECIST criteria. These findings highlight the potential of FAP IHC as a prognostic and predictive tool in advanced ccRCC and support further clinical validation.

Keywords: FAP; clear cell renal cell carcinoma; disease recurrence; fibroblast activation protein; metastasis; survival; tyrosine kinase inhibitors.

Figure 1

Hematoxylin/Eosin (H&E) and FAP immunohistochemical (IHC) staining in clear cell renal cell carcinoma (ccRCC). (a,b): High-grade ccRCC with prominent stromal proliferation (arrows) separating tumor cell nests showing prominent FAP positivity in stromal fibroblasts (arrows). (c,d): Low-grade CCRCC without apparent stromal proliferation and FAP negative staining. (Original magnification ×250).

Figure 2

Immunohistochemical expression of FAP in primary ccRCC tumors stratified by clinicopathological variables. Tumors were grouped according to histological grade (a), tumor size (b), local invasion (pT) (c), lymph node involvement (N) (d), presence of distant metastases (M) (e), and NCCN stage at diagnosis (f). IMDC risk classification (g) and ECOG performance status (h) were assessed at the time of initiating TKI therapy. FAP expression in CAFs was categorized as positive or negative. The Y-axis represents the percentage of tumors exhibiting FAP positivity or negativity. Statistical comparisons were performed using the χ² test. N0: No lymph node metastasis; N1: lymph node metastasis; M0: No distant metastasis; M1: synchronous distant metastasis.

Figure 3

Immunohistochemical expression of FAP in primary ccRCC tumors according to response to TKI therapy, evaluated using RECIST criteria (a) and MASS criteria (b). The percentage of FAP-positive tumors was significantly lower among cases with complete response according to RECIST. The Y-axis indicates the percentage of tumors classified as FAP positive or negative. Statistical analysis was performed using the χ² test.

Figure 4

FAP expression in primary ccRCC tumors and patient survival. Kaplan–Meier curves and log-rank tests show a significant association between FAP positivity and DFS at 10 years (a), as well as OS at 15 years (b). The number of patients at risk at specific time points is shown below each curve.