Non-Clear Cell Renal Cell Carcinoma of the Kidney
Non-clear cell renal cell carcinoma represents a diverse group of kidney cancers that behave differently from the more common clear cell type, presenting unique challenges in diagnosis and treatment.
Table of contents
- What is Non-Clear Cell Renal Cell Carcinoma?
- Types of Non-Clear Cell Kidney Cancer
- How Common is This Type of Cancer?
- Treatment Challenges
- Treatment Options
- Related Kidney Conditions
What is Non-Clear Cell Renal Cell Carcinoma?
Renal cell carcinoma (RCC) is the most common type of kidney cancer, accounting for approximately 85% of all malignant kidney tumors[1]. In RCC, cancerous cells develop in the lining of the kidney tubules and grow into a mass called a tumor[4]. While clear cell RCC is the most common form, making up about 75% to 80% of cases[4][5], non-clear cell renal cell carcinoma represents a heterogeneous group of malignancies that together account for about 20% to 25% of all kidney cancers[2][9].
Non-clear cell RCC is not a single disease but rather a collection of different cancer types, each with distinct characteristics when examined under a microscope. These subtypes differ from clear cell RCC in their appearance, behavior, and response to treatment. Unlike clear cell kidney cancer, which has been extensively studied and has well-established treatment protocols, non-clear cell types are less well understood[8].
- Kidney
- Renal pelvis
- Collecting ducts
- Renal tubules
Types of Non-Clear Cell Kidney Cancer
Non-clear cell RCC includes several different subtypes, each arising from different cells within the kidney and having unique characteristics[9].
Papillary renal cell carcinoma accounts for approximately 10% to 15% of kidney cancers[4]. These cancers form little finger-like projections called papillae. There are two types of papillary tumors, known as type 1 and type 2, which have different characteristics and behaviors[4].
Chromophobe renal cell carcinoma makes up about 3% to 5% of cases[4][5]. These cancer cells are larger than other types and have prominent cell borders. Under a microscope, they can appear pink or clear[4].
Clear cell papillary renal cell carcinoma represents approximately 2% to 4% of all cases[4]. This newer recognized subtype has features of both papillary and clear cell types. These tumors are often less aggressive than other forms[4].
Collecting duct carcinoma is a rare and aggressive type that accounts for approximately 1% of all cases[4]. It arises from the collecting system of the kidney and forms irregular tubules[4].
Medullary renal cell carcinoma also represents about 1% of cases[4]. This is a very aggressive type that often occurs in young African Americans with sickle cell trait. It is associated with a specific genetic characteristic called SMARCB1-deficient renal medullary carcinoma[5].
Unclassified renal cell carcinoma accounts for approximately 2% to 3% of tumors that do not fit into any other category[4].
Sarcomatoid renal cell cancer is not a separate subtype but rather a feature that can occur in any type of kidney cancer. Around 5% of renal cell cancers have sarcomatoid features, meaning that some of the cancer cells look like sarcoma cells under a microscope. Sarcomatoid renal cell cancer tends to grow more quickly than other types and is more likely to be diagnosed at an advanced stage[5].
How Common is This Type of Cancer?
Kidney and renal pelvis cancer affects tens of thousands of people each year[7]. Classically, kidney cancer has been divided into two main categories: clear cell and non-clear cell groups[8]. Clear cell RCC has emerged as the predominant cell type, comprising probably 80% of patients diagnosed with RCC or who develop metastasis[8].
Non-clear cell RCC, while less common overall, still represents a significant portion of kidney cancer cases. Because these cancers are less common, they have been less well studied, and it has been difficult to conduct large clinical trials specifically for non-clear cell histologies[8].
Treatment Challenges
Non-clear cell renal cell carcinoma presents unique challenges for both patients and doctors. Because of the rarity and diversity of these subtypes, treatment approaches have traditionally been extrapolated from studies conducted primarily on clear cell kidney cancer[2][8].
The field of kidney cancer therapeutics has been dominated by studies looking at clear cell RCC[8]. Clear cell kidney cancer has a better-understood biological basis, particularly involving the VHL gene and its role in blood vessel formation. This understanding has led to successful targeted therapies. However, non-clear cell histologies do not appear to be related to VHL in the same way, which means the clinical effectiveness of existing treatments designed for clear cell cancer is often limited when used for non-clear cell types[2].
Due to the low incidence of non-clear cell pathology, treatment evidence is mostly based on small phase II clinical trials or has been extrapolated from successful therapies in clear cell RCC[9]. Patient outcomes remain poorer compared to clear cell RCC, and optimal management of this disease remains unclear[9].
The heterogeneous nature of non-clear cell RCC makes classification, understanding underlying biology, and defining treatment targets particularly challenging[8]. Each subtype may require different treatment approaches based on its unique molecular characteristics[6].
Treatment Options
Treatment for non-clear cell renal cell carcinoma depends on several factors, including the specific subtype, the stage of the cancer, whether it has spread to other parts of the body, and the patient’s overall health.
Surgery remains an important treatment option for non-clear cell kidney cancer. Surgery may involve removing part of the kidney (partial nephrectomy) or the whole kidney (radical nephrectomy)[13]. Most people can live normally with one remaining kidney, though close monitoring may be needed[3].
Targeted therapies are medicines that target specific molecules on or in cancer cells. Vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors, such as sunitinib, have demonstrated efficacy in non-clear cell RCC and remain viable treatment options[9]. Novel targeted therapies like cabozantinib show improved outcomes in patients with papillary RCC because of targeted inhibition of specific proteins involved in cancer cell growth[8][9].
mTOR inhibitors, such as everolimus, have also shown effectiveness in treating non-clear cell kidney cancer[9]. Everolimus is particularly preferred in patients with chromophobe RCC because genetic mutations in these tumors activate the mTOR pathway[9].
Immunotherapy uses the body’s own immune system to fight cancer. More than three-quarters of patients with non-clear cell RCC survived for one year when treated with the immunotherapy combination of ipilimumab and nivolumab, compared to two-thirds of patients receiving standard care. The average overall survival time was two years and nine months for those receiving the combination treatment[11].
Platinum-based chemotherapy continues to be the recommended treatment strategy for collecting duct and medullary RCC, which tend to be more aggressive subtypes[9].
The current landscape for non-clear cell renal cell carcinoma is evolving rapidly, with ongoing efforts to design clinical trials that focus specifically on the various subtypes rather than grouping them together[6]. This more tailored approach allows researchers to better understand the distinct molecular characteristics of each subtype and develop targeted treatments accordingly[6].
Related Kidney Conditions
While non-clear cell renal cell carcinoma is cancerous, there are other types of kidney tumors and conditions that are not cancer.
Non-cancerous kidney tumors are growths that do not spread to other parts of the body. The most common non-cancerous kidney tumor is papillary renal adenoma. These tumors are small, grow slowly, and usually don’t cause any symptoms[3]. Other non-cancerous tumors include oncocytoma, which starts in the cells of the collecting ducts, and angiomyolipoma, which is made up of fat, blood vessels, and smooth muscle tissue[3].
Transitional cell cancer, now called upper urinary tract urothelial cancer, is a different type of kidney cancer that starts in the transitional cells lining the renal pelvis and ureter. The renal pelvis is the area of the kidney where urine collects before moving to the bladder[5][14]. This type of cancer has different characteristics and treatment approaches compared to renal cell carcinoma.
Clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma, renal medullary carcinoma, transitional cell cancer of the kidney, upper urinary tract urothelial cancer