Kidney Cancer

Renal Cysts

Types

1. Sporadic
2. Acquired — ACKD
3. Genetic — ADPKD, ARPKD

ACKD (Acquired Cystic Kidney Disease)

• Occurs in CKD; ~80% of dialysis patients develop cysts
• ~7% develop RCC after ~10 years
• Most common type → Papillary type 1 RCC

ADPKD

• Autosomal dominant | Chromosomes 4 & 16 | Associated with polycystin
• Diagnostic criteria: <30 yrs → ≥2 cysts | 30–60 yrs → ≥2 cysts/kidney | >60 yrs → ≥4 cysts/kidney
• Associated with: hepatic cysts, pancreatic cysts
• No increased risk of RCC

ARPKD

• Autosomal recessive | Chromosome 6
• Associated with: congenital hepatic fibrosis, biliary atresia

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Bosniak Classification

Class	HU	Management	Malignancy Risk
I & II	<10 HU	No follow-up	~0%
IIF	10–15 HU	Follow-up	~5–10%
III	>15 HU	Surgery	30–50%
IV	>15 HU + enhancement	Surgery	75–90%

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Benign Renal Tumours

Oncocytoma

• Most common benign enhancing renal mass; ~25% of masses <3 cm
• Slow growth: ~0.14 cm/year
• Imaging: central scar, hypervascular, spoke-wheel pattern
• Overlaps with eosinophilic chromophobe RCC; CK7 negative
• Associated with Birt-Hogg-Dubé (BHD)
• Biopsy PPV: ~67% (low — difficult to distinguish from chromophobe RCC)

Birt-Hogg-Dubé Syndrome

• Autosomal dominant | Chromosome 17 | Gene: Folliculin
• Triad: pulmonary cysts, fibrofolliculomas, renal tumours
• RCC types: chromophobe (25%), oncocytoma, papillary RCC

Angiomyolipoma (AML)

• Sporadic or genetic; associated with TSC and LAM
• CT: −20 HU (fat content = diagnostic)
• 5–10% are fat-poor
• Wunderlich syndrome (spontaneous retroperitoneal haemorrhage): occurs in 15%
• Management based on: size, symptoms, pregnancy status
• Everolimus (mTOR inhibitor) is first-line in TSC — reduces size by ~30% in 80% of patients

Tuberous Sclerosis Complex (TSC)

• Autosomal dominant | Chromosomes 9 & 16 | mTOR activation
• Classic triad: seizures, adenoma sebaceum, intellectual disability
• Features: ash leaf spots, shagreen patch, retinal hamartomas, cardiac rhabdomyoma
• 50% develop AMLs; 2% develop RCC

Papillary Adenoma (Premalignant)

• <1 cm | 47% progress to papillary RCC
• AMACR positive | Chromosomes 7 & 17

Metanephric Adenoma

• Benign; resembles Wilms histologically
• AMACR negative, WT1/CD57 positive
• Can cause polycythaemia (↑ EPO)
• Treatment: nephron-sparing surgery

Cystic Nephroma

• Children & adults; mimics Wilms and clear cell RCC
• Lacks blastemal and embryonal elements
• Treatment: nephron-sparing surgery

Mixed Epithelial & Stromal Tumour

• Perimenopausal women; oestrogen-related
• Bosniak III–IV appearance; malignant transformation reported

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RCC — Malignant Renal Masses

Risk Factors

• Smoking, hypertension, obesity, CKD → papillary RCC
• Established (4): Obesity (~30% of cases), Smoking (~20%), Hypertension, Acquired cystic disease
• No increased risk in ADPKD

Genetic Syndromes

Syndrome	Gene/Chr	RCC Type	Pathway	Risk	Key Features
VHL	AD, chr 3	Clear cell	HIF–VEGF	50%	2 types: Type 2 = RCC + Pheo
BHD	AD, chr 17	Chromophobe	mTOR	25%	Skin, lung, kidney
HLRCC*	AD, FH	Type 2 papillary	HIF–VEGF	15%	Aggressive; uterine fibroids
HPRC	AD, MET, chr 7	Type 1 papillary	MET kinase	—	Less aggressive
PTEN	AD	Clear cell	—	35%	Breast, endometrium
SDH-RCC*	SDH	Variable	HIF–VEGF	—	Aggressive; paraganglioma
TSC	AD, chr 9+16	Any	mTOR	2%	AML predominant

* More aggressive — prompt surgical management

VHL Overview

• VHL normally targets HIF for degradation
• VHL mutation → HIF accumulates → VEGF overexpression (primary angiogenic driver of ccRCC)
• VHL inactivation mutation: most common in sporadic RCC |
• Autosomal dominant chromosome 3p25-26
• RCC in 35–70% of VHL patients | bilateral + multifocal | median onset age 40
• RCC = most common cause of death in VHL patients
• Type 2 VHL = also has pheochromocytoma (restricted to certain families)

VHL Disease — Surgical Management

• Intervention threshold: 3 cm (NCI guideline; also applies to BHD and HPRC)

• Exception: HLRCC and SDH-RCC are more aggressive → treat even if <3 cm

• All solid + cystic renal lesions must be excised

• Nephron-sparing / enucleation preferred — multifocal disease requires renal preservation

• Screening: every 6 months from age 15–20

  Belzutifan (Welireg)

• Oral HIF-2α inhibitor | FDA approved 2021 | First drug approved specifically for VHL disease

• Mechanism: blocks HIF-2α/ARNT dimerization → ↓ VEGF + EPO transcription

• Indication: VHL-associated RCC, CNS hemangioblastomas, or pNETs not requiring immediate surgery

RCC Subtypes

Type	Frequency	Origin	Key Features
Clear cell	70–80%	Proximal tubule	Worst prognosis; responds to systemic Rx; clear cytoplasm; VHL mutation
Papillary	10–15%	Proximal tubule	Type 1 = good prognosis; Type 2 = aggressive (HLRCC); necrosis/haemorrhage; common in CKD; chr 7 & 17
Chromophobe	3–5%	Distal tubule/collecting duct	Good prognosis; tan/brown; CK7 +ve; Hale colloidal iron +ve
Collecting duct	<1%	Collecting duct	Aggressive; Ulex europaeus +ve; try cisplatin/gemcitabine
Medullary	Rare	Collecting duct	Dismal prognosis; sickle cell trait (not disease); mets at diagnosis; young African-Americans
Translocation (Xp11.2)	Rare	—	40% of paediatric RCC; TFE3 fusion
Unclassified	1–3%	—	Aggressive
Sarcoma	Rare	—	Leiomyosarcoma = most common in kidney; liposarcoma = most common in retroperitoneum

Sarcomatoid Differentiation

• Found in 1–5% of RCCs; not a distinct subtype
• Most common with ccRCC and chromophobe RCC
• Worse prognosis; multimodal approach

Grading

• Fuhrman grade (1–4): clear cell and papillary RCC
• High vs. low grade only: chromophobe, collecting duct, medullary RCC
• ISUP (2016) now preferred over Fuhrman; chromophobe not graded under ISUP

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TNM Staging (AJCC 8th Ed)

Stage	Definition
T1a	≤4 cm, confined to kidney
T1b	>4–7 cm, confined to kidney
T2a	>7–10 cm, confined to kidney
T2b	>10 cm, confined to kidney
T3a	Renal vein/segmental branches OR pelvicalyceal system OR perirenal/renal sinus fat (within Gerota)
T3b	IVC below diaphragm
T3c	IVC above diaphragm OR IVC wall invasion
T4	Beyond Gerota's fascia (incl. direct extension to ipsilateral adrenal)
N1	Regional lymph node metastasis — 5-yr survival 0–20%
M1	Distant metastasis — 5-yr survival 0–10%

• Ipsilateral adrenal by direct extension = pT4; by haematogenous route = pM1
• Perisinus fat (medial) invasion = worse prognosis than perirenal fat (lateral)

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Diagnosis and Evaluation

Screening Indications

• CKD (after 3rd year of dialysis)
• VHL → every 6 months (starting age 15–20)
• Positive family history | multiple renal tumours | RCC age <46 years

Presentation

• >50% diagnosed incidentally
• Classic triad (haematuria + flank pain + mass): <5% in contemporary series
• Right-sided or non-reducing varicocele, bilateral leg oedema → signs of advanced disease

Labs (AUA 2021)

• CBC, urinalysis (proteinuria), comprehensive metabolic panel (electrolytes, LFTs, GFR)
• Elevated ALP or bone pain → investigate for bone mets

Paraneoplastic Syndromes (NEW-HALF-CAP)

• Elevated ESR (56% — most common)
• Hypertension (38%) | Anaemia (36%) | Weight loss (34%)
• Fever (17%) | LFTs elevated/Stauffer syndrome (14%)
• Calcaemia (hyper) (5%) | Polycythaemia (4%) | Amyloidosis (2%) | Neuropathy (3%)
• Hypercalcaemia management: hydration → frusemide → steroids → bisphosphonates

Imaging

• Primary: triphasic CT abdomen/pelvis; MRI if CT contraindicated
• Thrombus present → Doppler US or MRI to stage IVC
• CXR in all (chest = most common visceral met site)
• CT chest if: pulmonary symptoms, abnormal CXR, or high-risk features (thrombus, adenopathy, large tumour, infiltrative appearance, necrosis)
• Bone scan: bone pain or ↑ ALP only | Brain imaging: neurologic symptoms only
• PET: no routine role

CT Interpretation

• <−20 HU = fat → diagnostic of AML
• >15 HU enhancement without fat = RCC until proven otherwise
• Clear cell enhances more than papillary and chromophobe RCC

Renal Mass Biopsy (RMB)

• Sensitivity 96.7% | Specificity 94.4% | Non-diagnostic rate ~14%
• Histologic concordance 90% | Grade concordance 62%
• 20% of benign biopsies may still harbour cancer
• Complications (8%): haematoma 4.9%, pain 1.2%, haematuria 1%, pneumothorax 0.6%, transfusion 0.4%
• No reported tumour seeding with contemporary technique

Indications (6)

1. Metastatic disease (prior to systemic therapy)
2. Suspected lymphoma
3. Non-operative management planned
4. Bilateral tumours
5. Active surveillance
6. Prior to systemic therapy

Adverse Prognostic Factors

• Poor performance status | Paraneoplastic syndrome | Large tumour | LN involvement
• Venous invasion | Metastasis | High nuclear grade | Sarcomatoid features
• Tumour necrosis | Microvascular invasion
• Stage = most important prognostic factor
• LN status = most important within stage

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Management of Localised RCC

Treatment Options (4)

1. Active Surveillance (AS)
2. Thermal Ablation (TA)
3. Partial Nephrectomy (PN)
4. Radical Nephrectomy (RN)

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Active Surveillance

• Median growth rate: 0.12–0.34 cm/year | Metastasis rate: 1–2% over 2–4 years
• ➡ Preferred for: <2 cm masses, elderly, life expectancy <5 yrs, CKD3b+, patient preference

Triggers for Intervention

• Tumour >3 cm (AUA) or >4 cm (CUA)
• Growth >5 mm/year (AUA) or >0.5 cm/year (CUA)
• Stage progression | Worrisome imaging | Unfavourable biopsy

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Thermal Ablation

• Options: Cryoablation (−40°C, 2 freeze-thaw cycles) | RFA (50–105°C)
• Best results for tumours <2.5–3 cm; unreliable >4 cm
• Avoid if near hilum, proximal ureter, or collecting system
• Bleeding: less with RFA; significant haemorrhage risk with cryo

Recurrence rates

• Cryo: 3–10% | RFA: 5–20% | PN: 0–3% | RN: 0%
• Local recurrence → salvage with repeat TA

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Partial vs Radical Nephrectomy

• PN GFR loss: ~10% | RN GFR loss: ~35–40%

Absolute Indications for PN (3)

• Solitary kidney | Bilateral tumours | Familial RCC syndrome

Relative Indications for PN

• cT1a (preferred over TA and RN) | Pre-existing CKD/proteinuria | Young age | Multifocal disease
• Comorbidities affecting future renal function: HTN, DM, urolithiasis, morbid obesity

Consider RN if:

• Cold ischaemia >45 min
• <20% functional nephron remaining (hyperfiltration injury risk)
• High tumour complexity
• Lymph node involvement

RN preferred over PN when ALL 3 met (AUA):

1. High tumour complexity (PN challenging even in experienced hands)
2. No pre-existing CKD or proteinuria
3. Normal contralateral kidney and expected post-RN eGFR >45 mL/min/1.73m²

Positive Margins After PN

• No gross tumour → observe
• Aggressive features or gross tumour → reoperate

Warm Ischaemia

• Limit to <25 minutes
• Hypothermia: tolerated up to 60–90 minutes

Surgical Approaches

Approach	Indication
Flank (subcostal)	UPJ / radical nephrectomy (not feasible for PN)
Dorsal lumbotomy	Paediatric / bilateral
Thoracoabdominal	Large or upper pole tumours
Anterior midline	Trauma / IVC involvement
Chevron	Bilateral or hepatic extension

Lymphadenectomy

• cN0: not routinely recommended (EORTC 30881: no OS or PFS benefit)
• cN+: perform for staging
• Landing zones: Right = interaortocaval | Left = para-aortic

Adrenalectomy

• Preserve ipsilateral adrenal if normal on imaging; incidence of adrenal mets <5%
• Remove if: imaging/intraoperative suggests involvement, or locally advanced tumour with close proximity

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Locally Advanced RCC

Setting	Management
N+	RN + LND
T3	RN + thrombectomy
T4	RN + LND
Unresectable	Embolisation / neoadjuvant therapy

Adjuvant Therapy — Pembrolizumab (Keynote-564)

Indicated for high-risk post-nephrectomy:

• T4 or T3
• N1
• T2b + Fuhrman ≥3 + ECOG ≥1
• T2a + Fuhrman 4 or sarcomatoid differentiation

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Follow-Up After Surgery

Low Risk

• PN: CT at 12 months → yearly ×3
• RN: CT at 12 months
• CXR yearly ×3

High Risk

• CT abdomen: every 6 months ×3 years → yearly to year 5
• CT chest: every 6 months ×3 years → yearly to year 5

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Metastatic RCC

Cytoreductive Nephrectomy — Indications

• Low IMDC risk (0 risk factors) + good performance status
• No brain metastases (lung only)
• Oligo-mets (<3)
• Palliative/symptomatic relief

IMDC Risk Stratification Criteria (6)

1. Karnofsky PS <80%
2. Time from diagnosis to systemic therapy <1 year
3. Haemoglobin <lower limit of normal
4. Corrected calcium >upper limit of normal
5. Neutrophils >upper limit of normal
6. Platelets >upper limit of normal

Systemic Therapy

IMDC Risk	Regimen
Favourable (0 factors)	Pembrolizumab + axitinib or Sunitinib
Poor (≥1 factor)	Ipilimumab + nivolumab or Pembrolizumab + axitinib

• Overall response rate: 30–40%

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