Renal Cell Carcinoma

Overview

RCC (hypernephroma/Grawitz tumour — “hypernephroma” = historic misnomer, thought to arise from adrenal rests due to clear-cell resemblance). Adenocarcinoma of TUBULAR epithelium. 70-80% of renal cancers. Age 50-70, male 2:1.

Etiology/pathogenesis

1. Tobacco — major factor, 20-30% of cases, smokers 2x risk
2. Genetic (mostly sporadic, ~5% inherited):
   • VHL disease — AD, cerebellar haemangioblastoma+retinal angiomas+multiple CLEAR CELL RCC+phaeochromocytoma+cysts. VHL tumour suppressor gene (chr 3p), usually homozygous loss. ~35% VHL → RCC
   • Hereditary clear cell RCC — confined to kidney, AD
   • Papillary RCC — bilateral/multifocal, MET gene (chr 7)
   • Chromophobe RCC — multiple chromosome losses, hypodiploidy
3. Cystic kidney disease — hereditary+acquired (incl. dialysis-associated) ↑risk; polycystic kidney disease/multicystic nephroma → papillary RCC specifically
4. Other: asbestos/heavy metals/petrochemicals, obesity+oestrogen therapy (women), analgesic nephropathy, tuberous sclerosis

Classification/morphology

Gross: pole origin (upper more), solitary/unilateral (1% bilateral), large golden-yellow circumscribed. Necrosis/cystic change/haemorrhage on cut section. FREQUENT RENAL VEIN TUMOUR THROMBUS (may extend to IVC) — distinctive/significant.

Clinical features

Slow-growing, present years before detection. Classic triad: haematuria+flank pain+palpable mass (BUT haematuria alone is commonest presenting sign, ~60%; triad is actually LATE-stage). Spread by detection: haematogenous (lung/brain/bone), local (liver/perirenal nodes).

Systemic: fatigue, weight loss, cachexia, intermittent fever (no infection).

Paraneoplastic syndromes (ectopic hormones) — high-yield:

• Polycythaemia — EPO
• Hypercalcaemia — PTH-rp + prostaglandins
• Hypertension — renin
• Feminisation/masculinisation — gonadotropins
• Cushing’s syndrome — glucocorticoid-axis hormone

Prognosis: depends on extent at diagnosis. 5yr survival ~70%. Poor factors: metastases, renal vein invasion, high nuclear grade.

Clinical relevance

Broad paraneoplastic hormone repertoire (EPO, PTH-rp, renin, gonadotropins, ACTH-like) directly explained by kidney’s own normal endocrine functions (EPO+renin = truly renal) plus genuine ectopic secretion (PTH-rp, gonadotropins, ACTH-like = truly ectopic) — distinguish which are normal-organ-function vs genuinely ectopic. Clear cell-VHL link (+VHL’s broader tumour spectrum: haemangioblastoma, phaeochromocytoma, RCC) = ONE tumour-suppressor loss → tissue-specific tumours across unrelated organs — remember as a syndrome, not isolated genetics facts. Frequent renal vein/IVC tumour thrombus = distinctive among solid tumours, direct surgical relevance — staging/resection specifically account for vascular extension unlike most visceral cancers. Classic triad = actually LATE-stage presentation despite being “classic” — most detected via haematuria alone or incidentally; over-reliance on full triad risks delayed diagnosis.

Overview

Renal cell carcinoma (RCC) — synonyms hypernephroma, Grawitz tumour (“hypernephroma” is a historic misnomer, from the mistaken belief the tumour arose from adrenal rests, based on tumour cells resembling adrenal cortical clear cells) — is an adenocarcinoma of tubular epithelium, comprising 70–80% of all renal cancers. Peak age 50–70, male preponderance (2:1).

Etiology and Pathogenesis

1. Tobacco — the major risk factor (chewed or smoked), accounting for 20–30% of cases; smokers carry 2× risk.
2. Genetic factors — mostly sporadic, but ~5% inherited:
   • Von Hippel-Lindau (VHL) disease — autosomal dominant, comprising cerebellar haemangioblastoma, retinal angiomas, multiple clear cell RCC, phaeochromocytoma, multi-organ cysts; germline VHL tumour suppressor gene mutation (chromosome 3p), typically homozygous loss; ~35% of VHL patients develop RCC.
   • Hereditary clear cell RCC — clear cell RCC confined to kidney (no other VHL features), autosomal dominant.
   • Papillary RCC — bilateral, multifocal, papillary growth; genetic defect in MET gene (chromosome 7).
   • Chromophobe RCC — multiple whole-chromosome losses (extreme hypodiploidy).
3. Cystic kidney disease — both hereditary and acquired (including dialysis-associated acquired cystic disease) raise RCC risk; adult polycystic kidney disease and multicystic nephroma associate with papillary RCC specifically.
4. Other risk factors — asbestos/heavy metal/petrochemical exposure; obesity and oestrogen therapy (women); analgesic nephropathy; tuberous sclerosis.

Classification and Morphology by Type

Current classification is cytogenetics-based, with six recognised types:

Gross: typically arises from a renal pole (more often upper), solitary and unilateral (~1% bilateral); large, golden-yellow, circumscribed; papillary tumours may show grossly visible papillae and multifocality. Cut surface commonly shows ischaemic necrosis, cystic change, haemorrhage. A distinctive and clinically significant feature: frequent renal vein tumour thrombus, which may extend into the vena cava.

Clinical Features

Typically slow-growing, often present for years before detection. Classic diagnostic triad: gross haematuria, flank pain, palpable abdominal mass — though haematuria alone is the most common presenting finding (~60%). By detection, spread has often occurred: haematogenous to lungs, brain, bone; local to liver and perirenal nodes.

Systemic features: fatigue, weight loss, cachexia, intermittent fever without infection.

Paraneoplastic syndromes (from ectopic hormone production) — a particularly high-yield feature:

• Polycythaemia — ectopic erythropoietin.
• Hypercalcaemia — PTH-related peptide and prostaglandins.
• Hypertension — ectopic renin.
• Feminisation/masculinisation — gonadotropins.
• Cushing’s syndrome — ectopic glucocorticoid-axis hormone.

Prognosis: depends on extent at diagnosis; overall 5-year survival ~70%. Poor prognostic factors: metastases, renal vein invasion, higher nuclear grade.

Clinical Relevance

• RCC’s paraneoplastic hormone repertoire (EPO, PTH-related peptide, renin, gonadotropins, glucocorticoid-axis hormones) is genuinely broad compared to most solid tumours, and is directly explained by the kidney’s own normal endocrine functions (erythropoietin and renin production) plus ectopic hormone secretion more generally — recognising which hormones are normally renal in origin (EPO, renin) versus genuinely ectopic (PTH-rp, gonadotropins, ACTH-like activity) clarifies why this tumour has such a wide paraneoplastic footprint.
• The clear cell type’s link to the VHL pathway (and VHL disease’s broader tumour spectrum — haemangioblastoma, phaeochromocytoma, RCC) is a clean example of one tumour-suppressor loss producing tissue-specific tumours across several unrelated organs, worth remembering as a syndrome rather than isolated facts about “kidney cancer genetics.”
• The frequent renal vein (and sometimes IVC) tumour thrombus is a distinctive behaviour of RCC among solid tumours, with direct surgical relevance — it is why RCC staging and resection specifically account for vascular extension in a way not routinely emphasised for most other visceral cancers.
• The classic triad (haematuria, flank pain, mass) is actually a late-stage presentation despite being the “classic” teaching triad — most tumours are detected via haematuria alone or incidentally on imaging well before all three features co-occur, which is worth flagging since over-reliance on the full triad risks delayed diagnosis.

• Six RCC subtypes compared: incidence, genetics, and histology
• VHL disease’s tumour spectrum branching from one tumour-suppressor loss
• RCC’s paraneoplastic hormones mapped to normal-renal vs genuinely-ectopic origin

Multiple Choice Questions (2)