Wild type VHL clear cell renal carcinoma: Is it a distinct clinical and histological entity?

Abstract

11057 Background: Determine whether wild type VHL Clear Cell RCC (CCRCC) could be a distinct clinical and histological entity. Methods: 59 patients with sporadic CCRCCs were included in this prospective study. Four amplimers covering the whole coding sequence were synthesized by PCR and sequenced by Big Dye.VHL gene deletions and methylations were analyzed by MLPA and MS-MLPA respectively. pVHL was determined by IHC on paraffin embedded slides. In addition to usual clinical and pathological variables, presence of sarcomatoid component, granular predominant pattern, presence and type of tumor necrosis, morphological pattern, presence of haemorrhagic zones, cystic features, micro vascular invasion (MVI) and lymphocyte infiltrates were recorded. Results: VHL gene mutations, deletions or promoter methylations were identified in 38 (64.4%), 38 (64.4%) and 11 cases (19%) respectively. At least one VHL abnormality was found in 51 cases (86.4%). pVHL expression was negative in 45 cases (76.3%). Based on these findings a VHL score was created which was recorded as “0” when at least 2 hits occurred (n=38 cases, 64.4%). It appeared that when VHL gene was not affected by 2 hits or more, T stage was significantly higher (T3-T4, 61.9% vs 31.6%, p=0.02), tumors were more likely to be metastatic (M1, 38.1% vs 13.2%, p=0.02), peri-nephritic fat and renal vein invasion were more frequent (47.6% vs 18.4%, p=0.02; 42.9% vs 18.4%, p=0.04). Similarly, higher Fuhrman grades, N Stages or multifocality, collecting system invasion, MVI rates tent to be observed in wild type VHL tumors. Among all histological variables analyzed, only presence of sarcomatoid component (28.6% vs 5.3%, p=0.01) and predominant granular pattern (42.9% vs 13.2%, p=0.01) were significantly associated with wild type VHL profile. Finally, unaffected VHL tumors were more likely to exhibit early progression (p=0.03). Conclusions: Wild type VHL CCRCCs appear to exhibit an aggressive clinical and pathological profile compared to their VHL dysfunctioning counterparts. The biological significance of predominant sarcomatoid and granular patterns in such tumors should be further explored at the molecular level. Determining what molecular pathways are involved in such tumors could have important therapeutic implications. No significant financial relationships to disclose.