Kidney Cancer: Types, Symptoms, Stages, and Treatment

Kidney cancer is among the ten most common cancers in the United States, with approximately 81,000 new cases diagnosed each year. Unlike many cancers that announce themselves through distinctive symptoms, roughly half of all kidney cancers are discovered entirely by accident — found on a CT scan or ultrasound ordered for an unrelated reason, such as abdominal pain or a urinary tract issue, while the patient remains completely unaware that anything is wrong. This incidental detection, while unsettling in its suddenness, often represents the best possible outcome: a small, localized tumor caught before it has had any opportunity to spread.

The most common form of kidney cancer is renal cell carcinoma (RCC), which accounts for 90 to 95 percent of all kidney malignancies in adults. Understanding what kind of kidney cancer you have, how it is staged, and what modern treatment options exist is essential for navigating what can otherwise be an overwhelming and confusing diagnosis.

Types of Kidney Cancer

Renal Cell Carcinoma — The Most Common Form

Renal cell carcinoma originates in the cells lining the proximal renal tubules — the microscopic tubes within the kidney responsible for filtering blood and reabsorbing nutrients. It is not one disease but a family of distinct subtypes, each with different biology, behavior, and response to treatment.

Clear cell RCC is the most common subtype, representing 70 to 75 percent of all RCC cases. It is characterized by cells that appear clear under a microscope due to high lipid and glycogen content. Most clear cell RCCs harbor mutations in the VHL (von Hippel-Lindau) tumor suppressor gene — either inherited (in VHL syndrome) or acquired as a somatic mutation in sporadic tumors. VHL loss leads to accumulation of hypoxia-inducible factors (HIF-1α, HIF-2α), which drive production of VEGF and other growth factors that promote tumor angiogenesis. This biology is why anti-VEGF targeted therapies are especially effective in clear cell RCC.

Papillary RCC (15–20% of RCC) presents as type 1 (lower grade, associated with MET gene mutations) or type 2 (higher grade, more aggressive, associated with fumarate hydratase mutations in hereditary leiomyomatosis and RCC). Papillary RCC tends to respond less predictably to the anti-VEGF agents effective in clear cell disease, though newer combination immunotherapy regimens have shown efficacy across subtypes.

Chromophobe RCC (5%) arises from intercalated cells of the collecting duct. It has a more indolent course than clear cell or papillary subtypes and a better prognosis stage for stage. It rarely metastasizes when localized.

Other Kidney Cancers

Transitional cell carcinoma (urothelial carcinoma) of the renal pelvis (approximately 5% of kidney cancers) arises from the urothelial cells lining the renal pelvis and ureter rather than the kidney tissue itself. It is biologically similar to bladder cancer and is treated differently from RCC — with urothelial-focused systemic therapies rather than the targeted and immunotherapy agents used for RCC. Smoking is a particularly strong risk factor.

Wilms tumor (nephroblastoma) is the most common kidney cancer in children, most often diagnosed in children ages 3 to 4. It is rarely seen in adults. Treatment involves surgery, chemotherapy, and sometimes radiation, with excellent cure rates in most cases.

Risk Factors for Kidney Cancer

Several modifiable and non-modifiable factors increase the probability of developing kidney cancer:

Smoking approximately doubles kidney cancer risk and accounts for an estimated 30 percent of cases in men. The carcinogens in tobacco smoke reach the kidneys during urine concentration, creating direct mucosal exposure. Risk decreases after cessation, though it takes many years to return to baseline.

Obesity is one of the fastest-growing risk factors for kidney cancer. A body mass index above 35 approximately doubles kidney cancer risk. The mechanism likely involves chronic insulin resistance, adipokine signaling, and low-grade systemic inflammation that promotes cellular proliferation.

Hypertension is independently associated with kidney cancer risk through mechanisms that may include chronic renal hypoxia, elevated insulin-like growth factor, and direct DNA damage from reactive oxygen species. The antihypertensive drugs themselves are not the risk factor — the hypertension itself is.

Chronic kidney disease and dialysis: Patients on long-term dialysis develop acquired cystic kidney disease, which carries substantially elevated kidney cancer risk. Transplant recipients also face increased risk due to immunosuppressive therapy.

Genetic syndromes: Von Hippel-Lindau (VHL) syndrome causes bilateral, multifocal clear cell RCC and requires lifelong surveillance beginning in early adulthood. Hereditary papillary RCC (MET germline mutations) causes bilateral papillary type 1 tumors. Birt-Hogg-Dubé syndrome causes chromophobe and clear cell RCC plus pulmonary cysts and fibrofolliculomas. Hereditary leiomyomatosis and RCC (HLRCC, fumarate hydratase mutations) causes aggressive type 2 papillary RCC. Patients with first-degree relatives diagnosed with kidney cancer before age 50 or with bilateral or multifocal tumors should consider genetic counseling.

Symptoms — When Kidney Cancer Makes Itself Known

The classic teaching triad of kidney cancer — hematuria (blood in the urine), flank pain, and a palpable abdominal or flank mass — is present in only 6 to 10 percent of patients at the time of diagnosis, and its presence generally indicates advanced disease. Most patients with localized kidney cancer have no symptoms whatsoever.

When symptoms do occur, hematuria is the most common. It may be gross (visibly red or cola-colored urine) or microscopic (detected only on urinalysis). Flank pain is typically a dull, persistent ache on one side of the back, below the ribs. A palpable mass in the flank or upper abdomen is rare and suggests a large tumor.

Paraneoplastic syndromes distinguish RCC from many other solid tumors — RCC produces hormones and cytokines that cause systemic effects distant from the kidney itself:

• Hypercalcemia: caused by PTHrP (parathyroid hormone-related protein) secretion; produces fatigue, confusion, constipation, and excessive urination
• Polycythemia: caused by ectopic erythropoietin (EPO) secretion; produces elevated red blood cell count
• Hypertension: caused by renin secretion or compression of the renal artery
• Fever and night sweats: cytokine-mediated; often mistaken for infection
• Anemia: despite EPO production capacity, most RCC patients develop anemia of chronic disease from inflammatory cytokines

Stauffer syndrome is a unique RCC paraneoplastic effect: non-metastatic hepatic dysfunction (elevated liver enzymes, elevated alkaline phosphatase) caused by cytokines secreted by the tumor — not liver metastasis. It resolves after nephrectomy. Symptoms that suggest metastatic disease include persistent cough or shortness of breath (pulmonary metastases, the most common site), bone pain or pathological fracture, headaches, and unexplained weight loss.

How Kidney Cancer Is Diagnosed

For most patients, the diagnostic pathway begins with imaging — either an incidental finding on ultrasound or CT ordered for another purpose, or imaging ordered to evaluate symptoms like hematuria or flank pain.

CT urogram (CT of the abdomen and pelvis with and without intravenous contrast) is the primary imaging modality for evaluating a suspected renal mass. The key diagnostic feature is contrast enhancement — a lesion that takes up contrast and washes out in later phases is consistent with a solid renal tumor. The CT also evaluates the renal vein and inferior vena cava for tumor thrombus, assesses regional lymph nodes, and can detect adrenal involvement.

MRI of the abdomen is preferred when patients have iodinated contrast allergy or significant renal insufficiency. MRI is superior to CT for characterizing the extent of venous thrombus — particularly distinguishing bland thrombus from tumor thrombus extending into the inferior vena cava, which changes the surgical approach significantly.

Renal mass biopsy is increasingly used for masses between 1 and 3 cm (T1a) in patients considering active surveillance, where knowing the histological subtype and Fuhrman grade can guide the decision between surveillance and intervention. Biopsy is not routinely needed for larger masses going to radical nephrectomy, where histological diagnosis comes from the surgical specimen. A Bosniak classification system (I–IV) is used for renal cysts identified on CT or MRI — Bosniak I and II are benign; Bosniak III and IV require biopsy or surgical consideration.

Staging: What the T, N, and M Numbers Mean

Kidney cancer is staged using the TNM system, which categorizes the tumor (T), lymph node involvement (N), and distant metastasis (M):

• T1a: ≤4 cm, confined within the kidney — most favorable; typically treated with partial nephrectomy
• T1b: 4–7 cm, confined within the kidney
• T2a: 7–10 cm, confined within the kidney
• T2b: >10 cm, confined within the kidney
• T3a: invades renal vein, peripelvic fat, or perisinus fat
• T3b: tumor thrombus extends into the IVC below the diaphragm
• T3c: tumor thrombus extends above the diaphragm or invades the IVC wall
• T4: extends beyond Gerota’s fascia or directly invades the ipsilateral adrenal gland
• N1: regional lymph node metastasis
• M1: distant metastasis — lungs most common, then bone, liver, brain, contralateral kidney

Stage groupings: Stage I (T1, N0, M0), Stage II (T2, N0, M0), Stage III (T3 or N1, M0), Stage IV (T4 or M1). Five-year survival: Stage I ~93%, Stage II ~78%, Stage III ~53%, Stage IV ~15% historically — though immunotherapy combinations have substantially improved metastatic outcomes since 2018.

Treatment of Localized Kidney Cancer

Partial nephrectomy (nephron-sparing surgery) is the preferred approach for T1a and T1b tumors when technically feasible. Removing only the tumor and a margin of normal tissue rather than the entire kidney preserves renal function — critically important for long-term cardiovascular health. Studies consistently show that partial nephrectomy achieves equivalent cancer control to radical nephrectomy for T1 tumors while preserving significantly more kidney function. Robotic-assisted partial nephrectomy has largely replaced open surgery at experienced centers.

Radical nephrectomy (removal of the entire kidney, often including regional lymph nodes) remains indicated for larger T2 tumors, tumors involving the renal hilum where nephron-sparing is not feasible, and tumors with venous thrombus. When IVC thrombus extends above the hepatic veins, surgery requires cardiothoracic expertise and possibly cardiopulmonary bypass.

Active surveillance is a safe and guideline-endorsed option for small renal masses (typically <3 cm T1a) in elderly patients or those with significant comorbidities. Median growth rates of small RCC are slow (approximately 0.28 cm/year). Many small masses turn out to be benign on biopsy. Surveillance typically involves CT or MRI at 3–6 months, then annually if stable.

Ablation (cryoablation or radiofrequency ablation) achieves local tumor control in patients medically unsuitable for surgery. Image-guided percutaneous ablation is typically reserved for T1a masses under 3 cm, with local recurrence rates higher than surgery but similar overall survival in selected patients.

Treatment of Advanced and Metastatic Kidney Cancer

Metastatic RCC was historically one of oncology’s most treatment-resistant cancers. Chemotherapy is largely ineffective. The landscape was transformed first by anti-VEGF targeted therapies (beginning 2006) and then by checkpoint immunotherapy combinations (since 2018).

Nivolumab + ipilimumab (dual checkpoint blockade) is first-line standard for intermediate- and poor-risk metastatic clear cell RCC per IMDC criteria. The CheckMate 214 trial showed 5-year overall survival of 43% — a dramatic improvement over the historical 15% 5-year survival for metastatic RCC. For all risk groups, pembrolizumab + axitinib and lenvatinib + pembrolizumab are standard first-line options with demonstrated OS benefit in the KEYNOTE-426 and CLEAR trials, respectively.

VEGF receptor tyrosine kinase inhibitors (TKIs) — sunitinib, pazopanib, cabozantinib, axitinib — target the VEGF signaling pathway that clear cell RCC uniquely depends on. Cabozantinib also targets MET and AXL, making it particularly active after checkpoint immunotherapy failure. mTOR pathway inhibitors (everolimus, temsirolimus) are primarily used in later lines of therapy.

Adjuvant pembrolizumab received FDA approval in 2021 for high-risk resected RCC (T2 grade 4, T3+, N1, or M0 post-resection). The KEYNOTE-564 trial showed significantly improved disease-free survival compared to placebo — the first adjuvant systemic therapy ever to demonstrate benefit in kidney cancer.

Life After Kidney Cancer Treatment

Patients who have undergone surgery for kidney cancer require ongoing surveillance imaging to detect recurrence. AUA guidelines recommend surveillance CT at 3–6 months, 1 year, then annually for 3–5 years for intermediate- and high-risk tumors. Chest CT detects pulmonary metastases, the most common site of RCC recurrence. Those with a solitary remaining kidney or pre-existing CKD should be co-managed with nephrology — adequate blood pressure control is essential to protect remaining kidney function.

Patients with hereditary kidney cancer syndromes (VHL, Birt-Hogg-Dubé, hereditary papillary RCC) require lifelong surveillance of the contralateral kidney, as bilateral multifocal tumors are characteristic of these genetic conditions. Even patients without known genetic syndromes should have the contralateral kidney assessed at each surveillance imaging. The understanding and treatment of kidney cancer shares important parallels with other organ cancers — just as patients with liver cancer benefit from understanding organ function and staging, kidney cancer patients must understand how remaining kidney function shapes treatment options and long-term quality of life. Similarly, the importance of surveillance in patients at elevated cancer risk is a theme shared across all solid tumor oncology, as discussed in our coverage of cirrhosis and liver cancer and pancreatic cancer.

Kidney cancer, when caught early, is among the more treatable solid tumors in oncology. The dramatic transformation in treatment options for metastatic disease over the past decade — from a disease where systemic treatment rarely produced durable benefit to one where combination immunotherapy produces multi-year remissions in a meaningful proportion of patients — means that even patients diagnosed with advanced disease face substantially better odds than they would have a generation ago. Early detection through appropriate imaging and prompt evaluation of hematuria or unexplained flank symptoms remains the most powerful tool available. Our article on recognizing cancer symptoms discusses the broader importance of symptom awareness across solid tumors.

Sources: National Cancer Institute — Kidney Cancer | National Kidney Foundation | American Cancer Society — Kidney Cancer

Managing Side Effects of Immunotherapy and Targeted Therapy

The therapeutic revolution in metastatic RCC has come with a distinct set of treatment-related toxicities that differ substantially from the side effects of traditional chemotherapy. Understanding these toxicities — and the importance of reporting them promptly — is critical for patients and their caregivers.

Checkpoint immunotherapy toxicities (from nivolumab, ipilimumab, pembrolizumab) are immune-related adverse events (irAEs) caused by the immune system attacking normal tissues in addition to cancer cells. Common irAEs include:

• Immune-mediated colitis: diarrhea, abdominal cramping, bloody stools; treated with corticosteroids; infliximab for severe refractory cases
• Immune-mediated hepatitis: elevated liver enzymes without symptoms; monitored with routine LFTs; treated with high-dose steroids
• Immune-mediated pneumonitis: cough, shortness of breath, chest discomfort; can be severe; requires imaging and prompt steroid treatment
• Immune-mediated endocrinopathies: thyroid dysfunction (hypothyroidism or hyperthyroidism), hypophysitis, adrenal insufficiency; typically require hormone replacement rather than steroids
• Skin toxicity: rash, vitiligo, pruritus; most common and usually manageable with topical treatments

The critical teaching point: irAEs can occur at any time during treatment — even weeks to months after the last infusion. Patients must report new symptoms to their oncology team immediately, as early intervention prevents serious complications. Holding or discontinuing immunotherapy and initiating steroids promptly is generally highly effective.

TKI toxicities (from axitinib, sunitinib, cabozantinib) arise from inhibition of VEGF signaling in normal tissues:

• Hypertension: occurs in 40–70% of patients; requires antihypertensive management; do not simply stop TKI without oncologist guidance
• Hand-foot syndrome (palmar-plantar erythrodysesthesia): painful redness and blistering of palms and soles; managed with dose reduction, urea-based creams, and footwear modifications
• Fatigue: most common complaint; can be severe; sleep hygiene, exercise, and managing contributing factors (anemia, thyroid dysfunction) all help
• Mucositis and diarrhea: require dietary modifications, antidiarrheals, and sometimes dose reduction
• Hypothyroidism: TKIs frequently cause thyroid dysfunction; TSH should be monitored routinely and thyroid replacement therapy initiated when indicated

Genetic Testing and Hereditary Kidney Cancer

Approximately 3 to 5 percent of kidney cancers are attributable to inherited germline mutations in a growing list of cancer predisposition genes. The clinical clues that suggest hereditary kidney cancer include: diagnosis before age 46, bilateral kidney tumors, multifocal tumors in a single kidney, family history of kidney cancer in two or more first-degree relatives, or kidney cancer in the context of other specific features (skin lesions, pulmonary cysts, uterine fibroids).

Major hereditary kidney cancer syndromes:

• Von Hippel-Lindau (VHL) syndrome: autosomal dominant VHL mutation; causes bilateral clear cell RCC plus hemangioblastomas of the brain/spine/retina, pheochromocytoma, and pancreatic neuroendocrine tumors; surveillance begins in childhood
• Hereditary papillary RCC (HPRC): germline MET mutations; bilateral type 1 papillary RCC; active surveillance until tumors reach 3 cm threshold for surgery
• Birt-Hogg-Dubé (BHD) syndrome: FLCN mutations; chromophobe + clear cell + oncocytoma hybrid tumors; fibrofolliculomas on skin; pulmonary cysts with pneumothorax risk
• Hereditary leiomyomatosis and RCC (HLRCC): fumarate hydratase germline mutations; aggressive type 2 papillary RCC even at small sizes — active surveillance thresholds do NOT apply; early surgery recommended; uterine and cutaneous leiomyomas in women
• SDH-deficient RCC: succinate dehydrogenase subunit mutations (B, C, D); also causes paragangliomas and gastrointestinal stromal tumors

Genetic counseling and germline testing is recommended for any patient with clinical features suggesting a hereditary syndrome. Identifying a germline mutation has major implications not only for the patient (surveillance protocols, treatment decisions in HLRCC) but for family members who may benefit from predictive testing and early surveillance.

Clinical Trials and the Future of Kidney Cancer Treatment

The pace of progress in kidney cancer treatment over the past decade has been rapid, and clinical trial participation remains one of the most important options available to patients with metastatic or recurrent disease. Current areas of active investigation include:

Triplet combinations: Studies are evaluating whether adding a third agent (a second TKI or a VEGF antibody) to standard dual-agent immunotherapy regimens can further improve outcomes. The COSMIC-313 trial tested cabozantinib + nivolumab + ipilimumab versus standard dual immunotherapy, with results showing improved PFS in intermediate/poor-risk patients.

HIF-2α inhibitors: Belzutifan (FDA approved 2021 for VHL disease-related RCC) directly inhibits HIF-2α — the transcription factor that accumulates when VHL is mutated. It is now approved for metastatic sporadic clear cell RCC after prior therapies (LITESPARK-005 trial). Unlike kinase inhibitors, belzutifan works downstream of the VHL-HIF axis, offering a mechanistically distinct approach.

Biomarker-driven treatment selection: Identifying which patients will respond to immunotherapy versus TKI monotherapy based on tumor genomics, PD-L1 expression, CD8+ T-cell infiltration, and other biomarkers is an active research priority. The goal is to replace the current population-level treatment recommendations with personalized regimens.

Neoadjuvant therapy: For patients with locally advanced, borderline resectable tumors, neoadjuvant (pre-surgical) targeted therapy or immunotherapy may downstage tumors to allow partial nephrectomy rather than radical nephrectomy, or to convert unresectable disease to resectable. This approach is being evaluated in prospective trials.

Patients interested in clinical trial participation can search cancer.gov or ask their oncologist to identify relevant open trials at their institution or nearby academic medical centers. Trial participation is particularly important for patients who have progressed through first-line immunotherapy combinations and are seeking next-line options.