Most common primary kidney malignancy; often incidental finding on imaging.
Also known as: RCC, renal cell carcinoma, kidney cancer, hypernephroma
Overview
A malignancy arising from renal tubular epithelium, most commonly the proximal convoluted tubule. Clear cell RCC is the predominant histologic subtype (~75%); other subtypes include papillary (~15%), chromophobe (~5%), and collecting duct.
Epidemiology
Most common primary renal malignancy in adults; ~80,000 new kidney cancer cases (about 90% RCC) and ~15,000 deaths annually in the US (ACS 2026 estimates). Male predominance 2:1. Peak incidence ages 60-70. Increasing incidence due to widespread cross-sectional imaging — most diagnoses now incidental.
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Question 1RenalMedium
A 55-year-old man presents with several months of intermittent gross hematuria and dull left flank pain. Exam reveals a firm, palpable mass in the left flank. CT of the abdomen and pelvis shows a 7-cm enhancing heterogeneous mass arising from the left kidney without evidence of metastatic disease. Renal function is normal. Which of the following is the most appropriate next step in management?
ATyrosine kinase inhibitor therapy
BObservation with serial imaging
CSurgical nephrectomy
DPercutaneous cryoablation
EPercutaneous renal biopsy
Reveal answer & full explanation
Correct answer: C — Surgical nephrectomy
ATyrosine kinase inhibitor therapy
BObservation with serial imaging
CSurgical nephrectomy✓
DPercutaneous cryoablation
EPercutaneous renal biopsy
Why Surgical nephrectomy is correct
Renal cell carcinoma (RCC) classic triad — hematuria, flank pain, and palpable mass — indicates advanced disease
CT enhancement confirms malignancy; biopsy is not routinely required preoperatively
For masses >4 cm, partial or radical nephrectomy is indicated; partial nephrectomy is preferred when feasible to preserve renal function
This patient has a 7-cm mass with no evidence of metastatic disease and normal renal function, making surgical resection the appropriate next step
Why the others are wrong
Percutaneous renal biopsy — not routinely required before surgery when CT enhancement is diagnostic for RCC
Tyrosine kinase inhibitor therapy — sunitinib and pazopanib (vascular endothelial growth factor receptor (VEGFR) inhibitors) and checkpoint inhibitors (nivolumab + ipilimumab) are used for metastatic RCC, not localized disease
Observation with serial imaging — not appropriate for a 7-cm enhancing renal mass without metastases in a surgical candidate
Percutaneous cryoablation — ablation is tempting as a minimally invasive nephron-sparing option, but it is used mainly for small cT1a masses, especially in patients who are poor surgical candidates (the AUA advises considering thermal ablation for masses under 3 cm), because local recurrence rises with tumor size; a 7-cm enhancing mass in a surgical candidate warrants nephrectomy
Question 2RenalMedium
A 60-year-old male smoker has hematuria and a 4-cm right kidney mass on CT. Biopsy shows clear cell histology. Which of the following paraneoplastic syndromes is most associated with this malignancy?
ACushing syndrome from ectopic adrenocorticotropic hormone (ACTH)
BHyponatremia from ectopic antidiuretic hormone (ADH)
CHypoglycemia from ectopic IGF-2 secretion
DErythrocytosis from ectopic erythropoietin
EHypocalcemia from tumor calcium consumption
Reveal answer & full explanation
Correct answer: D — Erythrocytosis from ectopic erythropoietin
ACushing syndrome from ectopic adrenocorticotropic hormone (ACTH)
BHyponatremia from ectopic antidiuretic hormone (ADH)
CHypoglycemia from ectopic IGF-2 secretion
DErythrocytosis from ectopic erythropoietin✓
EHypocalcemia from tumor calcium consumption
Why Erythrocytosis from ectopic erythropoietin is correct
Renal cell carcinoma (RCC) classically produces ectopic erythropoietin (EPO), leading to erythrocytosis; this is the most characteristic paraneoplastic syndrome of RCC and the only listed option that is a recognized hallmark of the tumor. Erythrocytosis is not the most frequent one: in a Mayo Clinic cohort of 2,865 patients undergoing nephrectomy, polycythemia occurred in about 1%, compared with anemia in 23% and hypercalcemia in 9% (Moreira, World J Urol 2016).
Other paraneoplastic syndromes of RCC include hypercalcemia (via parathyroid hormone-related protein (PTH-rP)), hypertension (via renin secretion), and Stauffer syndrome (paraneoplastic hepatic dysfunction without metastasis).
Why the others are wrong
Hypoglycemia from ectopic IGF-2 secretion — non-islet cell tumor hypoglycemia results from tumor secretion of incompletely processed (big) insulin-like growth factor 2 (IGF-2), classically by large mesenchymal tumors such as solitary fibrous tumor and by hepatocellular carcinoma; it is not a classic paraneoplastic syndrome of RCC.
Hypocalcemia from tumor calcium consumption — RCC is associated with hypercalcemia (from PTH-rP), not hypocalcemia.
Cushing syndrome from ectopic adrenocorticotropic hormone (ACTH) — ectopic ACTH is classically associated with small cell lung cancer and carcinoid tumors (especially bronchial) and is only rarely reported with RCC. The smoking history here is a risk factor for RCC, not a clue to lung cancer: the mass is in the kidney and the histology is clear cell.
Hyponatremia from ectopic antidiuretic hormone (ADH) — SIADH from ectopic antidiuretic hormone is the classic paraneoplastic syndrome of small cell lung cancer, so the smoking history can pull toward it, but it is not a characteristic syndrome of RCC; a clear cell kidney mass points instead to the RCC syndromes of erythropoietin, PTH-rP, or renin secretion.
Additional high-yield points
RCC is the most common primary kidney cancer in adults.
Risk factors: smoking (most important), obesity, hypertension, von Hippel-Lindau disease, dialysis (acquired cystic disease), occupational exposures (trichloroethylene; also cadmium, asbestos).
Histology: clear cell is the most common subtype.
Classic triad: hematuria, flank pain, palpable mass — present together in only 10% of cases.
Workup: CT abdomen/pelvis with contrast (RCC enhances), CT chest for metastases, bone scan if bone pain or elevated alkaline phosphatase (AUA 2021).
Treatment: partial or radical nephrectomy; tyrosine kinase inhibitors and immunotherapy for metastatic disease.
Needle-tract seeding after renal mass biopsy is rare; AUA (2021) supports biopsy when the result would change management.
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Clear cell RCC most commonly arises from loss of function of the von Hippel-Lindau (VHL) tumor suppressor on chromosome 3p, leading to constitutive activation of hypoxia-inducible factor (HIF) and downstream VEGF, PDGF, and other growth factor pathways. Tumors are highly vascular. Late metastases occur via hematogenous (lung, bone, liver, brain) and lymphatic spread; invasion of renal vein and inferior vena cava is characteristic.
Clinical presentation
Symptoms
Most patients asymptomatic — found incidentally on cross-sectional imaging
Classic triad (flank pain + hematuria + palpable mass) present in <10% and indicates advanced disease
Hematuria (gross or microscopic)
Flank pain or back pain
Constitutional symptoms: weight loss, fever, fatigue, night sweats
Renal abscess — Fever, leukocytosis, recent UTI; fluid collection with rim enhancement
Diagnostic workup
Diagnostic criteria
Tissue diagnosis (biopsy or surgical pathology) confirms RCC. Most clinically apparent tumors are resected without prior biopsy when imaging is characteristic. Biopsy increasingly used for small renal masses to inform active surveillance vs intervention. Staged by TNM (AJCC 8th edition).
Labs
CBC (anemia of chronic disease or polycythemia)
BMP with calcium (hypercalcemia common)
LFTs (Stauffer syndrome)
Urinalysis (hematuria)
LDH (prognostic marker for advanced disease)
No reliable tumor marker for screening
Imaging
Contrast-enhanced CT abdomen/pelvis — initial imaging of choice; characterizes mass and stages
RCC enhances on arterial phase, washes out on delayed phase
MRI — alternative if CT contraindicated; better for IVC thrombus characterization
Renal ultrasound often initial — distinguishes solid from cystic mass
Chest CT — staging for pulmonary metastases (most common metastatic site)
Bone scan if elevated alkaline phosphatase or bone pain
Brain MRI if neurologic symptoms
Diagnostic algorithm
Bosniak Category
Description
Malignancy Risk
Management
I
Simple cyst — thin wall, no septa, no enhancement
~0%
No follow-up
II
Few hairline septa, fine calcification
~0%
No follow-up
IIF
Minimally complex; needs follow-up
~5%
Surveillance imaging
III
Thick or irregular septa, enhancement
~50%
Resection (partial nephrectomy)
IV
Clearly enhancing soft tissue
~90%
Resection
Bosniak classification of renal cystic lesions guides management of cystic kidney masses.
Treatment
First-line
Localized disease (Stage I-III):
Partial nephrectomy — standard for T1a tumors (<4 cm) and feasible T1b (4-7 cm); nephron-sparing
Radical nephrectomy — for larger tumors (T2+) or when partial not feasible; remove the adrenal only if imaging or operative findings suggest adrenal invasion or metastasis; renal vein or IVC tumor thrombus without metastases (T3a-T3c) is still treated with curative intent by radical nephrectomy plus en bloc tumor thrombectomy (not IVC filter, caval ligation, or systemic therapy alone)
Active surveillance — small renal masses <2-3 cm in elderly or significant comorbidity; serial imaging
Thermal ablation (cryoablation, radiofrequency) — for small tumors in poor surgical candidates
Adjuvant pembrolizumab — for high-risk resected RCC (KEYNOTE-564)
Classic triad of flank pain + hematuria + palpable mass occurs in <10% — and when it does, indicates locally advanced disease.
Left-sided varicocele in an adult man that does NOT decompress when lying down = consider left renal vein invasion by RCC. (Right testicular vein drains directly to IVC; left drains to left renal vein.)
Paraneoplastic syndromes are common: PTHrP (hypercalcemia), EPO (polycythemia), renin (HTN), Stauffer syndrome (hepatic dysfunction without metastases).
Bosniak classification: I-II = benign; IIF = follow; III = ~50% malignant (resect); IV = ~90% malignant (resect).
RCC is the most common solid tumor associated with paraneoplastic polycythemia (EPO-mediated erythrocytosis); other causes include HCC and cerebellar hemangioblastoma.
Partial nephrectomy is preferred over radical when feasible to preserve renal function — important for long-term cardiovascular and CKD outcomes.
References
AUA 2021 — Renal Mass and Localized Renal Cancer: AUA Guideline (Campbell et al., J Urol 2021)
NCCN 2024 — NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer Version 2024
KEYNOTE-564 — Choueiri TK et al. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med 2021;385:683-694
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