Fumarate hydratase-deficient renal cell carcinoma (often called FH-deficient RCC) is a rare type of kidney cancer. It develops due to mutations (changes) in a gene called fumarate hydratase (FH). FH is important for normal cell metabolism. Changes in this gene lead to the formation of a tumour with specific microscopic features. This tumour often behaves aggressively, meaning it can grow quickly and sometimes spread beyond the kidney.
What are the symptoms of fumarate hydratase-deficient renal cell carcinoma?
Many people with FH-deficient RCC have noticeable symptoms.
Common symptoms include:
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Blood in the urine (which can appear pink, red, or brown).
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Pain or discomfort in the side or lower back.
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Feeling a mass or lump in the abdomen.
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Fatigue, unexplained weight loss, or fever.
These tumours are often larger by the time they are discovered. Sometimes they can spread to other parts of the body, causing additional symptoms depending on the areas involved.
What causes fumarate hydratase-deficient renal cell carcinoma?
FH-deficient RCC is caused by changes or mutations in the fumarate hydratase (FH) gene. This gene helps cells produce energy properly. When the FH gene is damaged, cells build up abnormal substances that lead to tumour growth.
Most cases happen by chance (sporadic), without any family history. However, some cases are hereditary, meaning people are born with an inherited genetic condition. One important inherited condition linked to FH-deficient RCC is called Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) syndrome. People with HLRCC syndrome often have multiple kidney tumours and non-cancerous tumours of the skin and uterus.
Who is most likely to develop fumarate hydratase-deficient renal cell carcinoma?
FH-deficient RCC is very rare, representing less than 1% of kidney tumours. It occurs more often in men than women. Most people diagnosed with this type of tumour are adults, usually between 30 and 74 years old, with an average age of around 58. However, FH-deficient RCC can also occur in younger adults and even in children, particularly when associated with hereditary conditions.
How is fumarate hydratase-deficient renal cell carcinoma diagnosed?
FH-deficient RCC is often found when imaging tests such as ultrasound, CT scans, or MRI scans are performed because of symptoms or for unrelated reasons. Doctors may notice a large mass in the kidney on these imaging tests.
To confirm the diagnosis, doctors usually recommend surgery to remove the tumour. Once the tumour is removed, a pathologist examines the tumour tissue under a microscope. Special laboratory tests, including immunohistochemistry, can also aid pathologists in confirming the diagnosis. Additionally, genetic testing may be performed to identify specific gene mutations.
What does fumarate hydratase-deficient renal cell carcinoma look like under the microscope?
Under the microscope, FH-deficient RCC is made up of cells that form various patterns, such as papillary (finger-like structures), tubular (small tubes), or cystic (fluid-filled spaces). Tumour cells have large, irregularly shaped centers (nuclei) and very prominent, noticeable structures inside the nuclei called nucleoli. Pathologists carefully examine these features to accurately diagnose FH-deficient RCC.
What other tests may be performed to confirm the diagnosis?
In addition to examining the tumour under a microscope, pathologists often perform a special laboratory test called immunohistochemistry (IHC) to help confirm the diagnosis. Immunohistochemistry uses special stains to identify proteins within tumour cells.
For FH-deficient RCC, pathologists typically use immunohistochemistry to look at proteins called FH and 2SC. Tumour cells in FH-deficient RCC usually do not show staining for FH (negative FH staining), even though normal cells in the same tissue are positive for FH. Additionally, tumour cells in FH-deficient RCC often show positive staining for a protein called 2SC. These staining patterns help pathologists confidently diagnose FH-deficient RCC, particularly when the diagnosis is unclear from microscopic examination alone.
How is fumarate hydratase-deficient RCC different from other types of kidney cancer?
FH-deficient RCC differs from other kidney cancers in several important ways:
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Genetic changes: FH-deficient RCC involves specific genetic mutations in the FH gene. Many other types of kidney cancer do not have these particular genetic changes.
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Microscopic appearance: Tumour cells in FH-deficient RCC exhibit distinctive prominent nucleoli and specific growth patterns (papillary, tubular, and cystic), which are not commonly seen in other kidney cancers.
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Associated hereditary condition: FH-deficient RCC is linked to an inherited condition known as hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. Most other types of kidney cancer are usually not associated with this genetic condition.
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Behavior: FH-deficient RCC can be more aggressive compared to some other kidney tumours, with a higher likelihood of spreading or returning after treatment.
Because of these differences, accurate diagnosis is important for guiding appropriate treatment and follow-up care.
What does tumour extension mean, and why is it important?
Tumour extension describes how far the tumour has grown beyond the kidney into nearby structures, such as surrounding fat, large veins, or adjacent organs. Tumour extension is carefully assessed and documented in your pathology report because it affects prognosis and helps doctors decide on the best treatment plan. Tumours that have grown into surrounding structures are usually more aggressive and might need additional treatments.
What are surgical margins, and why are they important?
Surgical margins are the edges of healthy tissue surrounding a tumour that surgeons remove during surgery. After the tumour is removed, pathologists examine these margins under a microscope to check for tumour cells.
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Negative margins: No tumour cells at the edges of the tissue, meaning the tumour was likely entirely removed.
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Positive margins: Tumour cells are present at the edges of the tissue, meaning some tumour cells might remain in the body, potentially requiring additional treatments such as further surgery or radiation therapy.
Your pathology report will clearly indicate margin status and help your doctor decide if more treatment is necessary.
What does lymphovascular invasion mean, and why is it important?
Lymphovascular invasion (LVI) means tumour cells have entered tiny blood or lymphatic vessels. Lymphatic vessels connect to lymph nodes, small immune organs throughout the body. If tumour cells enter these vessels, they can spread more easily to lymph nodes or other parts of the body. Finding lymphovascular invasion suggests a higher chance that the tumour might spread, and this information will guide further treatment and monitoring.
Were lymph nodes examined, and what do the results mean?
Lymph nodes are small, bean-shaped immune organs. Tumour cells sometimes spread from the tumour to lymph nodes through tiny lymphatic vessels.
If lymph nodes were removed during surgery, pathologists carefully examine them under a microscope to check for tumour cells.
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Negative lymph nodes: No tumour cells were found in any of the lymph nodes exa,mined. This means the tumour likely has not spread to lymph nodes.
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Positive lymph nodes: Tumour cells found in one or more lymph nodes examined. This means the tumour has spread, which might require additional treatments such as chemotherapy or immunotherapy.
Your pathology report will include details about the number of lymph nodes examined, their location, and whether any contain tumour cells.
Prognosis and treatment for fumarate hydratase-deficient renal cell carcinoma
FH-deficient RCC can behave aggressively, with a higher risk of spreading compared to other kidney tumours. However, the prognosis can vary significantly. Some tumours remain less aggressive, while others might spread or recur after treatment.
Treatment typically involves surgery to remove the tumour. Doctors may recommend additional treatments based on the tumour’s features and whether it has spread. Patients diagnosed with FH-deficient RCC are often advised to undergo genetic counselling and testing. Family members might also be recommended for genetic testing and monitoring due to potential inherited risks.
Pathologic staging (TNM system) for fumarate hydratase-deficient renal cell carcinoma
Your doctor uses the TNM staging system to clearly describe how advanced the tumour is. Staging helps determine the most appropriate treatment and prognosis.
Tumour stage (T)
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T1: Tumour is 7 cm or smaller and confined to the kidney.
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T2: Tumour is larger than 7 cm but remains entirely within the kidney.
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T3: Tumour has grown into the surrounding fat or a large vein attached to the kidney.
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T4: Tumour extends beyond the kidney into nearby structures or through Gerota’s fascia (the protective layer around the kidney).
Lymph node stage (N)
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N0: No tumour cells in lymph nodes.
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N1: Tumour cells found in lymph nodes.
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NX: No lymph nodes were examined.
Metastatic stage (M)
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M0: Tumour has not spread to distant body parts.
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M1: Tumour has spread to distant body parts.
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MX: Not enough information available to determine if the tumour has spread.
Higher stages mean the tumour is more advanced and may require more extensive treatments.
Questions to ask your doctor
- Will I need further testing, such as genetic counselling?
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What treatment options do you recommend for my tumour?
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How often should I have follow-up visits or imaging tests?
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Could my tumour return or spread, and what symptoms should I watch for?
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Are my family members at increased risk, and should they be tested?
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Should I make lifestyle or dietary changes after surgery?