In the last decade renal tumors incidence increased especially renal cell carcinoma (RCC). Following RCC incidence rate per year is approximately 20%. Many subtypes of RCC should be considered for their clinical importance, variable prognosis and variable management strategy because they have different prognosis and subsequently require different management plans. Clear cell renal cell carcinoma (ccRCC) is the most recognized form about 75% up to 85% of RCC cases followed by papillary RCC (pRCC), chromophore RCC (chRCC) and collecting duct carcinoma (1). Unfortunately, ccRCC is highly aggressive subtype of RCC that may be associated with inactivation of the Von-Hippel-Lindau (VHL) tumor suppressor gene (2). Routine histopathology categorize different RCC subtypes as tumors with clear cytoplasm, foci of papillary architecture and the cytoplasm is eosinophilic. All these features give a comperhensive idea about how to approach the unique morphology of RCC (3).
World Health Organization classification 2016 released with new entities and subtypes of RCC reach up to 12 entity. Each subtype behave with different biological perspective and there is great need for accurate classification is mandatory for clinical purposes and will reflect on patients treatment modalities. Recently selection of target therapy according to genetic analysis of the RCC subtypes may reduce risk of poor prognosis (3). There are genetic and histopathological features with shortage of molecular markers leads to poor prognosis in RCC patients and associated complications. Re-examination and analysis of RCC behavior may enhance early detection and emergence of new therapeutic targeting strategies (4).
About third of patients with localized renal cell carcinoma (RCC) treated by surgical resection will experience recurrence. However, there is currently no established adjuvant treatment for patients after complete tumor resection. A randomized trial conducted in the early 1980s comparing adjuvant radiotherapy after nephrectomy with observation showed no benefit of radiotherapy, with significantly increased post-radiation complications (5).
Identification of primary RCC with high genetic risk of recurrence or resistance to treatment might help therapeutic decision maker to recognize patients who will benefits more from adjuvant therapies. Automated predictive and prognostic biomarkers help to identify personalized medicine and unwanted over-diagnosis to avoid therapeutic toxicities in RCC (6). RCC profile includes its cell of origin from the nephron, molecular alteration, angiogenesis and microenvironment. The main factor to classify RCC on molecular basis is to define its histological subtypes. RCC is a heterogeneous tumor carry diversity of mutations and inactivation of VHL had a great role in clustering mutated tumors whether associated with clear cells or papillary subtype (7).
Carcinogenic and etiological factors for RCC has not been fully identified, however several risk factors has been explored such as obesity, hypertension, smoking, advanced kidney diseases particularly cases that requires dialysis, occupational exposure to cadmium or organic solvents as trichloroethylene (8). In addition, interaction of genetic susceptibility and environmental factors may have a crucial role in RCC, among the mostly accused genes within that context is Von Hippel Lindau (VHL) tumor suppressor gene. In fact, extensive studies concerning derangement and mutations of VHL that may lead to metabolic and genetic alterations allow better understanding of pathogenesis of RCC and identifying potentially useful biomarkers as well (9). VHL was identified more than 20 years ago and revolutionized molecular biology of RCC; it is located on the short arm of chromosome 3 amplicon and its mRNA encodes VHL suppressor protein (pVHL), which comprises 213–amino acid residues (10). VHL protein (pVHL) is multifunctional protein with several pivotal roles concerning cellular events as regulation of cell cycle, transcription, apoptotic and hypoxia response mechanisms (11). Epigenetic silencing, mutations or deletions with inactivation or loss of tumor suppression functions of VHL gene has been observed in most of the cases of familial and sporadic RCC (12, 13). Germ line mutations of VHL has been reported to be a cause of hereditary neoplastic syndrome or VHL familial disease which is an autosomal-dominant inherited familial cancer associated with occurrence of RCC of clear cell type (ccRCC) and with some other tumors in different organs and sites, such as angiomas, pheochromocytomas and hemangioblastomas (14). Moreover, somatic mutations, which subsequently inactivate VHL gene and pVHL, were observed in more than 60% of sporadic RCC, clear cell type, also about 50% of those patients presented with distant metastasis and carrying very poor prognosis (15).
On the other hand, in conditions with loss of VHL functions as a tumor suppressor gene, development of malignancy and tumorigenesis is the expected outcome with deregulation of signaling pathways of VHL, allowing proliferation, angiogenesis ,invasion of surrounding tissues and immortalization of malignant cells that escape apoptotic mechanisms (16).
The pVHL promotes degradation of a family of transcriptional factors involved essentially in hypoxia adaptation mechanisms, namely Hypoxia inducible factors (HIFs), pVHL acts as a recognition subunit of E3 ubiquitin ligase enzyme complex, comprising cullin 2, elongin B, elongin C, and Rbx1, that catalyzes polyubiquitylation of the α-subunit of HIF to be degraded within the proteasomes (17). Under hypoxic circumstances and in conditions of mutated VHL, absent, deficient or non-functioning pVHL, non-degraded HIF will be stabilized, accumulated and translocated into the nucleus enhancing expression of several targeted genes (18). HIFs are mainly engaged in expression of genes controlling metabolic regulation as glucose transporter-1(GLUT1), hexokinase-1, iron, heme metabolism, angiogenesis as vascular endothelial growth factor (VEGF) and other downstream signals for carcinogenesis as multidrug-resistance pump (MDR-1), transforming growth factor alpha (TGFα) (19). Figure 1 illustrate signaling pathway of VHL when pVHL is functioning normally and in ccRCC associated with loss of functions of pVHL. Two subtypes of HIFs had been extensively studied, HIF1-α and HIF2-α. However HIF2-α has been shown to have more crucial role for carcinogenesis in clear cell RCC, accumulation of HIF2-α leads to upregulation and over expression of proliferative and proangiogenic factors (20). Mutation or deletion of VHL may affect binding mechanisms between pVHL and HIFs leading to over expression of HIF (21, 22). Recently, HIF1-α and HIF2-α were observed to have opposing effects in tumor progression in ccRCC xenograft, final outcome of both isoforms in VHL inactivation models may be dependent upon the fine-tanning of their effects, assuming that HIF2-α would act as an oncogene while HIF1-α would act as a tumor suppressor gene(23). In cancerous cells associated with VHL mutation or alteration, also with intramural hypoxia and overexpressing HIFs, failure of treatment may be expected to occur in those patients; therefore, it is essentially important to control HIF (24).