Page 14 of 27

PA27.{14,16} | Renal & Urothelial Tumours — SDL Guide (Part 2)

RCC — Gross Pathology and Staging

A three-panel medical diagram shows clear cell renal cell carcinoma as a yellow-orange upper-pole renal mass, its classic venous tumour thrombus extension into the renal vein and IVC, and simplified TNM staging from T1 to M1. — **Panel A:** Coronal cut kidney showing upper-pole clear cell RCC with yellow-orange lipid-rich cut surface, haemorrhage, necrosis, cystic change, pseudocapsule, compressed renal parenchyma, and renal pelvis.. **Panel B:** Frontal vascular schematic showing RCC tumour thrombus extending continuously into the renal vein, inferior vena cava, and potentially the right atrium.. **Panel C:** Simplified TNM staging icons showing T1 ≤7 cm confined to kidney, T2 >7 cm confined to kidney, T3 major vein or perinephric fat invasion not beyond Gerota fascia, T4 beyond Gerota fascia or adrenal invasion, and M1 distant metastasis with prognosis note..

Gross features of clear cell RCC (the prototype):

Location: upper pole preference (70%)
Appearance: spherical mass, bright yellow-orange cut surface due to lipid content; haemorrhage and necrosis create a variegated pattern; cystic change common
Pseudocapsule: often present, giving a false sense of containment
Venous invasion: a critical and classic feature — RCC extends as a continuous tumour thrombus up the renal vein and into the inferior vena cava (IVC); the thrombus can reach the right atrium

Staging (simplified TNM for examination):

Stage	Criteria
T1	≤7 cm, confined to kidney
T2	>7 cm, confined to kidney
T3	Into major veins / perinephric fat (not beyond Gerota fascia)
T4	Beyond Gerota fascia / into adrenal
M1	Distant metastasis

Stage is the single most important prognostic factor. 5-year survival: Stage I ~95%, Stage IV ~10%.

A textbook-style diagram shows clear cell RCC in a kidney cross-section with golden tumour, haemorrhage, pseudocapsule, renal vein tumour thrombus, clinical triad, and key paraneoplastic syndromes. — **Panel A:** Gross cross-section of kidney showing upper-pole clear cell RCC, lipid-rich golden cut surface, haemorrhagic areas, pseudocapsule, renal cortex, renal medulla, renal pelvis, and tumour thrombus extending into the renal vein.. **Panel B:** Clinical presentation of RCC showing painless gross haematuria, flank pain, palpable flank mass, and note that the full classic triad occurs in only about 10% of cases and usually indicates advanced disease.. **Panel C:** Paraneoplastic syndromes of RCC showing ectopic EPO causing polycythaemia with increased haemoglobin and haematocrit, PTHrP causing hypercalcaemia with increased serum calcium, and renin or cytokine effects causing hypertension or systemic symptoms..

RCC — Clinical Features and Paraneoplastic Syndromes

A three-panel medical infographic shows renal cell carcinoma clinical features, incidental imaging detection, and major paraneoplastic syndromes with mechanisms and lab findings. — **Panel A:** Kidney, renal cortical tumour mass, renal vein, ureter, painless gross haematuria, flank pain, palpable flank mass, classic triad present together in ~10%.. **Panel B:** CT scanner, axial abdominal imaging slice, incidental renal cortical mass, label indicating most RCCs are now found incidentally.. **Panel C:** RCC tumour cell cluster, ectopic EPO secretion, HIF-1α activation, polycythaemia, ectopic PTHrP secretion, hypercalcaemia, Stauffer syndrome, non-metastatic hepatic dysfunction, hypertension or renin effect, key laboratory findings..

Classic triad:

Haematuria (most common single symptom — painless, gross)
Flank pain
Palpable flank mass

Importantly, all three together (the 'classic triad') is present in only ~10% of cases and usually indicates locally advanced disease. Most RCCs are now found incidentally on imaging done for other reasons.

Paraneoplastic syndromes (high-yield): RCC has more paraneoplastic associations than almost any other solid tumour — nicknamed the 'internist's tumour'.

Syndrome	Mechanism	Lab finding
Polycythaemia	Ectopic EPO secretion by tumour cells (HIF-1α → EPO gene)	↑ Hb, ↑ haematocrit
Hypercalcaemia	Ectopic PTHrP secretion	↑ Serum Ca²⁺
Stauffer syndrome	Non-metastatic hepatic dysfunction (mechanism unclear, possibly cytokine-mediated)	↑ LFTs without liver mets
Hypertension	Ectopic renin; vascular compression	Refractory HTN
Cushing syndrome	Ectopic ACTH (rare)	Hypercortisolaemia

Remember that resolution of paraneoplastic syndromes after nephrectomy is evidence of their tumour origin.

Spread:
• Haematogenous — most common route; characteristic 'cannonball' metastases in the lungs (multiple, well-defined round nodules); also bone, brain, liver, opposite kidney
• Lymphatic — para-aortic and paracaval nodes
• Direct — adrenal gland, perinephric fat, Gerota fascia
• Notorious for late metastasis — may present 10–20 years after nephrectomy ('late recurrence')
• Venous invasion and tumour thrombus (as above)

SELF-CHECK

A 55-year-old woman is found to have a renal mass incidentally. Histology shows nests of cells with optically clear cytoplasm separated by thin-walled sinusoidal vessels. Genetic analysis shows deletion at chromosome 3p25. Which protein is most directly responsible for the upregulated angiogenesis in this tumour?

A. p53

B. HIF-1α

C. BRCA1

D. c-MYC

Reveal Answer

Answer: B. HIF-1α

Loss of VHL (chromosome 3p25) prevents HIF-1α from being targeted for proteasomal degradation. Accumulated HIF-1α transcriptionally upregulates VEGF, PDGF, and EPO — driving angiogenesis, tumour growth, and paraneoplastic polycythaemia. p53, BRCA1, and c-MYC are not the primary drivers in clear cell RCC.

CLINICAL PEARL

The 'internist's tumour' rule: Whenever a clinical scenario gives you an unexplained polycythaemia, hypercalcaemia, or non-metastatic hepatic dysfunction (Stauffer syndrome) in a middle-aged man with a flank mass or haematuria, think RCC first. These paraneoplastic syndromes arise because HIF-1α drives ectopic EPO secretion, while tumour-derived PTHrP causes hypercalcaemia. Crucially, all three may resolve after nephrectomy — a point that often appears in MCQs.

Another high-yield point: 'cannonball' lung metastases on a chest X-ray in a patient with a renal mass = RCC until proven otherwise. The well-defined, multiple round nodules reflect haematogenous spread via the renal vein and IVC.

Wilms Tumour (Nephroblastoma)

A four-panel medical diagram summarizes Wilms tumour gross renal appearance, chromosome 11 genetic associations, triphasic histology, and key pathology concept. — **Panel A:** Child age 2-5 years, kidney, well-circumscribed grey-white fish-flesh tumour, residual renal parenchyma, haemorrhage, necrosis.. **Panel B:** Chromosome 11, 11p13 WT1 tumour suppressor, 11p15 WT2 locus, WAGR syndrome, Denys-Drash syndrome, Beckwith-Wiedemann syndrome.. **Panel C:** Blastemal component with small primitive cells, epithelial component with abortive tubules and glomeruloid structures, stromal component with loose mesenchyme and heterologous elements.. **Panel D:** Abnormal nephrogenesis, mixed triphasic differentiation, paediatric renal tumour, survival greater than 90% with modern multimodal therapy..

Wilms tumour is the commonest renal tumour of childhood, typically presenting between ages 2–5 years. It is one of the most successfully treated paediatric solid tumours, with overall survival >90% with modern multimodal therapy.

Genetics:
• WT1 gene (chromosome 11p13) — tumour suppressor encoding a transcription factor essential for normal kidney development; loss → failure of terminal differentiation
• WT2 locus (11p15) — associated with Beckwith–Wiedemann syndrome (macroglossia, hemihypertrophy, organomegaly + Wilms)
• WAGR syndrome: Wilms, Aniridia, Genitourinary anomalies, (intellectual) Retardation — 11p13 deletion
• Denys–Drash syndrome: WT1 point mutation → Wilms + diffuse mesangial sclerosis + male pseudohermaphroditism

Pathology — the diagnostic triphasic histology:
Wilms tumour recapitulates abnormal nephrogenesis. The classic pattern is triphasic:
1. Blastemal component — small, round, densely packed primitive cells with scant cytoplasm (resembles the metanephric blastema); the most cellular, mitotically active component
2. Epithelial component — abortive tubular and glomerular structures; recapitulates nephron formation
3. Stromal component — loose mesenchyme, may contain skeletal muscle, cartilage, or fat

Not all three components need be present in every tumour, but the triphasic pattern is the classic diagnostic image.

Gross: Large, well-circumscribed, soft, fish-flesh grey-white tumour, often with areas of haemorrhage, necrosis, and cyst formation. Pseudocapsule is common. Usually unilateral (5% bilateral — associated with WT1 germline mutations).

Clinical presentation:
• Painless abdominal mass in a child — the classic and most common presentation; often noticed by the parent while bathing
• Abdominal pain, haematuria, hypertension (less common)
• Never cross the midline on palpation (unlike neuroblastoma, which often does)

Unfavourable histology: Presence of anaplasia (diffuse > focal) is the strongest adverse prognostic factor.

H&E-style diagram of Wilms tumour showing blastemal, epithelial, and stromal components with magnified insets for each component. — **Panel A:** Medium-power H&E field of Wilms tumour showing triphasic pattern: Blastemal component, Epithelial component, Stromal component. **Panel B:** Blastemal component: dense sheets of small blue round cells with hyperchromatic nuclei. **Panel C:** Epithelial component: primitive tubular and rosette-like structures with small lumina. **Panel D:** Stromal component: loose pale mesenchyme with spindle cells and eosinophilic background.

SELF-CHECK

A 3-year-old child presents with a painless abdominal mass that does not cross the midline. CT shows a large unilateral renal mass. Histology demonstrates primitive tubular structures, dense small blue cells, and loose mesenchyme. Which gene mutation is most likely responsible?

A. RB1 on chromosome 13q14

B. WT1 on chromosome 11p13

C. VHL on chromosome 3p25

D. MYCN on chromosome 2p24

Reveal Answer

Answer: B. WT1 on chromosome 11p13

The triphasic histology (blastemal + epithelial + stromal) is pathognomonic of Wilms tumour (nephroblastoma). WT1 (chromosome 11p13) is the classic gene implicated. RB1 loss causes retinoblastoma; VHL loss causes clear cell RCC; MYCN amplification is characteristic of neuroblastoma — which can also present as an abdominal mass but crosses the midline and has adrenal origin.