Renal Cell Carcinoma

Origin and Subtypes

• RCC originates in the renal parenchyma, specifically from tubular epithelial cells. It is a heterogeneous disease with several histologically and genetically distinct subtypes:
  • Clear Cell RCC: The most common subtype, accounting for 70–90% of RCCs. Frequently associated with inactivation of the VHL gene and often presents as a solitary cortical lesion.
  • Papillary RCC: Comprises 10–15% of cases. These tumours are often multifocal or bilateral and are linked to MET gene mutations.
  • Chromophobe RCC: Represents 3–5% of cases. Typically presents as indolent tumours with a distinct cytogenetic profile involving multiple chromosomal losses.
  • Other subtypes: Include collecting duct carcinoma, medullary carcinoma, translocation-associated carcinomas, and unclassified renal carcinomas.

Hereditary Syndromes

• A number of autosomal dominant syndromes are associated with an increased risk of RCC. These include:
  • Von Hippel-Lindau (VHL) Syndrome: Strongly associated with bilateral, multifocal clear cell RCC. The VHL gene, located on chromosome 3p, functions as a tumour suppressor, and its inactivation is a central event in RCC pathogenesis.
  • Hereditary Papillary Renal Carcinoma (HPRC): Caused by germline MET mutations and characterised by bilateral, multifocal papillary tumours.
  • Birt-Hogg-Dubé Syndrome: Associated with chromophobe RCC, oncocytomas, and other oncocytic tumours. Caused by mutations in the FLCN gene.
  • Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC): Linked to fumarate hydratase (FH) mutations and aggressive papillary tumours.
  • Tuberous Sclerosis Complex (TSC): Associated with TSC1 or TSC2 mutations, with renal lesions more commonly being angiomyolipomas than carcinomas.

Key Characteristics

• Site of origin: Renal cortex
• Histological types: Predominantly clear cell, followed by papillary and chromophobe
• Nature: Malignant epithelial tumour
• Incidence: Most common renal tumour in adults
• Diagnosis: Often incidental due to increased imaging use
• Major risk factors: Smoking, obesity, hypertension, familial syndromes

 Environmental and Lifestyle Risk Factors

Tobacco Use

• Cigarette smoking is the most well-established risk factor for RCC. The risk increases in a dose-dependent manner and is observed not only in cigarette users but also in pipe and cigar smokers. It is estimated that smoking contributes to nearly one-third of RCC cases. Furthermore, smokers are more likely to present with advanced disease.

Obesity

• Obesity is a major risk factor, especially in women, with a linear correlation between increasing body mass index and RCC risk. Obesity may influence tumour development via mechanisms such as increased insulin-like growth factors and oxidative stress.

Hypertension

• Elevated blood pressure has been consistently associated with a higher risk of RCC, independently of other comorbidities. The risk rises with both systolic and diastolic pressures.

Diet and Alcohol

• Diets rich in fruits, vegetables, and long-term consumption of fatty fish may confer a protective effect. Moderate alcohol intake (up to two drinks per day) has also been associated with a reduced risk.

Occupational and Chemical Exposures

Trichloroethylene

• Chronic occupational exposure to this industrial solvent is linked to an increased RCC risk.

Other Industrial Agents

• Extended exposure to benzene, benzidine, cadmium, herbicides, and vinyl chloride has also been implicated.

Pelvic Radiation

•  Prior exposure to therapeutic pelvic radiation has been associated with a modest increase in RCC risk.

Medical Conditions and Pharmaceutical Agents

Chronic Kidney Disease and Dialysis

• Long-term dialysis increases the risk due to acquired cystic kidney disease, which predisposes to malignancy. This risk is also elevated in renal transplant recipients with similar cystic pathology.

Chronic Hepatitis C

• A recognised association exists between hepatitis C infection and RCC, potentially mediated by systemic inflammation and immune dysregulation.

Kidney Stones in Males

• A meta-analysis suggests a significant association between nephrolithiasis and kidney cancer in men.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

• Prolonged use of non-aspirin NSAIDs may be linked to RCC development. Phenacetin-containing analgesics, previously used widely, are particularly associated, though now banned in many countries due to nephrotoxicity.

Hereditary Syndromes and Genetic Mutations

Von Hippel-Lindau (VHL) Syndrome

• Associated with bilateral, multifocal clear cell RCC. VHL is a tumour suppressor gene located on chromosome 3p. Inactivation leads to dysregulated angiogenesis via hypoxia-inducible factors and VEGF. Lifetime RCC risk approaches 70%. RCCs in VHL are often indolent and rarely metastasise when smaller than 3 cm.

Hereditary Papillary Renal Carcinoma (HPRC)

• Linked to mutations in the MET proto-oncogene. Patients develop bilateral, multifocal type 1 papillary RCCs.

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)

• Caused by mutations in the fumarate hydratase (FH) gene. These tumours, often aggressive type 2 papillary RCCs, can metastasise early and are associated with uterine and cutaneous leiomyomas.

Birt-Hogg-Dubé Syndrome

• Results from mutations in the folliculin (FLCN) gene. It predisposes to chromophobe, oncocytic, and clear cell RCC. Patients may also present with pulmonary cysts and benign skin tumours such as fibrofolliculomas.

Succinate Dehydrogenase (SDH)-Deficient RCC

• These include tumours with clear cell morphology associated with mutations in SDH subunits, especially SDHB. RCC risk in SDHB mutation carriers is estimated at 10–15%. These mutations may co-occur with paragangliomas, phaeochromocytomas, or gastrointestinal stromal tumours.

Tuberous Sclerosis Complex (TSC)

• Caused by mutations in TSC1 or TSC2 genes encoding hamartin and tuberin. Although angiomyolipomas are more common, RCC may occur and is often early in onset.

Other Genetic Loci

• Additional genes associated with RCC include BAP1 (linked to aggressive disease), and ELOC (formerly TCEB1). Identification of such mutations is critical for risk stratification, surveillance strategies, and consideration of targeted therapies.

Molecular and Cytogenetic Foundations

Clear Cell RCC (CCRCC)

• Represents 70–90% of RCC cases.
• Histologically characterised by golden-yellow tumours with areas of haemorrhage, cystic change, and necrosis.
• Frequently involves deletion of the short arm of chromosome 3 (3p), where the von Hippel-Lindau (VHL) gene is located.
• Loss or inactivation of VHL results in accumulation of hypoxia-inducible factors (HIFs), which drive the transcription of genes such as VEGF (angiogenesis), PDGF (oncogenesis), and MMPs (invasion).
• Additional affected pathways include the PI3K-Akt-mTOR axis, further enhancing tumour growth and vascularisation.
• Sporadic CCRCC often shares molecular features with familial cases, including VHL mutations or epigenetic silencing.
• Prognosis is typically worse than other subtypes, though systemic therapy is often more effective.

Papillary RCC (PRCC)

• Accounts for 10–15% of RCCs.
• Tends to be bilateral and multifocal; more likely to demonstrate haemorrhage and necrosis.
• Genetic alterations include trisomy of chromosomes 7 and 17, loss of Y chromosome, and mutations in the MET proto-oncogene.
• PRCC is classified into two types:
  • Type 1 is associated with MET gene mutations, especially in hereditary forms.
  • Type 2 is more aggressive and associated with FH mutations (in hereditary leiomyomatosis RCC), NRF2-ARE pathway activation, CDKN2A deletion, and CpG island methylator phenotype (CIMP), which confers poorer prognosis.

Chromophobe RCC (ChRCC)

• Comprises 3–5% of RCC cases.
• Exhibits pale, eosinophilic cells with prominent cell borders.
• Generally has an indolent clinical course.
• Cytogenetic abnormalities include multiple chromosome losses (notably chromosomes 1, 2, 6, 10, 13, 17, and 21).
• Arises from intercalated cells of the collecting duct.

Mechanisms of Tumour Development and Progression

Angiogenesis

• VHL inactivation leads to constitutive expression of HIF-1α and HIF-2α, which upregulate VEGF and PDGF—key mediators of tumour angiogenesis. 
• These have become principal therapeutic targets with drugs such as tyrosine kinase inhibitors (e.g., sunitinib, axitinib) and anti-VEGF agents.

Metabolic Dysregulation and Obesity

•  Obesity is linked to increased RCC risk via:
  • Lipid peroxidation and DNA adduct formation
  • Elevated insulin-like growth factor (IGF) levels
  • Enhanced glomerular filtration, promoting carcinogen exposure
  • Nephrosclerosis contributing to chronic tubular injury

Hypertension

• Hypertension-induced renal damage may facilitate carcinogenesis through tubular epithelial injury and increased renal exposure to carcinogens.

Tobacco Smoke

• Carcinogens in tobacco (e.g., nitrosamines) contribute to RCC through oxidative DNA damage, while nicotine promotes angiogenesis and tumour proliferation.

Tumour Immune Evasion

Hereditary Syndromes and Genetic Mutations

VHL Syndrome

• Autosomal dominant condition with a ~70% lifetime risk of RCC.
• Associated with CNS haemangioblastomas, retinal angiomas, pancreatic and adrenal tumours.
• RCC is often bilateral and multifocal, with clear cell histology.

Hereditary Papillary Renal Carcinoma (HPRC)

• Caused by germline mutations in the MET gene.
• Manifests as multifocal, bilateral type 1 papillary tumours.

Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC)

• Due to FH gene mutations.
• Typically presents with aggressive type 2 papillary RCC and uterine or cutaneous leiomyomas.

Birt-Hogg-Dubé Syndrome

• Caused by FLCN mutations.
• Associated with chromophobe RCC, oncocytic tumours, pulmonary cysts, and benign skin lesions.

Succinate Dehydrogenase (SDH)-Deficient RCC

• Associated with mutations in SDH subunits, particularly SDHB.
• These patients may also present with pheochromocytomas or paragangliomas.

Tuberous Sclerosis Complex (TSC)

• Involves TSC1 or TSC2 gene mutations.
• RCC is rare but can occur alongside angiomyolipomas and systemic hamartomas.

Global and Regional Incidence Trends

• Since the mid-1970s, there has been a marked increase in the incidence of RCC, primarily attributed to widespread use of cross-sectional imaging modalities, which has led to more incidental detection of asymptomatic renal masses.
• In the United States, RCC incidence rose steadily through the 1990s and 2000s, with the overall rate reaching 15.4 cases per 100,000 people by 2019.
• Between 2010 and 2019, the annual increase in RCC incidence was approximately 1%, driven largely by increases in early-stage diagnoses.
• The incidence appears to have stabilised or declined in many parts of Europe, potentially reflecting successful public health efforts such as reductions in tobacco use.
• Worldwide, the age-standardised incidence rate of kidney cancer is estimated at 6.1 per 100,000 in men and 3.2 per 100,000 in women, though there is considerable variation by region.

Demographic Patterns

• RCC predominantly affects older adults, with a median age at diagnosis of approximately 65 years.
• Men are twice as likely to be affected as women, making RCC the sixth most common malignancy in men and the ninth in women in the US.
• In familial syndromes, the disease may present at a younger age.
• RCC is more common among individuals of Northern European and North American ancestry than those of Asian or African descent.
• In the US, American Indian/Alaska Native men have the highest reported incidence (up to 36.2 cases per 100,000), followed by non-Hispanic Black Americans and non-Hispanic Whites. The age-adjusted incidence in Black men is slightly higher than in White men (26.2 vs 24.3 per 100,000).

Mortality Trends

• RCC accounts for a substantial proportion of kidney cancer-related deaths. In the US, RCC is estimated to be responsible for approximately 14,000–14,400 deaths annually.
• Despite increasing incidence, mortality has declined in many high-income countries, particularly in Western Europe, North America, and Australia. This decline is attributed to:
  • Earlier detection through incidental imaging findings
  • Improved treatment modalities (e.g., targeted therapy and immunotherapy)
  • Reduced tobacco smoking prevalence
  • Enhanced access to health care services
• In Europe, male mortality fell from 4.8 per 100,000 (1990–1994) to 4.1 (2000–2004), and in women from 2.1 to 1.8 over the same period.
• The mortality-to-incidence ratio remains lower in high-income nations compared to lower-resource settings, underscoring the impact of healthcare infrastructure on outcomes.

Survival Outcomes

• The overall five-year relative survival for RCC in developed countries is about 75%.
• For patients diagnosed with early-stage disease, which accounts for approximately two-thirds of new diagnoses, the five-year survival rate exceeds 90%.
• Improved survival is linked to earlier detection, often during evaluations for unrelated conditions or imaging performed for other reasons.

Contributing Factors to Incidence Variation

• The rising incidence in high-income settings is strongly influenced by access to imaging, allowing for diagnosis of small, often asymptomatic tumours.
• Environmental and genetic factors may account for geographic and ethnic variations in incidence.
• The stabilisation or decline in incidence and mortality in many regions may reflect effective implementation of public health strategies, especially anti-smoking campaigns.

 Asymptomatic Presentation

• Over 50% of RCC cases are identified incidentally during imaging studies conducted for unrelated indications.
• Asymptomatic RCC is typically smaller and detected at earlier stages, often associated with improved prognosis.

Classic Triad (Rare and Late Finding)

• Only 7–10% of patients present with the traditional triad, which usually signifies locally advanced disease:
  • Flank pain – Constant or colicky; may be due to capsular stretching or bleeding.
  • Gross or microscopic haematuria – Occurs in approximately 40% of cases; clots or vermiform bleeding patterns suggest upper tract origin.
  • Palpable abdominal/flank mass – More commonly detectable in thin individuals; typically firm and moves with respiration.

Other Localised or Secondary Manifestations

• Scrotal varicocele – Observed in up to 11% of male patients, typically left-sided due to renal vein obstruction. Failure to decompress when recumbent is suggestive of RCC.
• Lower limb oedema, ascites, or hepatic dysfunction – May indicate inferior vena cava (IVC) invasion or Budd-Chiari-like physiology.

Systemic and Paraneoplastic Features

• RCC is notorious for producing systemic effects via cytokine release or ectopic hormone production, which may precede radiographic findings.
• Fever – Occurs in 20% of patients; usually intermittent and associated with night sweats and fatigue.
• Weight loss – Seen in approximately one-third; reflects systemic illness or cachexia.
• Malaise and fatigue – Non-specific but common.
• Night sweats – Reflects systemic inflammatory response.

Paraneoplastic Syndromes

Hypercalcaemia (up to 15%)

• Can result from lytic bone metastases, parathyroid hormone–related protein (PTHrP) secretion, or prostaglandin-mediated osteolysis.
• May be associated with concurrent IL-6 overproduction, enhancing calcium resorption.

Erythrocytosis (1–5%)

• Due to ectopic erythropoietin production.
• Linked to VHL mutations affecting hypoxia-inducible transcription factors.

Anaemia (29–88%)

• Normocytic or microcytic; often severe and may mimic anaemia of chronic disease.

Stauffer syndrome (hepatic dysfunction without metastasis)

• Manifests as raised alkaline phosphatase, hepatomegaly, and constitutional symptoms.
• Can resolve post-tumour resection.

Secondary (AA) amyloidosis (up to 5%)

• Due to sustained elevation of serum amyloid A during chronic inflammation.

Thrombocytosis

• Rare but a recognised marker of poor prognosis, potentially related to IL-6.

Polymyalgia rheumatica-like syndrome

• Presents with proximal muscle pain; unlike idiopathic cases, it responds to nephrectomy rather than steroids.

History Suggestive of Metastatic Disease

• Respiratory symptoms – Dyspnoea, cough, or haemoptysis (lung metastases).
• Bone pain or pathological fractures – Often indicates osteolytic bone involvement.
• Neurological deficits – May reflect brain or spinal cord metastases.
• Abdominal pain or gastrointestinal bleeding – Rare, but may suggest late metastasis to GI tract or pancreas.

Relevant Hereditary Features in History

• Family and personal history should screen for features suggestive of genetic syndromes:
  • Cutaneous lesions (e.g., fibrofolliculomas in Birt-Hogg-Dubé syndrome)
  • Endocrine abnormalities (e.g., phaeochromocytomas in VHL)
  • Visual changes (e.g., retinal angiomas in VHL)
  • Early onset or bilateral/multifocal tumours
  • Known family history of RCC or related syndromes

 General Observations and Constitutional Features

• Cachexia: Common in advanced RCC; may be accompanied by pallor and generalised weakness.
• Fever: Present in up to 20% of patients, typically intermittent and unexplained by infection.
• Night sweats and malaise: Non-specific, often part of the paraneoplastic syndrome spectrum.

Abdominal Examination

Flank or Abdominal Mass

• Palpable in a minority of patients, especially those with lower pole tumours or thin body habitus.
• Typically firm, non-tender, and moves with respiration.

Abdominal Bruit

• Rare, but may be auscultated over a hypervascular mass.

Signs of Hepatic Dysfunction

• Ascites, hepatomegaly, or spider naevi may indicate paraneoplastic hepatic dysfunction (Stauffer syndrome), particularly in the absence of liver metastases.

Scrotal Examination 

Varicocele

• Occurs in up to 11% of males with RCC, typically left-sided.
• Suggests obstruction of the testicular vein at its entry into the left renal vein.
• Persistence of varicocele in the recumbent position increases suspicion for RCC.

Peripheral Signs of Metastatic Spread

Pulmonary Involvement (75%)

• Decreased breath sounds, wheeze, or rales may suggest metastatic lung nodules or pleural effusion.

Bone Metastases (20%)

• Localised tenderness, especially over the spine, ribs, or long bones.
• Evidence of pathological fractures or deformity.
• Neurological deficits (e.g., radiculopathy, weakness, or bladder/bowel dysfunction) may suggest spinal cord compression from vertebral involvement.

Liver (18%)

• Hepatomegaly or nodular liver contour.
• Jaundice is rare but may occur if there is significant hepatic involvement or paraneoplastic cholestasis.

Central Nervous System (8%)

• Altered mental status, focal neurological signs, or raised intracranial pressure symptoms (e.g., papilloedema) may indicate brain metastases.

Soft Tissue and Cutaneous Lesions (8%)

• Palpable subcutaneous nodules or skin metastases.
• These may appear years after initial treatment and are associated with more indolent tumour types.

Supraclavicular Adenopathy

• Lymphadenopathy, particularly left-sided (Virchow node), may reflect thoracic or abdominal spread.

Lower Limb Oedema

• May suggest IVC obstruction due to tumour thrombus.
• Can also indicate lymphatic obstruction from nodal metastases or direct tumour compression.

Paraneoplastic Syndromes – Physical Clues

Hypercalcaemia

• May present with confusion, constipation, muscle weakness, or dehydration.

Cushingoid Features

• Facial fullness, proximal muscle wasting, or striae (if ACTH-producing tumour).

Erythrocytosis

• Physical findings are rare, but may cause plethora or ruddy complexion in severe cases.

Secondary Amyloidosis

• Signs include macroglossia, nephrotic syndrome (periorbital oedema), or purpura.

Polymyalgia Rheumatica-like Syndrome

• Pain and stiffness in proximal muscles without response to corticosteroids may suggest a paraneoplastic origin.

Dermatological and Genetic Clues

Birt-Hogg-Dubé Syndrome

• Facial fibrofolliculomas, trichodiscomas, and skin tags.

Hereditary Leiomyomatosis

• Multiple cutaneous leiomyomas.

Von Hippel-Lindau Syndrome

• Retinal angiomas seen on fundoscopy; patients may present with vision loss.

Tuberous Sclerosis

• Hypopigmented macules (ash-leaf spots), facial angiofibromas.

 Initial Imaging Evaluation

Abdominal CT with Contrast (Renal Protocol)

• First-line investigation for characterising a renal mass.
• Offers high sensitivity (>90%) and specificity (up to 100%) for distinguishing benign from malignant lesions.
• Evaluates local invasion, regional lymphadenopathy, and involvement of adjacent organs.
• Provides key information for surgical planning and TNM staging.

Ultrasound (US)

• Commonly used as an initial test or for incidental findings.
• Reliable for differentiating simple cysts (round, anechoic, smooth-walled, posterior enhancement).
• Limited in assessing complex masses or small tumours; contrast-enhanced US can improve diagnostic accuracy.

MRI Abdomen/Pelvis

• Indicated if iodinated contrast is contraindicated or CT findings are equivocal.
• Superior in assessing vascular invasion (e.g., renal vein, IVC), adrenal involvement, and differentiating tumour subtypes.
• Gadolinium-enhanced MRI is helpful in evaluating RCC subtype based on enhancement patterns.

Laboratory Investigations

Full Blood Count (FBC)

• May show anaemia of chronic disease or erythrocytosis due to paraneoplastic erythropoietin production.

Corrected Calcium

• Elevated levels suggest hypercalcaemia of malignancy (lytic bone metastases or PTHrP-mediated).
• Considered a poor prognostic marker.

Liver Function Tests (LFTs)

• Assess for metastatic disease or paraneoplastic hepatic dysfunction (e.g., Stauffer syndrome).

Lactate Dehydrogenase (LDH)

• Marker of tumour burden; elevated LDH is used in prognostic scoring for advanced RCC.

Coagulation Profile

• May show elevated PT in Stauffer syndrome.
• Relevant in patients with hepatic dysfunction or before surgery.

Renal Function Tests (Creatinine, eGFR)

• Baseline assessment to guide surgical planning and choice of imaging contrast agents.
• Important in evaluating suitability for nephron-sparing surgery or systemic therapies.

Urinalysis

• May reveal microscopic or gross haematuria and proteinuria.
• Non-specific but prompts further imaging evaluation.

Advanced Imaging for Staging

CT Chest

• Part of standard metastatic work-up; most common site of distant metastases is the lung.
• Chest radiograph may suffice for small, localised renal masses.

MRI Brain/Spine

• Indicated for patients with neurological symptoms or suspected CNS metastases.

Bone Scan

• Reserved for patients with bone pain or elevated alkaline phosphatase.
• May be falsely negative in osteolytic metastases.

PET/CT

• Not routinely used but can assist in evaluating metastases and response to therapy.
• 18F-FDG PET and Zr-89–girentuximab PET are under investigation for detecting primary and metastatic clear cell RCC.

Tissue Diagnosis

Surgical Pathology (Nephrectomy Specimen)

• Standard for localised RCC; allows histological classification, grading, and staging.
• Preferred over percutaneous biopsy due to accuracy and curative potential.

Percutaneous Biopsy

• Indicated in unresectable cases, suspicion of non-RCC pathology, or in high-risk surgical patients.
• Used for metastatic lesions or when tissue confirmation is needed prior to systemic therapy.

Staging

Abdominal CT for Local Staging

• High specificity (>95%) for renal vein and adjacent organ involvement.
• Sensitivity for perinephric extension is modest (~46%).
• Important for determining surgical approach and risk stratification.

TNM Staging (AJCC/UICC 8th Edition)

• T1–T2: Tumour confined to kidney, subclassified by size.
• T3: Tumour extends into major veins or perinephric tissues but not beyond Gerota fascia.
• T4: Tumour invades beyond Gerota fascia or into ipsilateral adrenal gland.
• Nodal and distant metastases categorised as N1 and M1, respectively.

Specialised and Emerging Tests

pKIM-1 Biomarker

• Plasma kidney injury molecule-1 (pKIM-1) is expressed in RCC; elevated levels correlate with recurrence risk and poor prognosis.
• Not yet incorporated into routine practice pending further validation.

Zirconium-89 (Zr-89) Girentuximab PET

• Targets CAIX expression in clear cell RCC.
• Demonstrated high sensitivity (86%) and specificity (87%) in early studies.

Screening

• Routine population screening is not recommended. However, targeted surveillance may be warranted in:
  • Individuals with hereditary syndromes (e.g., VHL, Birt-Hogg-Dubé).
  • Those with end-stage renal disease on long-term dialysis.
  • Strong family history of RCC
  • Previous exposure to therapeutic renal irradiation.
• Preferred imaging modalities for screening include ultrasound, CT, or MRI depending on risk level and renal function.

Differentials Based on Radiological Findings

Benign Renal Cyst

• Typically asymptomatic, found incidentally.
• Simple cysts are anechoic with smooth borders and posterior enhancement on ultrasound.
• Bosniak classification on CT helps stratify malignancy risk; low-score lesions usually benign.

Angiomyolipoma

• A benign mesenchymal tumour composed of blood vessels, muscle, and fat.
• Usually small and asymptomatic but may cause haematuria or flank pain when larger.
• Characteristic fat density on CT or MRI distinguishes it from RCC.
• Intermediate-size lesions (1–3 cm) or those with atypical features may require biopsy.

Renal Oncocytoma

• A benign epithelial tumour that may appear radiologically similar to RCC.
• Solid, non-enhancing, and typically well-circumscribed on imaging.
• Difficult to differentiate from chromophobe RCC; biopsy may be considered.

Renal Adenoma

• Small, benign epithelial tumour often <1 cm.
• Clinically silent and typically of no consequence unless part of a genetic syndrome.
• Cannot be reliably distinguished from small RCCs on imaging alone.

Renal Infarction

• Associated with vascular risk factors such as atrial fibrillation or hypertensive crises.
• May present with flank pain and haematuria.
• MRI and MR angiography show wedge-shaped areas of non-enhancement; may mimic neoplasm.

Renal Abscess or Infection

• Typically presents with systemic symptoms: fever, flank pain, or signs of sepsis.
• Imaging may reveal a mass-like lesion; differentiation from necrotic tumour may be difficult.
• Diagnosis supported by leukocytosis, positive blood or urine cultures, and resolution on follow-up imaging post-antibiotic therapy.

Congenital Renal Parenchymal Abnormalities

• Rare; usually asymptomatic and incidental.
• MRI often distinguishes these from neoplasms based on tissue characteristics and symmetry.

Differentials Based on Clinical Presentation

Urothelial Tumours (Upper Tract or Bladder Cancer)

• More likely to present with gross haematuria and irritative urinary symptoms.
• Urine cytology may detect carcinoma in situ or high-grade tumours.
• CT urography and ureteroscopy are used for diagnosis.

Non-Hodgkin Lymphoma (Renal Involvement)

• May present as bilateral, non-enhancing renal masses.
• Clinical features and systemic symptoms of lymphoma help distinguish.
• Histological confirmation via biopsy usually required.

Metastatic Lesions to the Kidney

• Most commonly from lung, breast, melanoma, or gastrointestinal primaries.
• Tend to be multifocal and smaller than primary RCC.
• Clinical history and imaging comparison with known primary tumour essential.

Sarcoma

• Primary renal sarcomas are rare but aggressive.
• Imaging may show large, heterogeneous masses with necrosis; biopsy often needed for diagnosis.

Adult Wilms Tumour

• Extremely rare in adults.
• May mimic RCC on imaging but has different histological features.

Other Inflammatory or Infective Mimics

Acute Pyelonephritis

• Associated with fever, flank pain, and dysuria.
• Urinalysis typically shows pyuria and bacteriuria.
• Imaging may show focal or diffuse renal enlargement; resolves with antibiotics.

Chronic Pyelonephritis

• History of recurrent urinary infections.
• Imaging shows cortical scarring, renal asymmetry, and loss of corticomedullary differentiation.

General Principles

• Surgical intervention remains the cornerstone of treatment for localised RCC, particularly for small renal masses (SRMs, <4 cm). Many of these are incidentally detected due to increased imaging utilisation.
• Treatment strategies are influenced by tumour stage, size, histology, patient comorbidities, and performance status. In metastatic disease, systemic therapy is guided by risk stratification models such as MSKCC and IMDC.
• Clear cell histology dominates treatment evidence, with management of non-clear cell subtypes often extrapolated from this.

Localised and Early-Stage RCC (Stage I and II)

Active Surveillance

• Considered for SRMs, particularly <2 cm, which may be benign or indolent. Growth rates are slow (<0.3 cm/year), with low risk of progression over 2–3 years.
• Ideal for elderly or comorbid patients, especially when life expectancy is limited.
• Surveillance involves periodic imaging (CT, MRI, or ultrasound) annually or more frequently based on risk.

Partial Nephrectomy (Nephron-Sparing Surgery)

• Preferred in SRMs (<4 cm) when technically feasible.
• Associated with equivalent oncological outcomes to radical nephrectomy but better preservation of renal function and reduced cardiovascular risk.

Radical Nephrectomy

• Reserved for large, central, or complex tumours where NSS is not technically feasible.
• Typically laparoscopic or robot-assisted if possible. Ipsilateral adrenalectomy is not routinely required unless radiologically involved.

Ablative Techniques

• Suitable for small tumours (<3 cm), especially in non-surgical candidates.
• Radiofrequency Ablation (RFA) and Cryoablation are the main options; the latter offers superior local control.
• Stereotactic Body Radiotherapy (SBRT) is a non-invasive alternative for poor surgical candidates.
• These approaches may benefit patients with solitary kidneys, hereditary syndromes, or multiple renal lesions.

Locally Advanced RCC (Stage III)

• Managed with radical nephrectomy, potentially requiring complex surgical techniques if the tumour invades the IVC.
• Neoadjuvant therapy (e.g., TKIs) to downsize tumours for resection is experimental but under investigation in clinical trials.

Adjuvant Therapy

• Pembrolizumab is approved in several jurisdictions for high-risk RCC following nephrectomy.
• KEYNOTE-564 trial demonstrated improved disease-free and overall survival compared to placebo.
• Shared decision-making is crucial, especially due to the increased risk of immune-related adverse events.

Metastatic RCC (Stage IV)

Surgery

• Cytoreductive nephrectomy remains selectively employed in patients with good performance status and low metastatic burden.
• Metastasectomy may be curative for oligometastatic disease, particularly in the lungs, and may be offered synchronously or metachronously.

First-Line Treatment

• Immune checkpoint inhibitor (ICI) combinations are now preferred:
  • Pembrolizumab + Axitinib
  • Nivolumab + Cabozantinib
  • Lenvatinib + Pembrolizumab
  • Nivolumab + Ipilimumab (for intermediate- and poor-risk patients)

VEGF-Targeted Therapies

• Indicated if ICI combinations are contraindicated or unavailable:
  • Sunitinib, Pazopanib, Sorafenib, Axitinib, Cabozantinib, Lenvatinib (often with everolimus).
  • Choice influenced by side effect profiles, patient preference, and comorbidities.

Checkpoint Inhibitors

• Pembrolizumab, nivolumab, avelumab, and ipilimumab target PD-1, PD-L1, or CTLA-4 pathways.
• Nivolumab plus ipilimumab has shown complete response rates in 10% of patients with durable control.
• Combination therapy has become standard, especially in treatment-naive clear cell mRCC.

Cytokine Immunotherapy

• Interleukin-2 (IL-2) is now rarely used, reserved for highly selected fit patients due to significant toxicity and limited efficacy.

Sequential and Salvage Therapy

• Post-progression strategies after first-line ICI+TKI include switching to alternate TKIs (e.g., cabozantinib) or salvage ICI combinations.
• Tivozanib is approved for patients who have progressed on multiple prior lines of therapy.

Radiotherapy

• SBRT is effective for oligometastatic disease or palliation, particularly in bone or CNS lesions.
• Conventional radiotherapy may be used for symptom control, though RCC is traditionally radioresistant.

Bone Metastasis Management

• Zoledronic acid or denosumab can reduce skeletal-related events and should be considered in patients with osseous metastases.

Special Populations and Considerations

• Older adults benefit similarly from systemic therapies but require tailored approaches considering organ function and frailty.
• Non-clear cell RCC is underrepresented in trials; enrolment in clinical trials is advised.
• Active surveillance may be appropriate for asymptomatic patients with limited burden metastatic disease and favourable risk.

 Overall Survival Trends

• Overall 5-year relative survival for RCC is approximately 78%, but highly dependent on disease stage.
• US death rates from kidney and renal pelvis cancer decreased by ~2% annually from 2013 to 2020.
• Five-year relative survival (SEER data 2014–2020):
  • Localised: 93.3%
  • Regional: 75.1%
  • Distant/metastatic: 18.2%
• Presentation with symptoms or paraneoplastic syndromes is associated with a poorer prognosis.

Stage-Based Survival Data

• Historical 5-year survival (Robson 1969):
  • Stage I: 66%
  • Stage II: 64%
  • Stage III: 42%
  • Stage IV: 11%
• Despite therapeutic advances, outcomes for advanced stages remain poor.

Early-Stage RCC

• Cancer-specific survival >95% for stage I–II across treatment modalities.
• Predictors of worse survival:
  • Increased age
  • Larger tumour size
  • Higher tumour grade
• Risk of local recurrence after surgery is ~2%, usually within the first 5 years.
• 20–30% of patients may develop metastatic recurrence within 5 years post-nephrectomy.

Advanced/Metastatic RCC

• Untreated median survival: ~5 months
• Cytokine therapy era: ~10.2 months
• Targeted therapy era (e.g., sunitinib): ~17.7 months
• Immune checkpoint inhibitors have further extended disease control.
• Median survival by risk group (COMPARZ study):
  • Favourable: ~42 months
  • Intermediate: ~26 months
  • Poor: <12 months

Prognostic Models in Metastatic RCC

MSKCC (Motzer) Criteria

•  Adverse factors:
  • Time from diagnosis to systemic therapy <1 year
  • Karnofsky Performance Status <80%
  • Low haemoglobin
  • High serum calcium
  • Elevated LDH

IMDC Criteria

•  Adverse factors (includes MSKCC + additional lab markers):
  • Low haemoglobin
  • High corrected calcium
  • Neutrophilia
  • Thrombocytosis
  • Karnofsky Performance Status <80%
  • Time from diagnosis to treatment <1 year

Risk Stratification

• Favourable (0 risk factors):
  • Median OS: ~20 months
  • 2-year OS: ~75%
• Intermediate (1–2 factors):
  • Median OS: ~10 months
  • 2-year OS: ~53%
• Poor (≥3 factors):
  • Median OS: ~4–8.8 months
  • 2-year OS: ~7%

Histological and Biological Factors

• Clear cell RCC: generally poorer prognosis
• Sarcomatoid differentiation: highly aggressive, worse outcomes across histologies
• Prognostic significance of histology may diminish when adjusted for grade and stage

Obesity as a Prognostic Factor

• BMI ≥25 kg/m² associated with longer survival
  • Median OS: 25.6 months (vs. 17.1 months in lower BMI)
• Lower expression of fatty acid synthase (FASN) in obese patients may contribute to improved outcomes

Metastatic Pattern and Timing

• Metachronous metastases (develop later) fare better than synchronous ones (present at diagnosis)
• Favourable prognostic indicators after metastasectomy:
  • Disease-free interval >12 months
  • Complete surgical resection (R0)
  • ≤6 metastases
• Long-term survival:
  • 5-year survival: 30–50% (especially with pulmonary metastasectomy)
  • 10-year survival: up to 33% in select pulmonary cases 

Tumour-related complications

• Hypertension due to renin secretion or compression of renal vasculature.
• Gastrointestinal symptoms, including constipation and abdominal distension, often result from tumour mass effect.
• Venous obstruction may lead to unilateral lower limb oedema or varicocele (typically left-sided due to left renal vein involvement).

Paraneoplastic syndromes 

• Affects up to 30–40% of patients
• Anaemia (normocytic or microcytic), often present at diagnosis and associated with poorer outcomes.
• Hypercalcaemia, frequently due to ectopic secretion of parathyroid hormone–related protein or bone metastases.
• Erythrocytosis from inappropriate erythropoietin production.
• Hepatic dysfunction without metastasis (Stauffer syndrome):
  • Characterised by elevated alkaline phosphatase, γ-glutamyl transferase, erythrocyte sedimentation rate, α-2-globulin, thrombocytosis, and occasionally hepatosplenomegaly.
• SIADH, Cushing’s syndrome, and neurological syndromes (e.g., myopathy, polyneuropathy) can also occur.

Metastatic complications

• Lung involvement: Cough, dyspnoea, haemoptysis.
• Bone metastases: Bony pain, pathological fractures, risk of spinal cord compression.
• Liver metastases: Jaundice, hepatomegaly, elevated transaminases.
• Brain metastases: Seizures, focal deficits, altered consciousness.
• Cutaneous and soft tissue lesions: Present as palpable nodules.

Complications of therapy

• Targeted therapies (e.g., VEGF inhibitors, TKIs)
  • Haematological toxicity: Neutropenia, thrombocytopenia, elevated liver enzymes.
  • Gastrointestinal: Diarrhoea, mucositis, risk of gastrointestinal perforation.
  • Dermatological: Rash, hand-foot syndrome.
  • Cardiovascular: Hypertension, thromboembolism.
  • Renal: Proteinuria, acute kidney injury.
  • Endocrine: Hypothyroidism.
• Immune checkpoint inhibitors:
  • Can induce immune-related adverse events such as:
    • Colitis, hepatitis, hypophysitis, thyroiditis, and dermatitis.
  • Require early recognition and often corticosteroid therapy to manage immune toxicity.

Surgical complications

• Nephrectomy may result in delayed renal recovery, especially in patients with reduced contralateral renal reserve.
• Wound complications, bleeding, or thromboembolic events can occur postoperatively.
• Patients with poor performance status are at higher operative risk and require careful preoperative assessment.

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