Striated Muscle Tissue: Development and Structure

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 to 70 nm in diameter and thick (myosin) filaments measuring 140 to 160 nm in diameter. The thin filaments are laid down first randomly and later are rearranged to form parallel bundles together with thick filaments and polyribosomes. In cross section the thin filaments are seen to surround 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. 18.1 ).

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

Classification of Rhabdomyomas

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 18.1 ).

Cardiac Rhabdomyoma

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. It often occurs in the setting of tuberous sclerosis and in association with other congenital abnormalities. In the Yinon et al. 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. In studies that have examined patients with tuberous sclerosis by repeated echocardiograms, 47% to 67% of patients harbor one or more cardiac rhabdomyomas.

Clinically, the lesion may be asymptomatic or may cause cardiac arrhythmia, tachycardia, ventricular outflow obstruction, Wolff-Parkinson-White syndrome, or even sudden death. 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. 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. 18.2 and 18.3 ). 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. 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. Further, the neoplastic cells lose expression of tuberin (protein coded for by TSC2 gene on chromosome 16) and hamartin (protein coded for by TSC1 gene on chromosome 9).

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. Several reports have found complete regression of cardiac rhabdomyoma following treatment with mammalian target of rapamycin (mTOR) inhibitors such as everolimus and sirolimus, an observation that is not completely surprising given the apparent role of mTOR pathway abnormalities in the pathogenesis of tuberous sclerosis–associated cardiac rhabdomyomas.

Adult Rhabdomyoma

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. 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. 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. 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. Most adult rhabdomyomas are solitary, but about 20% are multifocal, usually involving the general area of the neck.

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.

Microscopically, adult-type rhabdomyoma is composed of tightly packed, large, round or polygonal cells 15 to 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. 18.4 and 18.5 ). Many of the cells are vacuolated because intracellular glycogen has been removed during processing; 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. 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. 18.6 and 18.7 ). 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 MSA ( Fig. 18.8 ). Myogenin expression may also be seen. 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 Miettinen 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.