Search

Rhabdomyosarcomas generally respond well to chemotherapy, and the residual lesions often are better differentiated than their primaries. This phenomenon may be explained by selective multidrug resistance (MDR) of differentiated tumor cell populations. We assess the role of MDR proteins in chemotherapy-induced differentiation in rhabdomyosarcomas in a clinical setting. Paraffin-embedded samples of 13 pairs of primary untreated rhabdomyosarcomas and their residual, recurrent, or metastatic lesions after chemotherapy were assessed for expression of MDR proteins, including P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP-1), and lung resistance-related protein (LRP). Expression was semiquantitatively scored based on the percentage of isolated immunoreactive tumor cells as follows: 0, negative; 0.5, <5%; 1, 5% to 25%; 2, 26% to 50%; 3, 51% to 75%, and 4, >75%. All specimens after chemotherapy, except the late recurrences, were better differentiated than their primary, untreated specimens. Pgp or MRP-1 expression did not change significantly, but LRP expression increased significantly after chemotherapy. In both untreated and treated samples, LRP was expressed primarily in differentiated cells. The findings indicate that the in vivo expression of LRP, but not of Pgp and MRP-1, is induced by chemotherapeutic treatment in rhabdomyosarcomas. The preferential expression of LRP in differentiated cells and the subsequent more extensive expression after chemotherapy suggests that LRP plays a role in therapy-induced differentiation., (Copyright 2003, Elsevier Science (USA). All rights reserved.)

In a previous study, it was shown that rhabdomyosarcomas widely express "neural" markers, such as neural cell adhesion molecules (N-CAM) and neurofilament protein isoforms. In the current study, a series of Ewing's sarcomas of bone and soft tissue sarcomas other than rhabdomyosarcoma was probed for the same antigens. It was found that N-CAM was widely expressed in the various sarcoma types, except Ewing's sarcomas, though less than in rhabdomyosarcomas. Similar to rhabdomyosarcomas, neurofilament isoforms were found throughout all sarcoma types but were largely restricted to those expressed early in neurogenesis, that is, poorly phosphorylated medium-weight isoforms. Neurofilament expression was most extensive in Ewing's sarcomas. It was concluded that the expression of "neural" markers (N-CAM, neurofilaments) is widespread in sarcomas and does not signify a neural tumor. The absence of N-CAM expression in Ewing's sarcoma may be helpful in its distinction from other sarcomas.

A case of a 2-year-old boy with a palpable mass in the left thigh is presented. Incisional biopsy was performed and subsequent histopathological examination revealed an infiltrative tumor composed of relatively large cells. The tumor cells were immunoreactive for vimentin and keratin, but not for desmin or smooth muscle actin. Cytogenetic analysis showed a 46,XY,t(11;22)(q24;q12) karyotype. The translocation (11;22)(q24;q12) is said to be characteristic for the family of Ewing's sarcoma and related tumors. As a result of the t(11;22)(q24;q12) the EWS gene on chromosome 22q12 joins the 3' part of FLI-1 gene on chromosome 11q24, which encodes a member of the ets family of transcriptional regulators. Using reverse transcription polymerase chain reaction (RT-PCR) a corresponding EWS-FLI-1 fusion product was detected. Additional immunohistological staining for p30/p32MIC2, which is suggestive, but not specific for Ewing's sarcoma, appeared to be weakly positive. In the current case a diagnosis of Ewing's sarcoma was considered unlikely, because of the location of the tumor and the immunohistological profile. Nevertheless it was decided to treat the patient according to a Ewing's sarcoma protocol based on the genotype of the tumor. The findings were compared with other extraosseous pediatric small cell tumors showing the t(11;22)(q24;q12) described in the literature.

In a series of rhabdomyosarcomas, the expression of neural cell adhesion molecules (NCAM) and neurofilament isoforms was probed in frozen sections. It was found that NCAM was widely expressed in rhabdomyosarcomas without relation to subtype or differentiation level. Neurofilament isoforms were found throughout all subtypes but were largely restricted to those neurofilament isoforms that are expressed early in neurogenesis, that is, poorly phosphorylated low- and medium-weight isoforms. It was concluded that the expression of these "neural" markers is widespread and does not signify a neural tumor.

Juvenile xanthogranuloma (JXG) is considered to represent a lesion originating from histiocytes. Three cases of deeply located JXG and one case of cutaneous JXG were studied. One case with extensive mesenteric involvement presented with hypercalcemia and one case with liver involvement had hypergammaglobulinemia. Immunohistochemistry, electron microscopy, karyotyping, and DNA flow cytometry were used to determine the phenotype of the cells involved and to find further clues as to the histogenesis of these lesions. Immunohistochemically, all lesions studied expressed the CD1a antigen but showed no labeling for S-100 protein. The cells did not contain Birbeck granules. From these data it is suggested that the cells involved are of indeterminate dermal histiocyte lineage and that occurrence of deep located lesions of JXG may be due to migration of CD1 a-positive histiocytes.

In the current study DNA-ploidy was determined in a group of 11 desmin-positive rhabdomyosarcomas and found to be aneuploid in all of them. In three cases, synchronous metastases could be studied as well. In two of them a hypotetraploid peak was observed not present in the primary tumor. In two other cases residual tumors obtained after chemotherapy appeared to have DNA-profiles similar to those observed in their primary tumors. These findings suggest either a selection of metastasizing clones or tumor progression. No apparent selection of clones responding to therapy could be established. For comparison, a group of other childhood sarcomas (four Ewing's sarcomas, two primitive neuroectodermal tumors, and two epithelioid sarcomas) was also studied. All except one of these cases appeared to have diploid or near-diploid stemlines. These results suggest that DNA-ploidy may be used as an additional criterion in the differential diagnosis of childhood sarcomas.

Twenty-one childhood rhabdomyosarcomas were divided into three groups on the basis of cytologic composition. The tumors in group P consisted entirely of primitive mesenchymal cells, whereas those in groups M and W were characterized by the additional presence of numerous round rhabdomyoblasts and strap cells, respectively. The tumors were studied for the universal mesenchymal intermediate filament vimentin, and for the muscle-specific intermediate filament desmin. Vimentin positivity, which tended to be more prominent in primitive tumor cells, was found in all tumors, whereas desmin was found especially in round rhabdomyoblasts and strap cells. Desmin-positive primitive cells were found only in groups M and W, not in group P. It was concluded that the differentiation from primitive mesenchymal cells to morphologically recognizable myogenic tumor cells is accompanied by an increase in desmin positivity and, presumably, a decrease in vimentin positivity. Moreover, the observations suggest the existence of a group of "committed" cells that are morphologically primitive, but desmin-positive. These cells might play an important role in the observed further differentiation of rhabdomyosarcomas under chemotherapy.

Two children and one young adult with extremity sarcomas demonstrating an aggressive clinical behavior are described. Histologically, all three tumors displayed features compatible with a deep-seated epithelioid sarcoma or with a malignant rhabdoid tumor of soft tissue. Immunohistologically, both vimentin and epithelial antigens were demonstrated; however, no desmin was detectable. In all three cases, the DNA profile was diploid. In one case, a trisomy of chromosome 2 was found in the tumor cells, a phenomenon also observed in embryonal rhabdomyosarcomas. It is concluded that, although the immunohistologic findings support the epithelioid character of the tumors, this chromosomal finding suggests a relationship with rhabdomyosarcomas and justifies the designation of rhabdoid.

The effectiveness of polychemotherapy in young patients with rhabdomyosarcomas has been well established. The morphologic alterations in the tumor tissue, however, have not been widely reported. Therefore, in a group of 15 patients from 1 to 24 years of age, specimens of tumor tissue obtained before and after polychemotherapeutic treatment were compared. No morphologic changes, other than fibrosis and necrosis, occurred in patients who initially had virtually undifferentiated tumors. When moderately or well-differentiated areas were present in the initial specimens, these areas showed proportionate increases in the follow-up specimens. Moreover, the cellular characteristics of round rhabdomyoblasts and strap cells with or without cross-striations became more distinct after treatment. However, cell types that were not present in the initial specimens were never found in follow-up specimens. It was concluded that the major role of polychemotherapy is the selective destruction of undifferentiated tumor cells; further differentiated cells are stimulated either directly or indirectly to reach their maximal inherent differentiation levels, but it does not appear that transitions from one cell type to the other occur.