Diagnosis and Staging

Collecting duct RCC is different than other types of kidney cancer in that it behaves more similarly to bladder cancer, as both the bladder and collecting duct portion of the kidney share the same origin when the organs are formed in the body before birth.

Collecting duct RCC is frequently diagnosed in younger individuals, Black individuals, and males.

Currently, there are no known risk factors for developing collecting duct RCC. It is possible that risk factors exist but have not yet been studied.

Collecting duct RCC has many genetic mutations including genes such as NF2 and CDKN2A, which when mutated can lead to uncontrolled cell growth.

Due to the aggressive nature, collecting duct RCC can commonly spread to the lung, liver, and bone.

The treatment for metastatic collecting duct RCC is largely different than metastatic clear cell RCC. Because it behaves more like bladder cancer, collecting duct RCC is treated similarly to bladder cancer with combination chemotherapy medications. In contrast, clear cell RCC is typically treated with immunotherapy medications and/or targeted therapy medications. There is some data that collecting duct RCC may respond to a type of targeted therapy medication called tyrosine kinase inhibitors (TKIs). This includes a specific type of TKI, called vascular endothelial growth factor (VEGF) inhibitors.

*Clear cell RCC is the most common type of kidney cancer, making up about 70% of all kidney cancer diagnoses. Many published treatment recommendations for metastatic RCC are based on having a diagnosis of clear cell RCC, which may or may not also work for collecting duct RCC.

Since collecting duct RCC is a very rare cancer, there is not a lot of data on what is the best treatment approach. These tumors have not received a lot of research focus in the past. Clinical trials represent a wonderful opportunity to help find new and better therapies for patients with collecting duct RCC and other rare kidney cancers. Participation in clinical trials for patients with rare kidney cancers is highly recommended. You can find a clinical trial using the KCA’s Clinical Trial Finder.

RMC was first described in 1995. RMC grows very fast and behaves very differently from the other kidney cancer subtypes. In the initial study, half of the people diagnosed lived less than four months. Today, treatments have improved, and people can live about 18 months on average while up to 10% may be cured. Researchers are still working on better treatments.

RMC mostly affects young Black individuals with sickle cell trait (SCT) or sickle cell disease (SCD). It’s linked to sickled-shaped red blood cells (RBCs) damaging the kidney’s medulla and a gene called INI1. RMC can rarely occur in people with no known conditions affecting the RBCs.

RMC is the only kidney cancer associated with SCT, SCD, or other blood conditions (hemoglobinopathies) that cause RBCs to become sickled-shaped. Even though all sickled-shaped RBC conditions raise the risk of RMC, most people with RMC have SCT. This could be because SCT is much more common than other RBC conditions.

Studies suggest that high-intensity physical exercise in those with SCT may harm the kidneys and increase the risk of RMC.

RMC tumors do not have a protein called INI1, also known as SMARCB1, hSNF5, or BAF47. INI1 normally acts as a “tumor suppressor,” meaning it helps protect cells from turning into cancer.

RMC most commonly spreads to the lymph nodes, lung, liver, and bone.

Metastatic RMC is often treated with chemotherapy medications. In contrast, metastatic clear cell RCC is typically treated with immunotherapy medications and/or targeted therapy medications, which do not work to treat RMC.

*Clear cell RCC is the most common type of kidney cancer, making up about 70% of all kidney cancer diagnoses. Many published treatment recommendations for metastatic RCC are based on having a diagnosis of clear cell RCC, which may or may not also work for RMC.

Exercise is good for your health, whether you have RMC or not, and even if you have sickle cell trait, sickle cell disease, or another hemoglobinopathy. Animal studies show that doing moderate-intensity exercise may lower the risk of RMC when compared to not exercising at all. However, some early studies suggest that doing long, very hard workouts may harm the kidneys of people with sickle cell trait and raise the risk of RMC. So, exercising at a moderate level may help everyone, but pushing yourself too hard might be harmful. This matches the advice from the Centers for Disease Control and Prevention about safe exercise for people with sickle cell trait. Following this advice helps athletes stay safe and get the benefits of exercise.

Moderate-intensity exercise is when your heart rate is between 50% and 70% of your maximum heart rate. To figure out your maximum heart rate, subtract your age from 220. For example, if you are 40, then your maximum heart rate is 180 beats per minute. During moderate-intensity exercise, your breathing speeds up, but you are not out of breath. You might start sweating after 5 to 10 minutes, and you can still talk but not sing.

High-intensity exercise is when your heart rate is 80% or more of your maximum. During high-intensity exercise, you breathe deeply and quickly, start sweating within a few minutes, and can only say a few words before you need to take a breath.

Exercise is not banned for people with sickle cell trait if it is done safely. Athletes and military recruits with sickle cell trait follow simple rules to avoid problems and do well without developing any issues. These rules include staying hydrated by drinking enough water, avoiding a lot of caffeine or stimulants, and not doing many hard, timed drills without enough rest—especially during the first two weeks of a new training session. You should also slow down if you are sick, rest between “sprints” or tough drills, and make sure to take breaks and drink fluids often.

Translocation RCC has similar pathological features, when viewed under the microscope, compared with the more common forms of RCC such as clear cell RCC and papillary RCC, but it has its own unique biological and clinical characteristics.

Translocation RCC is more common in children, adolescents, and young adults, making up approximately 50% of all kidney cancers seen in those under 18 years old and about 20% of cases seen in individuals younger than 40 years old, but it can occur at any age.  Some reports suggest that females, Black individuals, and Asian individuals are at slightly higher risk for developing translocation RCC, though it has occurred in individuals of all racial and ethnic backgrounds.

Translocation RCC is associated with abnormalities in the TFE3 gene, or more rarely the TFEB, gene. These genes make special proteins called “transcription factors” that help turn other genes on or off. This controls how cells send and receive signals, including in cancer cells. In translocation RCC, the TFE3 gene is usually turned ‘on’ when it switches places and connects with another gene, like TFE3-ASPL or TFE3-PRCC. It can also join with other similar “partner genes”. Another way these genes can be turned on is through something called amplification, which means the gene, like TFEB, makes too many copies of itself.

If translocation RCC spreads outside of the kidney, several clinical patterns exist including a indolent pattern, or the unfortunately more common ‘aggressive’ pattern.  Most often, translocation RCC is diagnosed when the cancer is advanced, with common spread to the lymph nodes, more so than other forms of RCC.  It is not uncommon for translocation RCC to spread from lymph nodes in the abdomen into lymph nodes in the mediastinum.  Other common sites it can metastasize to include the lung, liver and bones.

In the setting of metastatic or unresectable translocation RCC, systemic therapy in addition to treatment directed at the tumor in the kidney would be appropriate. Use of a specific targeted therapy medication, called tyrosine kinase inhibitors (TKIs) has shown some promise to treat translocation RCC. This includes a type of TKI, called vascular endothelial growth factor (VEGF) inhibitors. Evidence is weaker and conflicting for the use of immunotherapy medications that are also commonly used for clear cell RCC, when used by itself in treatment of translocation RCC.  Recent studies have focused on a combination therapy approach using a TKI-targeting VEGF inhibitor together with an immunotherapy medication, similar to some standard of care treatment for clear cell RCC.  Research continues to identify other potential treatment options. 

*Clear cell RCC is the most common type of kidney cancer, making up about 70% of all kidney cancer diagnoses. Many published treatment recommendations for metastatic RCC are based on having a diagnosis of clear cell RCC, which may or may not also work for translocation RCC.

Diagnosing tRCC: tRCC is not always suspected by treating teams, and not all pathology teams routinely test for this form of RCC, but identifying it can be helpful in understanding prognosis, clinical behavior, and treatment options and expectations.  Patients with RCC < 40-50 years of age are particularly encouraged to request such testing if not done routinely by your treatment center. Such testing focuses on looking for the TFE changes through various approaches such as ‘TFE stains via immunohistochemistry’ or via tests that look for the TFE fusion itself (for example, a test called FISH – fluorescent in situ hybridization) since tRCC can mimic the ‘appearance’ of ccRCC or pRCC under the microscope and thus routine pathology review is not often sufficient to diagnosis tRCC. 

Clinical: More aggressive surveillance for lymph node involvement is a consideration when faced with tRCC, and the surgical approach to RCC may slightly change when tRCC is expected (more aggressive lymph node surgery, for example, is a consideration) given its unique clinical behavior compared to other forms of RCC.  Cooperative groups and others are trying to formally study tRCC such that advancements can be made.  It is not unreasonable to search for such clinical studies, be it typical medication trials or novel clinical trials (such as vaccines or newer targeted drugs or immunotherapies in development, for example), as unfortunately current medical therapies often fall short of long-term disease control when disease has spread.

Unclassified RCC tumors behave more aggressively than more commonly seen RCC subtypes, such as clear cell RCC or papillary RCC.

In some studies, there is a higher percentage of females and Black individuals with unclassified RCC when compared to “typical” RCC patients.

At this point we do not know of any specific risk factors. It is possible that there are risk factors that exist but have not yet been studied.

Several studies show that there is a higher incidence of NF2, SETD2, TP53, BAP1, KMT2C and MTOR mutations in unclassified renal cell carcinoma.

Unclassified RCC metastases are most common in the lung, lymph nodes, liver, and bone.

At this time, the recommended treatment for metastatic unclassified RCC would be similar to metastatic clear cell RCC: a combination of a specific class of targeted therapy medication, called tyrosine kinase inhibitors (TKIs) and an immunotherapy medication. 

*Clear cell RCC is the most common type of kidney cancer, making up about 70% of all kidney cancer diagnoses. Many published treatment recommendations for metastatic RCC are based on having a diagnosis of clear cell RCC, which may or may not also work for unclassifed RCC.

As we gain more knowledge about the different subtypes of renal cell carcinoma, the “unclassified” subtype will become less common.  Our goal is to be able to properly classify all renal cell carcinomas into groups where we have specific therapies.  We hope this category will eventually cease to exist!