Non-renal cell carcinoma of the kidney represents a diverse group of less common kidney cancers that differ in their behavior, appearance under the microscope, and treatment response compared to the more familiar clear cell type that affects most patients.

Understanding Non-Clear Cell Kidney Cancer

Kidney cancer is not just one single disease. Rather, it consists of many different types of cancer, each starting from different kidney cells and behaving in its own distinct way. Renal cell carcinoma, or RCC, is the most common form of kidney cancer overall, accounting for approximately 85% of all kidney malignancies. Within this category, the clear cell subtype is by far the most frequent, representing about 75 to 80% of all renal cell cancers.^[2][4]

The remaining kidney cancers fall into a category often called non-clear cell renal cell carcinoma, or non-renal cell carcinoma of the kidney when discussing all kidney cancers that are not the typical clear cell type. This group makes up roughly 20 to 25% of all kidney cancer cases.^[2][9] What makes this category particularly challenging is that it includes many different subtypes, each with unique characteristics, genetic changes, and responses to treatment.

Epidemiology: How Common Is This Disease

Kidney cancer overall is among the top ten most common cancers diagnosed in the United States, with more than 80,000 new cases appearing each year.^[7] When we look at non-clear cell kidney cancers specifically, these represent the minority of kidney cancer cases, but their impact should not be underestimated.

Among the non-clear cell subtypes, papillary renal cell carcinoma is the most common, accounting for approximately 10 to 15% of all kidney cancers.^[4][5] Chromophobe renal cell carcinoma makes up about 3 to 5% of cases, while clear cell papillary subtype represents roughly 2 to 4%.^[4] Rarer forms such as collecting duct carcinoma and medullary renal cell carcinoma each account for only about 1% of kidney cancers.^[4]

Kidney cancer tends to affect men more frequently than women, and the risk increases significantly with age, particularly after age 60.^[7] Certain ethnic groups face higher risks: African Americans, American Indians, and Alaskan Natives all have elevated rates of kidney cancer compared to other populations.^[7] Medullary renal cell carcinoma, a particularly aggressive and rare form, occurs most often in young African Americans who carry the sickle cell trait.^[4]

Causes of Non-Clear Cell Kidney Cancers

The underlying causes of non-clear cell kidney cancers differ from those of clear cell kidney cancer. Clear cell kidney cancer is strongly associated with changes in the VHL gene, which leads to abnormal blood vessel growth feeding the tumor. However, non-clear cell kidney cancers do not appear to be related to VHL gene changes, which is one reason why treatments designed for clear cell cancer often work less effectively in these other types.^[2]

Each subtype of non-clear cell kidney cancer has its own molecular and genetic characteristics. For instance, papillary renal cell carcinoma has been linked to alterations in the MET gene, which controls cell growth and division.^[9] Chromophobe renal cell carcinoma may involve mutations in the folliculin (FLCN) gene, which affects a cellular pathway called mTOR that regulates metabolism and growth.^[9]

Some rare forms have very specific genetic causes. Renal cancers associated with fumarate hydratase or succinate dehydrogenase gene inactivation represent distinct hereditary syndromes.^[22] Understanding these genetic differences is crucial because it opens the door to targeted therapies that address the specific molecular problems driving each cancer type.

Risk Factors

Several factors increase the likelihood of developing kidney cancer, including non-clear cell types. Smoking stands out as one of the strongest risk factors. It not only raises the initial risk of developing kidney cancer but also increases the chances of the cancer returning after treatment.^[7][18]

Being overweight or having obesity significantly increases kidney cancer risk.^[7] The kidneys must work harder in people carrying excess weight, and the hormonal and metabolic changes associated with obesity may contribute to cancer development. High blood pressure is another important risk factor, though it remains unclear whether the elevated blood pressure itself or the medications used to treat it contribute to increased risk.^[7]

Long-term use of certain pain medications and exposure to specific chemicals also pose risks. Workers who handle a chemical called trichloroethylene, used for removing grease from metal, face higher kidney cancer rates.^[7] Chronic kidney disease, kidney stones, and long-lasting hepatitis C infection have all been linked to increased kidney cancer risk.^[7]

Certain genetic conditions also predispose individuals to kidney cancer. People with a family history of kidney cancer or those with inherited conditions such as tuberous sclerosis may develop specific kidney tumors.^[3] Genetic testing and counseling can help identify people at higher risk who might benefit from earlier or more frequent screening.^[12]

Symptoms and How They Affect Patients

One of the challenging aspects of kidney cancer, including non-clear cell types, is that many tumors cause no symptoms in their early stages. In fact, more than half of kidney tumors are discovered accidentally during imaging tests performed for completely unrelated medical reasons.^[3] This incidental discovery is both fortunate, as it may catch cancer early, and concerning, as it means symptoms often don’t appear until the disease is more advanced.

When symptoms do occur, blood in the urine, called hematuria, is one of the most common signs. The urine may appear pink, red, or cola-colored depending on the amount of blood present.^[7] However, the amount of blood may be so small that it’s only detected through laboratory testing.

Pain or discomfort in the side, back, or abdomen is another frequent symptom. This pain may feel like a dull ache that doesn’t go away, or it may be related to a lump or mass that can be felt in the kidney area.^[7] Some people experience lower back pain that isn’t connected to any injury or strain.

General symptoms that can accompany kidney cancer include unexplained weight loss, loss of appetite, persistent tiredness, and recurring fever without an obvious infection.^[7] Anemia, a condition where the body doesn’t have enough healthy red blood cells, may develop and contribute to feelings of fatigue and weakness. In some cases, intestinal blockage or a general feeling of poor health may be the first noticeable sign.^[7]

Prevention Strategies

While not all kidney cancers can be prevented, there are meaningful steps people can take to reduce their risk. Maintaining a healthy weight is one of the most important protective measures. Eating a balanced diet rich in fruits and vegetables, staying physically active, and keeping weight within a healthy range all help protect kidney health.^[7][16]

If you smoke, quitting is absolutely critical. Smoking is the strongest modifiable risk factor for kidney cancer, and stopping tobacco use significantly reduces risk over time.^[7][18] Many resources are available through healthcare providers, including medications and counseling programs, to support people who want to quit.

Controlling high blood pressure through lifestyle changes or medication helps protect the kidneys from damage that could increase cancer risk.^[7] Similarly, managing other health conditions such as diabetes prevents kidney damage that might contribute to cancer development.^[17]

People who work with certain chemicals, especially trichloroethylene used in metal work, should take extra precautions to minimize exposure through proper ventilation, protective equipment, and following workplace safety guidelines.^[7] Limiting alcohol consumption is also advisable, as heavy drinking over long periods can damage the kidneys.^[18]

Reducing salt intake helps protect kidney function and maintain healthy blood pressure. Processed foods contain significant amounts of added salt, so focusing on fresh, whole foods and limiting added salt at the table can make a real difference.^[17] Avoiding overuse of over-the-counter pain medications such as NSAIDs (nonsteroidal anti-inflammatory drugs) like ibuprofen and naproxen also helps preserve kidney health.^[16]

Pathophysiology: What Happens in the Body

To understand non-clear cell kidney cancers, it helps to know how the kidneys normally function. The kidneys are bean-shaped organs, about five inches long and three inches wide, located on each side of the backbone above the waist.^[14] Each kidney contains between one and two million tiny filtering units called nephrons, which clean the blood by removing waste products and excess water.^[5]

These nephrons create urine, which collects in the center of the kidney in a funnel-shaped area called the renal pelvis.^[14] From there, urine flows through tubes called ureters to the bladder, where it’s stored until released from the body. The kidneys also play important roles beyond waste removal: they help control blood pressure and stimulate bone marrow to produce red blood cells.^[7]

Non-clear cell kidney cancers develop when genetic changes cause kidney cells to grow and divide abnormally. Unlike clear cell kidney cancer, which typically involves VHL gene changes that lead to excessive blood vessel formation, non-clear cell cancers involve different molecular pathways.

In papillary renal cell carcinoma, the cancer cells form finger-like projections called papillae under the microscope.^[4] There are two subtypes of papillary cancer (type 1 and type 2), which have different genetic changes and prognoses. Many papillary cancers involve alterations in the MET gene, which normally controls how cells respond to growth signals.

Chromophobe renal cell carcinoma originates in the collecting ducts of the kidney. Under the microscope, these cancer cells appear larger than normal cells with prominent borders, and they may look pink or pale.^[4] Chromophobe cancers often involve mutations affecting the mTOR pathway, which regulates how cells use nutrients and energy.

Some non-clear cell cancers involve specific hereditary syndromes. Tumors associated with fumarate hydratase or succinate dehydrogenase gene inactivation disrupt normal cellular metabolism. These genes are involved in the Krebs cycle, the series of chemical reactions cells use to generate energy. When these genes don’t work properly, abnormal metabolic byproducts accumulate, contributing to cancer development.^[22]

Collecting duct carcinoma and medullary renal cell carcinoma are particularly aggressive forms that arise from the collecting system of the kidney. These cancers form irregular tube-like structures and tend to spread rapidly to other parts of the body.^[4] Medullary carcinoma specifically is associated with sickle cell trait and often affects younger patients.

Understanding these different biological mechanisms is crucial because it explains why treatments that work well for clear cell kidney cancer may not be as effective for non-clear cell types. Each subtype requires treatment strategies tailored to its specific molecular characteristics.