Case 256 -- Solid Alveolar-Type Rhabdomyosarcoma (RMS)

FINAL DIAGNOSIS:

SOLID ALVEOLAR-TYPE RHABDOMYOSARCOMA

DISCUSSION:

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.

REFERENCES:

  1. Gurney, J.G. et al. "Incidence of cancer in children in the U.S. Sex, race and 1-year age-specific rates by histologic subtype." Cancer 1995 Apr 75:2186-95.
  2. Horn R.C.,Jr. et al. "Rhabdomyosarcoma: a clinicopathological study and classifiation of 39 cases". Cancer 1958 11:181.
  3. Enzinger, F.M., Weiss, S.W. eds. Soft Tissue Tumors 2nd ed. 1988 460-471.
  4. Tsokos, M. "The diagnosis and classification of childhood rhabdomyosarcoma." Semin Diagn Pathol. 1994 Feb 11:26-38.
  5. Dias, P., Chen, B., Dilday, B., Palmer, H., Hosoi, H., Singh, S., Wu, C., Li, X., Thompson, J., Parham, D., Qualman, S., Houghton, P., "Strong immunostaining for myogenin in rhabdomyosarcoma is significantly associated with tumors of the alveolar subclass." Am J Pathol. 2000 Feb 156:399-408.
  6. Kumar, S., Perlman, E., Harris, C.A., Raffeld, M., Tsokos, M. "Myogenin is a specific marker for rhabdomyosarcoma: an immunohistochemical study in paraffin-embedded tissues." Mod Pathol. 2000 Sep 13:988-93.
  7. Heim, S., Mitelman, F. eds. Cancer Cytogenetics 2nd ed. 1995.
  8. Barr, F.G., Galili, N., Holick, J., Biegel, J.A., Rovera, G., Emanuel, B.S. "Rearrangement of the PAX3 paired box gene in the paediatric solid tumour alveolar rhabdomyosarcoma." Nat Genet. 1993 Feb 3:113-7.
  9. Galili, N., Davis, R.J., Fredericks, W.J., Mukhopadhyay, S., Rauscher, F.J., Emanuel, B.S., Rovera, G., Barr, F.G. "Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma." Nat Genet. 1993 Nov 5:230-5.
  10. Barr, F.G., Nauta, L.E., Davis, R.J., Schafer, B.W., Nycum, L.M., Biegel, J.A. "In vivo amplification of the PAX3-FKHR and PAX7-FKHR fusion genes in alveolar rhabdomyosarcoma." Hum Mol Genet. 1996 Jan 5:15-21.
  11. Gunawan, B. et al. "Clinical Aspects of alveolar rhabdomyosarcoma with translocation t(1;13)(p36;q14) and hypotetraploidy". Pathol Oncol Res 1999 20:211-213.
  12. Weber-Hall, S. et al. "Gains, losses and amplification of genomic material in rhabdomyosarcoma analysed by comparative genomic hybridization." Cancer Res. 1996 56:3220-3224.
  13. Cotran, R.S., Kumar, V., Collins, T. eds. Robbins Pathologic Basis of Disease 6th ed. 1999 1265-1266.
ADDITIONAL RESOURCES:

  1. UPMC online case of the month (January 2000) by Anna Mnuskin, MD
  2. Oncolink electronic case of the month (January 1998) by Penny Anderson, MD
  3. Current literature on alveolar rhabdomyosarcoma (through PubMed)

Contributed by J. Thomas Molina, M.D., Ph.D., Burhan Gharaibeh, Ph.D. , Ronald Jaffe, M.B., B.Ch., Urvashi Surti, Ph.D.



Case IndexCME Case StudiesFeedbackHome