Hereditary Leiomyomatosis and Renal Cell Carcinoma

 Hereditary Leiomyomatosis and Renal Cell Carcinoma

OVERVIEW

Hereditary Leiomyomatosis and renal cell carcinoma, also known as HLRCC, is a rare genetic disorder characterized by smooth muscle growths (leiomyomas) on the skin and uterus and an increased risk of developing kidney (renal) cancer. Skin growths may appear as appear as small, firm bumps (papules) or tiny lumps (nodules) and are not cancerous (benign). Uterine leiomyomas, also known as uterine fibroids, may be numerous and are also benign, but can cause symptoms such as heavy menstrual periods or pelvic pressure or pain. Affected individuals are at an increased risk of developing kidney cancer, particularly a form known as type II papillary renal cell carcinoma. Kidney cancer associated with HLRCC is cancerous (malignant) and can be aggressive and spread (metastasize) to other areas of the body. HLRCC is caused by mutations in the fumarate hydratase (FH) gene and is inherited in an autosomal dominant pattern.

HLRCC is classified as a hereditary renal cancer syndrome, a group of disorders characterized by a genetic predisposition to renal cancer along with other symptoms. There are at least 10 identified hereditary renal cancer syndromes including Von-Hippel-Lindau disease, Birt-Hogg-Dube syndrome, and hereditary papillary renal cell carcinoma. The association of leiomyomas and uterine fibroids as a genetic disorder was first described in the medical literature by Dr. Reed in 1973 and subsequently termed multiple cutaneous and uterine leiomyoma (MCUL) or Reed’s syndrome. The additional association with renal carcinoma was not established until 2001 (Launonen et al.).

SYMPTOMS

The symptoms and progression of HLRCC can vary widely from one person to another, even among members of the same family. Some individuals who inherit a mutated gene for HLRCC will not develop any symptoms. The susceptibility to develop symptoms varies among family members as well. For example, if a parent develops kidney cancer, it does not mean necessarily that an affected child will.

The most common symptom is benign skin lesions called leiomyomas or leiomyomata. Leiomyomas are small growths that are usually skin-colored, brownish, or reddish. Sometimes they can resemble a rash. They most often appear on the trunk, arms and legs (extremities) and face. These lesions are sensitive to touch and cold temperatures and, in rare cases, may be painful. Some individuals may have widespread disease, with multiple small leiomyomas covering a large area of the body; other individuals may only develop a few bumps. Some individuals may only have one small skin growth (leiomyoma) or have no detectable growths. Leiomyomas usually become apparent between 10 and 50 years of age (with a mean age of 25) and generally increase in size and number as an affected individual ages.

Women with HLRCC may develop leiomyomas in the uterus (uterine fibroids). These growths are common in women in the general population and often go unnoticed because they do not cause any symptoms (asymptomatic). In women with HLRCC, uterine fibroids are more numerous, larger and have an early age of onset, most often being diagnosed between 18 and 52 years of age (with a mean age of 30). Affected women may have abnormally heavy menstrual periods and feel pelvic pressure or pain. Women with HLRCC tend to undergo a hysterectomy or myomectomy for symptomatic relief at a younger age than women in the general population.

Individuals with HLRCC are at an increased risk of developing kidney (renal) cancer than individuals in the general population. However, most affected individuals do not develop kidney cancer. In individuals who have developed kidney cancer, the most common form has been type II papillary renal cell carcinoma, a potentially aggressive malignant cancer that can spread (metastasize) quickly. Most affected individuals develop a solitary kidney tumor, but even a small primary tumor can spread. Individuals with kidney cancer may not develop any outward symptoms. Symptoms that can develop include blood in the urine (hematuria), lower back pain, and the presence of mass that can be felt (palpable). Additional forms of kidney cancer have occurred in individuals with HLRCC including tubulo-papillary and renal collecting duct carcinomas.

In extremely rare cases, some affected women have developed uterine leiomyosarcomas, a malignant tumor that arises from the smooth muscle lining the walls of the uterus (myometrium). (For more information on this disorder, choose “uterine leiomyosarcoma” as your search term in the Rare Disease Database.)

Several other benign and malignant forms of cancer have been described in individuals with HLRCC including breast cancer, bladder cancer, gastrointestinal stromal tumors (GISTs), adrenal incidentaloma, Leydig-cell tumors of the testes, and ovarian cystadenomas. However, it is unknown whether these are simply coincidental findings or somehow related to HLRCC.

Causes

HLRCC is an inherited condition and is passed down in families. It’s caused by mutations in the fumarate hydratase (FH) gene. The FH gene provides your body with instructions to make an enzyme called fumarase. Mutations may result in a buildup of a molecule called fumarate in your body. This buildup of fumarate is thought to contribute to the development of leiomyomas.

HLRCC is inherited in an autosomal dominant pattern. This means that only one copy of the mutated gene is enough to cause the condition. Children born with two mutated copies of the FH gene have a different condition called fumarase deficiency, which is typically fatal in infancy.

In some cases, new mutations in the gene can occur in people with no history of the condition in their family.

AFFECTED POPULATIONS

HLRCC affects males and females in equal numbers. The disorder may be recognized more readily in females because of the development of uterine fibroid and associated symptoms. The exact incidence and prevalence of HLRCC in the general population is unknown.

DISORDERS WITH SIMILAR SYMPTOMS

Symptoms of the following disorders can be similar to those of HLRCC. Comparisons may be useful for a differential diagnosis.

There are several rare disorders that are characterized by a genetic predisposition to renal cell cancer. These disorders have additional symptoms as well. Such disorders include Von-Hippel-Lindau disease, Birt-Hogg-Dube syndrome, and hereditary papillary renal carcinoma, tuberous sclerosis complex, hereditary papillary renal cell carcinoma, and familial renal oncocytoma. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

DIAGNOSIS

A diagnosis of HLRCC is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Criteria required for diagnosing HLRCC have been proposed:

1. Multiple cutaneous leiomyomas with at least one histologically confirmed leiomyoma.

2. A single leiomyoma in the presence of a positive family history of HLRCC.

Because of the additional symptom of uterine fibroids, a diagnosis is usually suspected earlier in females than in males.

Clinical Testing and Workup

A skin biopsy, which is the surgical removal and microscopic study of a small sample of skin tissue, is necessary in order to confirm the presence of leiomyomas. A leiomyoma cannot be diagnosed by its appearance on the skin because of it can resemble other skin conditions.

The activity of fumarate hydratase, the enzyme encoded by the FH gene, can be measured in certain types of cells including skin fibroblasts and lymphoblastoid cells. Reduced activity of functional fumarate hydratase is indicative of HLRCC.

Molecular genetic testing can confirm a diagnosis of HLRCC. In individuals suspected of having HLRCC, molecular genetic testing can detect mutations in the FH gene known to cause the disorder and so confirm the diagnosis.

Pathologists may stain sections of leiomyomas and kidney cancers to detect protein changes which indicate the presence of increased fumarate in the tumor tissue.

Individuals with HLRCC should receive regular (annual) screening for renal tumors may include a computed tomography (CT) scan or magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An ultrasound is another x-ray technique sometimes used to detect kidney cancer. However, in HLRCC, kidney tumors have unique qualities that may be seen on a CT scan or MRI, but missed on an ultrasound. In general, MRI scanning is preferred for screening in HLRCC as it avoids repeated radiation associated with regular CT scans. The exact age at which kidney screening should start requires careful discussion between parents and doctors and can differ between families but experts agreed that screening could be considered from age 10/11 years (Menko et al 2014).

STANDARD THERAPIES

Treatment

The treatment of HLRCC is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, plastic surgeons, dermatologists, kidney specialists (nephrologists), gynecologists, oncologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families and genetic testing can usually determine which family members may be at risk of symptoms and require surveillance.

Skin lesions may not require treatment and many dermatologists do not recommended surgical excision because it can lead to scarring and damage to the skin. Surgical excision is most often used for a solitary, painful lesion. If painful or unsightly or tightly-packed together skin lesions do require removal two methods that have been used are cryotherapy and CO2 laser ablation.

Cryotherapy is the use of extreme cold to freeze and destroy the tissue and cells of skin lesions and is a minimally invasive treatment option. With cryotherapy a freezing substance such as liquid nitrogen or argon gas is applied directly to the lesion. Cryotherapy is most effective for single or small lesions. CO2 laser ablation is the use of a laser beam to directly destroy skin lesions.

Pain relief is necessary for some individuals with HLRCC and can include a variety of medications including calcium channel blockers, alpha blockers, anti-depressants, nitroglycerine, and anti-seizure (anti-epileptic) medications.

When uterine fibroids cause symptoms treatment may include the gonadotropin-releasing medications, anti-hormonal medications, and pain relievers. Uterine fibroids, in women with HLRCC, often eventually require surgical intervention including surgery designed to remove symptomatic fibroids and repair the damage to the uterus (myomectomy). In some cases, the surgical removal of the uterus (hysterectomy) may be necessary. These procedures generally prove necessary at a younger age than is normally found in the general population.

Kidney tumors may be removed surgically. Because even a small, solitary tumor can be aggressive and metastasize, complete removal of the kidney (total nephrectomy) should be considered if there is any doubt that a partial nephrectomy would be curative.

Type of Doctor Department :A Urologist oncologist.