Kidney Cancer

Renal Cysts

• Pathogenesis — 3 processes essential for cyst development and enlargement:
  • Epithelial proliferation in normal tubule segments
  • Fluid accumulation in the expanding segment
  • Disturbed extracellular matrix organization and metabolism
• Mechanism: secretory–absorptive imbalance in proliferating tubular epithelial cells → net fluid accumulation in otherwise normal tubules
  • cAMP-stimulated secretion competes with the more powerful reabsorption

Types

• Sporadic
• Acquired — ACKD
• Genetic — ADPKD, ARPKD

ACKD (Acquired Cystic Kidney Disease)

• Occurs in CKD; ~80% of dialysis patients develop cysts
  • ACKD present in 44% by 3 years on dialysis
• ~7% develop RCC after ~10 years
  • Renal malignancy 5–50× more common in dialysis patients than the general population
  • RCC 3× more likely when ACKD is present
• 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
  • e.g., 47-year-old with 2 simple (Bosniak I) cysts in each kidney → ADPKD; 1 cyst per kidney, or cysts in only one kidney → does not suggest ADPKD
• Associated with: hepatic cysts, pancreatic cysts
• No increased risk of RCC

ARPKD

• Autosomal recessive | Chromosome 6
• Associated with: congenital hepatic fibrosis, biliary atresia
  • Hepatic fibrosis → ARPKD, not ADPKD (polycystin-1 mutation) — in ADPKD, childhood renal US ranges from normal to severe bilateral cystic disease

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Bosniak Classification

• Enhancement on IV contrast = the key CT finding separating III–IV from I–IIF
• II: smooth thin wall, few hairline non-enhancing septa, fine calcifications, HU ≤10 (exam answer) → no further surveillance, imaging or biopsy
• IIF: minimally thickened wall, smooth minimally thickened septa, or many hairline septa → re-evaluate every 6–12 months; biopsy not indicated
• III (v2019): enhancing thick (≥4 mm) wall or septa, or enhancing nodule with ≤3 mm convex protrusion and obtuse margins
  • Biopsy generally non-diagnostic (minimal targetable solid component) → avoid
• Cyst size is not a Bosniak criterion at any level — a large simple cyst stays Bosniak I

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Benign Renal Tumors

• Renal cysts are the most common benign renal lesion overall
• Renal lymphangioma — cystic mass surrounding the renal capsule and compressing the kidney → renal colic, hypertensive urgency

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
  • Oncocytoma stains NEGATIVE for Hale colloidal iron — the pairing to remember, since chromophobe RCC stains positive
• Associated with Birt-Hogg-Dubé (BHD)
• Biopsy PPV: ~67% (low — difficult to distinguish from chromophobe RCC)
• Biopsy-proven oncocytoma (e.g., 3 cm, healthy 75-year-old, normal renal function, no metastases) → observation with follow-up renal imaging

Birt-Hogg-Dubé Syndrome

• Autosomal dominant | Chromosome 17 | Gene: Folliculin
  • FLCN mutation at 17p11.2
• Triad: pulmonary cysts, fibrofolliculomas, renal tumors
  • Pulmonary cysts → spontaneous pneumothorax; pneumothorax + renal mass + skin fibrofolliculomas → think BHD
• RCC types: chromophobe (25%), oncocytoma, papillary RCC
  • Also typical: hybrid oncocytic/chromophobe tumors

Angiomyolipoma (AML)

• Sporadic or genetic; associated with TSC and LAM
• AML stains HMB-45 positive
• CT: −20 HU (fat content = diagnostic)
  • Only a small area below −20 HU is needed, on non-enhanced CT
  • 5–10% are fat-poor
• For AML, use MRI — T2 with fat suppression
  • Exam answer: high signal on T1 with loss of signal on fat-saturation images = pathognomonic → no biopsy or PET-CT needed
• Wunderlich syndrome (spontaneous retroperitoneal hemorrhage): occurs in 15%
  • Ruptured, actively bleeding AML: manage hemorrhagic shock first → selective arterial embolization (bleeding control 96–100% in emergencies) → radical nephrectomy only if embolization fails

Management

• Management based on: size, symptoms, pregnancy status
  • Treat with selective arterial embolization or nephron-sparing surgery if: large (>4 cm) or symptomatic, woman of childbearing age, or inadequate follow-up/emergency access
  • e.g., 6.2 cm AML in a woman anticipating pregnancy → risk of spontaneous hemorrhage → prophylactic selective angioembolization, partial nephrectomy or ablation; radical nephrectomy = overtreatment
  • Embolization spares nephrons but often needs repeat procedures; complication rate ~10% (similar to partial nephrectomy)
  • Secondary treatment rate: ~31% after embolization vs 0.85% after surgery
  • Post-embolization syndrome (fever, nausea, pain, leukocytosis) is expected → self-limiting in ~86%
• Everolimus (mTOR inhibitor) is first-line in TSC — reduces size by ~30% in 80% of patients
  • Phase III: ≥50% reduction in 42%; stabilization or partial response in 100% (the 80% above = ≥30% reduction)
  • At 4 years: some response in 92%; only 14% progressed

Tuberous Sclerosis Complex (TSC)

• Autosomal dominant | Chromosomes 9 & 16 | mTOR activation
  • Genes: TSC1/TSC2
• Classic triad: seizures, adenoma sebaceum, intellectual disability
• Features: ash leaf spots, shagreen patch, retinal hamartomas, cardiac rhabdomyoma
• Diagnosis: 2 major features (e.g., renal AML + cardiac rhabdomyoma) or 1 major + 2 minor
  • Multiple renal cysts and hamartomatous rectal polyps count only as minor
• 50% develop AMLs; 2% develop RCC
  • Other renal lesions: renal cysts, polycystic kidney disease, oncocytoma; ↑ risk of clear cell RCC
• Classic picture: bilateral flank masses + gross hematuria + calyceal deformity with normal BUN/creatinine, plus seizures or intellectual disability → bilateral AMLs
  • Renal function preserved because AMLs displace rather than destroy nephrons

Papillary Adenoma (Premalignant)

• Papillary adenoma is the most common SOLID benign renal mass
• <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 polycythemia (↑ 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 Tumor

• Perimenopausal women; estrogen-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

* More aggressive — prompt surgical management

• All familial RCC syndromes are autosomal dominant, and together they account for 5–10% of all RCC cases
  • Exam answer: only 4–6% of incident RCC
  • Bilateral renal masses in a young patient = hereditary until proven otherwise
• HLRCC = the hereditary RCC syndrome most likely to show aggressive tumor behavior
  • Germline mutation → cutaneous as well as uterine leiomyomas
  • Suspect it when a woman and her mother both had hysterectomies for fibroids
• HLRCC — if there are positive margins after a partial nephrectomy, do a radical nephrectomy
  • Tumors need wide resection at diagnosis → the radical nephrectomy includes a lymphadenectomy
• MEN2 (RET gene, chr 10q11 — a receptor tyrosine kinase) counts as a GU tumor syndrome because of pheochromocytoma (adrenal treated as part of the GU tract)
  • Pheo risk 50% in both MEN2A and MEN2B (3% malignant)
  • MEN2 pheos mainly secrete epinephrine; VHL pheos secrete norepinephrine

VHL Overview

• VHL normally targets HIF for degradation
• VHL mutation → HIF accumulates → VEGF overexpression (primary angiogenic driver of ccRCC)
  • Wild-type VHL suppresses VEGF by down-regulating HIF1 → VHL loss = dysregulated VEGF → RCC neovascularity; this pathway is the target of tyrosine kinase inhibitors
• VHL inactivation mutation: most common in sporadic RCC
  • Found in >75% of sporadic clear cell RCC
• Autosomal dominant chromosome 3p25-26
  • Classic tumor suppressor gene → Knudson two-hit model: germline or somatic mutation of one allele, then deletion or promoter hypermethylation of the other
• 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)
  • Exam answer: pheochromocytoma is common in type 2 VHL families and only rarely seen in type 1

Diagnosis

• Multiple or bilateral renal masses → suspect VHL, especially with:
  • Intracranial hemorrhage from a bleeding CNS hemangioblastoma
  • Cerebellar (posterior fossa) hemangioblastoma
  • Epididymal cyst (papillary cystadenoma of the epididymis) — the scrotal manifestation; highly specific
  • Hearing loss in an adolescent → endolymphatic sac tumor of the inner ear (not seen in hereditary papillary RCC or HLRCC)
• VHL is most commonly diagnosed via retinal angiomas
  • Retinal angiomas = the most frequent finding in VHL; inspecting the retina is often the easiest way to make the diagnosis
• Not VHL:
  • Renal angiomyolipomas → tuberous sclerosis
  • Thyroid carcinoma → seen more commonly in MEN
  • Café-au-lait spots → neurofibromatosis

VHL Disease — Surgical Management

• Intervention threshold: 3 cm (NCI guideline; also applies to BHD and HPRC)
  • <3 cm → active surveillance | ≥3 cm → excision
  • BHD tumors are less aggressive than HLRCC or SDH-deficient RCC → same rule, with excision preferably nephron-sparing
• 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
  • Reason: lifelong multifocal recurrence
• Screening: every 6 months from age 15–20

Belzutifan (Welireg)

• Oral HIF-2α inhibitor | FDA approved 2021 | First drug approved specifically for VHL disease
  • Overall response rate 49% in VHL-associated RCC
• Mechanism: blocks HIF-2α/ARNT dimerization → ↓ VEGF + EPO transcription
• Indication: VHL-associated RCC, CNS hemangioblastomas, or pNETs not requiring immediate surgery
  • The RCC indication is non-metastatic — by contrast axitinib, pazopanib, nivolumab + ipilimumab and axitinib + pembrolizumab are approved only for metastatic RCC
  • VHL + localized hilar tumor in a solitary kidney → give belzutifan first to make partial nephrectomy more technically feasible

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RCC Subtypes

• Clear cell — chromosome 3p abnormalities are characteristic (uncommon in other subtypes)
  • VHL (3p25) mutated in ~50%, inactivated by mutation or promoter hypermethylation in 70–90%
  • VHL loss drives HIF–VEGF signaling → why clear cell responds to systemic therapy; current systemic therapies are ineffective against papillary RCC
• Papillary Type I — basophilic cytoplasm; hereditary papillary RCC; MET mutation; chromosomes 7 & 17
  • Characterized by trisomy of chromosomes 7 and 17
• Papillary Type II — eosinophilic cytoplasm; worse prognosis; chromosomes 7 & 17
• Papillary = the most likely RCC in kidney transplant recipients → 56% of de novo graft RCCs; common in ESRD and acquired cystic kidney disease
• Chromophobe — arises from intercalated cells of the collecting duct; better prognosis than clear cell or papillary RCC
  • Commonly seen in BHD (folliculin tumor suppressor, chr 17 → loss activates mTORC1 and mTORC2), though most cases are sporadic
• Collecting duct RCC — often seen in the 3rd–5th decades
  • Resists clear cell and papillary therapies (IL-2, sunitinib, sorafenib, bevacizumab, temsirolimus) → cisplatin-based chemotherapy, possibly reflecting its biologic similarity to urothelial carcinoma
  • Gemcitabine + cisplatin or carboplatin → 26% response rate and improved overall survival
• Medullary RCC presents in the 3rd decade of life
  • Many are locally advanced or metastatic at diagnosis → <15% survive beyond 2 years; median survival 8–13 months

Multifocality by subtype

• Papillary (historically chromophilic) = the subtype most likely to be multifocal in sporadic disease → field effect from multiple precursor papillary adenomas in the cortex

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)

T category

• Ipsilateral adrenal by direct extension = pT4; by hematogenous route = pM1
  • Hematogenous = non-contiguous involvement; adrenal involvement occurs in only 1–2% of RCC
  • Ipsilateral adrenal involvement → 5-yr OS <30% (0–30% for pT4); most die of systemic disease progression
• Perisinus fat (medial) invasion = worse prognosis than perirenal fat (lateral)
  • Medial sinus fat invasion places the tumor close to the venous system
• Renal vein involvement upstages a 6 cm tumor from T1b → pT3a — T3 has no size subdivisions
• A positive surgical margin does not change the T category
• IVC wall invasion = pT3c whatever the thrombus level; IVC extension below the diaphragm without wall invasion = T3b

Nodal staging

• N1 survival (exam answer): 5-yr 5–30%, 10-yr 0–5% — approaching metastatic disease
• Nodal staging has only NX, N0, N1 → any number or size of positive regional nodes = N1 (6 cm tumor invading perinephric fat + positive nodes = pT3aN1)
• Stage III = T3N0M0 or any T1–T3 with N1M0
• Worked example: main renal vein (pT3a) + 6 cm bulky regional node (still N1) + contralateral adrenal involvement (M1) = pT3aN1M1

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Diagnosis and Evaluation

Screening Indications

• CKD (after 3rd year of dialysis)
  • Start with ultrasound + CT at about 3 years on dialysis, then every 6 months: ultrasound alone if kidneys clear; both if cysts or tumors <2 cm
• 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 tumors | RCC age <46 years
• Kidney transplant: ~90% of post-transplant RCCs arise in the native kidneys, not the graft — yet KDIGO does not recommend routine screening of the native kidneys

Presentation

• >50% diagnosed incidentally
• Classic triad (hematuria + flank pain + mass): <5% in contemporary series
• Right-sided or non-reducing varicocele, bilateral leg edema → 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 tumor resection — if a syndrome persists after resection, metastatic disease is probably present and the prognosis is poor
• Elevated ESR (56% — most common)
• Hypertension (38%)
• Anemia (36%)
• Weight loss (34%)
• Fever (17%)
• LFTs elevated/Stauffer syndrome (14%)
• Calcemia (hyper) (5%)
  • Hypercalcemia results from a PTH-like peptide; management: hydration → furosemide → steroids → bisphosphonates → calcitonin
• Polycythemia (4%)
• Amyloidosis (2%)
• Neuropathy (3%)

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 tumor, 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 hematuria, 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%
  • Non-diagnostic rate drops substantially with a repeat biopsy
• Histologic concordance 90% | Grade concordance 62%
• 20% of benign biopsies may still harbor cancer
  • 20–30% of clinically localized solid enhancing cT1 masses are benign, but oncocytic neoplasms remain a diagnostic dilemma on biopsy → a benign result still leaves some doubt
• Complications (8%): hematoma 4.9%, pain 1.2%, hematuria 1%, pneumothorax 0.6%, transfusion 0.4%
• No reported tumor 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
• 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

Indications (6)

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

• Also biopsy an enhancing mass suspected to be metastatic (e.g., prior thyroid cancer), hematologic, inflammatory or infectious
  • → a confirmed metastasis usually gets systemic therapy rather than nephrectomy
• Biopsy is recommended before any renal mass ablation
• Don't start ipilimumab + nivolumab (therapy for known metastatic RCC) without a histologic diagnosis
• Skip biopsy when the result won't change management
  • → e.g., an older, comorbid patient choosing non-surgical care for a small renal mass, who will be managed conservatively whatever the biopsy shows, goes straight to active surveillance

Adverse Prognostic Factors

• Poor performance status
• Paraneoplastic syndrome
• Large tumor
• LN involvement
• Venous invasion
• Metastasis
• High nuclear grade
• Sarcomatoid features
• Tumor necrosis
• Microvascular invasion
• Stage = most important prognostic factor
  • The single most important — ahead of tumor size, grade, histologic subtype and performance status
• LN status = most important within stage
  • LN involvement = worst prognosis, approaching metastatic disease (N1 survival → TNM Staging), and stays the worst factor even after complete excision
• Venous tumor thrombus with otherwise kidney-confined RCC → 45–69% 5-yr survival after aggressive surgery; drops markedly when nodal or systemic metastases are also present

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Management of Localized 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

• Tumor >3 cm (AUA) or >4 cm (CUA)
• Growth >5 mm/year (AUA) or >0.5 cm/year (CUA)
• Stage progression | Worrisome imaging | Unfavorable biopsy
• Symptomatic tumor | Aggressive features on biopsy | Infiltrative features on CT

Follow-up

• 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 tumors <2.5–3 cm; unreliable >4 cm; meant for non-cystic masses
  • Success rate (cryoablation or RFA) is much lower for tumors >3 cm
• Avoid if near hilum, proximal ureter, or collecting system
• Bleeding: less with RFA; significant hemorrhage risk with cryo
• The most common complication of cryoablation is hemorrhage
  • Bleeding is the most common complication of percutaneous renal ablation overall → hematomas on imaging in up to 27%, transfusion in 2–3%
• Major complications of RFA — ureteric obstruction, pyelocalyceal injury, bowel injury, pancreatic injury, gross hematuria requiring intervention
• RFA causes less post-operative hemorrhage than cryoablation — so in a patient with bleeding tendencies, choose RFA
  • Same for a patient on antiplatelet therapy → RFA preferred: heat coagulates the tissue; cryoablation has no coagulating effect (theoretically higher bleeding risk)

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 tumors
• 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
• cT1b (e.g. a 5 cm mass) → offer PN if feasible even with a normal contralateral kidney and creatinine (strong recommendation)
  • RN is linked to CKD, cardiovascular disorders and cardiovascular mortality
• cT2 → PN only for a solitary kidney or CKD, and only if technically feasible (weak recommendation)

Relative Contraindications to PN

Technical

• Cold ischemia 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 tumor
• Diffuse invasion of the central collecting system
• Tumor thrombus involving the major renal veins
  • Even in a solitary kidney (absolute PN indication), a renal vein tumor thrombus (T3a) → RN with en bloc thrombus extraction, accepting dialysis rather than an incomplete resection
• Adjacent organ invasion (cT4)
• Regional lymphadenopathy (cTxN1)
• High tumor complexity

RN preferred over PN when ALL 3 met (AUA)

1. High tumor complexity (PN challenging even in experienced hands)
   • e.g. a large mass with a R.E.N.A.L. nephrometry score of 10–12
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, dyslipidemia, steroids, high-protein diet
  • After PN of a solitary kidney, the most effective screening test for hyperfiltration nephropathy is the albumin-to-creatinine ratio
• Transplant candidate with a small, incidental, asymptomatic renal tumor → no waiting period: simultaneous RN + transplantation; avoid contrast CT when renal function is borderline

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

PN Techniques

• Resection margin: 2–3 mm of negative tissue is sufficient
• In bilateral tumors, 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 tumors) and observe the line of ischemia
• 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
• Urine leak complicates up to 15% of PNs; longer warm ischemia time is directly related to its development

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
• Delayed leak with a urinoma → percutaneous drainage of the urinoma first; add a JJ stent if unresolved within 48 hours; nephrostomy only if a stent cannot be placed
• Fistula persisting despite urinoma drainage → search for ureteral or bladder obstruction or bladder dysfunction

Bleeding

• ABCs → bed rest → IV fluids → consider angioembolization

Warm Ischemia

• Limit to <25 minutes
  • Kidney damage is expected beyond ~30 minutes → keep warm ischemia under 25–30 minutes
• Hypothermia: tolerated up to 60–90 minutes
• The number of preserved nephrons is the primary determinant of renal function after PN; ischemic injury plays a secondary role

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Surgical Approaches

Thoracoabdominal

• Suits a large right upper pole tumor, including one with renal vein thrombus → exposes the IVC, great vessels and retroperitoneum for early vascular control
• Made above the 9th–10th rib bed; going above the 10th rib enters the pleura → chest tube + two-layer diaphragm closure

Midline

• Open RN in poor cardiac function → supine midline transperitoneal laparotomy: best tolerated, quick to open and close, less painful, early great-vessel control
• Drawbacks: relatively poor renal hilar access (needs wide mobilization of the colon, liver or spleen), plus ileus, late bowel obstruction and incisional hernia

Laparoscopic nephrectomy in pregnancy

• Keep pneumoperitoneum at 8–12 mm Hg — ≥15 mm Hg further cuts venous return → hypotension; prolonged CO2 → maternal hypercarbia and acidosis
• Second trimester is preferred; place trocars higher, away from the fundus; laparoscopy becomes much less feasible after 20 weeks

Intraoperative Troubleshooting

Vascular

• Ligation of the SMA or the celiac trunk is a catastrophic event — it occurs predominantly with LEFT-sided nephrectomy and must be rapidly reversed
  • With a large left tumor encroaching on the aorta, the SMA is the vessel most often mistaken for the renal artery and divided
• The IMV can be safely ligated without consequence
• SMV ligation → systemic hypotension / splanchnic hypertension syndrome, characterized by venous thrombosis, bowel ischemia and necrosis
• The lumbar vein is the most common source of bleeding after hilar control in a LEFT radical nephrectomy
  • Acute bleeding after ligating and dividing the left hilum → the lumbar vein enters the renal vein posteriorly and is met when ligation is too close to the IVC
• Arterial bleeding during PN despite a clamped renal artery = incomplete inflow control → search for an accessory artery or a malpositioned clamp, rather than clamping the vein or converting
  • Renal vascular anatomy varies in 25–40% of kidneys; supernumerary renal arteries are the most common variant
• After right colon mobilization, develop the plane lateral to the gonadal vein to find the ureter → a plane medial to it risks IVC injury and gonadal vein avulsion

Laparoscopic RN

• Clips alone are contraindicated for renal artery ligation (fatal clip failures) → en bloc hilar stapling is a safe alternative
• A retrieval bag is mandatory when morcellating → prevents tumor spillage
• Do not bluntly hand-dissect the adrenal off the upper pole → causes bleeding

Bowel injury

• Mobilizing the ascending colon in a right nephrectomy → find the avascular plane between the brighter-yellow mesenteric fat and the pale-yellow Gerota's fat: the key to avoiding colonic injury
• Colon perforation on postoperative day 4 after laparoscopic RN → most likely an electrocautery injury: the coagulated wall looks intact at surgery, then sloughs and perforates days later
• Hallmarks of thermal bowel injury after laparoscopic or robotic surgery: neutropenia + tenderness near a port site
• Suspected delayed bowel injury (e.g. after robotic PN) → CT with oral and IV contrast
  • IV contrast also shows a urine leak or renal artery branch pseudoaneurysm
  • Giving antibiotics first can mask the diagnosis

Duodenal injury

• Most intramural hematomas are managed expectantly
• If the hematoma is large and narrowing the lumen, incise the serosa and muscularis — but not the mucosa — to drain it and achieve hemostasis
  • 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
  • Established pancreatic fistula (e.g. after left PN: amylase-rich drain fluid, ileus) → conservative first: NG tube for the ileus + parenteral nutrition to limit pancreatic secretions from oral intake
• If the injury is deep or involves the pancreatic duct, consult a gastrointestinal surgeon

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Lymphadenectomy

• cN0: not routinely recommended (EORTC 30881: no OS or PFS benefit)
• cN+: perform for staging
  • AUA: resect only the clinically evident nodes, though a regional lymphadenectomy is more common
    • Nephrectomy alone, or with stereotactic radiotherapy to the node, is not recommended
• Landing zones: Right = interaortocaval | Left = para-aortic
• A node > 2 cm usually harbors malignancy; < 2 cm is usually reactive
• Lymphadenectomy gives staging information, but not a therapeutic benefit for all patients with RCC

Indications for regional lymphadenectomy

• Enlarged nodes on imaging
• Cytoreductive surgery for metastatic disease
• Tumor size > 10 cm
• Nuclear grade 3 or higher
• Sarcomatoid histology
• Tumor necrosis on imaging
• Extrarenal tumor extension
• Tumor 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

Chylous leak

• Prevention — ligate small lymphatic vessels, particularly those close to the cisterna chyli below the right crus
• Milky white drain output that surges once a regular diet starts → chylous leak; confirm with a high drain-fluid fat and total protein (a urine leak is clear)

Adrenalectomy

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

Adrenalectomy is indicated when there is:

• Diffuse involvement by tumor
• Large tumor size (> 10 cm)
• Extrarenal tumor extension
• Tumor thrombus — particularly thrombus at the level of the adrenal vein
• Lymphadenopathy and regional metastasis
• An adrenal mass on imaging
  • A lesion bright on T2-weighted MRI → suspicious for pheochromocytoma → remove it at the time of PN, with careful preoperative and intraoperative management

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Locally Advanced RCC

• N+ (M0): enlarged regional para-aortic / interaortocaval nodes = limited, resectable disease → RN + LND upfront — not systemic therapy, biopsy or PET-CT (PET-CT is not indicated in RCC)

Adjuvant Therapy — Pembrolizumab (Keynote-564)

Indicated for high-risk clear cell RCC post-nephrectomy (preferably within 12–16 weeks) — the current adjuvant standard:

• pT2 with grade 4 or sarcomatoid differentiation, N0 M0
• pT3, any grade, N0 M0
  • = KEYNOTE-564 intermediate-high risk (e.g. pT3aN0M0) → offer pembrolizumab after restaging
  • Histology matters — pT3b clear cell qualifies; pT3b papillary does not
• pT4, any grade, N0 M0
• Any pT with N+, M0
• M1 with no evidence of disease after resection of oligometastases within 1 year of nephrectomy

Older trial: S-TRAC (adjuvant sunitinib).

• Benefit is drug-specific: pembrolizumab improves disease-free and overall survival; adjuvant atezolizumab, nivolumab and nivolumab + ipilimumab did not improve disease-free survival
• Adjuvant sunitinib showed an oncologic benefit after nephrectomy in patients at high risk of recurrence; pazopanib, high-dose IL-2, interferon-alpha and autologous tumor vaccine did not

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IVC Thrombus

Level classification

Management and outcomes

• RCC with venous tumor thrombus: ~90% clear cell · ~15% node-positive · 20–25% metastatic
• Thrombus height alone is not a contraindication — e.g. Mayo level III (retrohepatic) → RN + IVC thrombectomy
• An aggressive approach (RN + IVC thrombectomy) cures 45–70% of patients with RCC and IVC thrombus — even level IV thrombi can be cured by resection
• Venous thrombus is salvageable — 5-year survival 45–69% if otherwise kidney-confined
  • After RN + thrombectomy for a level II thrombus (kidney-confined, node-negative) ~31–50%

Pre-operative assessment

• MRI is preferred for defining thrombus extent (CT may be adequate)
• Transesophageal 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 embolization is neither essential nor recommended for the routine management of IVC thrombi
• Angioembolization 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 mobilization of the relevant IVC segment and occlusion of the lumbar veins
  • Left-sided tumor: 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 collateralization
• Levels III and IV — more extensive dissection, veno-venous bypass, or cardiopulmonary bypass with hypothermic circulatory arrest
  • Level III — mobilizing 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 maneuver 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 maneuver
• If the IVC is clamped BELOW the major hepatic veins and the accessory hepatic veins are ligated, the Pringle maneuver 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

AUA vs EAU: AUA 2021 sorts patients into four risk groups by stage and grade, and allows a chest X-ray in low and intermediate risk. EAU 2026 uses three groups by the Leibovich score, with CT (or abdominal MRI) and no chest X-ray.

AUA 2021 — four risk groups

• Low: pT1 and grade 1–2
• Intermediate: pT1 and grade 3–4, or pT2 any grade
• High: pT3 any grade
• Very high: pT4 or pN1, or sarcomatoid/rhabdoid dedifferentiation, or a macroscopic positive margin
• A microscopically positive margin moves the patient up at least one risk level
  • After partial nephrectomy, low-risk pathology + microscopic positive margin → surveil as intermediate: chest X-ray + abdominal CT or MRI at 6 months — not XRT, ablation or completion nephrectomy
  • pT3b with a microscopic positive IVC-wall margin → very high risk: CT chest + abdomen at 3 months · no XRT · IVC re-resection only for a delayed, visible recurrence (at least 1–2 years after surgery) without metastases

• Image for at least 5 years. After 2 years, abdominal ultrasound may alternate with CT/MRI in low and intermediate risk; after 5 years, further imaging is a shared decision
• Labs after nephrectomy: recheck blood pressure, eGFR and proteinuria soon after surgery and at 3–6 months — progressive renal insufficiency or proteinuria (hyperfiltration injury) → nephrology referral

EAU 2026 — three risk groups

Who is in each group

• Clear cell RCC (Leibovich score): low 0–2 · intermediate 3–5 · high ≥ 6
  • Points: pT1b 2, pT2 3, pT3–4 4 · pN+ 2 · size ≥ 10 cm 1 · grade 3 = 1, grade 4 = 3 · necrosis 1
• Non-clear cell: low pT1a–T1b N0, grade 1–2 · intermediate pT1b N0 and/or grade 3–4 · high pT2–T4 any grade, or any pT N1

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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
  • = CT chest + abdominal CT or MRI before resection
    • Synchronous metastasis significantly lowers survival, whereas time to recurrence, site (fossa or adrenal) and size are not independently associated with a worse outcome
• Surgical resection of an isolated local recurrence is worth considering — it gives long-term cancer-free status in 30–40%
  • Isolated renal fossa recurrence, no distant disease → surgical excision with negative margins
    • The only option shown to improve survival (median OS 70.3 vs 27.4 months with vs without local treatment)

After partial nephrectomy

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

After thermal ablation

• Often reflects incomplete tumor eradication
  • Persistent central enhancement of the tumor bed or local recurrence after cryoablation or RFA = treatment failure
• Options — repeat ablation, active surveillance, or salvage surgery
  • Repeat ablation is the usual management; surgery is reserved for disease progressing despite repeat ablation

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Metastatic RCC

Cytoreductive Nephrectomy — Indications

• CARMENA — intermediate and high-risk patients derive no benefit from cytoreductive nephrectomy before systemic therapy
  • Nephrectomy then sunitinib was no better than sunitinib alone → in intermediate/poor risk, start systemic therapy rather than upfront nephrectomy
• 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)
  • Oligometastatic (exam answer): 1–5 lesions → offer metastasectomy when completely resectable in a fit patient
    • Only complete resection prolongs overall and cancer-specific survival
  • Metastasectomy benefits most when metastases appear >2 years after nephrectomy, are isolated, and sit in favorable sites (lung, thyroid, bone, pancreas, adrenal)
    • Isolated lung metastases are most often curatively resectable
• Palliative/symptomatic relief
• Metastatic renal medullary carcinoma with ECOG PS 2 → no cytoreductive nephrectomy, RPLND or metastasectomy

IMDC Risk Stratification Criteria (6)

• Karnofsky PS <80%
• Time from diagnosis to systemic therapy <1 year
• Hemoglobin <lower limit of normal
• Corrected calcium >upper limit of normal
• Neutrophils >upper limit of normal
• Platelets >upper limit of normal

• Scoring: 1 point per adverse factor — the 0-point group is also called low (favorable) risk
• MSKCC vs IMDC — shared: KPS <80%, <1 year from diagnosis to treatment, low hemoglobin, raised corrected calcium
  • MSKCC adds LDH >1.5 × normal
  • IMDC adds raised neutrophils and platelets
  • Performance status is the parameter most predictive of response to immune-based therapy

Systemic Therapy

First line

• Temsirolimus is FDA-approved as a front-line choice specifically in poor-risk patients
• EAU (Strong) first line for IMDC intermediate/poor-risk clear cell: nivolumab + ipilimumab · pembrolizumab + axitinib · lenvatinib + pembrolizumab · nivolumab + cabozantinib
• Nivolumab + ipilimumab beats sunitinib on response rate and overall survival in intermediate/poor risk (CheckMate 214) → sunitinib is no longer standard
  • Sarcomatoid features → ipilimumab (anti-CTLA-4) + nivolumab (anti-PD-1) — the same objective response and overall survival gain over sunitinib holds with sarcomatoid histology
  • Poor risk after cytoreductive nephrectomy (e.g. KPS <80, Hb <12 g/dL, raised platelets) → nivolumab + ipilimumab, even if tumor PD-L1 <1%
• Pembrolizumab (PD-1 inhibitor) + axitinib (selective VEGFR inhibitor) — superior to sunitinib in KEYNOTE-426 (2019, 861 patients)

Second line

• 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
  • Sickle cell trait-associated collecting duct tumor · adriamycin = doxorubicin
• Overall response rate: 30–40%
  • Applies to front-line nivolumab + ipilimumab in clear cell RCC — reported as 42% in the phase 3 trial vs sunitinib

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Categories of Therapeutic Agents

Immune checkpoint inhibitors — monoclonal antibodies that release a brake on T cells, so they attack the cancer again. Kidney cancer cells can express PD-L1, which switches T cells off through PD-1; CTLA-4 is a second brake, engaged by B7 on antigen-presenting cells.

• Side effects: fatigue, musculoskeletal pain, diarrhea, nausea, decreased appetite, rash, pruritus, fever, cough, dyspnea, constipation, abdominal pain, peripheral edema, infusion-related reactions
• Immune-related (autoimmune) side effects: colitis, hepatitis, dermatitis, pneumonitis, hypophysitis
• CTLA-4 blockade is the most toxic:
  • Ipilimumab alone — grade 3–4 side effects in up to a third, mainly autoimmune enteritis and hypophysitis
  • Nivolumab + ipilimumab — grade 3–4 in 46%, with 35% needing high-dose steroids.
  • Nivolumab alone — grade 3–4 in 19%
• Do not rechallenge after stopping for toxicity without expert and MDT support

VEGF-targeted therapy

Monoclonal antibody against VEGF — binds and sequesters the VEGF ligand

• Bevacizumab (Avastin) ± IFN-α — bevacizumab 10 mg/kg IV every 2 weeks; IFN-α 9 MU SC three times a week. Now superseded as first line
  • Humanized monoclonal antibody that neutralizes circulating VEGF-A (overproduced when VHL loss lets HIF accumulate) — it does not block the VEGF receptor tyrosine kinase
  • Clear cell RCC, at this dose vs placebo → PFS 4.8 vs 2.5 months
• Side effects: bleeding, hypertension, fatigue, proteinuria

Tyrosine kinase inhibitors (oral) — block the VEGF and PDGF receptors

• Sunitinib (Sutent) — 50 mg orally daily, 4 weeks on / 2 off · VEGFR-2, PDGFR-β, c-Kit, Flt3
• Sorafenib (Nexavar) — VEGFR-2, PDGFR-β, raf-1
• Axitinib (Inlyta) — selective VEGFR-1–3
• Pazopanib (Votrient) — VEGFR, PDGFR · more hepatotoxicity (ALT rise) than sunitinib
  • COMPARZ (2013, 1,110 patients) — pazopanib noninferior to sunitinib, with a better side-effect profile
• Newer: Cabozantinib — VEGFR + MET + AXL · Lenvatinib — VEGFR-1–3 + FGFR-1–4
• Hand-foot syndrome, vomiting, diarrhea, altered taste, raised LFTs, hypertension, hypothyroidism, fatigue, headache, MI, stroke.
  • Sunitinib causes more fatigue, thrombocytopenia and hand-foot syndrome than pazopanib

mTOR inhibitors (mammalian target of rapamycin) — blocking mTOR stops translation of new HIF protein

• Temsirolimus (Torisel) — 25 mg IV weekly
• Everolimus (Afinitor) — 10 mg orally daily
• Weakness, edema, nausea, vomiting, diarrhea, raised LFTs, raised blood glucose, anemia
• 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 Tumors

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
  • Leiomyosarcoma = 50–60% of renal sarcomas
• High-grade sarcomas often metastasize, 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 tumor grade
• Retroperitoneal liposarcoma resected with an R1 (microscopically positive) margin, no metastases → adjuvant radiotherapy — liposarcomas are largely chemotherapy-resistant
  • Well-differentiated liposarcoma recurs locally in up to 40%; perioperative radiotherapy improves local control and survival (HR 0.70 preoperative, 0.78 postoperative)

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
  • Lymphadenopathy out of proportion to a small renal mass, or outside RCC landing zones → think lymphoma; percutaneous biopsy before any treatment
• Renal involvement is more common with non-Hodgkin lymphoma
• Commonly silent, but can cause hematuria, flank pain or progressive renal failure — B symptoms (fever, weight loss, fatigue) are much more common
• If lymphoma or leukemic 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 hematologic 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, diarrhea
• Other neuroendocrine tumors (small cell, primary large cell neuroendocrine) occur in the kidney but are even less common

Adult Wilms tumor

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

Wilms tumor — WT1 syndromes

• Denys-Drash syndrome — WT1 missense mutation (chromosome 11p13)
  • → Wilms tumor (penetrance approaching 90%) + genital anomalies (e.g. 46,XY undervirilization) + progressive nephropathy (diffuse mesangial sclerosis)
• WT1-mutant Wilms tumors (WAGR and Denys-Drash) → stromal-predominant favorable histology, intralobar nephrogenic rests, early onset, genitourinary abnormalities in males

Upper tract urothelial carcinoma (UTUC)

• Renal pelvis is the most common site — about twice the ureter (1.2 vs 0.8 per 100,000 person-years); the distal ureter (70%) leads only within the ureter
• Lymphatic drainage — renal pelvis and upper ureter → hilar, para-aortic and paracaval nodes first; distal ureter → pelvic nodes
• Positive selective ureteral cytology + normal cystoscopy + negative CT urography → ipsilateral flexible ureteroscopy with biopsy
  • Diagnostic ureteroscopy is indicated when imaging and cytology are insufficient (Strong)
  • Ureteroscopic biopsy determines grade in >90% but often understages
  • Ureteroscopy before nephroureterectomy → higher risk of intravesical recurrence
• Staging (renal pelvis) — invasion of renal parenchyma or peripelvic (renal sinus) fat = pT3; through the kidney into perinephric fat = pT4 → highest metastatic risk
• Prognosis after radical nephroureterectomy — stage and grade; stage is the most important, and non-organ-confined (>pT2) disease is the strongest predictor of metastasis
  • Grade is the most important preoperative surrogate for stage and aggressiveness — 5-year OS 40–87% G1–2 vs 0–33% G3–4
• Follow-up after kidney-sparing treatment (endoscopic or segmental resection) of low-risk UTUC → cystoscopy + CT urography at 3 and 6 months, then yearly for 5 years; ureteroscopy optional
  • A segmental ureterectomy specimen with no upstaging or upgrading replaces the second-look ureteroscopy at 6–8 weeks otherwise needed before low-risk surveillance