Renal/Urology · PANCE / PANRE

Renal Cell Carcinoma (RCC)

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; ~76,000 new cases and ~13,000 deaths annually in the US. 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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Risk factors

Smoking (2× risk; dose-dependent)
Obesity
Hypertension
Chronic kidney disease, dialysis-acquired cystic disease
Family history (5-8% hereditary)
Hereditary syndromes: von Hippel-Lindau (clear cell), hereditary papillary RCC (papillary type 1), Birt-Hogg-Dubé (chromophobe), tuberous sclerosis
Occupational: trichloroethylene, cadmium, asbestos
Acquired cystic disease in ESRD/dialysis

Pathophysiology

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
Paraneoplastic manifestations: hypercalcemia (PTHrP), polycythemia (EPO), HTN (renin), Stauffer syndrome (reversible hepatic dysfunction without metastases)
Symptoms of metastatic disease: bone pain, dyspnea, hemoptysis, neurologic deficits

Signs / physical exam

Palpable flank or abdominal mass (advanced disease)
Left-sided varicocele in male (new or non-decompressing supine) — suggests left renal vein involvement
Lower extremity edema if IVC involvement
Hepatomegaly with Stauffer syndrome
Findings of metastatic disease

Classic findings

Adult-onset varicocele on the LEFT side that does not decompress when supine suggests left renal vein involvement by RCC — image with CT.

Differential diagnosis

Simple renal cyst — Bosniak I — anechoic, thin-walled, no enhancement; benign and stable
Complex renal cyst (Bosniak II-IV) — Increasing complexity; Bosniak III-IV warrant biopsy or resection
Angiomyolipoma — Macroscopic fat on CT (low Hounsfield units); associated with tuberous sclerosis; bleeding risk if >4 cm
Oncocytoma — Benign tumor; difficult to distinguish from chromophobe RCC on imaging — often resected
Transitional cell carcinoma of upper tract — Centrally located in renal pelvis, smoking history; hematuria
Wilms tumor — Pediatric (median 3 years); palpable abdominal mass; WT1 mutation
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; en bloc with adrenal if upper pole or adrenal involvement
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)
Metastatic disease (Stage IV):
First-line immune checkpoint inhibitor combinations: ipilimumab + nivolumab (intermediate/poor risk), or pembrolizumab + axitinib, nivolumab + cabozantinib, lenvatinib + pembrolizumab
Cytoreductive nephrectomy — selected patients with good performance status, low metastatic burden
Stereotactic body radiation (SBRT) for oligometastatic disease or palliation

Second-line / adjunct

Tyrosine kinase inhibitors (VEGFR-targeted): sunitinib, pazopanib, cabozantinib, axitinib, lenvatinib
mTOR inhibitors: everolimus, temsirolimus
Belzutifan (HIF-2α inhibitor) — for VHL-associated RCC and after prior TKI/ICI
Continue follow-up imaging post-treatment (CT chest/abdomen every 6-12 months)
Genetic counseling if young onset, bilateral/multifocal, family history, or syndromic features

Complications

Metastatic disease — lung most common, followed by bone, liver, brain, adrenal
Paraneoplastic syndromes (hypercalcemia, polycythemia, Cushing-like, Stauffer)
Vena cava tumor thrombus (clear cell RCC characteristic)
Post-operative: CKD (nephron loss), bleeding, urine leak, infection
Treatment toxicities: hypertension (VEGF), immune-related adverse events (ICI)
Renal vein invasion → varicocele, varices, embolism risk

PANCE pearls

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 — Pembrolizumab as Post Nephrectomy Adjuvant Therapy for RCC (Choueiri et al., NEJM 2021)

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