Renal Cell Carcinoma & Renal Tumours

Renal tumours are a perennial NEET PG favourite, mostly tested through "buzzword" associations — gross appearance, genetics, histology, and named syndromes. This note covers adult epithelial tumours (clear cell, papillary, chromophobe RCC, oncocytoma), urothelial carcinoma of the renal pelvis, and the paediatric chart-topper, Wilms tumour (nephroblastoma).

Classification of renal tumours

Renal neoplasms are broadly split by cell of origin and age group. The single most important division is adult renal parenchymal (tubular epithelial) tumours versus the paediatric Wilms tumour (metanephric blastema), with urothelial carcinoma arising separately from the pelvicalyceal lining.

Category	Tumour	Cell of origin
Adult malignant epithelial	Clear cell RCC (70-80%)	Proximal convoluted tubule
	Papillary RCC (10-15%)	Proximal convoluted tubule
	Chromophobe RCC (5%)	Intercalated cells, collecting duct
	Collecting duct (Bellini) carcinoma	Medullary collecting duct
Adult benign	Oncocytoma	Intercalated cells of collecting duct
	Angiomyolipoma	Perivascular epithelioid cell (PEComa)
Urothelial	Transitional cell (urothelial) carcinoma	Urothelium of renal pelvis
Paediatric	Wilms tumour (nephroblastoma)	Metanephric blastema
	Mesoblastic nephroma	Mesenchyme (neonate)

High-yield: Clear cell RCC is the commonest adult renal malignancy and the commonest RCC subtype overall. RCC accounts for ~85-90% of all adult primary renal malignancies.

Renal Cell Carcinoma (RCC)

Epidemiology & risk factors

RCC is a tumour of older adults, peaking in the 6th-7th decade, with a male predominance (~2:1). It is overwhelmingly sporadic, but a minority is hereditary.

Risk factors — remember "STOPCH":

• Smoking (strongest acquired risk factor)
• Tuberous sclerosis / Trichloroethylene exposure
• Obesity
• Polycystic kidney disease (acquired cystic disease of dialysis)
• Cadmium, Chronic dialysis
• Hypertension; von Hippel-Lindau

Genetics & the VHL story

The unifying genetic event in clear cell RCC is loss of the VHL tumour suppressor gene on chromosome 3p25. VHL protein normally targets HIF-1α (hypoxia-inducible factor) for degradation; when VHL is lost, HIF accumulates and drives transcription of VEGF and PDGF, explaining the characteristically hypervascular tumour and the rationale for anti-angiogenic therapy.

High-yield: Clear cell RCC = loss of VHL gene on chromosome 3p. This is true for both sporadic (somatic) and hereditary (germline VHL syndrome) cases.

Von Hippel-Lindau syndrome (autosomal dominant) features: bilateral/multifocal clear cell RCC, CNS and retinal haemangioblastomas, phaeochromocytoma, pancreatic cysts/neuroendocrine tumours, and endolymphatic sac tumours.

Subtype	Cytogenetics / mutation	Notable association
Clear cell	VHL loss, 3p deletion	VHL syndrome, hypervascular
Papillary	Trisomy 7, 17; loss of Y; MET mutation	Hereditary papillary RCC
Chromophobe	Multiple chromosome losses (hypodiploid)	Birt-Hogg-Dubé syndrome
Collecting duct	—	Aggressive, young patients

Pathology of RCC subtypes

Clear cell RCC — Gross: arises in the upper pole, well-circumscribed, with a characteristic golden-yellow cut surface (due to abundant lipid and glycogen), with areas of haemorrhage and necrosis giving a variegated appearance. Microscopy: rounded/polygonal cells with clear cytoplasm (lipid and glycogen dissolved during processing) and a delicate branching vasculature. Has a strong tendency for renal vein → inferior vena cava invasion.

High-yield: Golden-yellow tumour of the upper pole with clear cells and propensity to invade the renal vein/IVC = clear cell RCC.

Papillary RCC — Cells arranged in papillae with fibrovascular cores; foamy macrophages and psammoma bodies within cores; often bilateral and multifocal. Most common subtype in patients on chronic dialysis / acquired cystic disease. Associated with trisomy 7 and 17, MET proto-oncogene.

Chromophobe RCC — Pale, eosinophilic cells with prominent (distinct) cell membranes and a perinuclear halo; Hale colloidal iron stain positive (diffuse cytoplasmic). Best prognosis among RCC subtypes. Linked to Birt-Hogg-Dubé syndrome (folliculin gene; fibrofolliculomas, lung cysts, spontaneous pneumothorax).

Clinical features

The classic triad of flank pain + haematuria + palpable abdominal mass is seen in only ~10% and usually signals advanced disease.

High-yield: RCC is the "internist's tumour" / "great mimic" because of varied paraneoplastic syndromes.

Paraneoplastic syndromes (commonly tested):

• Polycythaemia — ectopic erythropoietin (the classic one).
• Hypercalcaemia — PTHrP secretion.
• Hypertension — renin secretion.
• Cushing syndrome — ectopic ACTH.
• Stauffer syndrome — reversible non-metastatic hepatic dysfunction (raised ALP, transaminases) without liver metastasis; resolves after nephrectomy.

A left-sided varicocele that does not decompress on lying down suggests left renal vein obstruction by tumour thrombus (the left gonadal vein drains into the left renal vein).

Spread & staging

RCC spreads haematogenously (renal vein → IVC), classically producing "cannonball" metastases in the lungs and lytic bone metastases. RCC is one of the tumours that can metastasise late, even decades after nephrectomy.

Staging flow (clinical reasoning): Confined to kidney (T1/T2) → Perinephric fat / renal vein, within Gerota fascia (T3) → Beyond Gerota fascia / adrenal / distant (T4/M1).

Diagnosis & investigation of choice

Contrast-enhanced CT abdomen is the investigation of choice for diagnosis and staging — RCC shows heterogeneous enhancement with washout. Renal mass biopsy is generally avoided when imaging is diagnostic and surgery is planned. MRI/IVC venography assesses tumour thrombus extent.

Diagnostic approach: Haematuria / incidental mass → Ultrasound (solid vs cystic, Bosniak grading of cysts) → CECT abdomen & chest (staging, investigation of choice) → Surgery / biopsy as indicated.

Management / treatment of choice

• Localised RCC: Partial nephrectomy (nephron-sparing) for small/T1 tumours; radical nephrectomy for larger tumours — surgery is the treatment of choice and only curative modality.
• RCC is radioresistant and chemoresistant.
• Metastatic RCC: Anti-angiogenic targeted therapy — tyrosine kinase inhibitors (sunitinib, pazopanib, sorafenib), mTOR inhibitors (temsirolimus, everolimus), and immune checkpoint inhibitors (nivolumab/ipilimumab, pembrolizumab + axitinib) now first-line in many settings.

High-yield: RCC is radioresistant and chemoresistant; surgery is curative for localised disease, and targeted/immunotherapy is used for metastatic disease.

Prognosis

Subtype prognosis: Chromophobe > Papillary > Clear cell > Collecting duct (worst). Stage and Fuhrman nuclear grade are key prognostic determinants.

Oncocytoma (benign)

A benign epithelial tumour from intercalated cells.

• Gross: mahogany-brown / tan tumour with a characteristic central stellate scar.
• Microscopy: cells packed with eosinophilic cytoplasm full of mitochondria (oncocytes).
• Electron microscopy: abundant mitochondria (the defining ultrastructural clue).
• Can be radiologically indistinguishable from chromophobe RCC; often resected to be safe.

High-yield: Mahogany-brown tumour with a central stellate scar + mitochondria-packed eosinophilic cells = oncocytoma (benign).

Angiomyolipoma

A benign PEComa composed of blood vessels, smooth muscle, and mature fat (hence the name). Strongly associated with tuberous sclerosis (often bilateral and multiple). Macroscopic fat on CT is virtually diagnostic. Risk of spontaneous retroperitoneal haemorrhage (Wunderlich syndrome) when >4 cm.

Transitional (Urothelial) Cell Carcinoma of the Renal Pelvis

Arises from the urothelium lining the pelvicalyceal system; it is the commonest tumour of the renal pelvis.

• Risk factors: smoking, aniline dyes / aromatic amines, cyclophosphamide, phenacetin (analgesic) abuse, Balkan endemic nephropathy, aristolochic acid.
• Field defect / "field cancerisation": urothelium is at risk along its entire length, so these tumours are often multifocal and may recur in the ureter or bladder — mandating surveillance of the whole urinary tract.
• Clinical: painless gross haematuria is the classic presentation.
• Investigation: CT urography (filling defect in the pelvis) + urine cytology + ureteroscopy with biopsy.
• Treatment of choice: radical nephroureterectomy with excision of a bladder cuff.

High-yield: Phenacetin abuse and Balkan nephropathy → urothelial carcinoma of the renal pelvis; treat with nephroureterectomy because of the multifocal field defect.

Wilms Tumour (Nephroblastoma)

The commonest primary renal malignancy of childhood and the most common abdominal malignancy in children, peaking at 2-5 years of age.

Genetics

• WT1 gene on chromosome 11p13 (a transcription factor essential for normal genitourinary development).
• WT2 locus on 11p15 (associated with Beckwith-Wiedemann).
• Associated WAGR syndrome — Wilms tumour, Aniridia, Genitourinary anomalies, mental Retardation (11p13 deletion involving WT1 + PAX6).
• Denys-Drash syndrome — Wilms + gonadal dysgenesis (pseudohermaphroditism) + progressive nephropathy (diffuse mesangial sclerosis); point mutation in WT1.
• Beckwith-Wiedemann syndrome — organomegaly, macroglossia, hemihypertrophy, omphalocele; WT2 (11p15) — also predisposes to hepatoblastoma.

High-yield: Wilms tumour = WT1 mutation, chromosome 11p13. Memorise the trio WAGR, Denys-Drash, Beckwith-Wiedemann.

Pathology — triphasic histology

Gross: large, solitary, well-circumscribed, soft tan-grey mass that displaces rather than infiltrates surrounding kidney (compresses normal parenchyma into a rim).

Classic triphasic microscopy — three components:

1. Blastemal — small round blue cells (metanephric blastema).
2. Epithelial — abortive tubules and glomeruloid structures.
3. Stromal — fibroblastic/myxoid mesenchyme.

High-yield: Triphasic histology (blastema + epithelial + stroma) = Wilms tumour. Anaplasia is the adverse histological feature defining "unfavourable histology" and poorer prognosis.

Precursor

Nephrogenic rests (persistent embryonal metanephric tissue) are precursor lesions; their diffuse presence is termed nephroblastomatosis.

Clinical features

• Asymptomatic abdominal mass noticed by a parent during bathing — the classic vignette; the mass usually does not cross the midline.
• Hypertension (renin), haematuria, abdominal pain.
• Contrast with neuroblastoma (see differentials).

Investigation & management

• Investigation: abdominal ultrasound first, then CECT abdomen for staging; assess renal vein/IVC.
• Management: Wilms tumour is chemosensitive and radiosensitive — managed with multimodal therapy: surgery (nephrectomy) + chemotherapy (vincristine + actinomycin D ± doxorubicin) ± radiotherapy.
• Prognosis is excellent — favourable-histology Wilms has >90% long-term survival.

High-yield: Wilms tumour is chemo- and radio-sensitive (opposite of adult RCC) with excellent prognosis after multimodal therapy.

Key differentials

Feature	RCC (adult)	Wilms tumour	Neuroblastoma
Age	60-70 yrs	2-5 yrs	<2 yrs (infants)
Origin	Renal tubular epithelium	Metanephric blastema	Adrenal medulla / sympathetic chain
Crosses midline	—	No (rarely)	Yes, encases vessels
Calcification	Uncommon	Uncommon	Common
Markers	—	WT1	↑VMA/HVA, NSE, N-myc amplification
Therapy response	Radio/chemo-resistant	Radio/chemo-sensitive	Variable

High-yield: Distinguish Wilms vs neuroblastoma — neuroblastoma crosses the midline, encases vessels, calcifies, and raises urinary VMA/HVA; Wilms is intrarenal, displaces vessels, and is WT1-positive.

Other differentials of a renal mass: angiomyolipoma (fat on CT), oncocytoma (central scar), renal abscess, complex (Bosniak III/IV) cyst, and metastasis/lymphoma.

Complications

• RCC: tumour thrombus in renal vein/IVC → may extend to right atrium; pulmonary "cannonball" metastases; pathological fractures from lytic bone deposits; paraneoplastic syndromes; left varicocele.
• Angiomyolipoma: life-threatening retroperitoneal haemorrhage (Wunderlich syndrome).
• Urothelial carcinoma: multifocal recurrence; ureteric obstruction/hydronephrosis.
• Wilms: pulmonary metastases; rarely tumour rupture causing peritoneal spread.

Recently asked / exam angle

• VHL gene on chromosome 3p → clear cell RCC: the single most repeated genetics MCQ.
• Golden-yellow cut surface and clear cytoplasm (lipid + glycogen) image-based identification.
• Stauffer syndrome — reversible hepatic dysfunction without liver mets — as a "which paraneoplastic" question.
• Polycythaemia due to EPO as the classic RCC paraneoplastic effect.
• Oncocytoma — central stellate scar + mitochondria-rich oncocytes (EM clue).
• Chromophobe RCC — perinuclear halo, Hale colloidal iron positive, best prognosis, Birt-Hogg-Dubé.
• Wilms tumour — WT1, 11p13, triphasic histology, WAGR/Denys-Drash/Beckwith-Wiedemann.
• Wilms vs neuroblastoma differentiation (crossing midline, VMA/HVA).
• Phenacetin / Balkan nephropathy → renal pelvis urothelial carcinoma.
• Cannonball lung metastases classically from RCC (and choriocarcinoma).
• Subtype prognosis ordering: chromophobe best, collecting duct worst.
• Treatment of choice: partial/radical nephrectomy for RCC; nephroureterectomy for urothelial carcinoma; multimodal therapy for Wilms.

Rapid revision

• Clear cell RCC = commonest RCC; VHL loss, chromosome 3p; golden-yellow, upper pole, clear cells; invades renal vein/IVC.
• HIF-1α accumulation → VEGF/PDGF → hypervascular tumour; rationale for TKIs (sunitinib, pazopanib).
• Papillary RCC — bilateral/multifocal, foamy macrophages + psammoma bodies, trisomy 7 & 17, MET, dialysis-associated.
• Chromophobe RCC — perinuclear halo, Hale colloidal iron +, best prognosis, Birt-Hogg-Dubé.
• Oncocytoma — benign, mahogany-brown with central stellate scar, mitochondria-packed oncocytes.
• Angiomyolipoma — vessels + muscle + fat; tuberous sclerosis; fat on CT; Wunderlich haemorrhage.
• RCC paraneoplastics — polycythaemia (EPO), hypercalcaemia (PTHrP), HTN (renin), Stauffer syndrome; left non-reducible varicocele.
• RCC is radio- and chemo-resistant; surgery curative; cannonball lung metastases.
• Renal pelvis cancer = urothelial (TCC); phenacetin, Balkan nephropathy, aniline dyes; multifocal field defect; nephroureterectomy.
• Wilms tumour = commonest childhood renal cancer (2-5 yrs); WT1, 11p13; triphasic histology; anaplasia = unfavourable.
• Wilms syndromes — WAGR, Denys-Drash, Beckwith-Wiedemann; nephrogenic rests are precursors.
• Wilms is chemo/radio-sensitive (vincristine + actinomycin D), excellent prognosis; neuroblastoma crosses midline + raises VMA/HVA.
• Investigation of choice for adult renal mass = CECT abdomen; ultrasound first in children.