Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare kidney cancer susceptibility syndrome caused by autosomal dominant mutations in the FH gene. The three main symptoms of HLRCC are red skin papules called cutaneous piloleiomyomas; multiple early-onset uterine leiomyomas; and susceptibility to type 2 papillary renal cell carcinoma.
Clinical guidelines for HLRCC were the subject of a panel discussion at the 5th BHD and 2nd HLRCC Symposium in Paris last summer. The panel was led by Professor Fred Menko, and included Professor Eamonn Maher, Professor Stéphane Richard, Dr W. Marston Linehan, Dr Laura Schmidt and Graham Lovitt, chairman of the HLRCC Family Alliance. The results of this discussion have now been published in Familial Cancer (Menko et al., 2014).
Menko et al. suggest that patients who have histologically confirmed multiple cutaneous piloleiomyomas, or at least two of the following – symptomatic uterine leiomyomas before age 40, type 2 papillary carcinoma before age 40, or a first-degree relative who meets one of these criteria – meet clinical diagnostic criteria and should be referred for genetic testing where possible. Up to 24% of families with clinical features of HLRCC have been reported to not have a detectable FH mutation. In these families, immunohistochemical staining of tumours to demonstrate increased protein succination can confirm a diagnosis of HLRCC.
Expert opinion suggests that 15% of HLRCC patients are at risk of developing kidney cancer, most commonly type 2 papillary renal cell carcinoma. The mean age of diagnosis is 41 years, with a range of 11 to 90 years of age. While the risk is low, an estimated 1-2% of patients of HLRCC patients developing kidney cancer before the age of 20, and HLRCC patients as young as 10 have presented with kidney cancer.
Given the aggressive nature of HLRCC-associated kidney cancer, and the fact it can develop at a young age, Menko et al. suggest that DNA testing should be considered from the age of 8-10, although decisions should be made on an individual basis in collaboration with the family. Tumour surveillance should be offered annually from this age to children with a confirmed mutation and to those who are at risk of inheriting HLRCC, but who have not undergone gene testing. MRI is the preferred screening method, using 1-3mm slices through the kidneys in order to find small tumours.
HLRCC renal tumours are usually unilateral and solitary. Tumours tend to be more aggressive, with an increased chance of metastasising, even when the tumour is small, meaning that the 3cm rule and nephron sparing surgery used to manage BHD and VHL tumours is not appropriate. In HLRCC, once a tumour is found, the tumour should be promptly resected with wide surgical margins, and retroperitoneal lymphadenectomy should be considered. Where there is doubt that a partial nephrectomy would be curative, radical nephrectomy should be performed. In the authors’ experience, patients had a good prognosis and showed no evidence of disease when tumours were found early and managed surgically.
Loss of FH leads to dysregulation of the TCA cycle and glycolysis and several therapies targeting these pathways have been recently developed, which may be appropriate systemic treatments for HLRCC patients with metastatic disease. However, access to these treatments is currently only available through clinical trials.
While publication of these guidelines will help clinicians diagnose HLRCC patients and to manage their renal tumours optimally, the authors discuss the need for clinicians to share data internationally in order to ensure that these guidelines meet the needs of HLRCC patients, and can be refined if necessary. In particular, more data about childhood cases of HLRCC renal cancer would help determine the best age to perform germline genetic testing and to start tumour surveillance.
- Menko FH, Maher ER, Schmidt LS, Middelton LA, Aittomäki K, Tomlinson I, Richard S, & Linehan WM (2014). Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Familial cancer PMID: 25012257