TFE3-rearranged RCC is a distinct molecular subtype, as defined by the 2022 WHO classification [4], exhibiting a low incidence [14]. In our series, the incidence of TFE3-rearranged-RCC was 1.15% (8 out of 695 cases). A previous meta-analysis by Cheng et al. [14] highlighted a significantly higher incidence in females compared to males, with a pooled odds ratio (OR) of 5.13. Interestingly, survival features were found to be comparable between genders. TFE3-rearranged-RCC is characterized by the translocation of the Xp11.2 chromosome, which may explain the higher incidence in women. In contrast to some studies indicating gender-based differences [10, 11, 16,17,18], our results reveal an equal incidence in both men and women (50%/50%).

Since its recognition by WHO in 2004, the diagnosis of TFE3-rearranged renal cell carcinoma (RCC) relied on microscopic appearance and TFE3 IHC. However, several studies have demonstrated the limited accuracy of TFE3-IHC [6, 12, 13]. Klatte et al. [5] found that the positive predictive value of TFE3 immunostaining for TFE3-rearranged-RCC was only 12%, highlighting that IHC should not serve as a surrogate marker for diagnosis. Green et al. [9] conducted an immunohistochemical panel to identify consistently positive markers in these tumors, and some studies attempted combinations such as cathepsin K, HMB45, and others. However, the accuracy of these combinations did not reach a satisfactory level [6, 12, 13].

Lately, some studies have incorporated second-generation sequencing for the diagnosis of TFE3-rearranged RCC, as it can overcome the false negatives associated with FISH in specific fusion subtypes like NONO [10]. However, it’s important to note that these advanced sequencing techniques may not be universally available in all laboratories [6, 11, 12]. Currently, TFE3 break-apart FISH remains the gold standard for diagnosing TFE3-rearranged RCC [6, 11, 12]. In our current study, only 36% (8/22) of the TFE3 immunohistochemistry-positive samples were confirmed positive in the FISH assay.

According to previous studies, TFE3-rearranged RCC is more commonly diagnosed in young adults and has been suggested to exhibit aggressiveness comparable to ccRCC [10, 11, 16,17,18]. However, there is insufficient evidence to determine whether it independently contributes to lower PFS and OS. The current study revealed comparable tumor characteristics between ccRCC and TFE3-rearranged-RCC. Notably, patients with TFE3 rearrangement were significantly younger than those with ccRCC (median age, 49 vs. 58 years; p = 0.02) and demonstrated a markedly higher recurrence rate (50% vs. 18.8%; p = 0.04). This aligns with the findings of Lin et al. [12], supporting the notion that even with an early tumor stage at the initial diagnosis, recurrence and new metastasis are relatively common [12].

To our knowledge, this is the first study that compares TFE3-rearranged-RCC with ccRCC; survival analysis indicated that TFE3-rearranged RCC exhibited a significantly shorter progression-free survival, compared to ccRCC. However, given that only one patient with TFE3-rearranged-RCC died during the follow-up period, there were no significant differences observed in OS. The results of univariate and multivariate Cox proportional hazard models revealed that TFE3 rearrangement is an independent prognostic factor for recurrence, alongside tumor stage (HR = 4.6; 95% CI 1.1–21.2; p = 0.05).

Recent studies have highlighted that positive TFE3 IHC is linked to tumor progression and poor prognosis, regardless of the presence of TFE3 translocation [5, 10, 11]. Klatte et al. [5] conducted a reassessment of 75 RCC with morphological features suggestive of TFE3 translocation, revealing that 17 cases exhibited positive TFE3 IHC, while only 2 cases (2.6%) were genetically confirmed for the translocation through FISH or polymerase chain reaction (PCR). Their study demonstrated that positive TFE3 HIC had significantly worse disease-specific survival compared to RCC with negative HIC staining (HR: 3.3; CI 95% 1.03–11.1; p = 0.3). Notably, the presence of nuclear TFE3 immunostaining was associated with poor prognosis in the univariate analysis but not in the multivariate analysis [5].

We performed univariate and multivariate Cox proportional hazard models that suggest positive TFE3 IHC is not an independent prognostic factor for recurrence. On the other hand, Dong et al. [11], in both univariate and multivariate analyses, identified TFE3 positive IHC as an independent factor associated with poor progression-free survival (PFS). Lin et al. [12] found that both FISH-confirmed TFE3 rearrangement and positive IHC expression contribute to a poor prognosis in RCC. Our findings indicated that 42% of patients with RCC with positive TFE3 IHC died from cancer. Larger cohort studies are imperative to further delineate the implications of positive TFE3 immunostaining, not only as a screening marker for TFE3 rearrangement but also as a prognostic factor for recurrence and mortality.

However, it is crucial to acknowledge the limitations of our study. Firstly, its retrospective nature poses inherent constraints. Secondly, the relatively small population of TFE3-rearranged-RCC and the heterogeneity of the groups, given that ccRCC had a larger follow-up time, could introduce potential selection and information bias. Thirdly, RNA sequencing was not performed beyond the FISH assay, potentially impacting the accuracy of the diagnoses leading to classification bias.

In summary, TFE3-rearranged RCC represents a rare subtype, accounting for 1.15% of cases in the current study. The diagnosis of this subtype should be verified through FISH due to the IHC’s low specificity. Our study highlights TFE3 rearrangement as an independent prognostic factor linked to recurrence, leading to a compromised PFS. This underscores the importance of vigilant follow-up. Moreover, further investigations are warranted to validate TFE3 immunohistochemistry staining as a reliable prognostic indicator for recurrence and mortality.