Continuing Education Activity

Piloleiomyomas are a type of cutaneous leiomyoma. Patients with one or more piloleiomyomas should be evaluated for Reed syndrome, also known as Hereditary Leiomyomatosis with Renal Cell Carcinoma, which is likely an underdiagnosed condition. Affected patients suffer from early onset type 2 papillary renal cell carcinoma, which, in 50% of patients, is metastatic at the time of diagnosis. This activity illustrates the evaluation and management of cutaneous leiomyomas, and highlights the role of the interprofessional team in improving care for patients with cutaneous leiomyomas.

Objectives:

• Describe the presentation of a cutaneous piloleiomyoma.
• Outline the diagnostic criteria for Reed's Syndrome, also known as Hereditary Leiomyomatosis. with Renal Cell Carcinoma.
• Review the annual screening guidelines for patients with a diagnosis of Reed's Syndrome, also known as Hereditary Leiomyomatosis with Renal Cell Carcinoma.
• Explain the importance of improving care coordination amongst the interprofessional team to enhance the delivery of care for patients with cutaneous leiomyomas.

Introduction

Cutaneous leiomyomas are rare, benign, smooth muscle tumors that are subcategorized based on the origin of the smooth muscle within the tumor. The most common type of cutaneous leiomyomas, angioleiomyomas, arise from the tunica media of blood vessels. The 2 other subtypes, piloleiomyomas and genital leiomyomas, arise from the arrector pili musculature of the hair follicle and from the smooth muscle found in the scrotum, labia, or nipple, respectively. Although the smooth muscle tumors themselves are benign, patients with multiple cutaneous leiomyomas (piloleiomyomas) may be harboring an underlying genetic mutation which increases their susceptibility to developing renal cell carcinoma. In addition, both the piloleiomyomas and genital leiomyomas may be problematic due to pain or discomfort.[1][2][3]

Etiology

Piloleiomyomas can develop sporadically or present as part of an autosomal dominant genetic syndrome. Multiple cutaneous and uterine leiomyomatosis (MCUL), also known as Reed syndrome, often occurs as a result of a heterozygous germline mutation in the gene encoding fumarate hydratase (FH), an important enzyme in the Krebs’s cycle, which assists with the conversion of fumarate to malate. When piloleiomyomas occur as a result of a genetic syndrome, they tend to occur earlier in life, with an average age of onset of lesions at 25 years old (ranges from 10 to 50 years old). The pathophysiology of the relationship between heterozygous fumarate hydratase deficiency and the production of leiomyomas remains unknown, but it is suspected that fumarate hydratase may function to some degree as a tumor suppressor.[4][5][6]

According to an article published in JAMA Dermatology in 2005 by Alam et al., approximately 89% of patients with multiple cutaneous leiomyomas do possess a heterozygous germline mutation in fumarate hydratase (FH). Female patients with FH mutations commonly display both piloleiomyomas (85%) and symptomatic uterine fibroids (greater than 90%). Generally, the uterine leiomyomas associated with FH mutation are larger (up to 10 cm), more numerous, develop at a younger age, and more frequently require hysterectomy in comparison to non-hereditary uterine leiomyomas. However, by far, the most concerning feature of an FH mutation is the association with an aggressive variant of renal cell carcinoma (type 2 papillary renal cell carcinoma) which develops in approximately 15% of patients. Unfortunately, in this subset of patients who do indeed develop renal cell carcinoma, the malignancy tends to be metastatic at the time of diagnosis in approximately 50% of patients. Generally, the malignant renal lesions are unilateral, small, and solitary and there have been reports of metastatic disease in malignant lesions as small as 1 cm. Hereditary Leiomyomatosis with Renal Cell Carcinoma (HLRCC), is synonymous with Reed’s syndrome; and despite the fact that the title includes renal cell carcinoma, patients do not need to have RCC to be diagnosed with HLRCC. 

Epidemiology

Data regarding the prevalence and incidence of cutaneous leiomyomas is limited. Piloleiomyomas tend to occur much more frequently in adults than children, all races seem to be equally affected, and there is no increase in incidence between males or females. As previously mentioned, angioleiomyomas are thought to be the most common variant, followed by piloleiomyomas, then genital leiomyomas.

Pathophysiology

The pathophysiology of the three variants of cutaneous leiomyomas remains elusive, but as previously mentioned, underlying fumarate hydratase mutations are likely driving the development of multiple cutaneous piloleiomyomas in HLRCC (Reed syndrome).

Histopathology

Histological examination of piloleiomyomas reveal interweaving bundles of smooth muscle cells with characteristic “blunt-ended cigar-shaped nuclei” and eosinophilic cytoplasm admixed with collagen bundles. Piloleiomyomas are typically found in the reticular dermis, close to a hair follicle. Mitotic figures are rarely seen, but if present or abundant, should raise suspicion for leiomyosarcoma. Usually, piloleiomyomas are easily identified on H and E staining, but “special stains” may occasionally be needed to confirm smooth muscle origin. Masson's trichrome stain, smooth muscle myosin (SMS), Van Gieson, stain, and immunohistochemical stains for smooth muscle markers, actin, and desmin, may be required for appropriate staining. Additional immunohistochemical testing may be performed to identify fumarate hydratase deficiency in the specimen or accumulation of precursor substances.

Angioleiomyomas are deeper, well-circumscribed neoplasms, mostly located in the upper subcutaneous tissues. The pathological examination will reveal tightly compact myocytes in a world pattern around vascular channels.

Genital leiomyomas, particularly scrotal lesions, tend to have a more spindle cell appearance, while vulvar lesions display more epitheloid cells.

History and Physical

Piloleiomyomas characteristically present as either a solitary dermal nodule or multiple dermal nodules in a clustered, linear, dermatomal, or scattered distribution. When multiple piloleiomyomas are present, it is not unusual to have two separate collections in different anatomical locations. The nodules range in size from 2 mm to 20 mm and may be skin-tone, pink, red, or red-brown in color. Solitary piloleiomyomas tend to present on the lower extremity, while multiple piloleiomyomas frequently present on the extensor surface of extremities and trunk.  The most common presenting complaint amongst patients with multiple piloleiomyomas is a pain, which may occur spontaneously or with provocation by pressure, cold temperatures, strong emotion, or light touch. The pain is typically described as a sharp, shooting, or aching in quality. Most patients begin to develop these lesions between 20 to 40 years of age. 

Genital leiomyomas, as their name implies typically develop on the genitals, including the scrotum, penis, and vulva, but they may also be found on the nipple-areolar complex. The lesions are generally an asymptomatic, solitary nodule. On occasion, they may present as a pedunculated lesion which may lead to their dismissal as an acrochordon or a genital wart.

Angioleiomyomas usually present in females in their 40s to 60s as a firm, often painful, subcutaneous nodule on the lower extremity.

Evaluation

History and physical examination will often direct physicians toward the diagnosis of a cutaneous leiomyoma, but histological examination via biopsy is usually performed to confirm a suspected diagnosis. Additional workup beyond biopsy is generally not indicated for genital leiomyomas or angioleiomyomas. However, further history and workup are indicated in patients with multiple piloleiomyomas due to the strong correlation with HLRCC or Reed syndrome. Some authors even recommend further evaluation in patients with one, isolated, histologically confirmed piloleiomyoma.

Both major and minor clinical diagnostic criteria have been published to aid in the “likely” diagnosis of hereditary leiomyomas and renal cell carcinoma. The only major criterium is the presence of multiple histologically confirmed piloleiomyomas, and the minor criteria include surgical treatment for uterine leiomyomas before age 40, type 2 papillary renal cell carcinoma before age 40, or a first-degree family member who meets one of the previously mentioned criteria. The diagnosis of HLRCC should be strongly considered if a patient displays either the 1 major diagnostic criteria or 2 of the 3 minor criteria. Note that heterozygous fumarate hydratase is not considered as either a major or minor criteria because on rare occasions patients affected with HLRCC may test negative for a fumarate hydratase deficiency. In such scenarios, either the piloleiomyomas or the uterine leiomyomas may be immunohistochemically stained to evaluate for excessive accumulation of fumarate. A fumarate enzyme assay may also be performed to evaluate for fumarate hydratase deficiency, and FH activity less than 60% of normal is indicative of HLRCC.

HLRCC is a relatively novel disease process initially recognized in 2001, and there is limited long-term data regarding the development of renal cell carcinoma among patients with the condition. Patient’s as young as ten years old have been diagnosed with HLRCC associated renal cell carcinoma, which makes screening at a young age essential. Children should be initially screened for fumarate hydratase deficiency between the ages of 8 to 10, and if positive, they should receive an annual MRI to screen and monitor for the development of renal cell carcinoma. The same protocol stands true for adults diagnosed with HLRCC with positive fumarate hydratase mutation. In addition, patients should undergo a complete physical and gynecological exam (if indicated) yearly, along with dermatological examinations biannually. First-degree family members of affected patients should also be appropriately screened for HLRCC with genetic testing for fumarate hydratase deficiency, along with appropriate abdominal or pelvic screening.

Treatment / Management

 Effective treatment of symptomatic piloleiomyomas is often frustrating for both the physician and the patient due to a high rate of recurrence after surgical intervention and lack of successful pharmacological treatment options. The method of treatment is based upon the number of lesions present, the anatomical location of the lesions, and the degree of discomfort they cause the patient. The gold standard of therapy is surgical excision if a patient has a small, localized amount of piloleiomyomas. An in-depth discussion regarding the significant risk of local recurrence, sometimes as early as six weeks after removal, should be held with the patient prior to implementing treatment. Additional ablative treatment options include cryosurgery and carbon dioxide (CO2) laser.[7][8][9]

Pharmacological therapy may be indicated for patients who are not considered to be surgical candidates (i.e., extensive, widespread piloleiomyomas or patient is unwilling to accept the possibility of recurrence). Most therapies, such as nifedipine, nitroglycerin, and doxazosin center around reducing contraction of the smooth muscle of the pilosebaceous unit. Gabapentin, pregabalin, and duloxetine may be used to help control pain associated with the lesions. Injection of botulinum toxin into the lesions has shown mixed results for symptomatic relief.

Differential Diagnosis

The differential diagnosis of cutaneous leiomyomas can be extensive given the non-specific appearance of solitary lesions. However, multiple cutaneous leiomyomas, specifically piloleiomyomas, tend to have a distinct clinical appearance. Should the patient voice concerns or pain or discomfort associated with the lesions, additional clinical entities that should be entertained include: blue rubber bleb nevus, angiolipomas, neuromas, glomus tumors, neurilemmoma, endometrioma, granular cell tumor, and eccrine spiradenomas which are part of the painful skin lesion differential. Dermatofibromas may also be considered in the differential diagnosis.

Enhancing Healthcare Team Outcomes

Cutaneous leiomyomas are rare lesions that are difficult to diagnose and treat. Thus, they are best managed with an interprofessional team that includes the primary care provider, nurse practitioner, dermatologist, plastic surgeon, and pathologist. The problem with the treatment is that the lesions tend to recur. While surgery is the ideal method of treatment, excessive excision for a benign lesion is considered too aggressive. Pharmacological means of treatment have not met with much success. Observation in asymptomatic patients is a reasonable alternative. All patients need follow up because these lesions can grow and compress adjacent structure. Some patients with inherited lesions are prone to renal cell cancer and thus close follow up is necessary.[2]