RENAL CELL CARCINOMA

Renal cell carcinoma: epidemiology and aetiology
Renal cell carcinoma also known as hypernephroma (since it was erroneously believed to originate in the adrenal gland), clear cell carcinoma, and Grawitz's tumour is an adenocarcinoma. It is the most common of renal tumours, accounting for 85% of renal malignancies and 2% of all cancer deaths. In the UK, 3676 patients were diagnosed (1999) and just over 2000 patients died of renal cell carcinoma (RCC) (2001). RCC is the most lethal of all urological tumours, approximately 40% of patients dying of the condition. Incidence has increased since the 1980s when ultrasound was introduced to investigate non-specific abdominal symptoms. It occurs in sporadic (common) and hereditary (rare) forms.

Aetiology
Males are affected twice as commonly as females; peak incidence of sporadic RCC is 6th - 8th decade.

Environmental
- Studies have shown associations with:
- urban dwelling
- low socio-economic status
- tobacco chewing
- smoking cigarettes, pipe, or cigars (1.4 - 2.3-fold risk)
- renal failure and dialysis (30-fold risk)
- obesity
- hypertension (1.4 - 2-fold risk)
- asbestos exposure
- the analgesic phenacitin
- thorium dioxide

Nutrition is considered important: Asian migrants to Western countries are at increased risk of RCC; vitamins A, C, E, and fruit/vegetable consumption are protective.
Anatomical risk factors include polycystic and horseshoe kidneys.

Genetic
von Hippel Lindau (VHL) syndrome 50% of individuals with this autosomal dominant syndrome, characterized by phaeochromocytoma, renal and pancreatic cysts, and cerebellar haemangioblastoma, develop RCC, often bilateral and multifocal. Patients typically present in 3rd, 4th, or 5th decades. VHL syndrome occurs due to loss of both copies of a tumour suppressor gene at chromosome 3p25 - 26; this and other genes on 3p are also implicated in causing the common sporadic form of RCC. Inactivation of the VHL gene leads to effects on gene transcription, including dysregulation of hypoxia inducible factor 1 (HIF-1), an intracellular protein that plays an important role in the cellular response to hypoxia and starvation. This results in upregulation of vascular endothelial growth factor (VEGF), the most prominent angiogenic factor in RCC, explaining why some RCCs are highly vascular.

A papillary variant of RCC also has an autosomal dominant familial component, characterized by trisomy 7 and 17, with activation of the c-MET proto-oncogene. c-MET encodes the receptor tyrosone kinase for hepatocyte growth factor, which regulates epithelial proliferation and differentiation in a wide variety of organs, including the normal kidney.

Renal cell carcinoma: pathology, staging, and prognosis
RCC is adenocarcinoma of the renal cortex, believed to arise from proximal convoluted tubule. Usually tan coloured and solid, 7 - 20% are multifocal, 10 - 20% contain calcification, and 10 - 25% contain cysts or are predominantly cystic. Rarely grossly infiltrative, they are usually circumscribed by a pseudocapsule of compressed tissue.

Spread
- By direct extension to adrenal gland (7.5% in tumours >5cm), through the renal capsule, into renal vein (5% at presentation), inferior vena cava (IVC), right atrium
- By lymphatics to hilar and para-aortic lymph nodes
- Haematogenous to lung (75%), bone (20%), liver (18%), and brain (8%).

Histological classification of RCC
- Conventional (70 - 80%): arise from the proximal tubule; highly vascular; cells clear (glycogen, cholesterol) or granular (eosinophillic cytoplasm, mitochondria)
- Papillary (10 - 15%): papillary, tubular, and solid variants; 40% multifocal; small incidental tumours could equate with Bell's legendary benign adenoma
- Chromophobe (5%): arises from the cortical portion of the collecting duct; possess a perinuclear halo of microvesicles
- Collecting duct (Bellini): rare; young patients; poor prognosis
- Medullary cell: rare; arises from calyceal epithelium; young, black, sickle-cell sufferers; poor prognosis.

The term sarcomatoid  is used to describe an infiltrative, poorly differentiated variant of any type. RCC is an unusually immunogenic tumour, expressing numerous antigens (e.g. RAGE-1, MN-9). Reports of spontaneous regression, prolonged stabilization, and complete responses to immunotherapy support this. Tumour-infiltrating lymphocytes are readily obtained from RCCs including T-helper, dendritic, natural killer, and cytotoxic T cells. Efforts are ongoing to refine immunotherapy for RCC. RCC is also unusually vascular, overexpressing angiogenic factors, principally VEGF but also basic FGF and TGF β.

Grading
is by the Fuhrman system (1 = well-differentiated; 2 = moderately differentiated; 3 and 4 = poorly differentiated) based on nuclear size, outline, and nucleoli.

Staging
is by the TNM (1997) classification following histological confirmation of the diagnosis. All rely upon physical examination and imaging; the pathological classification (prefixed p ) corresponds to the TNM categories. Staging is the most important prognostic indicator for RCC.