Hereditary leiomyomatosis and renal cell carcinoma (HLRCC)

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HLRCC is a cancer syndrome that mainly affects the skin, uterus, and kidneys.

Individuals with HLRCC typically develop multiple benign smooth muscle tumors called leiomyomas that appear as small, firm bumps, or nodules. Doctors refer to these growths as fibroids when they affect the uterus.

People with HLRCC also have an increased risk of developing kidney cancer, specifically type 2 papillary RCC. This malignant cancer is aggressive and often spreads, or metastasizes, to other areas.

HLRCC is a genetic condition people inherit from their parents. It occurs due to a change in a specific gene known as the fumarate hydratase (FH) gene.

This gene is crucial for energy production in cells. The FH gene encodes the enzyme fumarate hydratase, which is involved in the Krebs cycle. The Krebs cycle is a series of reactions in the body that generate energy in the mitochondria, which powers cells.

Specifically, this enzyme helps fumarate turn into another enzyme known as malate. When a person has HLRCC, the FH gene cannot efficiently catalyze this reaction. As a result, fumarate accumulates within the cells, contributing to the formation of tumors.

HLRCC inheritance follows an autosomal dominant pattern. This means that for a person to inherit the condition, they only need a single copy of the FH gene from one parent. Every child of an individual with HLRCC has a 50% chance of inheriting the syndrome.

Because only one copy of the FH gene is necessary to develop HLRCC, the condition can appear in every generation of a family. The severity and specific symptoms can also vary significantly among family members.

Experts consider HLRCC a rare disorder, though its exact prevalence is unclear.

Doctors have identified HLRCC in around 300 families worldwide. However, due to its rarity and the variability of symptoms, it may be underdiagnosed, making accurate data challenging to collect.

HLRCC symptoms vary widely, from no noticeable symptoms to life threatening cancer.

One common symptom is leiomyoma, which is a benign but sometimes painful tumor that develops in muscle tissue surrounding a hair follicle. People with leiomyomas may notice small, skin-colored, brown or red bumps on their arms, legs, chest, and abdomen.

These tumors can also develop in the uterus, forming uterine fibroids. People with this symptom may experience heavy, painful periods and abdominal pain or swelling.

Around 10% to 16% of those living with HLRCC go on to develop RCC. The symptoms of RCC include:

• abdominal lumps
• blood in the urine
• unexplained weight loss
• lower back pain
• reduced appetite
• fatigue

Genetic testing helps doctors diagnose HLRCC. It involves analyzing DNA to detect changes in the FH gene.

Healthcare professionals may recommend testing when multiple family members have leiomyomas or RCC, or when an individual develops symptoms suggestive of HLRCC.

Early genetic identification can help with risk assessment and managing the condition through surveillance and preventive measures.

Before undergoing genetic testing, individuals receive genetic counseling to understand the implications of the test results, the nature of HLRCC, and the possible outcomes. This counseling ensures that they are adequately informed and prepared for the psychological impact of the results.

Testing involves taking a blood or saliva sample, which a medical professional then sends to a laboratory for analysis. A positive result confirms the presence of a change in the FH gene, indicating an HLRCC diagnosis.

A negative result might reduce uncertainty, but doctors also consider the family history and clinical symptoms in their diagnosis due to the possibility of false negatives.

After receiving the test results, further counseling provides an opportunity to discuss the results, plan the next steps, and consider the psychological and social aspects of living with HLRCC.

Treating HLRCC requires a comprehensive approach that includes managing individual symptoms and conducting preventive surveillance for kidney cancer. It typically involves a collaborative effort from a team of specialists, including:

• dermatologists
• oncologists
• surgeons
• genetic counselors

Treating leiomyomas

Doctors do not always recommend removing leiomyomas, as the procedure can scar and damage the skin. However, it may be appropriate for those that cause significant discomfort or affect bodily functions.

In these cases, doctors may use cryotherapy to freeze and destroy the tissue or CO2 laser ablation.

Treating fibroids

A person with uterine fibroids that cause symptoms may benefit from medications, such as:

• gonadotropin-releasing medications
• hormone-blocking medications
• pain medications

Some fibroids may require surgery to remove them and repair the damage. In some cases, a hysterectomy to remove the whole uterus may be necessary.

Monitoring and treating RCC

Individuals with HLRCC require regular monitoring for RCC through advanced imaging techniques, such as MRI or CT scans. These tests allow doctors to detect tumors early on.

Should a person develop RCC, they may require surgery to remove part or all of the affected kidney. If this approach is not suitable or sufficient to manage the cancer, doctors may recommend targeted therapy, which focuses on specific molecular targets associated with cancer growth.

Additional cancer treatments, such as radiation therapy or chemotherapy, may form part of the treatment regimen.

The life expectancy of individuals with HLRCC can vary significantly, as it often depends on whether a person develops RCC or not.

Not everyone with HLRCC gets RCC. Those who never develop this cancer may have a typical life expectancy. However, close monitoring and treatment for any other symptoms will be necessary throughout their life.

For those who do have RCC, the outlook depends on the location and stage of the cancer and how it responds to treatment.

The survival rates for RCC 5 years from diagnosis are:

• 90% for stage 1 RCC, when the cancer is confined to the kidney
• 50% for stage 2, when the cancer is more advanced but still only within the kidney
• 30% for stage 3, when the cancer has spread to nearby tissues or lymph nodes
• 5% for stage 4, when the cancer has spread to distant tissues or organs

These figures indicate the percentage of people who live at least 5 years after an RCC diagnosis. Some people may live longer.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a genetic condition that causes benign tumors and increases the risk of renal cell carcinoma (RCC).

It occurs due to a change in a gene that influences cell energy production. When this gene does not work as it should, it results in the accumulation of an enzyme, which can contribute to tumors.

HLRCC is a complex disorder that demands a proactive management approach, including genetic counseling, routine health screenings, and, when necessary, medical treatments.