Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function.

Journal ArticleAlveolar rhabdomyosarcoma is an aggressive childhood muscle cancer for which outcomes are poor when the disease is advanced. Although well-developed mouse models exist for embryonal and pleomorphic rhabdomyosarcomas, neither a spontaneous nor a transgenic mouse model of alveolar rhabdomyosarcoma has yet been reported. We report the first mouse model of alveolar rhabdomyosarcoma using a conditional Pax3:Fkhr knock-in allele whose activation in late embryogenesis and postnatally is targeted to terminally differentiating Myf6-expressing skeletal muscle. In these mice, alveolar rhabdomyosarcomas occur but at low frequency, and Fkhr haploinsufficiency does not appear to accelerate tumorigenesis. However, Pax3:Fkhr homozygosity with accompanying Ink4a/ARF or Trp53 pathway disruption, by means of conditional Trp53 or Ink4a/ARF loss of function, substantially increases the frequencies of tumor formation. These results of successful tumor generation postnatally from a target pool of differentiating myofibers are in sharp contrast to the birth defects and lack of tumors for mice with prenatal and postnatal satellite cell triggering of Pax3:Fkhr. Furthermore, these murine alveolar rhabdomyosarcomas have an immunohistochemical profile similar to human alveolar rhabdomyosarcoma, suggesting that this conditional mouse model will be relevant to study of the disease and will be useful for preclinical therapeutic testing

Inflammatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases.

Inflammatory myofibroblastic tumor (IMT) is a neoplasm of intermediate biologic potential. In this study, we report a subset of IMTs with histologic atypia and/or clinical aggressiveness that were analyzed for clinicopathologic features, outcome, and immunohistochemical expression of anaplastic lymphoma kinase (ALK) and other markers to identify potential pathologic prognostic features. Fifty-nine IMTs with classic morphology (5 cases), atypical histologic features (21 cases), local recurrence (27 cases), and/or metastasis (6 cases) were studied. Immunohistochemistry was performed for ALK1 and other markers (Mib-1, c-Myc, cyclin D1, caspase 3, Bcl-2, Mcl-1, survivin, p27, CD56, p53, MDM-2) using standard techniques. The 59 IMTs had an age at diagnosis ranging from 3 weeks to 74 years (mean 13.2 y, median 11 y, 44% in the first decade). The mean tumor size was 7.8 cm. Sites included the abdomen or pelvis in 64%, lung in 22%, head and neck in 8%, and extremities in 5%. The follow-up ranged from 3 months to 11 years, with a mean of 3.6 years and a median of 3 years. Thirty-three patients had local recurrences, including 13 with multiple local recurrences and 6 patients with both local recurrences and distant metastases. Six patients died of disease, 5 with local recurrences, and 1 with distant metastases. Histologic evolution to a more pleomorphic cellular, spindled, polygonal, or round cell morphologic pattern was observed in 7 cases. Abdominal and pelvic IMTs had a recurrence rate of 85%. Recurrent and metastatic IMTs were larger, with mean diameters of 8.7 and 11 cm, respectively. Cytoplasmic ALK reactivity was seen in 56%. ALK-negative IMTs occurred in older patients (mean age 20.1) years and had greater nuclear pleomorphism, atypia, and atypical mitoses. All 6 metastatic IMTs were ALK-negative. Nuclear expression of p53 was detected in 80% of IMTs overall, but in only 25% of the metastatic subset. There were no significant differences among the subgroups for c-Myc, cyclin D1, MDM-2, Mcl-1, Bcl-2, CD56, p27, caspase 3, or survivin expression. In conclusion, among these 59 IMTs, ALK reactivity was associated with local recurrence, but not distant metastasis, which was confined to ALK-negative lesions. Absent ALK expression was associated with a higher age overall, subtle histologic differences, and death from disease or distant metastases (in a younger subset). Other proliferative, apoptotic, and prognostic markers did not correlate well with morphology or outcome. Thus, ALK reactivity may be a favorable prognostic indicator in IMT and abdominopelvic IMTs recur more frequently

Adipose and Myxoid Tumors of Childhood and Adolescence

none2Adipose and myxoid tumors in children are an unusual and challenging group of neoplasms that have some unique aspects in contrast to these tumors in adults. Less than 10% of soft tissue neoplasms in the 1st 2 decades of life have an adipose phenotype and most are benign. The most common are various types of lipoma and lipoblastoma. Liposarcoma in young patients is rare and has a distinctive distribution of histologic subtypes, including classic myxoid liposarcoma, and unusual variants, such as pleomorphic-myxoid liposarcoma. Pathologic examination enhanced by adjunct techniques, such as immunohistochemistry and cytogenetic or molecular genetic studies, is useful for classification of difficult cases. Myxoid tumors can overlap with adipose tumors and are included in this review because of the morphologic similarities and importance of diagnostic accuracy. This article reviews the clinicopathologic features of adipose and myxoid tumors with an emphasis on the unique aspects of these neoplasms in children and adolescents and the differential diagnosis.noneCheryl M. Coffin;Rita AlaggioCheryl M., Coffin; Alaggio, Rit

The evolution of pediatric soft tissue sarcoma classification in the last 50 years

This review discusses the history of the classification of soft tissue sarcomas in children and adolescents, the current transition toward integration of morphology and molecular genetics as new entities emerge, and future perspectives

Myogenic tumors in children and adolescents

Neoplasms of striated and smooth muscle in children are a diverse group of neoplasms that have some unique aspects in contrast to these tumors in adults. Rhabdomyosarcoma is the most common soft tissue sarcoma of infancy and childhood and is relatively common in adolescents. In contrast, smooth muscle tumors are relatively rare, and the various types of rhabdomyoma and smooth and skeletal muscle hamartomas are very uncommon. In recent years, the understanding of the pathologic and genetic aspects of rhabdomyosarcoma has been enhanced by adjunct techniques, such as immunohistochemistry and cytogenetic or molecular genetic analysis. The current classification of rhabdomyosarcoma emphasizes the histologic-prognostic correlations. This article reviews the clinicopathologic features of striated and smooth muscle tumors with an emphasis on the unique aspects of these neoplasms in children and adolescents and the differential diagnosis