SOLID ALVEOLAR-TYPE RHABDOMYOSARCOMA
Rhabdomyosarcoma (RMS) is the most common malignant neoplasm of the soft tissues in infants and children. RMS comprises 2-4% of all malignant tumors in children less than 15 years of age. The annual incidence of RMS is 4.5 cases per million in U.S. children less that 15 years old. 1 The incidence rate is lower in African-American and Oriental children. The median age at diagnosis is approximately 4 years, with a male : female ratio of 1.4 : 1.
RMS arises from embryonic mesenchymal cells with the potential for differentiating into striated muscle. The conventional classification system proposed by Horn and Enterline2 consists of four histologic subtypes of RMS: embryonal, alveolar, pleomorphic and mixed. The embryonal subtype is the most common histology found in children, and is the most common histology of the head and neck and RMSs. Sarcoma botryoides is a subtype of the embryonal RMS, with a gross appearance that resembles a cluster of grapes. These polypoid masses most commonly develops in the walls of hollow, mucosal-lined structures, such as the nasopharynx, common bile duct, bladder, and vagina. The alveolar subtype is uncommon and is most often found in the extremities and trunks of young adults and teenagers. Pleomorphic RMS is rare and usually occurs in adults. The mixed cell subtype comprises tumors made up of more than one of the above histologic subtypes.
The alveolar type of rhabdomyosarcoma is composed largely of ill-defined aggregates of poorly differentiated round or oval tumor cells that frequently show central loss of cellular cohesion and formation of irregular "alveolar" spaces. The individual cellular aggregates are separated and surrounded by frameworks of dense, frequently hyalinized fibrous septa that surround dilated vascular channels.3 Not infrequently, portions of the tumor lack an alveolar pattern entirely and are composed only of solidly packed groups or masses of tumor cells, as is seen in this case. These are presumably the same neoplasms that Tsokos et al.4 singled out as "solid variants of rhabdomyosarcoma". Furthermore, the strong nuclear staining with myogenin correlates with alveolar rhabdomyosarcoma, solid-variant.5-6
Alveolar rhabdomyosarcoma has been consistently shown to be associated with a specific translocation, t(2;13)(q37;q14) or its variant t(1;13)(p36;q14). 7 Barr et al.8 showed that the PAX3 gene in 2q35 is disrupted by the t(2;13). PAX3 encodes a developmentally regulated transcription factor with a 5' DNA-binding domain (paired box and homeodomain); the breaks in the rearrangement seem to cluster to an intron downstream of this domain. The translocation leads to the formation of a chimeric gene in which the 5' portion of PAX3 is fused to the remains of a locus on chromosome 13. The latter is the site of the gene FKHR that encodes a transcription factor identified by Galili et al9 as a member of the fork head domain family. Combined RNA and protein analyses demonstrated that the t(2;13) results in the formation of a consistent and presumably tumorigenic chimeric transcription-regulating protein consisting of an intact PAX3 DNA-binding domain, a truncated fork head DNA-binding domain, and C-terminal FKHR regions. The variant translocation t(1;13)(p36;q14) fuses the PAX7 gene on chromosome 1 with the FKHR on chromosome 13. The chimeric transcript consists of 5' PAX7 and 3' FKHR, in parallel with the generation of the 5' PAX3-3' FKHR formed by the t(2;13). In some alveolar rhabdomyosarcomas,the fusion genes are amplified,10-11 and extra copies of chromosomes 2, 8, 9, 11,12,13 and 20 can be typically seen.12
The combination of histology, immunohistochemistry, chromosome analysis, and molecular cytogenetics played an important role in the diagnosis of this tumor. Refinement of soft tissue tumor classification and a better understanding of tumor pathophysiology is becoming possible as molecular cytogenetics becomes increasingly useful in the diagnosis, characterization and classification of soft tissue tumors.
Contributed by J. Thomas Molina, M.D., Ph.D., Burhan Gharaibeh, Ph.D. , Ronald Jaffe, M.B., B.Ch., Urvashi Surti, Ph.D.