Introduction
Leiomyomas are benign smooth muscle tumors of the skin and uterus. The cutaneous development of leiomyoma occurs in the third decade of life. The growth is seen around the hair follicles of the skin. The tumors appear clinically as bumps on the trunk, arms, legs, or face and appear darker or the same color as the skin. The tumors are initially few and increase progressively in size and number. The tumor responds more to cold and light touch than normal skin and is painful. Uterine leiomyomas appear as large fibroids in the uterus. Few patients with leiomyoma develop renal cell cancer, and their symptoms are kidney mass, blood in urine, and lower back pain. Patients with leiomyomas are diagnosed with kidney cancer in middle age, and most of them are asymptomatic until the last stage.
What Is Epidemiology For HLRCC?
It is an autosomal dominant rare condition, with few reported cases worldwide. However, children with two abnormal gene copies exhibit fumarate deficiency that can be fatal.
What Is the Cause Of HLRCC?
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Mutations in the FH gene responsible for generating fumarate hydratase cause this disorder. This enzyme is a part of the Krebs cycle and enables the conversion of fumarate to malate for energy production.
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The condition is inherited in an autosomal dominant pattern. The second gene copy can undergo mutation when subjected to ultraviolet radiation or error in DNA (deoxyribonucleic acid) replication.
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A mutated FH gene causes a buildup of fumarate in the cell, disrupting cell oxygen regulation.
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Two mutated gene copies and chronic hypoxia result in hereditary leiomyomatosis and renal cell cancer.
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Renal tumors display heterozygosity due to second mutations in FH, suggesting that the FH gene has a tumor-suppressing function.
What Are the Symptoms Of HLRCC?
The age of onset, severity and clinical manifestations of HLRCC is difficult to predict.
1. Cutaneous Leiomyomas:
They present pinkish or reddish-brown nodules on the trunk and extremities, sometimes in a segmental pattern, and rarely occur on the face. The nodules are first noticed in the mid-twenties and increase in number with age. They are tender with sensitivity to light touch and cold. The nodules indicate HLRCC and must be carefully examined.
The nodules arise from pilorum muscles attached to hair follicles.
On histological examination, smooth muscle cells contain blunt-ended nuclei in the center.
2. Uterine Leiomyomas:
The fibroids appear at a younger age in women and are large and multiple. The symptoms are pelvic pain with irregular and heavy periods. Therefore, the treatment must be initiated early. If the condition does not resolve with treatment, the woman might undergo a hysterectomy (womb removal) or myomectomy (uterine fibroid removal) at a young age. Histologically there are single or multinucleated cells with nucleoli bounded by a perinuclear halo.
3. Renal Cell Cancer:
Most patients with renal cancers are asymptomatic, but some may develop hematuria, palpable mass in the abdomen, and back pain. Typically a single tumor in one of the kidneys appears as a renal tumor, benign renal cyst, and cystic renal tumor. However, renal tumors are aggressive, the five-year survival rate is poor in metastatic cases, and metastasis occurs even when the tumor is small.
4. Uterine leiomyosarcomas are aggressive cancer and require early intervention. However, the occurrence is uncertain in HLRCC.
5. Other conditions are breast cancer, bladder cancer, a macronodular adrenocortical disease with Cushing syndrome, and Pheochromocytoma of the adrenal gland.
However, their association with HLRCC remains to be examined.
How to Diagnose HLRCC?
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Medical history assessment to check for a history of HLRCC in the family.
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Genetic testing of the FH gene. HLRCC is associated with pathological variants of the FH gene.
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Prenatal genetic testing among expecting parents
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MRI (magnetic resonance imaging) or ultrasound to detect uterine leiomyoma.
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CT (computed tomography) scan with contrast or MRI with gadolinium to diagnose renal cancer.
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Renal ultrasound to characterize the tumor.
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Diagnostic criteria used by experts to confirm HLRCC is
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Surgical treatment of uterine leiomyoma before 40 years
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Diagnosis of type 2 papillary renal cancer by 40 years intends to metastasize early
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Diagnosis of HLRCC among close relatives
If any of the two criteria is diagnosed, HLRCC is likely in such patients.
What Is the Differential Diagnosis Of HLRCC?
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Cutaneous lesions:
Nodules on the skin can appear in various conditions. However, multiple nodules in cutaneous leiomyoma are a rare and diagnostic feature for HLRCC.
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Uterine leiomyomas are benign tumors in women that may or may not be associated with HLRCC.
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Renal cell cancer may develop independently of HLRCC.
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Hereditary papillary renal carcinoma.
How to Treat HLRCC?
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Surveillance of skin, uterus, and kidneys in high-risk individuals using imaging studies. MRI annually with two to three millimeters slices through the kidney is done to detect renal tumors.
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In small and localized tumors, partial nephrectomy is advised. However, some studies suggest complete resection.
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A hysterectomy is done if large fibroids are present. Fibroids diagnosed early are treated with hormonal therapies, pain medications, or endovascular procedures.
Cutaneous Nodules:
Asymptomatic nodules do not require treatment. However, surgical excision of single painful nodules is done. Multiple nodules are difficult to treat. Other methods include lasers, cryoablation (cold liquid or cryoprobe destroys abnormal tissue), and medications like calcium channel blockers, antidepressants, and antiepileptic drugs to relieve pain. Studies have also suggested the use of Botox to relieve pain.
Uterine Leiomyomas:
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Medical intervention.
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Gonadotropins- releasing hormone agonists.
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Anti-hormonal medications.
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Pain relievers.
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They are used to reduce the size of fibroids for further surgical intervention like myomectomy or hysterectomy. Myomectomy is the preferred surgical treatment as it preserves uterine function.
Renal Cell Cancer
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Due to the disease's aggressive nature, early intervention is recommended.
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Nephron-sparing therapy is advised for small renal tumors.
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Surgical excision of the tumor is done in the initial stage. If retroperitoneal lymph node involvement is detected, lymph nodes must be dissected completely.
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Radical nephrectomy or partial nephrectomy is advised when there is a palpable mass.
What Is the Prognosis Of HLRCC?
Early intervention in HLCC with partial or complete nephrectomy and localized tumor mass has a better survival rate among patients and no sign of disease after follow-up. However, in delayed diagnoses where metastasis has occurred, the prognosis is poor and is fatal.
Conclusion
Identifying at-risk individuals is important to diagnose HLRCC. The renal tumor can metastasize even when tumors are small, leading to a poor prognosis. Clinical trials are underway for targeted therapy of HLRCC, which can improve prognosis.
