Introduction:

Von Hippel-Lindau (VHL) disease is a hereditary multi-organ tumor syndrome that places affected patients at risk of developing renal cell carcinoma (RCC), often with multiple tumors requiring repeated surgeries throughout their lifetime. Tumor grade is a prognostic factor in renal cell carcinoma (RCC) and is associated with both local recurrence and development of metastatic disease. Suspicion of high-grade disease has the potential to impact the timing and extent of surgical management and the use of targeted therapies like belzutifan in the localized setting. While predictors of high-grade disease have been studied in sporadic RCC, factors unique to the VHL population have not been assessed. In this study, we evaluate the proportion of VHL patients with high-grade disease and analyze the potential role of clinical, pathologic, and genetic factors as predictors of high-grade disease.

Methods:

RCC specimen resected from VHL patients who underwent surgical management between 2006 and 2021 at the National Cancer Institute were evaluated. Tumor grade, tumor size demographics, and genetic data were abstracted from clinical records. Fuhrman or ISUP nuclear grade 3-4 were designated as high grade and grade 1-2 was low grade. Comparative statistics and multivariate logistic regression models analyzed correlation between pathologic grade and age at time of surgery, sex, race, tumor size, positive versus negative previous ipsilateral renal surgery (PIRS) status, and VHL mutation type (nonsense, partial deletion, missense, frameshift, splice, and amino acid deletion). Tumor size was defined as the largest dimension and evaluated by comparing one centimeter size increments.

Results:

A total of 2,392 RCC specimens from 237 patients was available for analysis, 167 (6.98%) were high-grade. High-grade tumors tended to be from older patients (47.1 vs 40.7 years, p < 0.0001), with 5.01% of tumors from patients under 40 being high-grade compared to 10.26% for patients over 40. High-grade tumors were also larger (3.0 vs 1.8 cm, p < 0.0001). On multivariate analysis, older age (OR 1.02, p < 0.0001) and increasing tumor size (OR 1.58, p < 0.0001) increased risk for high-grade tumor pathology.

PIRS (OR 2.10, p = 0.002) and frameshift VHL mutations (OR 2.38, p = 0.01) were also found to increase risk for high-grade pathology. On the other hand, partial deletion (OR 0.47, p < 0.0001) and splice (OR 0.24, p = 0.017) mutations were found to protect against high-grade pathology.

Conclusion:

Older age at time of surgery, increased tumor size, history of ipsilateral renal surgery, and presence of VHL germline frameshift mutation are independently and significantly associated with high grade disease in VHL patients.  Patients who have older age, larger tumors, a history of ipsilateral renal surgery, frameshift VHL mutation, or some combination of the above may be candidates for more prompt and extensive surgical intervention. Future studies on RCC and its relevant tumor syndromes will be essential to better understanding the relationship between tumor pathologic grade and these and other potential predictive factors. 

Funding: N/A