Comparative analysis of clinicopathological characteristics and prognostic outcomes in fumarate hydratase-deficient renal cell carcinoma versus high-grade papillary renal cell carcinoma.

Background: Papillary renal cell carcinoma (pRCC) is characterized by pronounced molecular and phenotypic heterogeneity. The traditional dichotomous classification was discontinued in the 2022 World Health Organization (WHO) Fifth Edition Classification, leading to the introduction of new renal cancer categories, including fumarate hydratase (FH)-deficient renal cell carcinoma (RCC). But there remains a significant risk of misdiagnosis between FH-deficient RCC and high-grade pRCC. Furthermore, existing studies rarely provide comprehensive comparative analyses of these types of renal cancer. This study aims to investigate the clinical and pathological characteristics, as well as the prognosis, of FH-deficient RCC and high-grade pRCC, thereby providing a basis for precise diagnosis.

Methods: We retrospectively analyzed the clinical and pathological data of patients diagnosed with high-grade pRCC (n=40) or FH-deficient RCC (n=20) between May 2012 and May 2023.

Results: Compared to high-grade pRCC, FH-deficient RCC exhibited significant differences in several parameters: age (P<0.001), presence of necrosis (P=0.007), sarcomatoid differentiation (P=0.03), vascular cancer thrombus formation (P=0.02), lymph node metastasis (P=0.001) renal sinus invasion (P=0.042), perirenal fat invasion (P=0.01), adrenal gland invasion (P=0.003), and pathological tumor (pT) stage (P=0.009). Patients with FH-deficient tumors tended to be younger and were more likely to exhibit features such as necrosis, sarcomatoid differentiation, renal sinus and perinephric fat invasion, adrenal gland involvement, lymph node metastasis, and more advanced pathological stages compared with those with high-grade pRCC. However, FH-deficient RCC demonstrated a significantly lower incidence of lymphovascular invasion when compared to high-grade pRCC. The 3-year progression-free survival (PFS) rates were 16.9% for FH-deficient RCC and 76.2% for high-grade pRCC. Patients with FH-deficient RCC had significantly worse outcomes than those with high-grade pRCC (P<0.001).

Conclusions: Patients who are younger, have advanced pathological stages, or exhibit sarcomatoid differentiation should undergo mandatory immunohistochemical staining for FH and molecular testing to prevent misdiagnosis as conventional pRCC. Despite its aggressive local behavior and poorer clinical outcomes, FH-deficient RCC shows a significantly lower frequency of vascular invasion relative to high-grade pRCC. Further investigation into the mechanisms underlying the metastasis of these tumors is warranted to identify potential therapeutic targets.