Dermatology

Infantile Myofibromatosis(myofibroma, congenital generalized myofibromatosis)

Infantile Myofibromatosis (myofibroma, congenital generalized myofibromatosis)

Are You Confident of the Diagnosis?

The diagnosis of infantile myofibromatosis (IMF) may arise in patients with congenital (50%) lesions or acquired lesions during the first 2 years of life (40%). Only anecdotal cases of lesions beginning during adulthood have been reported. IMF presents as subcutaneous tumors. Their clinical appearance is highly heterogeneous. Solitary lesions are the most common, but multiple lesions affecting skin or various organs (such as muscle, bones and other organs) can also be seen.

Solitary IMF (also known as myofibroma) is a single lesion that can be found mainly in skin or muscle of the head, neck or trunk. This type of presentation accounts for more than 75% of all cases.

When lesions are multiple, multicentric IMF (25% of the cases) they can be divided according to the absence or presence of visceral involvement (25% of those with multiple lesions also known as generalized multicentric IMF). Multiple lesions without visceral involvement can range from two to hundreds and may affect only the skin or the skin and the musculskeletal system. Solitary lesions and multicentric lesions without visceral involvement have an excellent prognosis. Multiple lesions with visceral involvement can affect virtually any internal organ, and are associated with a poor prognosis.

Characteristic findings on physical examination

Skin lesions usually present as firm-rubbery, flesh-colored to purple tumors (Figure 1) or subcutaneous masses underlying normal skin, ranging in size from 0,3 to 7 cm in diameter, though bigger lesions have been reported. They may also be highly vascularized, resembling hemangiomas. Pedunculated lesions, diffuse plaques and lesions resembling cysts, have also been described. Some lesions can show ulceration and bleeding (Figure 2), especially if localized to areas subject to trauma (the tongue, lips, axillae, etc).

Figure 1.

Small purple lesion with an anemic halo.

Figure 2.

Ulcerated nodule over the right thigh.

Expected results of diagnostic studies

A biopsy of an accessible lesion (usually skin) should be performed in order to confirm the diagnosis. Histopathology shows a well-circumscribed nodule with a typical biphasic feature. Spindle-shaped cells in interweaving bundles or a whorled disposition in the periphery (smooth-muscle-like fascicles) and rounded cells with a perivascular disposition (hemangiopericytoma-like) in the center of the lesion are observed (Figure 3). These findings are usually localized extending from the dermis to the subcutaneous tissue.

Figure 3.

Ulcerated nodule over the right thigh.

Immunohistochemical staining may further aid to arrive to a correct diagnosis. Muscle actin, desmin and vimentin are usually positive, while S-100 is negative. The histologic differential includes: hemangiopericytoma, piloleiomyoma, congenital fibrosarcoma.

As soon as a patient is diagnosed with IMF, internal organ involvment should be ruled out in every patient. A work-up should include a chest X-ray, an abdominal ultrasound, an echocardiogram, and a skeletal survey. If the patient has relevant symptoms, further studies such as magnetic resonance imaging, and/or computed tomography scan with contrast of the gastrointestinal and genitourinary systems might also be performed.

Diagnosis confirmation

The clinical differential diagnosis of single lesions include: deep infantile hemangioma, histiocytoma, mastocytoma, leiomyoma, rhabdomyosarcoma, hemangiopericytoma, dermoid cysts, teratoma, lipoma, or infantile digital fibroma. Multiple myofibromas may resemble metastasic neuroblastoma or leukemia, sarcomas, hemangiomatosis, and multiple juvenile xanthogranulomas.

Who is at Risk for Developing this Disease?

Most cases are sporadic. Hereditary cases have been described, both with an autosomal dominant and an autosomal recessive inheritance; therefore family members of patients with IMF may be at a higher risk.

It is worth mentioning that there have been two different reports of patients with infantile myofibromatosis and café-au-lait macules, one with type 1 neurofibromatosis (confirmed by fluorescent in vitro hybridization [FISH]) and another with the Childhood Cancer Syndrome (caused by the biallelic mutation of the MMR gene, that, when heterozygous, is responsible for Lynch syndrome) associated with café-au-lait macules, hematological malignancies. and brain or intestinal tumors. Although these findings might be coincidental, special attention should be paid to the presence of café-au-lait macules in these patients.

Other genetic alterations that have been reported in patients with IMF are Turner syndrome and a chromosome 6p deletion, in one patient each.

What is the Cause of the Disease?

Etiology

The etiology remains unknown.

Pathophysiology

Increased estrogen receptors in smooth muscle cells leading to in utero stimulation by maternal hormones have been postulated. Although it has been refuted by several studies, the role of the transfer of maternal cells during pregnancy (microchimerism) has also been hypothesized as being responsible for this disease.

Systemic Implications and Complications

Solitary IMF and multicentric IMF without systemic involvement have an excellent prognosis. Lesions that affect soft tissue and bones can lead to spontaneous fractures and functional alterations.

Systemic IMF can virtually affect any organ. Involvement of internal organs such as lungs, heart, gastrointestinal tract, and spleen have occasionally been reported, while lesions in the liver, pancreas, and central nervous system are exceptional. The extent and severity of the internal organ involvement is directly related to the morbidity and mortality of these diseases.

Treatment Options

Treatment options are summarized in Table I.

Table I.

Treatment options for infantile myofibromatosis
Medical treatment  Surgical treatment Physical modalities
Observation of lesions Surgical excision of the lesions  Radiotherapy
Intralesional steroids, Chemotherapy -  Vincristine - Vinblastine - Methotrexate - Actinomycin D - Cyclophosphamide - Interferon alpha- 2b    

Optimal Therapeutic Approach for this Disease

Most patients have an excellent prognosis. The vast majority of lesions will undergo spontaneous resolution secondary to massive apoptosis, within the first 2 years of life; therefore, in most of the cases only observation without active treatment is advisable.

Surgical excision might be an option when lesions affect vital organs or for functional concerns. In some cases (specially in those with visceral involvement) patients might also require chemotherapy, together with supportive care. Radiotherapy has also been postulated as a therapeutic alternative.

Patient Management

After IMF is diagnosed, every patient should be checked to rule out internal organ involvement, because the prognosis varies widely according to these. Work-up should include a chest X-ray, an abdominal ultrasound, an echocardiogram, and a skeletal survey. When internal involvement it is absent, active “non-intervention” is advisable, although simple surgical excision might be a choice for functional or even aesthetic concerns. Between 7 to 10% of surgically excised lesions can recur.

When internal organs are affected, surgical excision, chemotherapy or radiotherapy might be needed. Referral to a pediatric or adult hematology/ oncology expert is required. Low-dose chemotherapy with vinblastine (5mg/m2) and methotrexate (30mg/m2) has shown to be effective, as well as low doses of INF alpha-2b.

Unusual Clinical Scenarios to Consider in Patient Management

If during the course of illness the lesions fail to resolve or grow very fast, diagnosis should be reconsidered, especially for its histological similarities with fibrosarcomas.

What is the Evidence?

Larralde, M, Hoffner, MV, Boggio, P, Abad, ME, Luna, PC, Correa, N. "Infantile myofibromatosis: report of nine patients". Pediatr Dermatol. vol. 27. 2010. pp. 29-33.

(A description of 9 cases diagnosed on the basis of cutaneous manifestations with a thorough review of the up-to-date review of the subject.)

Gopal, M, Chahal, G, Al-Rifai, Z, Eradi, B, Ninan, G, Nour, S. "Infantile myofibromatosis". Pediatr Surg Int. vol. 24. 2008. pp. 287-9.

(A description of 12 cases seen at a pediatric surgery center and a review of the literature.)

Arcangeli, F, Calista, D. "Congenital myofibromatosis in two siblings". Eur J Dermatol. vol. 16. 2006. pp. 181-3.

(A description of IMF occurring in siblings with a review of the literature of familial cases.)

Stanford, D, Rogers, M. "Dermatological presentations of infantile myofibromatosis: a review of 27 cases". Australas J Dermatol. vol. 41. 2000. pp. 156-61.

(A review of 27 cases of IMF with cutaneous involvement and literature review.)

Yousefi, P, Khosrotehrani, K, Oster, M, De Prost, Y. "Neonatal case of infantile myofibromatosis do not derive from maternal cells transferred during pregnancy". Br J Dermatol. vol. 160. 2009. pp. 1335-62.

(An evaluation of the hypotheses that microchimerism might be responsible of congenital myofibromatosis. Using the FISH technique targeting X and Y chromosomes in tissue of myofibromas from male patients, the authors found that tumor cells are not derived from maternal cells.)

Fukasawa, Y, Ishikura, H, Takada, A, Yokoyama, S. "Massive apoptosis in infantile myofibromatosis. A putative mechanism of tumor regression". Am J Pathol. vol. 144. 1994. pp. 480-5.

(The authors report massive apoptosis in two biopsies of IMF and propose that this mechanism is responsible for the spontaneous tumor regression observed in IMF.)

Krüger, S, Kinzel, M, Walldorf, C, Gottschling, S, Bier, A, Tinschert, S. "Homozygous PMS2 germline mutations in two families with early-onset haematological malignancy, brain tumours, HNPCC-associated tumours, and signs of neurofibromatosis type 1". Eur J Hum Genet. vol. 16. 2008. pp. 62-72.

(A very interesting description of two families with the Childhood Cancer syndrome, associating hematologic malignancies, café-au-lait macules, and brain and gastrointestinal tumors, with one of the patients also presenting with a myofibroma.)

Azzam, R, Abboud, M, Muwakkit, S, Khoury, N, Saab, R. "First-line therapy of generalized infantile myofibromatosis with low-dose vinblastine and methotrexate". Pediatr Blood Cancer. vol. 52. 2009. pp. 308.

(Report of the treatment of intracranial IMF with low-dose chemotherapy with an excellent response; the authors propose it as a first-line therapy.)

Auriti, C, Kieran, MW, Deb, G, Devito, R, Pasquini, L, Danhaive, O. "Remission of infantile generalized myofibromatosis after interferon alpha therapy". J Pediatr Hematol Oncol. vol. 30. 2008. pp. 179-81.

(The authors report the case of a patient with generalized IMF successfully treated with INF-alpha-2b and they propose that this drug might act by limiting the transcription and expression of growth factors inhibiting tumor growth with very low toxicity.)
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