Leiomyoma of the skin: causes, symptoms, treatment

Cutaneous leiomyoma is a benign tumor of smooth muscle cells. Three main forms occur on the skin: piloleiomyoma, which arises from the erector pili muscles; angioleiomyoma, which arises from the smooth muscle fibers of the vascular wall; and genital leiomyoma, which is associated with the smooth muscles of the scrotum, penis, labia majora, nipple, and areola. All forms are considered benign; however, they are often accompanied by severe pain with pressure, cold, or emotional stress, which is important for quality of life. [1]

Piloleiomyomas are often multiple, arranged in groups or dermatomally, range in color from flesh-colored to reddish-brown, and typically range in diameter from 2 to 20 mm. Angioleiomyomas are often solitary, forming subcutaneous nodules, often on the lower extremities and feet; they are firm and tender to palpation. Genital leiomyomas are less common but can reach large sizes and require surgical removal due to discomfort or cosmetic defects. [2]

The key clinical symptom is pain. It is paroxysmal and often triggered by cold, pressure, or stress. In some patients, the pain significantly limits daily activities, highlighting the need for proper diagnosis and individualized treatment. [3]

Of particular importance is the hereditary syndrome of "cutaneous and uterine leiomyomas with risk of kidney cancer," also known as hereditary leiomyomatosis and kidney cancer. It is caused by mutations in the fumarate hydratase gene and is accompanied by multiple cutaneous leiomyomas, early and multiple uterine fibroids, and an increased risk of aggressive kidney cancer, which requires oncological surveillance. [4]

Code according to ICD-10 and ICD-11

In the International Classification of Diseases, Tenth Revision, benign skin tumors are coded in block D23 "Other benign neoplasms of the skin" with localization specified in subheadings D23.0-D23.9. In clinical practice, for cutaneous leiomyoma, the corresponding subheading for the anatomical region is used; in the absence of specification, D23.9 "Other benign neoplasms of the skin, unspecified" is used. In individual cases, with a deep location and involvement of soft tissues, D21.* "Other benign neoplasms of connective and other soft tissues" is used, indicating the region. [5]

In the eleventh version of the ICD-11 classification, code 2E86 "Benign tumor of smooth or skeletal muscle tissue" is provided for benign smooth muscle neoplasms, with post-coordination of the anatomical location of the skin through expansion codes. In the absence of detailed coding, 2E86.Z "Benign tumor of smooth or skeletal muscle tissue, unspecified" is used. Separate oncogenetic categories are used to describe the associated hereditary condition, and for benign skin tumors, assignment to "other specified benign skin neoplasms" of block 2F2Y is allowed when post-coordination is not available. [6]

Table 1. Codes for cutaneous leiomyoma

System	Preferred code	Alternative codes	Comment
ICD-10	D23.x by localization	D23.9 if unspecified; D21.x if soft tissue is involved	The choice depends on the depth and exact area of the skin.
ICD-11	2E86 + post-coordination "skin"	2E86.Z; 2F2Y if postcoordination is not possible	It is preferable to indicate anatomy with an extension code

[7]

Epidemiology

Piloleiomyomas are rare, and their exact prevalence is unknown due to underreporting and similarities to other nodular dermatoses. They are often diagnosed in adults aged 20–50 years, and are often multiple, increasing the likelihood of seeking dermatological attention due to pain and cosmetic concerns. [8]

Angioleiomyoma is a more well-studied form. According to clinical series and reviews, it accounts for approximately 4.5-5.0% of all benign soft tissue tumors, with the proportion in the foot and ankle region accounting for approximately 0.2% of benign lesions. It is most commonly localized in the lower extremities in adults, with a slightly higher prevalence in women. [9]

Angioleiomyoma is extremely rare in the head and neck: in one retrospective series over 34 years, it was recorded in only 0.18% of all benign head and neck tumors. These figures highlight the rarity of diagnosis and potential diagnostic delays. [10]

Hereditary leiomyomatosis and kidney cancer are considered a rare genetic syndrome; according to expert centers and cancer guidelines, it accounts for a small proportion of hereditary kidney cancer syndromes. Early detection of cutaneous leiomyomas and annual renal oncology screening are recommended in high-risk groups. [11]

Table 2. Epidemiological landmarks

Indicator	Meaning
The proportion of angioleiomyoma among benign soft tissue tumors	~4.5-5.0%
The prevalence of angioleiomyoma among benign neoplasms of the foot and ankle	~0.2%
The prevalence of angioleiomyoma among benign tumors of the head and neck	~0.18%
Typical age	30-60 years old

[12]

Reasons

Piloleiomyoma originates from the smooth muscle of the erector pili muscles. Triggers for localized smooth muscle cell growth have not been identified; microtrauma and local growth factors are discussed, but there is no convincing evidence. [13]

Angioleiomyoma develops from the smooth muscle elements of the vascular wall, primarily the venous wall. Tumor formation is accompanied by smooth muscle proliferation and thickening of the walls of intratumoral vessels, which is reflected in the histological picture. [14]

Genital leiomyomas arise from the dartonius muscle of the scrotum, smooth muscle of the penis, vulva, or areola; the cause is considered to be local proliferation of smooth muscle cells due to unknown stimuli; in some cases, hormonal influences have been described. [15]

Hereditary leiomyomatosis, caused by mutations in the fumarate hydratase gene, is a separate entity. Fumarate accumulation leads to a pseudohypoxic signaling response and oncogenic activation, which explains the multiple skin nodules and high risk of renal cell carcinoma. [16]

Risk factors

The presence of multiple, early-onset skin nodules, especially in adults under 40 years of age, increases the likelihood of a hereditary syndrome with a mutation in the fumarate hydratase gene and requires genetic counseling. A family history of uterine fibroids in female relatives on the maternal side also increases suspicion of the syndrome. [17]

Hypothermia and mechanical irritation do not increase the risk of tumor development, but they do reliably provoke pain in existing nodes. This is important to consider when assessing "pain triggers" and selecting non-pharmacological measures. [18]

No specific risk factors have been identified for angioleiomyoma, but the tumor is more often found on the lower extremities in adults, which may reflect the influence of local hemodynamics and microtrauma. [19]

Dartonic leiomyoma of the scrotum occurs in middle-aged and older men. In most cases, it is solitary and grows slowly, leading to delayed presentation. [20]

Pathogenesis

Piloleiomyoma develops due to clonal proliferation of smooth muscle cells of the erector pili muscle, forming bundles of spindle-shaped cells. Pain is caused by increased innervation and mechanical compression of nerve endings, as well as smooth muscle contraction caused by cold and stress stimuli. [21]

Angioleiomyoma is characterized by a combination of smooth muscle proliferation and multiple thin- and thick-walled vessels. These morphological features create conditions for local ischemia and nociceptor irritation upon palpation, which clinically manifests as pain. [22]

In hereditary leiomyomatosis, loss of fumarate hydratase function leads to accumulation of the oncometabolite fumarate, stabilization of hypoxia-inducible factor, and activation of pseudohypoxia pathways, which increases smooth muscle cell proliferation and oncogenic risk in the renal parenchyma. [23]

Immunohistochemically, benign smooth muscle tumors of the skin express alpha-smooth muscle actin, desmin, and h-caldesmon, which allows confirmation of smooth muscle differentiation and distinction from fibrous and neurogenic tumors. [24]

Symptoms

Piloleiomyomas typically present as multiple, dense papules and nodules 2-20 mm in diameter, flesh-colored or reddish-brown in color. Often, lesions are grouped or segmented across the dermatome. The main complaint is pain upon touch, cold, or spontaneous attacks. [25]

Angioleiomyomas are usually solitary, round, subcutaneous nodules with well-defined borders, most commonly found on the shin, ankle, or foot. They grow slowly and are often painful when pressed or at rest, prompting patients to seek surgical treatment. [26]

Genital leiomyomas, including dartonotic leiomyoma of the scrotum, are usually painless and grow slowly, reaching sizes from 1 to 14 cm; when significantly enlarged, they cause discomfort, a feeling of heaviness and a cosmetic problem. [27]

In hereditary syndromes, tens and hundreds of nodes are often present, which is accompanied by severe pain, decreased quality of life and the need for combination therapy aimed at pain control. [28]

Classification, forms and stages

There are three clinical forms of cutaneous leiomyoma: piloleiomyoma, angioleiomyoma, and genital leiomyoma. Each form has a typical tissue type, clinical presentation, and histological features, which are important for choosing treatment strategies. [29]

Piloleiomyoma is often multiple and segmental; angioleiomyoma is more often solitary, nodular, and subcutaneous; genital leiomyoma is associated with areas rich in specific smooth muscle. These differences determine the indications for surgical removal or conservative analgesic management. [30]

Histologically, angioleiomyoma is subdivided into solid, venous, and cavernous variants, reflecting the relative proportions of smooth muscle and vascular components. The practical significance of this detailing is limited and is mostly descriptive. [31]

Staging is not used for cutaneous leiomyomas, as the tumors are benign. Critical features that require exclusion of leiomyosarcoma include rapid growth, ulceration, severe atypia, and high mitotic activity based on histology. [32]

Table 3. Forms of cutaneous leiomyoma

Form	Source fabric	Typical age and localization	Pain	Comment
Piloleiomyoma	The erector muscle of the hairs	20-50 years; trunk, limbs; multiple	Often	Often segmental distribution
Angioleiomyoma	Vascular smooth muscle	30-60 years; lower limbs, feet	Often	Solitary subcutaneous node
Genital	Dartonic and other genital smooth muscles	Middle age; scrotum, nipple, areola, vulva	Variable	Often large sizes

[33]

Complications and consequences

The primary problem is chronic pain, which impairs sleep, performance, and mood. Vasovagal reactions during pain attacks have been reported in some patients. Timely analgesic management and discussion of surgical options significantly improve quality of life. [34]

Recurrence after excision is possible with incomplete removal, especially for multiple pyloleiomyomas, when removal of all lesions is technically impossible. For angioleiomyoma, complete excision usually results in a cure. [35]

Malignant transformation into leiomyosarcoma is extremely rare for cutaneous leiomyomas. However, if signs of rapid growth, ulceration, or atypia appear on biopsy, repeated diagnosis and oncological monitoring are required. [36]

In hereditary leiomyomatosis, the consequences extend beyond dermatology: there is an increased risk of aggressive kidney cancer. Therefore, the patient and their relatives require genetic counseling, annual renal magnetic resonance imaging, and gynecological monitoring. [37]

When to see a doctor

A doctor should be consulted if a new, firm skin nodule appears, is particularly painful with pressure or cold, or if the nodule is rapidly enlarging. Clinical evaluation can help differentiate benign from potentially dangerous lesions and determine the need for a biopsy. [38]

In cases of multiple nodules and a family history of uterine fibroids or kidney cancer, consultation with a dermatologist and geneticist is necessary to rule out hereditary leiomyomatosis. Early detection of the syndrome allows for preventive cancer screening. [39]

If a nodule in the foot or lower leg is painful, firm, and mobile, angioleiomyoma should be considered as a possible cause and referred for imaging or biopsy. This will expedite diagnosis and allow for timely surgical excision. [40]

In case of nodes in the area of the scrotum, nipple or areola, genital leiomyoma and other soft tissue tumors of this area should be excluded; early excision solves the problem of pain and cosmetics. [41]

Table 4. Red flags requiring prompt assessment

Sign	Possible meaning
Rapid growth, ulceration	Rule out leiomyosarcoma
Tens of nodes, early age	Rule out a hereditary syndrome
Intense pain, sleep disturbances	Plan for active pain control
Foot or shin knot	Consider angioleiomyoma

[42]

Diagnostics

The first step is a clinical examination with palpation and pain assessment, pain provocation with cold or pressure, and dermatoscopy. Dermatoscopy is nonspecific, so the decision to proceed with invasive verification is made with a low threshold. [43]

The second step is a biopsy. Histology of piloleiomyoma reveals bundles of spindle-shaped smooth muscle cells with "cigar-shaped" nuclei; in angioleiomyoma, a characteristic combination of smooth muscle bundles and multiple thin- and thick-walled vessels. This is the "gold standard" for diagnosis. [44]

The third step is immunohistochemistry to confirm smooth muscle differentiation and exclude mimics. Positive results for alpha-smooth muscle actin, desmin, and h-caldesmon are expected, which helps differentiate from myofibroblastic, neurogenic, and fibrous tumors. [45]

The fourth step is evaluation for a hereditary syndrome in patients with multiple nodules, early onset, and a positive family history. Genetic counseling and fumarate hydratase gene mutation testing are recommended, as well as baseline nephro-oncology imaging according to a surveillance protocol. [46]

Table 5. Histology and immunoprofile

Sign	Piloleiomyoma	Angioleiomyoma
Histology on H&E	Intertwined bundles of smooth muscle	Bundles of smooth muscles + numerous vessels with thickened walls
SMA	Positive	Positive
Desmin	Positive	Positive
h-caldesmon	Positive	Positive

[47]

Differential diagnosis

The most common confusion is with "painful" skin tumors. Classic mnemonic sequences include leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemma, endometrioma, glomus tumor, and granular cell tumor. Targeted biopsy and immunohistochemistry resolve the issue. [48]

Angioleiomyoma should be differentiated from glomus tumors and other vascular nodes, as well as from angiolipoma. Localization, pain pattern, dermatoscopy, and histology with a pronounced smooth muscle component and typical vessels are helpful. [49]

For foot nodules, the differential diagnosis includes fibromas, schwannomas, and ganglion cysts. Magnetic resonance imaging of soft tissues is used for deep lesions or preoperative planning. [50]

For genital nodules, benign soft tissue tumors of the scrotum and areola, including epidermoid cysts and fibroepithelial polyps, are considered; biopsy or excision usually clarifies the diagnosis.[51]

Table 6. Differential diagnosis of painful skin nodes

State	Distinguishing features	Confirmation
Leiomyoma	Pain with cold and pressure, dense knot	SMA, desmin, h-caldesmon "plus"
Eccrine spiradenoma	A bluish, very painful nodule	Histology of adnexal tumor
Glomus tumor	Severe sensitivity to cold, subungual localization	Histology, clinical presentation
Angiolipoma	Softer, fatty component	Histology of lipomatous tumor

[52]

Treatment

The first principle is individualization. For solitary nodules, especially angioleiomyomas, complete surgical excision within healthy tissue is preferred. This ensures a high probability of cure and relieves pain. Recurrence is rare with complete removal. [53]

For multiple pyelomyomas, complete surgical removal is impractical. In such cases, targeted excision of the most painful lesions is chosen, combined with medical pain control. The decision is made at a consultation, taking into account the location, number of nodes, and the patient's expectations. [54]

Medication-induced analgesia is based on reducing smooth muscle contractility. Calcium channel blockers, primarily nifedipine, have been shown to reduce pain attacks, especially during the cold season. They are prescribed in courses under monitoring of blood pressure and tolerance. [55]

Neuropathic pain modulators such as gabapentin and pregabalin are used adjuvantly, reducing the frequency and intensity of attacks. The combination of nifedipine and gabapentin has been described as effective for refractory pain in patients with multiple nodules. [56]

Alpha-blockers, such as phenoxybenzamine, may reduce cold-induced pain in some patients. Prescribing this class requires cardiac vigilance and monitoring for side effects, so it is used in selected cases. [57]

Local methods include applying 5% lidocaine patches to the most painful areas, which provides temporary numbness. This approach is useful for distributed nodules and moderate pain and can be combined with systemic therapy. [58]

Botulinum toxin type A injections have demonstrated clinical benefit in small series and individual studies, reducing pain at rest and with palpation, improving quality of life. This method is considered for multiple painful nodules when surgery is limited. Individual selection of the dose and number of injection sites is necessary. [59]

Laser techniques—carbon dioxide laser ablation and fractional carbon dioxide laser—are used to reduce the number of nodules and destroy nerve fibers in lesions. Publications have shown pain reduction and satisfactory cosmetic results, especially for multiple superficial lesions. This technique requires experience and informed consent regarding the risk of scarring. [60]

Cryotherapy and electrosurgery have been shown to be ineffective against piloleiomyoma and are associated with a higher risk of recurrence and cosmetic defects, so they are not generally recommended as treatments of choice.[61]

For genital leiomyomas and dartonotic leiomyomas of the scrotum, the standard procedure is complete excision with histological verification. In cases of atypia or close resection margins, repeat excision is advisable. The patient is advised of the low risk of recurrence with complete excision and the need for observation for the appearance of new nodes. [62]

Table 7. Comparison of treatment methods

Method	Indications	Advantages	Restrictions
Complete excision	Solitary, angioleiomyoma	High chance of cure	Scar, not applicable for multiple
Targeted excision	The most painful nodes	Quick effect	Multiple residual foci
Nifedipine	Attacks of pain	Decreases contractility	Hypotension, monitoring
Gabapentin	Neuropathic pain	Good tolerability	Drowsiness
Lidocaine patches	Local pain	Immediate local effect	Temporary action
Botulinum toxin	Multiple painful nodes	Reducing pain and triggers	Repeated procedures
CO₂ laser	Multiple superficial	Pain relief, cosmetics	Risk of scarring

[63]

Prevention

There is no specific prevention for the development of cutaneous leiomyoma. It is recommended to avoid pain triggers, including local cooling and mechanical irritation, and to wear warm and soft clothing during cold weather. [64]

Patients with multiple nodules benefit from pain self-management training, including topical agents and regimen measures. If non-pharmacological measures are ineffective, medication and laser treatments will be considered. [65]

If hereditary leiomyomatosis is suspected, genetic counseling, informing first-degree relatives and organizing kidney cancer screening according to expert recommendations are mandatory. [66]

Women from risk families are recommended to have early gynecological monitoring, as uterine fibroids in these families are often large and multiple and may require surgical correction. [67]

Forecast

The prognosis for cutaneous leiomyoma is favorable: the tumor is benign, does not metastasize, and complete excision of the angioleiomyoma results in a cure. The primary goal of treatment is pain control and cosmetic improvement. [68]

In multiple pyelomyomas, the prognosis is determined by symptom control. A combination of medication and procedural approaches can significantly improve quality of life. [69]

The risk of malignant transformation is extremely low, but if signs of atypia or rapid growth appear, exclusion of leiomyosarcoma and repeated morphological revision are required. [70]

In patients with hereditary leiomyomatosis, life prognosis depends on the timely detection and treatment of renal cell carcinoma. Regular annual renal magnetic resonance imaging from an early age improves cancer outcomes. [71]

FAQ

Is it cancer?
No. Cutaneous leiomyoma is a benign tumor. However, with multiple nodules, it is important to rule out a hereditary syndrome associated with an increased risk of kidney cancer and organize observation. [72]

Why does the node hurt so much when pressed or exposed to cold?
The pain is caused by smooth muscle contraction and compression of nerve endings; cold and pressure trigger attacks. This explains the effectiveness of nifedipine and local analgesics. [73]

What is the most reliable treatment method?
For single nodes, the best option is complete excision. For multiple lesions, a combined approach is used: targeted excision of painful nodes, medical pain control, local treatments, and, if necessary, laser treatments. [74]

Is it possible to avoid surgery?
Yes, for multiple piloleiomyomas, conservative treatment is used: nifedipine, gabapentin, lidocaine patches, botulinum toxin injections, and laser ablation. The choice depends on the severity of pain, location, and patient preference. [75]

Should the kidneys be examined?
If there are multiple nodules, early onset, or a family history of uterine fibroids and kidney cancer, genetic counseling and annual renal magnetic resonance imaging (MRI) are recommended according to the hereditary leiomyomatosis protocol. [76]