Maria I. Carlo, MD:This is a 38-year-old man who presented to the emergency department with new hematuria and right-flank pain. On imaging, he had a 10-cm mass infiltrating the right kidney with some small lymph nodes. Otherwise, there was no evidence of metastatic disease. On review of systems, he had this right-side flank pain for a few weeks. He had no other medical history. He was a nonsmoker. For family history, his father died of colon cancer at age 60. His mother had a hysterectomy for uterine fibroids at a young age. No other personal cancer history.

He had a CT scan of the chest that was normal. His labs were otherwise normal, and he proceeded with the right radical nephrectomy. The pathology was read as renal cell carcinoma [RCC]: fumarate hydratase [FH]–deficient, grade 3, no sarcomatoid features, stage III. He was referred for genetic counseling and was identified to have a germline FH pathogenic variant in the fumarate hydratase gene. He proceeded with cascade testing of his family, and it was also found in his mother and 1 sibling, both without a history of cancer. After surgery, we repeated imaging about 3 months later. That revealed areas with high FDG [fluorodeoxyglucose] avidity in the liver and mediastinal lymphadenopathy. The patient enrolled in a clinical trial with cabozantinib-nivolumab with partial response.

Robert J. Motzer, MD: That’s a great case as well. It illustrates some nice points. This entity is linked to genetics, is that right? This is a more of a genetic-based kidney cancer?

Maria I. Carlo, MD:Correct. Fumarate hydratase–deficient RCC is also called HLRCC, RCC-based hereditary leiomyomatosis, which is the genetic syndrome. Sometimes it’s called papillary RCC. When you do staining, FH is not retained, indicating a lack of protein. Sometimes it’s called unclassified or renal cell carcinoma—we can’t further specify. The clue here is the young age of the patient with a renal mass that’s not obviously a clear cell mass. Essentially, anybody who is young and has a kidney cancer that cannot be further specified merits discussion of genetics. This is the entity I’m most concerned about because it’s by far the most common. It’s missed in a lot of cases. As you saw with this case, the family history isn’t that strong. It’s a much lower penetrance gene than we used to think. We used to know these cases with a strong family history of kidney cancer. Also, the women tend to have fibroids—those are common in the population—and cutaneous leiomyomas, which are plush-colored bumps that are sometimes irritating or painful to the patients but not harmful. For most of my patients—like this 1, where we diagnose them with the genetic condition—if you really look, you can see a cutaneous leiomyoma, but the patient wasn’t aware. I wouldn’t use that as a feature to think that it’s not genetic.

Robert J. Motzer, MD: When we say that these patients are referred for familial counselor and genetic counseling, what’s the process for their family members? Do they get their germlines studied, or is there screening? What’s the impact when we send patients for their families to get assessed for this not common but familial type of RCC?

Maria I. Carlo, MD:That’s a great question. If we know the genetic mutation in the family—in this case, we’ve tested the patient, we know what we’re looking for—then we invite the family, starting with first-degree relatives, to get genetic testing. We look for just 1 thing. It’s a yes-or-no answer: Do they have the gene? If they don’t, we counsel them at our population-level risk of kidney cancer. But if they have the germline mutation, we estimate—this is imprecise—that there’s a 5% to 10% chance of kidney cancer during their lifetime. Because FH-deficient kidney cancer can be aggressive and metastatic even when quite small, if you have a small renal mass and genetic condition, it’s not something you observe. It's indication for surgery. We recommend cross-sectional abdominal imaging once a year because they can grow quickly. Usually, MRI is preferred because it gives you good resolution but no radiation. Obviously, if you can’t have an MRI, a CT scan is acceptable. It’s unclear if renal ultrasound picks up most of these when they’re small, but that’s an alternative as well. MRI is my preferred mode to screen the family members who haven’t been diagnosed with kidney cancer. We send them to dermatology to look for cutaneous leiomyomas. Women should see a gynecologist for early identification of uterine fibroids.

Transcript edited for clarity.