Pathologic Classification of Rhabdomyosarcomas and Correlations with Molecular Studies

Abstract

Rhabdomyosarcoma, the most common soft-tissue malignancy of childhood and adolescence, comprises a group of differing pathobiologic entities linked by their common propensity for formation of neoplastic skeletal muscle, a feature that results from biological forces related to aberrant transcription signals and the resultant production of myogenic proteins. At a molecular level, however, rhabdomyosarcomas form a heterogeneous group that can be subdivided into distinct clinicopathologic entities based on morphologic appearance and genetic makeup. These differing morphologic features were recognized in the mid-1900s by Horn and Enterline with their division of rhabdomyosarcomas into embryonal, alveolar, botryoid, and pleomorphic subtypes. More recent histologic and biologic studies have resulted in description of additional entities, such as spindle cell and anaplastic rhabdomyosarcoma, and refinements in recognition of the original entities, such as solid-alveolar rhabdomyosarcoma. Familiarity with newer classifications and their relationship to molecular aberrations is key to stratifying patients on current therapeutic protocols and proposed innovative genetic therapies.

Aberrant expression of epithelial and neuroendocrine markers in alveolar rhabdomyosarcoma: a potentially serious diagnostic pitfall

“…Solid forms of alveolar rhabdomyosarcomas lack the prominent nested pattern and cellular discohesion seen in classic alveolar rhabdomyosarcomas and may closely mimic a variety of other 'small round cell tumors'. 9,10 By immunohistochemistry, alveolar rhabdomyosarcomas typically express vimentin, desmin, muscle actins (including smooth muscle isoforms), myogenin, and MyoD1. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] Myogenin and MyoD1, two of the myogenic transcriptional regulatory proteins, are highly sensitive and are specific markers of rhabdomyoblastic differentiation.…”

FOXO1–FGFR1 fusion and amplification in a solid variant of alveolar rhabdomyosarcoma

“…2 A rare solid variant of alveolar rhabdomyosarcoma has been described that is often morphologically indistinguishable from poorly differentiated embryonal rhabdomyosarcoma and may be confused with other 'small, round, blue cell tumors'. 3 A study of a large pediatric cohort of 171 patients with rhabdomyosarcoma by the children's oncology group (COG) has demonstrated the role of genetics in the development of rhabdomyosarcoma. 4 In the subtype of alveolar rhabdomyosarcoma, approximately 80% of cases harbored two signature chromosomal translocations, t(2;13)(q35;q14) in 60%, and t(1;13) (p36;q14) in 20% of cases.…”

Rhabdomyosarcoma: Current Challenges and Their Implications for Developing Therapies

“…R habdomyosarcomas (RMSs) are exceedingly rare and varied mesodermal cancers, linked by their common propensity to undergo aberrant, partial skeletal muscle differentiation (Parham 2001). RMS tumors can occur at any age, but most diagnoses are made in children and adolescents with an annual RMS incidence of 4.3 cases per one million people younger than 20 years of age (Sultan et al 2009;Perez et al 2011).…”

“…Differing clinicopathologic RMS phenotypes were recognized first based on their histological appearance and, more recently, based on the genetic makeup of tumors (Parham 2001). The two main histological subtypes diagnosed in the pediatric population are alveolar and embryonal RMS, whereas tumors with pleomorphic and not otherwise specified (NOS) histology account for the majority of RMS diagnosed in individuals .18 years of age (Parham 2001;Sultan et al 2009;Hawkins et al 2013).…”

“…The two main histological subtypes diagnosed in the pediatric population are alveolar and embryonal RMS, whereas tumors with pleomorphic and not otherwise specified (NOS) histology account for the majority of RMS diagnosed in individuals .18 years of age (Parham 2001;Sultan et al 2009;Hawkins et al 2013). Chromosomal translocations resulting in fusion of the DNA-binding domain of the PAX3 or PAX7 genes to the transactivation domain of the FOXO1 gene ( previously known as FKHR) have been detected in approximately 55% (PAX3-FOXO1) and 20% (PAX7-FOXO1) of alveolar histology RMS (Sorensen et al 2002).…”