Skeletal muscle is formed primarily within myotomes, which are arranged in segmental pairs along the spine and make their first appearance in the cephalic region during the third week of intrauterine life. In the region of the anterior head and neck, skeletal muscle may also develop from mesenchyme derived from the neural crest (mesectoderm).

At the earliest stage of muscle development, primitive mesenchymal cells differentiate along two lines: (1) as fibroblasts, which are loosely arranged spindle-shaped cells with the capacity to form collagen, and (2) as myoblasts, which are round or oval cells with single, centrally positioned nuclei and granular eosinophilic cytoplasm. Over the next few weeks, the individual myoblasts assume a more elongated, bipolar shape with slender, symmetrically arranged processes and nonstriated longitudinal myofibrils that are laid down first in the peripheral portion of the cytoplasm. This phase is followed by successive alignment and fusion of the individual myoblasts into myotubules with multiple centrally placed nuclei (myotubular stage). During the 7th to 10th weeks of intrauterine development, as differentiation progresses, the myofibrils become thicker and more numerous by longitudinal division, and they develop increasingly distinct cross-striations. Finally, during the 11th to 15th weeks, the nucleus is moved from its initial central position toward the periphery of the myocyte. Muscles derived from the cervical and thoracic myotomes mature earlier than those arising more distally.

Ultrastructurally, the individual myofibrils are composed of two types of myofilaments: thin (actin) filaments measuring 50–70 nm in diameter and thick (myosin) filaments measuring 140–160 nm in diameter. The thin filaments are laid down first randomly and later rearranged to form parallel bundles together with thick filaments and polyribosomes. In cross-section, the thin filaments are seen surrounding the thick filaments in distinct, evenly spaced hexagonal patterns.

Mature striated muscle consists of parallel arrays of closely packed myofibrils embedded within sarcoplasm and enveloped by a thin sarcolemmal sheath. Each of the myofibrils shows distinct cross-banding, with light and dark bands caused by the periodic arrangement and interdigitation of the thin and thick myofilaments. In this arrangement, isotropic (I) bands, anisotropic (A) bands, and H bands can be distinguished. The I band consists solely of thin (actin) filaments and is divided at its center by the Z line or disk, which is thought to serve as an attachment site for the sarcomeres, the repeating individual units of the muscle fiber. The adjacent A band is a zone of overlapping thin and thick (actin and myosin) filaments; it is separated by the H band, which consists of thick myofilaments only. The width of the individual bands and sarcomeres varies and depends on the state of muscle contraction (Fig. 19.1 ).

Muscle fiber, myofibril, and sliding actin and myosin filaments during rest phase of muscle contraction.

Although, as a general rule, benign soft tissue neoplasms outnumber malignant neoplasms by a sizable margin, this does not hold true for neoplasms showing skeletal muscle differentiation; rhabdomyomas are considerably less common than rhabdomyosarcomas and account for no more than 2% of all striated muscle tumors.

There are two broad categories of rhabdomyomas: cardiac and extracardiac. Among the extracardiac rhabdomyomas, three clinically and morphologically different subtypes can be distinguished: (1) the adult type , a slowly growing lesion that is almost always found in the head and neck area of elderly persons; (2) the fetal type , a rare tumor that also principally affects the head and neck region and occurs in both children and adults; and (3) the genital type , a polypoid mass found almost exclusively in the vagina and vulva of middle-aged women. A related lesion is the rhabdomyomatous mesenchymal hamartoma , a peculiar striated muscle proliferation that occurs chiefly in the periorbital and perioral region of infants and young children (Table 19.1 ).

Cardiac rhabdomyoma occurs almost exclusively in the hearts of infants and young children, often as multiple intramural lesions in the right and left ventricles, although the interventricular septum and atria may be involved as well.1–3 It often occurs in the setting of tuberous sclerosis and in association with other congenital abnormalities. In the Yinon et al.4 study, 33 of 40 fetal cardiac tumors were cardiac rhabdomyomas, 88% of which proved to have tuberous sclerosis. Patients with a cardiac rhabdomyoma and a family history of tuberous sclerosis and those with multifocal lesions are much more likely to have tuberous sclerosis.5 In studies that have examined patients with tuberous sclerosis by repeated echocardiograms, 47%–67% of patients harbor one or more cardiac rhabdomyomas.6 ^, 7

Clinically, the lesion may be asymptomatic or may cause cardiac arrhythmia, tachycardia, ventricular outflow obstruction, Wolff–Parkinson–White syndrome, or even sudden death.8 The concurrence of cardiac and extracardiac rhabdomyomas in the same patient has not been observed, although rare examples of adult rhabdomyoma may occur in the heart.9 These lesions tend to be more cellular, composed of smaller cells, and have fewer spider cells. Extracardiac rhabdomyoma is not associated with the tuberous sclerosis complex.

Histologically, the lesions are composed predominantly of large polygonal spider cells with large cytoplasmic vacuoles secondary to loss of glycogen during processing (Figs. 19.2 and 19.3 ). The cells stain for muscle markers, including muscle-specific actin (MSA) and desmin. It has recently been shown that cardiac rhabdomyomas specifically express cardiac α-actin isoforms (α-cardiac actin), rather than α-skeletal actin, indicating differentiation from cardiac-type muscle rather than somatic-type skeletal muscle. Extracardiac adult rhabdomyomas show the opposite pattern of expression.10 HMB-45 immunoreactivity has also been reported, supporting a relation with angiomyolipoma and lymphangioleiomyomatosis (members of the PEComa family) as components of the tuberous sclerosis complex.11 Further, the neoplastic cells lose expression of tuberin (protein coded for by the TSC2 gene on chromosome 16) and hamartin (protein coded for by the TSC1 gene on chromosome 9).12

Cardiac Rhabdomyoma.

The lesion is composed predominantly of large polygonal spider cells with large cytoplasmic vacuoles.

Cardiac rhabdomyoma with vacuolated spider cells. Cross-striations are rare but can be identified.

As cardiac rhabdomyomas tend to naturally regress over time, treatment is reserved for patients with life-threatening obstructive symptoms or arrhythmias refractory to medical therapy.13 ^, 14 Several reports have found complete regression of cardiac rhabdomyoma following treatment with mammalian target of rapamycin (mTOR) inhibitors such as everolimus and sirolimus,15 ^, 16 an observation that is not completely surprising given the apparent role of mTOR pathway abnormalities in the pathogenesis of tuberous sclerosis–associated cardiac rhabdomyomas.17

The adult type of rhabdomyoma is the most common subtype of extracardiac rhabdomyoma but still occurs infrequently. The lesion usually presents as a solitary round or polypoid mass in the head and neck region of adults that causes neither tenderness nor pain. It may compress or displace the tongue or may protrude into and partially obstruct the pharynx or larynx. As a consequence, it may cause hoarseness or progressive difficulty with breathing or swallowing.18 It is a slowly growing process, and several of the reported cases were present for many years before surgery. Most tumors occur in adults older than 40 (median age: 60), although there are case reports of adult-type rhabdomyoma arising in children.19 Men are affected three to four times more often than women, but there is no predilection for any particular ethnicity. The principal site of involvement is the neck, where the tumor arises from the branchial musculature of the third and fourth branchial arches. It is found most frequently in the region of the pharynx, oral cavity (e.g., floor of mouth, base of tongue), and larynx.20 It may also involve the soft palate and the uvula, usually as an extension of a pharyngeal rhabdomyoma. Rare tumors have been described outside the head and neck region in a myriad of locations.21 Most adult rhabdomyomas are solitary, but about 20% are multifocal, usually involving the general area of the neck.22

Pathologic Findings

As a rule, the tumor is well-defined, rounded, or coarsely lobulated and ranges from 0.5 to 10.0 cm in greatest diameter (median: 3.0 cm). Some are multinodular, and others form a sessile or pedunculated polypoid submucosal mass. On cut section, it has a finely granular, gray-yellow to red-brown appearance (Fig. 19.4 ).

Adult rhabdomyoma from the neck area. The tumor has a homogeneous tan-brown cut surface.

Microscopically, adult-type rhabdomyoma is composed of tightly packed, large, round or polygonal cells 15–150 μm in diameter and separated from one another by thin, fibrous septa and narrow vascular channels. The cells have deeply acidophilic, finely granular cytoplasm, one or (rarely) two centrally or peripherally placed vesicular nuclei, and one or more prominent nucleoli (Figs. 19.5 and 19.6 ). Many of the cells are vacuolated because they contain glycogen; some of the vacuolated cells contain merely a small, central, acidophilic cytoplasmic mass connected by thin strands of cytoplasm to a condensed rim of cytoplasm at the periphery (spider cells); these cells are much more conspicuous in cardiac than extracardiac rhabdomyomas. Rare tumors with extensive clear cell change have been reported.23 Mitotic figures are almost always absent. Cross-striations can be discerned in most cases but sometimes are detected only after a prolonged search; in many cases, intracytoplasmic rodlike or jackstraw-like crystalline structures are also present (Figs. 19.7 and 19.8 ). Both cross-striations and crystalline structures are identified much more readily with the phosphotungstic acid–hematoxylin (PTAH) stain than with hematoxylin-eosin. On immunohistochemistry (IHC), as one would expect, the cells stain strongly for desmin and muscle specific actin10 (Fig. 19.9 ). Myogenin and MyoD1 expression may also be seen.24 Few cytogenetic data are available pertaining to adult-type rhabdomyoma. In a cytogenetic study of a recurrent parapharyngeal rhabdomyoma in a 64-year-old man, Gibas and Miettinen25 found a reciprocal translocation of chromosomes 15 and 17 and abnormalities in the long arm of chromosome 10.

Low-power view of adult rhabdomyoma composed of admixture of deeply eosinophilic polygonal cells and cells with vacuolated cytoplasm.

Adult rhabdomyoma composed of variously sized, deeply eosinophilic polygonal cells with small, peripherally placed nuclei, and occasional intracellular vacuoles.

Adult rhabdomyoma with rare jackstraw-like crystalline structures within the cytoplasm of some of the eosinophilic polygonal cells.

High-power view of adult rhabdomyoma with crystalline intracellular structures, probably representing Z-band material.

Adult rhabdomyoma showing immunoreactivity for desmin. Note accentuation of cross-striations.

Fetal rhabdomyoma is even rarer than adult-type rhabdomyoma, and only a small number of cases have been recorded in the literature. Fetal rhabdomyomas are so named for their histologic resemblance to primitive skeletal muscle rather than for the demographic they affect. Awareness of the existence of this tumor, however, is of considerable importance because of its close resemblance to embryonal rhabdomyosarcoma. The lesion has a variable histologic pattern, with a spectrum of skeletal muscle differentiation that ranges from immature, predominantly myxoid tumors to those showing a high degree of cellular differentiation and almost no myxoid matrix. The former has been described as myxoid 27 or classic 30 fetal rhabdomyomas, and the latter as intermediate ,30 cellular ,27 or juvenile 31 ^, 32 fetal rhabdomyomas. Intermediate forms may be seen between these two types. There is also a third, still poorly defined morphologic variant of this tumor marked by prominent neural involvement and showing some similarity to neuromuscular hamartoma.33

Pathologic Findings

On gross examination, the tumors are generally well-circumscribed, and most are 2–6 cm in greatest diameter at excision. Mucosal lesions tend to be smooth and polypoid or pedunculated. On sectioning, they are gray–white to pink, often with a mucoid, glistening surface. Unlike rhabdomyosarcoma, fetal rhabdomyoma is primarily a superficial tumor and is found more often in the subcutis or submucosa than in muscle. Most are solitary, but multicentric fetal rhabdomyomas have been reported in association with nevoid basal cell carcinoma syndrome.44

Histologically, the myxoid type is chiefly composed of primitive oval or spindle-shaped cells with indistinct cytoplasm, interspersed immature skeletal muscle fibers reminiscent of fetal myotubules seen during the 7th to 10th weeks of intrauterine life, and a richly myxoid matrix (Figs. 19.10 and 19.11 ). The immature skeletal muscle cells have small, uniform nuclei with delicate chromatin and inconspicuous nucleoli with bipolar or sometimes unipolar, finely tapered eosinophilic cytoplasmic processes. Cross-striations are rare and often difficult to discern; they are best seen with PTAH or Masson trichrome stains or with immunohistochemical stains for desmin or MSA. The cells may be arranged in short bundles or isolated within the myxoid matrix. Sometimes, focal proliferation of abundant muscle fibers makes it difficult to draw a sharp line between tumor and normal muscle tissue. The primitive undifferentiated cells have oval nuclei with slight nuclear hyperchromasia and scanty, indistinct cytoplasm.

Fetal Rhabdomyoma, Myxoid Type.

The lesion is composed of an intimate mixture of primitive, round, and spindle-shaped mesenchymal cells and differentiated myofibrils within a richly myxoid background.

Fetal Rhabdomyoma, Myxoid Type.

Unlike embryonal rhabdomyosarcoma, the muscle cells vary little in size and shape, and there is no mitotic activity. The cells are deposited in an abundant myxoid matrix.

The intermediate type is characterized by the presence of numerous differentiated muscle fibers, less conspicuous or absent spindle-shaped mesenchymal cells, and little or no myxoid stroma (Fig. 19.12 ). In any given case, there may be a wide spectrum of skeletal muscle differentiation. The predominant cells are broad, strap-shaped muscle cells with abundant eosinophilic cytoplasm, centrally located vesicular nuclei, and frequent cross-striations reminiscent of the cells seen in adult rhabdomyomas; many of the cells contain glycogen and are often vacuolated. Others have prominent ganglion-like rhabdomyoblasts with large vesicular nuclei and prominent nucleoli. Mucosa-based lesions tend to have the widest spectrum of rhabdomyoblastic differentiation and the most mature-appearing cells. Some cases show mild cellular pleomorphism, but marked cellular atypia is not a feature of this tumor. Transitional forms between the myxoid and intermediate types do occur. In fact, age and duration may play a role in the maturation of some tumors, as suggested by the older mean age of patients with the intermediate (cellular) type and the reported long duration of some cases. In both types, mitotic figures are rare or absent. In addition to the myxoid and intermediate types, sporadic fetal rhabdomyoma–like tumors are intimately associated with peripheral nerves reminiscent of neuromuscular choristoma (benign Triton tumor). On IHC, similar to other rhabdomyoma subtypes, the muscle cells stain positively for desmin, MSA, MyoD1, and myogenin.45

Fetal Rhabdomyoma, Intermediate (Cellular) Type.

( A ) Intersecting bundles of differentiated eosinophilic myofibrils contain cross-striations. Myofibrils are separated by small, undifferentiated spindle cells. ( B ) Higher-magnification view of interspersed spindled cells with differentiated myofibrils. ( C ) High-magnification view.

Case courtesy of Dr. Cyril Fisher, Royal Marsden Hospital, London.

Although genital rhabdomyoma bears some resemblance to both adult and fetal rhabdomyomas, it has sufficiently different clinical and microscopic characteristics to qualify as a separate entity. This is a very rare tumor, and only a small number of cases have been described, including some that were reported as fetal rhabdomyoma.27 ^, 47 Almost all arise as a slowly growing polypoid mass or cyst in the vagina or vulva of young or middle-aged women,47–49 although rare cases arise in the male genital region (epididymis).50–52 Most are asymptomatic and are found on routine physical examination; some cause dyspareunia or vaginal bleeding secondary to mucosal erosion.

Microscopically, the tumor usually forms a polypoid or cauliflower-like mass covered by epithelium and rarely measures more than 3 cm in greatest diameter. It consists of scattered, more or less mature muscle fibers showing distinct cross-striations and a matrix containing varying amounts of collagen and mucoid material (Figs. 19.13–19.15 ). As with other rhabdomyomas, the cells are immunoreactive for desmin, MSA, MyoD1, and myogenin.53

Genital (Vaginal) Rhabdomyoma.

Submucosal proliferation of striated muscle cells is separated by varying amounts of myxoid material and collagen.

Genital rhabdomyoma composed of loosely arranged striated muscle cells and fibroblasts.

High-power view of genital rhabdomyoma showing rare striated muscle cells with cross-striations.

Genital rhabdomyoma, which pursues a benign course, is adequately treated by local excision. No distinct genetic alterations have been identified in the few cases studied thus far.47

The differential diagnosis includes benign vaginal polyps and botryoid embryonal rhabdomyosarcoma (sarcoma botryoides). Benign vaginal polyps are characterized by atypical single or multinucleated stromal cells, but they lack classic strap cells with cross-striations. The stromal cells of vaginal polyps are routinely positive for desmin, a potential pitfall, but are myogenin negative. Botryoid embryonal rhabdomyosarcoma usually occurs in young children, who present with a rapidly growing lesion that frequently ulcerates the overlying epithelium. In contrast, genital rhabdomyoma usually occurs in middle-aged women and is generally a slowly growing tumor associated with an intact overlying epithelium. The subepithelial cambium layer characteristic of sarcoma botryoides is not found in genital rhabdomyomas. In addition, nuclear pleomorphism and mitotic figures are much more prominent in rhabdomyosarcomas than in rhabdomyomas (Table 19.4 ).

Table 19.4

Distinguishing Features of Genital Rhabdomyoma and Botryoid Rhabdomyosarcoma

Parameter	Genital Rhabdomyoma	Botryoid Rhabdomyosarcoma
Peak age	Young to middle-aged adults	Birth to 15 years
Gender (M/F)	Almost all females	1:1
Growth	Slowly growing	Rapidly growing
Epithelial ulceration	Absent	Often present
Cambium layer	Absent	Present
Mitotic figures	Absent or rare	Easily identified
Pleomorphism	Absent or slight	Moderate or marked

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