Agreement among and within groups of pathologists in the classification of rhabdomyosarcoma and related childhood sarcomas. Report of an international study of four pathology classifications

Asmar, Lina; Gehan, Edmund A.; Newton, William A.; Webber, Bruce L.; Marsden, H. B.; Unnik, Adrian J. M. Van; Hamoudi, Ala B.; Shimada, Hiroyuki; Tsokos, Maria; Harms, D.; Ninfo, Vito; Schmidt, Dietmar; Cavazzana, Andrea; Gonzales-Crussi, Frank; Parham, David M.; Reiman, Herbert M.; Beltangady, Mohan; Sachs, Nancy; Triche, Timothy J.; Maurer, Harold M.

doi:10.1002/1097-0142(19941101)74:9<2579::aid-cncr2820740928>3.0.co;2-a

Cited by 87 publications

(24 citation statements)

References 9 publications

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“…The ultimate goal of this group was to stratify rhabdomyosarcoma into prognostically significant and diagnostically consistent morphologic subgroups. To this end, Newton and colleagues assembled a panel of experts representing each classification, tested the overall agreement reached among these pathologists when using all schemas, and devised a new system based on the level of agreement and power of prognostic prediction (9,32). The result, an International Classification for Rhabdomyosarcoma, is shown in Table 1.…”

Section: International Classificationmentioning

confidence: 99%

Pathologic Classification of Rhabdomyosarcomas and Correlations with Molecular Studies

2001

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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.

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Section: International Classificationmentioning

confidence: 99%

Pathologic Classification of Rhabdomyosarcomas and Correlations with Molecular Studies

2001

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“…The clinical relevance of making accurate diagnoses and predicting outcome in rhabdomyosarcoma is not trivial, as some of the progress made in rhabdomyosarcoma treatment over the last 30 years is overshadowed by misdiagnosis that often leads to suboptimal treatment of patients (52,53). The diversity of outcomes for rhabdomyosarcoma patients has led to an intense search for prognostic indicators useful for therapeutic stratification.…”

Section: Discussionmentioning

confidence: 99%

Identification of a PAX-FKHR Gene Expression Signature that Defines Molecular Classes and Determines the Prognosis of Alveolar Rhabdomyosarcomas

Davicioni¹,

et al. 2006

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Alveolar rhabdomyosarcomas (ARMS) are aggressive softtissue sarcomas affecting children and young adults. Most ARMS tumors express the PAX3-FKHR or PAX7-FKHR (PAX-FKHR) fusion genes resulting from the t(2;13) or t(1;13) chromosomal translocations, respectively. However, up to 25% of ARMS tumors are fusion negative, making it unclear whether ARMS represent a single disease or multiple clinical and biological entities with a common phenotype. To test to what extent PAX-FKHR determine class and behavior of ARMS, we used oligonucleotide microarray expression profiling on 139 primary rhabdomyosarcoma tumors and an in vitro model. We found that ARMS tumors expressing either PAX-FKHR gene share a common expression profile distinct from fusion-negative ARMS and from the other rhabdomyosarcoma variants. We also observed that PAX-FKHR expression above a minimum level is necessary for the detection of this expression profile. Using an ectopic PAX3-FKHR and PAX7-FKHR expression model, we identified an expression signature regulated by PAX-FKHR that is specific to PAX-FKHR-positive ARMS tumors. Data mining for functional annotations of signature genes suggested a role for PAX-FKHR in regulating ARMS proliferation and differentiation. Cox regression modeling identified a subset of genes within the PAX-FKHR expression signature that segregated ARMS patients into three risk groups with 5-year overall survival estimates of 7%, 48%, and 93%. These prognostic classes were independent of conventional clinical risk factors. Our results show that PAX-FKHR dictate a specific expression signature that helps define the molecular phenotype of PAX-FKHR-positive ARMS tumors and, because it is linked with disease outcome in ARMS patients, determine tumor behavior.

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“…Rhabdomyosarcomas can be broadly subdivided into embryonal and alveolar histological types, with spindle cell and botryoid variants of the former and a solid variant of the latter. [1][2][3] In recent years, molecular correlates with histology have been described. In particular, the translocation t(2;13)(q35;q14) and the rare variant translocation t(1;13)(p36;q14) 4,5 that result in the generation of the fusion proteins PAX3-FKHR and PAX7-FKHR, respectively, 6 -8 are characteristic of alveolar rhabdomyosarcoma (ARMS).…”

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PAX3-FKHR Induces Morphological Change and Enhances Cellular Proliferation and Invasion in Rhabdomyosarcoma

Anderson

Ramsay

Gould

et al. 2001

The American Journal of Pathology

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Alveolar rhabdomyosarcoma (ARMS) is consistently associated with the characteristic translocations t(2;13)(q35;q14) and t(1;13)(p36;q14), which encode for the PAX3-FKHR and PAX7-FKHR fusion oncoproteins respectively. We have investigated the relationship between PAX3-FKHR expression and ARMS histogenesis in primary tumors and cell culture systems. In a blinded histological review of discrepant primary tumors in which there was PAX3-FKHR expression but embryonal histology, we found small areas of alveolar histology in 6 of 11 cases. This suggests that histology alone may under-represent the association between PAX3-FKHR and ARMS, and we investigated this link by examining the effect of ectopic PAX3-FKHR expression on RMS cells. Two cell lines, RD and HX170C, were stably transfected with a PAX3-FKHR expression construct. In cloned transfectants derived from both lines, PAX3-FKHR expression resulted in increased proliferative rate in vitro and promoted cell growth in the absence of added growth factors. Tumors that formed as xenografts in immunodeficient mice were faster growing, more locally invasive, and had a denser, more pleomorphic architecture than untransfected or empty vector transfected tumors. Rhabdomyosarcomas can be broadly subdivided into embryonal and alveolar histological types, with spindle cell and botryoid variants of the former and a solid variant of the latter. [1][2][3] In recent years, molecular correlates with histology have been described. In particular, the translocation t(2;13)(q35;q14) and the rare variant translocation t(1;13)(p36;q14) 4,5 that result in the generation of the fusion proteins PAX3-FKHR and PAX7-FKHR, respectively, 6 -8 are characteristic of alveolar rhabdomyosarcoma (ARMS). These two translocations involve the fusion of the DNA binding elements of the PAX transcription factors with the transactivation domain of the FKHR protein, and may be referred to collectively as FKHR disrupting translocations. Embryonal rhabdomyosarcoma (ERMS) cells express wild-type PAX3 that binds the same DNA targets as PAX3-FKHR but has weaker transcription activation. FKHR fusions have been reported to occur in about 80% of ARMS cases. Cytogenetic and comparative genomic hybridization studies have shown that ERMS tumors have a pattern of whole chromosome gains and losses whereas ARMS tumors have a high incidence of translocations and discrete amplicons, the significance of which, if any, has yet to be determined. 9 There are also molecular changes in common between the different histological subtypes, including disruption of the p53 pathway through mutation or mdm2 amplification, 10,11 and deregulation of imprinted genes at chromosome region 11p15.5. 12,13 Hence it is an attractive hypothesis that ERMS and ARMS represent distinct pathologies, rather than being part of a spectrum, and that the essential difference resides in the presence of the FKHR disrupting translocations. The implication is that both ERMS and ARMS are derived from cells committed to myogenic differentiation, but that PAX3-FKH...

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Agreement among and within groups of pathologists in the classification of rhabdomyosarcoma and related childhood sarcomas. Report of an international study of four pathology classifications

Cited by 87 publications

References 9 publications

Pathologic Classification of Rhabdomyosarcomas and Correlations with Molecular Studies

Pathologic Classification of Rhabdomyosarcomas and Correlations with Molecular Studies

Identification of a PAX-FKHR Gene Expression Signature that Defines Molecular Classes and Determines the Prognosis of Alveolar Rhabdomyosarcomas

PAX3-FKHR Induces Morphological Change and Enhances Cellular Proliferation and Invasion in Rhabdomyosarcoma

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