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

• Papillary adenoma is the most common SOLID benign renal mass
• Renal cysts are the most common benign renal lesion overall
• AML stains HMB-45 positive
• Oncocytoma stains NEGATIVE for Hale colloidal iron — the pairing to remember, since chromophobe RCC stains positive

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
• CHEK2 — also a breast cancer gene
• No increased risk in ADPKD

Genetic Syndromes

Syndrome	Gene/Chr	RCC Type	Pathway	Risk	Key Features
VHL	AD, VHL, chr 3p	Clear cell	HIF–VEGF	50%	Type 1 = no pheo · Type 2 = pheo
BHD	AD, FLCN, chr 17	Chromophobe	mTOR	25%	Skin, lung, kidney — pneumothorax
HLRCC*	AD, fumarate hydratase, chr 1q	Type 2 papillary	HIF–VEGF	15%	Aggressive; uterine fibroids in women; typically solitary and unilateral
HPRC	AD, MET, chr 7	Type 1 papillary	MET kinase	—	Less aggressive
PTEN (Cowden)	AD, chr 10q	Clear cell	—	35%	Breast, endometrium, thyroid
SDH-RCC*	SDH	Variable	HIF–VEGF	—	Aggressive; paraganglioma
TSC	AD, TSC1 chr 9 / TSC2 chr 16	Any	mTOR	2%	AML in 60%

* More aggressive — prompt surgical management

• All familial RCC syndromes are autosomal dominant, and together they account for 5–10% of all RCC cases
• HLRCC — if there are positive margins after a partial nephrectomy, do a radical nephrectomy

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

• Papillary Type I — basophilic cytoplasm; hereditary papillary RCC; MET mutation; chromosomes 7 & 17
• Papillary Type II — eosinophilic cytoplasm; worse prognosis; chromosomes 7 & 17
• Medullary RCC presents in the 3rd decade of life

Multifocality by subtype

Subtype	Incidence of multifocality
Clear cell	~2%
Chromophobe	~2%
Papillary	10%

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 → CT or ultrasound every 6 months (starting age 15–20), plus screening of the other involved organs (eyes, brain)
  • Annual urinary metanephrines from age 5
• 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
• In an OSCE, examine: blood pressure, varicocele, skin and breast

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)

• 10–20% of patients with RCC have a paraneoplastic syndrome. They are reversible with tumour resection — if a syndrome persists after resection, metastatic disease is probably present and the prognosis is poor

• 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 results from a PTH-like peptide; management: hydration → frusemide → steroids → bisphosphonates → calcitonin

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 urography is the workhorse; add MRI if a renal vein thrombus is suspected
• If the patient has haematuria, do a cystoscopy
• Refer to nephrology BEFORE nephrectomy if there is proteinuria, GFR < 45, diabetes or hypertension

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
• ~70% of arteriovenous fistulae after renal needle biopsy close spontaneously within 18 months — expectant management is an appropriate first step
• For a large, invasive retroperitoneal mass, keep a broad differential: adrenocortical carcinoma, urothelial carcinoma, sarcoma and lymphoma, in addition to locally invasive RCC

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

• Symptomatic tumour | Aggressive features on biopsy | Infiltrative features on CT

• After electing AS, the first two follow-up scans should be CT or MRI at 3 and 6 months — even if the biopsy was negative — then annual imaging + renal profile + CXR

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Thermal Ablation

• Options: Cryoablation (−20°C to −40°C, 2 freeze-thaw cycles) | RFA (50–105°C)
• Best results for tumours <2.5–3 cm; unreliable >4 cm; meant for non-cystic masses
• Avoid if near hilum, proximal ureter, or collecting system
• Bleeding: less with RFA; significant haemorrhage risk with cryo
• The most common complication of cryoablation is haemorrhage
• Major complications of RFA — ureteric obstruction, pyelocalyceal injury, bowel injury, pancreatic injury, gross haematuria requiring intervention
• RFA causes less post-operative haemorrhage than cryoablation — so in a patient with bleeding tendencies, choose RFA

Recurrence rates

• Cryo: 3–10% | RFA: 5–20% | PN: 0–3% | RN: 0%
• Recurrence falls to ~3% if two ablation sessions are performed
• Local recurrence → salvage with repeat TA
• To assess recurrence after ablation, the CT must be at 3–6 months — not immediately post-ablation

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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

Relative Contraindications to PN

Technical

• Cold ischaemia time > 45 minutes — consider an extracorporeal approach
• < 20% of global nephron mass would be retained (hyperfiltration injury risk)

Cancer-related

• Diffuse encasement of the renal pedicle by tumour
• Diffuse invasion of the central collecting system
• Tumour thrombus involving the major renal veins
• Adjacent organ invasion (cT4)
• Regional lymphadenopathy (cTxN1)
• High tumour complexity

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

• Pre-operatively: heparin, and stop smoking 4–6 weeks before
• Counsel for the risk of dialysis and the possibility of ending up with a radical rather than a partial
• Hyperfiltration injury is most common when the total nephron mass of both kidneys is reduced by more than 80%. Risk factors — diabetes, hypertension, obesity, dyslipidaemia, steroids, high-protein diet

Positive Margins After PN

• Most positive margins are managed with close surveillance, not reflex completion nephrectomy — though completion may occasionally be valid if the margins are grossly involved and the contralateral kidney is cancer-free and functioning well
• Surveillance means: history, examination, labs and CT at 3 months

Finding	Order of preference
Microscopic positive margin, no gross disease on CT	AS first, then PN or RN
Macroscopic positive margin	RN first, then PN, with AS as the last option
Aggressive features	Radical nephrectomy — or a repeat partial if the patient is at high risk for ESRD and dialysis

PN Techniques

Technique	Description
Enucleation	Blunt dissection along the pseudocapsule
Wedge resection	5–10 mm margin
Polar nephrectomy	See below
Extracorporeal PN with auto-transplantation	For complex cases; consider when cold ischaemia would exceed 45 min

• Resection margin: 2–3 mm of negative tissue is sufficient
• In bilateral tumours, do the partial nephrectomy FIRST

Polar nephrectomy technique

• Give IV mannitol and furosemide
• Dissect the renal pedicle completely, including the segmental branches
• Apply a bulldog clamp to the apical segmental artery (or the basilar segmental artery for lower pole tumours) and observe the line of ischaemia
• The avascular line can be further demarcated by injecting 5 mL of indigo carmine directly into the clamped artery
• If a ureteric stent is used, do not remove it for 4–6 weeks

PN Complications

Urinary fistula

• After a deep renal resection, keep the closed-suction abdominal drain in place for 7–10 days
• Diagnosis — send creatinine from the drain: positive if 5–10× the serum creatinine. Alternatively, IV indigo carmine will appear in the drain
• Urine leaks usually heal over 4–6 weeks, but can take as long as 80 days or more

Management, stepwise:

1. Put back or keep the Foley catheter
2. Retrograde pyelogram and JJ stent
3. Keep the JP drain off suction
4. Nephrostomy or a second JJ stent
5. Ureteroscopy + caliceal fulguration and fibrin sealant

• Many small series report success with novel techniques, but the mainstay remains proper drainage and management of the drains and catheters

Bleeding

• ABCs → bed rest → IV fluids → consider angioembolisation

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

Intraoperative Troubleshooting

Vascular

• Ligation of the SMA or the coeliac trunk is a catastrophic event — it occurs predominantly with LEFT-sided nephrectomy and must be rapidly reversed
• The IMV can be safely ligated without consequence
• SMV ligation → systemic hypotension / splanchnic hypertension syndrome, characterised by venous thrombosis, bowel ischaemia and necrosis

Duodenal injury

• Most intramural haematomas are managed expectantly
• If the haematoma is large and narrowing the lumen, incise the serosa and muscularis — but not the mucosa — to drain it and achieve haemostasis; close the defect in one layer with interrupted 3-0 silk
• Minor electrocautery or full-thickness lacerations — careful debridement of non-viable tissue and closure in two layers: mucosa with continuous 4-0 chromic or Vicryl on a tapered needle, serosa and muscularis with 3-0 silk interrupted

Pancreatic injury

• The first step is thorough inspection of the organ
• Superficial lacerations and contusions — apply fibrin glue and insert a closed suction drain
• Monitor the drain for an alkaline pH and lipase/amylase to detect a developing pancreatic fistula
• If the injury is deep or involves the pancreatic duct, consult a gastrointestinal surgeon

Lymphadenectomy

• cN0: not routinely recommended (EORTC 30881: no OS or PFS benefit)
• cN+: perform for staging
• Landing zones: Right = interaortocaval | Left = para-aortic
• A node > 2 cm usually harbours malignancy; < 2 cm is usually reactive

Indications for regional lymphadenectomy

• Enlarged nodes on imaging
• Cytoreductive surgery for metastatic disease
• Tumour size > 10 cm
• Nuclear grade 3 or higher
• Sarcomatoid histology
• Tumour necrosis on imaging
• Extrarenal tumour extension
• Tumour thrombus
• Direct tumoral invasion of adjacent organs

Incidental N1 disease found at the time of nephrectomy

• If it's a radical → proceed as planned
• If it's a partial → genuinely controversial. Two positions:
  • (A) If the CT was recent, the node is unlikely to be malignant (more likely reactive) — so proceed with the partial + lymphadenectomy. If the node comes back positive, there is no additional benefit from a radical, since the patient is already N1
  • (B) Some advocate a frozen section: proceed with the partial if the node is negative; go radical if it is positive

Adrenalectomy

• Preserve ipsilateral adrenal if normal on imaging; incidence of adrenal mets <5%

Adrenalectomy is indicated when there is:

• Diffuse involvement by tumour
• Large tumour size (> 10 cm)
• Extrarenal tumour extension
• Tumour thrombus — particularly thrombus at the level of the adrenal vein
• Lymphadenopathy and regional metastasis
• An adrenal mass on imaging

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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

Adjuvant Therapy — Sunitinib (S-TRAC)

For non-metastatic clear cell RCC with high-risk features:

• T4
• T3N0+ with Fuhrman grade ≥ 2 and performance status ≥ 1
• Node positive

Adjuvant sunitinib, 4 weeks on / 2 weeks off, for 1 year, increased disease-free survival by 1.2 years.

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IVC Thrombus

Level classification

Level	Extent
I	Adjacent to the ostium of the renal vein
II	Extends to the lower aspect of the liver, below the hepatic veins
III	Involves the intrahepatic portion of the IVC, but below the diaphragm
IV	Extends above the diaphragm

Pre-operative assessment

• Transoesophageal echocardiography is recommended for level II to IV thrombi
• Venacavography is rarely used — reserved for patients in whom MRI and CT are equivocal, or where they are contraindicated
• Pre-operative renal artery embolisation is neither essential nor recommended for the routine management of IVC thrombi
• Angioembolisation can be considered when: the caval thrombus appears to invade the IVC · the thrombus invades the intrahepatic or suprahepatic veins and cannot be excised · the thrombus is associated with a bleeding kidney · deep hypothermic arrest is planned (coronary patency can be assessed at the same time)

Vascular control by level

• Level I — isolated with a Satinsky clamp or vascular stapler

• Level II — sequential clamping of the caudal IVC, the contralateral renal vasculature, and the cephalad IVC, with mobilisation of the relevant IVC segment and occlusion of the lumbar veins

  • Left-sided tumour: optionally clamp the contralateral renal artery to prevent renal engorgement while venous outflow is clamped. This matters more on the left, because the right kidney lacks significant venous collateralisation

• Levels III and IV — more extensive dissection, veno-venous bypass, or cardiopulmonary bypass with hypothermic circulatory arrest

  • Level III — mobilising the liver and exposing the intrahepatic IVC often lets the thrombus be milked caudad to the hepatic veins, after which it is handled as a level II. Alternatively, clamp the IVC above the liver and perform a Pringle manoeuvre to occlude the portal triad
  • Level IV — traditionally cardiopulmonary bypass with hypothermic circulatory arrest; still preferred in complex cases

• Total hepatic vascular occlusion = clamping the IVC above and below the hepatic veins while performing a Pringle manoeuvre

• If the IVC is clamped BELOW the major hepatic veins and the accessory hepatic veins are ligated, the Pringle manoeuvre may not be necessary

• Before final closure of the cava, release the caudal clamp and let 5–10 mL of venous blood escape from the cavotomy — this removes air, debris and clot before the cranial clamp comes off

• Up to 50% of the IVC diameter can be removed

• Distal bland thrombus — removal is reasonable, but it may be left in situ if resection carries undue risk. When left, consider ligation of the IVC cephalad to it, or a filter, to prevent pulmonary embolism

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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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Local Recurrence

After radical nephrectomy

• Local recurrence includes the renal fossa, ipsilateral adrenal gland, renal vein stump or adjacent IVC, and ipsilateral retroperitoneal nodes
• Only 20–40% of local recurrences are isolated — the majority also have systemic disease, so a thorough metastatic evaluation should be pursued
• Surgical resection of an isolated local recurrence is worth considering — it gives long-term cancer-free status in 30–40%

After partial nephrectomy

• Local recurrence in the remnant kidney occurs in 1.4–10%
• Main risk factors — advanced T stage or high tumour grade
• Options for isolated recurrence — repeat PN, completion nephrectomy, thermal ablation, or active surveillance

After thermal ablation

• Often reflects incomplete tumour eradication
• Options — repeat ablation, active surveillance, or salvage surgery

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Metastatic RCC

Cytoreductive Nephrectomy — Indications

• CARMENA — intermediate and high-risk patients derive no benefit from cytoreductive nephrectomy before systemic therapy
• Cytoreductive nephrectomy is for good-risk patients only — good performance status, lung-only metastases
• SURTIME — in intermediate-risk patients, deferred cytoreductive nephrectomy preceded by sunitinib gave better overall survival
• 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

Risk group	Adverse factors	Median overall survival
Good	0	43.2 months
Intermediate	1–2	22.5 months
Poor	3–6	7.8 months

MSKCC (Motzer) Criteria (5)

Derived in patients treated with chemotherapy or immunotherapy.

1. Karnofsky performance score < 80%
2. Elevated LDH (> 1.5× upper limit of normal)
3. Low haemoglobin (< lower limit of normal)
4. Elevated corrected calcium (> 10 mg/dL)
5. Absence of prior nephrectomy

Risk group	Adverse factors	Median overall survival
Good	0	20 months
Intermediate	1–2	10 months
Poor	3–5	4 months

Note the difference from IMDC: MSKCC uses LDH and absence of prior nephrectomy; IMDC uses neutrophils and platelets.

Systemic Therapy

First line

IMDC risk	Standard of care	Alternative if immune checkpoint inhibitors can't be given
Favourable	Pembrolizumab + axitinib · Nivolumab + cabozantinib	Sunitinib · Pazopanib
Intermediate and poor	Pembrolizumab + axitinib · Nivolumab + cabozantinib · Nivolumab + ipilimumab	Cabozantinib · Sunitinib · Pazopanib · Temsirolimus

• Temsirolimus is FDA-approved as a front-line choice specifically in poor-risk patients

Second line

Prior therapy	Standard of care	Alternative
Prior immunotherapy	Any VEGF-targeted therapy not used before, + immunotherapy	—
Prior TKIs	Cabozantinib or Nivolumab — either one, not both	Axitinib

• Non-clear cell → cabozantinib or sunitinib, or a clinical trial
• Lenvatinib + everolimus for patients who have progressed on prior anti-angiogenic therapy
• Metastatic renal medullary carcinoma — 1st line carboplatin + paclitaxel; 2nd line gemcitabine + adriamycin
• Overall response rate: 30–40%

Categories of Therapeutic Agents

Immune checkpoint inhibitors — pembrolizumab, nivolumab, ipilimumab

• Fatigue, musculoskeletal pain, diarrhoea, nausea, decreased appetite, rash, pruritus, fever, cough, dyspnoea, constipation, abdominal pain, peripheral oedema, infusion-related reactions

VEGF-targeted therapy

• Older agents: bevacizumab, sorafenib, sunitinib, pazopanib, axitinib
• Newer agents: cabozantinib, lenvatinib
• Hand-foot syndrome, vomiting, diarrhoea, altered taste, raised LFTs, hypertension, hypothyroidism, fatigue, headache, MI, stroke

mTOR inhibitors — everolimus, temsirolimus

• Weakness, oedema, nausea, vomiting, diarrhoea, raised LFTs, raised blood glucose, anaemia
• Temsirolimus improves overall survival in poor-risk mRCC, and is more effective given IV once weekly

Cytokines

• Interferons — good initial response, but long-term survival is rare
• IL-2 — for patients with no brain metastases and good performance status. Side effects: fever, chills, vascular leak syndrome, weight gain, fluid retention, renal and hepatic insufficiency, hypotension
• High-dose IV IL-2 remains a reasonable option in carefully selected patients with metastatic clear cell RCC, given that newer targeted agents rarely induce durable responses

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Other Malignant Renal Tumours

Renal sarcoma

• Presents in the 5th decade
• Leiomyosarcoma is the most common sarcoma in the kidney, followed by liposarcoma — the order reverses in the retroperitoneum, where liposarcoma is most common
• High-grade sarcomas often metastasise, the lung being the primary site; prognosis is poor. Low-grade sarcomas are more indolent, but local recurrences often need repeat resection
• The most important prognostic factors for sarcoma are margin status and tumour grade

Renal lymphoma

• CT is the radiographic modality of choice for diagnosis and for monitoring response
• Suspect it with massive retroperitoneal lymphadenopathy, splenomegaly, or lymphadenopathy in other or atypical regions
• Renal involvement is more common with non-Hodgkin lymphoma
• Commonly silent, but can cause haematuria, flank pain or progressive renal failure — B symptoms (fever, weight loss, fatigue) are much more common
• If lymphoma or leukaemic involvement is suspected → percutaneous biopsy or aspiration. If exploratory surgery is necessary, intraoperative biopsy and frozen section take priority
• Extirpative surgery should be AVOIDED — the primary treatment is systemic chemotherapy ± radiotherapy
• The classic regimen for non-Hodgkin lymphoma is R-CHOP

Metastases to the kidney

• Most frequent sources — lung, breast, gastrointestinal cancers, malignant melanoma, and haematologic malignancies

Carcinoid

• Derived from neuroendocrine cells; stains positive for neuron-specific enolase and chromogranin
• Urinary or plasma serotonin or its metabolites can be diagnostic
• A minority present with carcinoid syndrome — episodic flushing, wheezing, diarrhoea
• Other neuroendocrine tumours (small cell, primary large cell neuroendocrine) occur in the kidney but are even less common

Adult Wilms tumour

• Multimodal therapy is recommended — nephrectomy plus chemotherapy/radiotherapy
• Worse prognosis than the paediatric disease

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Exam Pearls

• The lumbar vein is the most common source of bleeding after hilar control in a LEFT radical nephrectomy
• VHL is most commonly diagnosed via retinal angiomas
• The VHL manifestation that clusters within a subset of affected families is phaeochromocytoma
• For AML, use MRI — T2 with fat suppression
• Progressed on pazopanib → give cabozantinib
• A 3 cm renal mass with a distant lymph node → biopsy the NODE, not the mass. A renal biopsy, even if positive for RCC, will not exclude lymphoma

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