Hereditary leiomyomatosis and renal cell cancer

ALSO KNOWN AS: HLRCC, leiomyomatosis and renal cell cancer, LRCC, Reed's syndrome, multiple cutaneous leiomyoma (MCU), multiple cutaneous and uterine leiomyomata (MCUL), leiomyomatosis and renal cell cancer (LRCC)

DEFINITION: Hereditary leiomyomatosis and renal cell cancer (HLRCC) represents a tumor predisposition syndrome characterized by cutaneous leiomyomas, or smooth muscle tumors of the skin; uterine leiomyomas, more commonly known as uterine fibroids; and renal cell carcinoma (kidney cancer). This syndrome is inherited in an autosomal dominant manner.

Risk Factors

The primary risk factor for developing HLRCC is harboring a germline mutation in the fumarate hydratase (FH) gene. Relatives of an individual with an FHgene mutation are also at risk for carrying the familial mutation and developing some or all of the syndrome’s clinical features.

Etiology and Genetics

HLRCC results from a mutation in the FH gene located on chromosome 1q42.1. The FH gene encodes the enzyme fumarate hydratase, which catalyzes the conversion of fumarate to malate in the tricarboxylic acid (TCA) cycle. Evidence supports that FH acts as a tumor-suppressor gene in HLRCC in two ways—loss of heterozygosity has been demonstrated in cutaneous, uterine, and renal tissue, and FH enzyme activity is reduced or absent in these tumors from individuals with HLRCC. Thus, developing HLRCC-associated tumors follows Knudson’s two-hit hypothesis, a model that explains the genetic basis of autosomal dominantly inherited familial cancer syndromes. In this model, one mutated FH allele is inherited through the germline and thus present in all body cells that contain genetic material. When the gene pair's second (previously normal) FH allele becomes inactivated by a mutation in a particular somatic cell, this process can lead to unchecked cell proliferation and tumorigenesis.

Symptoms

Three classic clinical features occur with this disorder—cutaneous leiomyomas, uterine leiomyomas, and renal cell cancer. Approximately 76 percent of affected individuals have single or multiple cutaneous leiomyomas distributed over their trunk and extremities. Skin findings present at a mean age of twenty-five. Uterine leiomyomas occur in almost all women with HLRCC. Fibroids generally develop at a younger age than women in the general population and are typically large and multifold. Renal tumors have been observed to develop in up to 62 percent of individuals with HLRCC. The average age at diagnosis of renal cell carcinoma (RCC) is forty-one years, but the disease has been found in patients as young as ten. Pathology reveals mostly papillary renal cancer, although other types of renal carcinoma have been described. The characteristics of HLRCC-associated renal tumors tend to be solitary, unilateral, and more aggressive than those renal cancers associated with other hereditary cancer syndromes.

Screening and Diagnosis

Diagnostic criteria in the HLRCC literature are inconclusive, but a clinical dermatologic diagnosis does exist. HLRCC is defined by multiple cutaneous leiomyomas with at least one histologically confirmed leiomyoma or a single leiomyoma in the presence of a positive family history of HLRCC. Genetic testing is available for molecular diagnosis to identify disease-causing mutations in the FH gene. Data show that FH mutations can be detected by DNA sequence analysis in most clinically diagnosed individuals. Most FH gene alterations are frame-shift and missense mutations occurring proximal to the enzyme’s active site, while nonsense and splice-site mutations have been reported less frequently. Several partial and complete FH gene deletions have also been observed.

Treatment and Therapy

Treatment of cutaneous lesions by surgical excision or cryoablation may be appropriate for isolated and painful lesions. Many women with HLRCC need medical or surgical intervention for uterine fibroids. Gonadotropin-releasing hormone agonists, antihormonal medications, and pain relievers can help decrease fibroids' size in preparation for surgical removal or provide temporary pain relief. Myomectomy, a surgery to remove fibroids while preserving the uterus, is the preferred treatment for many women. However, hysterectomy remains a management option.

Traditional therapy has not been effective in treating RCC in HLRCC patients. Some success has been had treating with erlotinib plus bevacizumab. A phase II trial using this treatment had an overall response rate of 60 percent (Catarina et al., 2022).

Prevention and Outcomes

A comprehensive skin examination is recommended every one to two years to evaluate any changes suggestive of leiomyosarcoma. Regular gynecologic evaluations are strongly encouraged for women to assess uterine fibroid severity and look for changes associated with leiomyosarcoma. For renal surveillance, if b baseline and first annual follow-up abdominal CT scan with contrast or MRI (if CT is impossible) are normal, a repeat evaluation is recommended every two years. Any suspicious renal lesion seen at a previous examination should be followed with a CT scan with and without contrast. Renal ultrasound alone is not a sufficient screening tool. Due to the aggressive nature of HLRCC-associated renal cancers, total nephrectomy (removal of the kidney) may be appropriate in individuals with a detectable renal mass.

Individuals with cancer localized in the kidneys have a five-year survival rate of around 93 percent. For those whose cancer has only spread to nearby tissue, the survival rate is 71 percent. Those whose diagnosis includes distant organs have a survival rate of around 14 percent. Early diagnosis increases the prognosis of HLRCC.

Bibliography

Catarina, Tavares, Maria Sofia Quental, Jose Ricardo Brandao, and Miguel Silva-Ramos. "Hereditary Leiomyomatosis and Renal Cell Cancer--Recognizing Patterns May Save Lives." Journal of Kidney Cancer and VHL, vol. 9, no. 2, 2022, pp. 27-31, doi: 10.15586/jkcvhl.v9i2.222. Accessed 10 Sept. 2024.

Chayed, Zahraa. "Hereditary Leiomyomatosis and Renal Cell Carcinoma: A Case Series and Literature Review." Orphanet Journal of Rare Diseases, vol. 16, no. 34, 18 Jan. 2021, doi.org/10.1186/s13023-020-01653-9.

"Hereditary Leiomyomatosis and Renal Cell Cancer." Medline Plus, 1 Feb. 2018, medlineplus.gov/genetics/condition/hereditary-leiomyomatosis-and-renal-cell-cancer. Accessed 20 June 2024.

"Hereditary Leiomyomatosis and Renal Cell Cancer (PDQ®)–Health Professional Version." National Cancer Institute, 22 Mar. 2024, www.cancer.gov/publications/pdq/information-summaries/genetics/hlrcc-syndrome-hp-pdq. Accessed 10 Sept. 2024.

Kamihara, Junne, et al. "FH Tumor Predisposition Syndrome." National Library of Medicine, 13 Aug. 2020, www.ncbi.nlm.nih.gov/books/NBK1252. Accessed 20 June 2024.

Schmidt, Laura S., and W. Marston Linehan. “Hereditary Leiomyomatosis and Renal Cell Cancer.” International Journal of Nephrology and Renovascular Disease, vol. 7, 2014, pp. 253–60. doi:10.2147/IJNRD.S42097.

Smit, D. L., et al. “Hereditary Leiomyomatosis and Renal Cell Cancer in Families Referred for Fumarate Hydratase Germline Mutation Analysis.” Clinical Genetics, vol. 79, no. 1, 2011, pp. 49–59. doi:10.1111/j.1399-0004.2010.01486.x.