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PubMed2000

Strong immunostaining for myogenin in rhabdomyosarcoma is significantly associated with tumors of the alveolar subclass.

Rhabdomyosarcomas are a heterogeneous group of tumors with respect to their molecular basis, degree of differentiation, histology, and clinical behavior. Because of the wide variation of tumor morphology, it is often difficult to distinguish between the distinct subtypes of rhabdomyosarcomas. By using cryosections of tumor specimens and immunohistochemistry, in the present study we show that strong expression of myogenin in rhabdomyosarcoma is associated with alveolar histology (P = <0.0001, Fisher's exact test). Although staining for myogenin was observed in 22 of 26 rhabdomyosarcomas, all alveolar rhabdomyosarcomas (nine of nine) showed high levels of staining for myogenin, as defined by the frequency and intensity of staining of the tumor cells. The staining pattern suggests that the tumor cells are clonally derived from myogenin-positive progenitor cells. In contrast, most embryonal rhabdomyosarcomas (13 of 15) were either negative or showed a low level of staining for myogenin. In these tumors a larger proportion of tumor cells were distinctly negative for myogenin. Six of seven alveolar rhabdomyosarcomas that strongly stained for myogenin were also positive for Pax3-7/Forkhead (FKHR) by polymerase chain reaction/reverse transcriptase-polymerase chain reaction. One of two embryonal rhabdomyosarcomas that strongly stained for myogenin was retrospectively found to be positive for Pax3/FKHR transcripts. Quantitative analysis for myogenin by Western blotting using a smaller subset of rhabdomyosarcomas revealed that in general there was a good correlation between immunohistochemical staining and Western blotting (P = 0.01, Pearson Correlation), although the former technique was more sensitive for detecting tumors with low levels of the protein. On average, alveolar rhabdomyosarcomas expressed at least threefold more myogenin than embryonal rhabdomyosarcomas. Our data show that staining for myogenin will be a simple, rapid, and accurate adjunct for distinguishing between alveolar and embryonal rhabdomyosarcomas. We propose that embryonal rhabdomyosarcomas result from an early block in myogenesis, before the expression of myogenin. In contrast, we propose that alveolar rhabdomyosarcomas either originate from a late block in myogenesis (after expression of myogenin) or that the pathological mechanisms involved in these neoplasms also induce strong expression of this protein.

Antibodies, Monoclonal↗

PubMed1975

Rhabdomyosarcoma of the extremities and trunk: analysis of 150 patients treated by surgical resection.

This report details the clinical experience of 150 patients with rhabdomyosarcomas treated by one group of surgeons. Of the 150 patients, 103 suffered from pleomorphic rhabdomyosarcomas, 40 patients had embryonal rhabdomyosarcomas, and 7 had alveolar cell type of rhabdomyosarcoma. The males suffered almost twice as much as the females from this form of cancer (96 males to 54 females). The fifth decade had the highest incidence of all rhabdomyosarcomas. The younger patients generally suffered from embryonal rhabdomyosarcomas and the older ones from pleomorphic rhabdomyosarcomas, although age was no barrier to the occurrence of embryonal rhabdomyosarcomas in some of the older patients and pleomorphic rhabdomyosarcomas in some of the younger patients. Caucasians were almost exclusively afflicted by this form of cancer (93% of this series). The lower extremity was the most frequent site of the lesion, occurring in 50.7% of the 150 cases. The upper extremity was the second most frequently involved site (28%), and the trunk was the least involved site (21.3%). Of the 150 patients studied, 40 were considered indeterminate. Thirteen patients are alive and free of cancer, but were treated less than 5 years ago; 12 patients reported for consultation only. There were 13 who were free of sarcomas at periods in excess of 2 years but were lost to follow-up. Two patients in this series died before the 5-year period, and autopsy revealed the death to be due to causes other than the rhabdomyosarcoma. Of the 110 determinate patients, 75 (68%) died as a result of the cancer. The 5-year survival rate equals 32%. The fact of the 30% 5-year survival after treatment for recurrences should help dismiss the pessimism which prevails once a recurrence is noted subsequent to major therapy. Age per se had no great effect on prognosis. The poorest results occurred in the 11-20 age range, with a 5-year survival of 15%. This value reflects on increased incidence of embryonal rhabdomyosarcomas which tend to be more malignant and metastasize earlier than do the pleomorphic type. The effect of location upon survival revealed that of 76 patients with involvement of the lower extremity, 34% survived 5 years or longer, and those with sarcomas of the trunk had the poorest survival (26%). The fact that the trunk, by virtue of its anatomy, limits the degree of surgery that can be perfomred, probably helps to explain this difference. The role of radiation therapy and chemotherapy awaits elucidation. Reports of combined surgery, radiation therapy, and chemotherapy are encouraging.

Adolescent↗

PubMed2006

Myogenin and desmin immunohistochemistry in the assessment of post-chemotherapy genitourinary embryonal rhabdomyosarcoma: prognostic and management implications.

PURPOSE: Posttreatment genitourinary embryonal rhabdomyosarcoma often shows well differentiated rhabdomyoblasts, which are detectable on routine histological staining. Definite areas of residual undifferentiated rhabdomyosarcoma indicate residual/recurrent disease. However, the recent use of immunohistochemical staining with desmin and myogenin in resected specimens and surveillance biopsies following adjuvant therapy may demonstrate scant positive staining cells that appear undifferentiated on light microscopy. To our knowledge the clinical significance of this finding is currently unknown. Therefore, we reviewed our retrospective experience with genitourinary embryonal rhabdomyosarcoma to examine the relationship between immunostain positive undifferentiated cells and subsequent clinical outcome. MATERIALS AND METHODS: A total of 14 children with a median age of 2.75 years (range 8 months to 7 years) with genitourinary embryonal rhabdomyosarcoma were identified in the histopathology database. All had biopsy confirmation of the diagnosis, followed by multi-agent chemotherapy. Two children in whom there was obvious residual active tumor at the resection margins were excluded from further analysis. Histopathological findings in all patients on the resection/posttreatment biopsy were reviewed. All specimens were immunostained with desmin and myogenin to detect residual undifferentiated rhabdomyoblasts. The relation between histopathological findings and outcome was determined. RESULTS: There were 14 cases of genitourinary embryonal rhabdomyosarcoma. In 2 cases (14%) residual embryonal tumor was pathologically confirmed following initial treatment. In 12 cases no obvious residual tumor was present following initial therapy. Rhabdomyosarcoma affected the bladder in 10 cases and the vagina in 2. There were no distant metastases in any child. Ten patients underwent local resection following chemotherapy and 2 underwent followup biopsies only without resection. A total of 11 cases showed well differentiated, posttreatment rhabdomyoblasts that was identifiable on routine hematoxylin and eosin staining with margins apparently free of tumor and 1 showed no morphological evidence of residual rhabdomyosarcoma. However, all cases demonstrated at least scant abnormal desmin and myogenin positive cells in the specimens. Four patients had no further treatment and none had clinical recurrence. All were well 10 years (range 8 to 13) after treatment. Eight patients received further treatment (chemotherapy and/or radiotherapy) based on clinical and pathological findings, followed by further resection in 3. One patient died of disease but 7 were well a median of 7.2 years (range 8 months to 13 years) after treatment. CONCLUSIONS: The significance of undifferentiated myogenin/desmin positive cells in genitourinary embryonal rhabdomyosarcoma in the absence of morphological residual/recurrent embryonal rhabdomyosarcoma remains unclear since such cells can be detected in all cases of posttreatment embryonal rhabdomyosarcoma. In some cases findings are associated with clinical disease recurrence, while others with identical histopathological findings following initial treatment have no clinical sequelae even in the absence of further treatment. In genitourinary embryonal rhabdomyosarcoma close and regular clinical surveillance is essential. Desmin/myogenin immunohistochemistry to detect scattered undifferentiated cells does not appear to provide useful prognostic information.

Child↗

PubMed2004

Gene expression signatures identify rhabdomyosarcoma subtypes and detect a novel t(2;2)(q35;p23) translocation fusing PAX3 to NCOA1.

Rhabdomyosarcoma is a pediatric tumor type, which is classified based on histological criteria into two major subgroups, namely embryonal rhabdomyosarcoma and alveolar rhabdomyosarcoma. The majority, but not all, alveolar rhabdomyosarcoma carry the specific PAX3(7)/FKHR-translocation, whereas there is no consistent genetic abnormality recognized in embryonal rhabdomyosarcoma. To gain additional insight into the genetic characteristics of these subtypes, we used oligonucleotide microarrays to measure the expression profiles of a group of 29 rhabdomyosarcoma biopsy samples (15 embryonal rhabdomyosarcoma, and 10 translocation-positive and 4 translocation-negative alveolar rhabdomyosarcoma). Hierarchical clustering revealed expression signatures clearly discriminating all three of the subgroups. Differentially expressed genes included several tyrosine kinases and G protein-coupled receptors, which might be amenable to pharmacological intervention. In addition, the alveolar rhabdomyosarcoma signature was used to classify an additional alveolar rhabdomyosarcoma case lacking any known PAX3 or PAX7 fusion as belonging to the translocation-positive group, leading to the identification of a novel translocation t(2;2)(q35;p23), which generates a fusion protein composed of PAX3 and the nuclear receptor coactivator NCOA1, having similar transactivation properties as PAX3/FKHR. These experiments demonstrate for the first time that gene expression profiling is capable of identifying novel chromosomal translocations.

Base Sequence↗

PubMed1993

Expression of the retinoblastoma susceptibility gene in childhood rhabdomyosarcomas.

BACKGROUND: Alveolar and embryonal rhabdomyosarcomas are soft-tissue tumors that occur mainly in childhood. The more aggressive alveolar subtype has been found to possess a characteristic chromosomal abnormality located near the retinoblastoma susceptibility gene (RB1). RB1 is a tumor suppressor gene implicated in the development of retinoblastoma and other, unrelated malignancies, especially osteogenic sarcomas and other second malignancies in retinoblastoma survivors. PURPOSE: The goals of our study were (a) to determine whether abnormalities of RB1 occur routinely in sporadic rhabdomyosarcomas, as reported for other sporadic malignancies, especially bone and soft-tissue sarcomas of adulthood; and (b) to assess differences in the functional status of the gene in embryonal and alveolar rhabdomyosarcomas that might explain the differing clinical aggressiveness of these two variants. METHODS: Analyses of messenger RNA (mRNA) and protein expression and immunohistochemical studies were performed on 11 rhabdomyosarcoma cell lines from patients with no family history of retinoblastoma, and RB1 protein expression was studied by immunoprecipitation in primary tumor biopsy tissue from 18 patients with sporadic rhabdomyosarcoma (five embryonal and 13 alveolar). RESULTS: The RB1 gene appears to be normal in structure, expression, and function and is comparably phosphorylated in both forms of childhood rhabdomyosarcoma. Normal-size RB1 mRNA was present in all rhabdomyosarcomas, whereas clearly abnormal expression was documented in the controls, as expected: mRNA transcripts were truncated in Y79 retinoblastoma and absent in DU4475 breast carcinoma. In addition, immunoprecipitation with antibody to RB1 protein indicated the presence of normal RB1 protein in all rhabdomyosarcomas. CONCLUSIONS: These findings are distinct from those for other adult asarcomas, in which RB1 expression frequently is reported as abnormal. They are particularly surprising in view of the high incidence of RB1 abnormalities in osteosarcoma, the bone tumor most associated with retinoblastoma. The etiology and biologic behavior of rhabdomyosarcoma are, thus, unlikely to be dependent on RB1 mutations. IMPLICATIONS: The findings reported here clearly imply that the RB1 gene is structurally and functionally normal in childhood rhabdomyosarcoma. Other, as yet unidentified, genetic defects are apparently etiologic in this particular sarcoma.

Breast Neoplasms↗

PubMedDate not supplied

From the archives of the AFIP. Genitourinary rhabdomyosarcoma in children: radiologic-pathologic correlation.

Rhabdomyosarcoma is the most common tumor of the lower genitourinary tract in children in the first 2 decades of life. Most cases of genitourinary rhabdomyosarcoma are of the embryonal histologic subtype and include tumors of the bladder, prostate, testes and paratesticular sites, penis, perineum, vagina, and uterus. The natural history, pattern of metastatic spread, treatment, and prognosis of childhood rhabdomyosarcoma vary with the anatomic site of the lesion. In children with rhabdomyosarcoma of the bladder or prostate, presenting signs and symptoms include urinary or fecal retention, dysuria, urinary tract infection, and hematuria. Paratesticular rhabdomyosarcoma produces painless scrotal swelling, which may be ignored until the tumor has reached a large size. Vaginal tumors may manifest as a prolapsing mass in the introitus. Radiologic studies of children with genitourinary rhabdomyosarcoma reflect the nonspecific gross features of the tumor, which may be ill defined with infiltrative margins or well circumscribed by a pseudocapsule of compressed tissue. The botryoid variant of embryonal rhabdomyosarcoma results when submucosal tumor produces a polypoid mass resembling a cluster of grapes within a hollow structure. Botryoid morphology is characteristic, but not specific, for rhabdomyosarcoma within the vagina or urinary bladder, since yolk sac tumor and "tumoral" cystitis may have a similar appearance. Invasion of adjacent structures by the primary tumor may make the precise anatomic origin of genitourinary rhabdomyosarcoma difficult to determine on cross-sectional images. Recent refinements in multidisciplinary therapeutic regimens combining chemotherapy, radiation therapy, and surgery have dramatically improved outcome for children with genitourinary rhabdomyosarcoma. Diagnostic imaging plays an important role in monitoring response to therapy.

Adolescent↗

PubMedDate not supplied

Association of ataxia telangiectasia mutated (ATM) gene mutation/deletion with rhabdomyosarcoma.

Rhabdomyosarcoma is a common malignancy in children. There are two major types of rhabdomyosarcomas, the embryonal and the alveolar, differing in cytogenetic and morphologic features. The alveolar type of rhabdomyosarcoma is frequently associated with chromosome translocation t(2; 13) and poor clinical prognosis. Pathogenesis of rhabdomyosarcoma remains obscure, and especially it occurs in the location where skeletal muscle is absent. We report here that there is a high frequency of association of rhabdomyosarcoma with ataxia telangiectasia mutated (ATM) gene mutation/deletion. Totally 17 cases of rhabdomyosarcoma specimens were studied by immunohistochemical or immunofluorescent staining with ATM antibody and revealed that 7 of the 17 cases were negative for ATM expression (41%). Further analyses of rhabdomyosarcoma cell lines with RT-PCR revealed that in Rh30 cells, an alveolar rhabdomyosarcoma cell line, there are three separate deletions/mutations of the ATM mRNA. Western blotting analysis of the Rh30 cellular extract with anti-ATM antibody showed that there is an aberrant form of ATM protein within the Rh30 cells that are smaller than normal control. These results suggest, for the first time, a link of ATM gene deletion/mutation with rhabdomyosarcoma, and since ATM kinase is a crucial regulatory protein in DMA damage repair signaling pathway, and ATM deletion/mutation may contribute to pathogenesis of rhabdomyosarcoma.

Adolescent↗

PubMed1986

Metastatic behavior of rhabdomyosarcoma.

Embryonal and alveolar rhabdomyosarcoma probably have the same histogenesis, yet alveolar rhabdomyosarcoma has a considerably worse prognosis and is generally less responsive to treatment. The metastatic behavior of rhabdomyosarcoma in 22 autopsied subjects was analyzed with respect to the histologic subtypes of the tumors to determine whether the more aggressive behavior of alveolar rhabdomyosarcoma was related to greater tumor burden and/or more widely disseminated metastases. Subjects with embryonal rhabdomyosarcoma tended to survive longer and had greater numbers of metastatic sites at autopsy compared to subjects with alveolar rhabdomyosarcoma, but these differences were not statistically significant. In addition, there were no significant differences in the overall distribution of metastases between embryonal and alveolar rhabdomyosarcoma. The most frequent sites of metastases from both types of tumor were soft tissues (73%), serosal surfaces (64%), lymph nodes (64%), lungs (55%), and bone marrow (50%). The findings suggest that the metastatic behavior of rhabdomyosarcoma does not vary as a function of length of survival, mode of therapy, or histologic subtype. We propose that factors such as stage of disease at presentation and location of the primary tumor, rather than histologic subtype, are probably the most important variables governing the therapeutic responsiveness of rhabdomyosarcoma.

Adolescent↗

PubMed1985

Soft-tissue sarcomas in childhood. A study of 262 cases including 169 cases of rhabdomyosarcoma.

Although numerous investigations of soft-tissue sarcomas of childhood have been done, there are still many unsolved problems in the diagnosis, histogenesis, and biological behaviour of such tumours. In the present study, the soft-tissue sarcomas collected at the Paediatric Tumour Registry in Kiel were investigated. There was a total of 262 cases, including 169 (64.5%) in which a definite diagnosis of rhabdomyosarcoma had been made. An analysis of the age distribution showed that rhabdomyosarcoma is more than three times as frequent as non-rhabdomyosarcomatous soft-tissue tumours in the first quinquennium. Rhabdomyosarcoma exhibited male predominance (male-to-female ratio 1.45:1), whereas non-rhabdomyosarcomatous tumours showed an approximately equal sex distribution. Among the cases of rhabdomyosarcoma, the embryonal type clearly predominated (approx. 70%); the alveolar type was less common (approx. 20%). Correlation of histology with prognosis revealed that even tumours showing tiny foci with an alveolar pattern in otherwise solid, undifferentiated rhabdomyosarcoma, must be classified as alveolar rhabdomyosarcoma. Cases of alveolar rhabdomyosarcoma showed a higher incidence of local recurrence, lymph node metastasis, distant metastatic spread, and death, than did cases of embryonal rhabdomyosarcoma. It is concluded that "cytological differentiation" does not improve the prognosis of rhabdomyosarcoma.

Adolescent↗

PubMed1989

Rhabdomyosarcoma in middle-aged and elderly individuals.

In a review of a national series of malignant tumors in middle-aged and elderly individuals (over 40 years of age), in all 107 cases primarily diagnosed and reported to the Swedish Cancer Registry as rhabdomyosarcomas during the period 1972-1981, 4 cases were accepted as botryoid, embryonal or alveolar rhabdomyosarcoma, using light-microscopic criteria for the diagnosis. An electron-microscopic and immunohistochemical analysis was performed on the 4 cases along with 7 cases of botryoid, embryonal and alveolar rhabdomyosarcoma in patients of over 40 years of age obtained from our own files. Rhabdomyoblastic differentiation was established ultrastructurally by the presence of myofilaments and Z-like densities in 10 of these 11 cases. There were tumor cells in the formaldehyde-fixed, paraffin-embedded material which were positively stained for desmin in all cases, for myoglobin in 7/11 cases, for vimentin in 5/11 cases and for actin in all cases, using monoclonal antibodies. The demonstration of desmin by the monoclonal antibody which was used on the formaldehyde-fixed, paraffin-embedded material is of particular value in the diagnosis of rhabdomyosarcoma. Another tumor, located in the minor pelvis, lacked the light-microscopic features of botryoid, embryonal or alveolar rhabdomyosarcoma, but presented ultrastructural and immunohistochemical evidence of a rhabdomyoblastic differentiation. This tumor was epithelioid in appearance and shared features with alveolar soft part sarcoma. The label epithelioid rhabdomyosarcoma is proposed for this tumor. Nine pleomorphic sarcomas were selected from the national series as possible pleomorphic rhabdomyosarcomas because of the presence of ribbon-shaped tumor cells with an eosiniphilic cytoplasm. There was no electron-microscopic or immunohistochemical evidence of a myogenic differentiation in any of these 9 tumors. The present investigation indicates that a pleomorphic type of rhabdomyosarcoma, indistinguishable from embryonal, botryoid and alveolar rhabdomyosarcoma, is extremely rare or non-existent.

Adult↗

PubMed2004

Inhibition of connective tissue growth factor (CTGF/CCN2) expression decreases the survival and myogenic differentiation of human rhabdomyosarcoma cells.

Connective tissue growth factor (CTGF/CCN2), a cysteine-rich protein of the CCN (Cyr61, CTGF, Nov) family of genes, emerged from a microarray screen of genes expressed by human rhabdomyosarcoma cells. Rhabdomyosarcoma is a soft tissue sarcoma of childhood deriving from skeletal muscle cells. In this study, we investigated the role of CTGF in rhabdomyosarcoma. Human rhabdomyosarcoma cells of the embryonal (RD/12, RD/18, CCA) and the alveolar histotype (RMZ-RC2, SJ-RH4, SJ-RH30), rhabdomyosarcoma tumor specimens, and normal skeletal muscle cells expressed CTGF. To determine the function of CTGF, we treated rhabdomyosarcoma cells with a CTGF antisense oligonucleotide or with a CTGF small interfering RNA (siRNA). Both treatments inhibited rhabdomyosarcoma cell growth, suggesting the existence of a new autocrine loop based on CTGF. CTGF antisense oligonucleotide-mediated growth inhibition was specifically due to a significant increase in apoptosis, whereas cell proliferation was unchanged. CTGF antisense oligonucleotide induced a strong decrease in the level of myogenic differentiation of rhabdomyosarcoma cells, whereas the addition of recombinant CTGF significantly increased the proportion of myosin-positive cells. CTGF emerges as a survival and differentiation factor and could be a new therapeutic target in human rhabdomyosarcoma.

Cell Differentiation↗

PubMed2006

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma.

Both epidermal growth factor receptor (EGFR) and ErbB-2 play an important role in cancer biology and constitute promising molecular targets of therapy. EGFR and ErbB-2 expression has been observed in rhabdomyosarcoma cell lines but not analyzed systematically in rhabdomyosarcoma tumors. Tissue microarray sections representing 66 rhabdomyosarcoma tumors (34 embryonal rhabdomyosarcoma, 32 alveolar rhabdomyosarcoma) were surveyed by immunohistochemistry using antibodies specific for EGFR and ErbB-2. Immunostains were assessed for intensity (0: no immunostaining; 1: weak; 2: moderate; 3: strong) and percentage of at least 500 neoplastic cells exhibiting membranous or membranous and cytoplasmic immunostaining. EGFR and ErbB-2 expression was considered positive if the product of intensity and percentage was greater than 10. Patients had a median age of 5.7 years (range 8 months-19.1 years), and of 65/66 patients, 38 were males and 27 were females. Expression of ErbB-2 was identified in 22/66 (33%) cases and tended to be more frequent in the alveolar subtype (13/32, 41%, vs 9/34, 26%, P=0.30). Expression of EGFR was identified in 31/66 (47%) cases and correlated with the embryonal subtype (26/34, 76%, vs 5/32, 16%, P<0.0001) independent of stage, age, and gender. Coexpression of EGFR and ErbB-2 was identified in eight tumors, of which six were embryonal rhabdomyosarcoma. None of the cases exhibited EGFR or ErbB-2 gene amplification, as assessed using fluorescence in situ hybridization. Furthermore, analysis of 11 additional rhabdomyosarcoma tumors (six alveolar; five embryonal) revealed no evidence of mutations in EGFR exons 18, 19, 20, and 21. In summary, expression of EGFR and/or ErbB-2 is detected in a sizeable subset of rhabdomyosarcoma tumors without evidence of EGFR or ErbB-2 amplification or mutations in the EGFR tyrosine kinase domain. Notably, expression of EGFR correlates with the embryonal subtype, which is also more likely to coexpress EGFR and ErbB-2.

Adolescent↗

PubMed2006

Mirk/Dyrk1b mediates cell survival in rhabdomyosarcomas.

Rhabdomyosarcoma is the most common sarcoma in children and is difficult to treat if the primary tumor is nonresectable or if the disease presents with metastases. The function of the serine/threonine kinase Mirk was investigated in this cancer. Mirk has both growth arrest and survival functions in terminally differentiating skeletal myoblasts. Maintenance of Mirk growth arrest properties would cause down-regulation of Mirk in transformed myoblasts. Alternatively, Mirk expression would be retained if rhabdomyosarcoma cells used Mirk survival capability. Mirk expression was significant in 12 of 16 clinical cases of rhabdomyosarcoma. Mirk was detected in each rhabdomyosarcoma cell line examined. Mirk was a functional kinase in each of three rhabdomyosarcoma cell lines, where it proved to be more active than in C2C12 skeletal myoblasts. Mirk mediated survival of the majority of clonogenic rhabdomyosarcoma cells. Knockdown of Mirk by RNA interference reduced the fraction of RD and of Rh30 rhabdomyosarcoma cells capable of colony formation 3- to 4-fold in multiple experiments. Depletion of Mirk induced cell death by apoptosis, as shown by increased numbers of terminal deoxynucleotidyl transferase-mediated nick-end labeling-positive cells and by increased binding of Annexin V. Mirk is a stress-activated kinase that mediates expression of contractile proteins in differentiating myoblasts, but Mirk is not essential for muscle formation in the embryo. It is likely that Mirk also facilitates survival of satellite cell-derived rhabdomyoblasts in regenerating skeletal muscle and aids their differentiation. This survival function is maintained in rhabdomyosarcoma, where Mirk may be a novel therapeutic target.

Adolescent↗

PubMed1982

Diagnosis of human childhood rhabdomyosarcoma of antibodies to desmin, the structural protein of muscle specific intermediate filaments.

Four embryonal rhabdomyosarcomas, one tumor diagnosed as an undifferentiated sarcoma, probably a rhabdomyosarcoma, and six different non-muscular sarcomas were investigated with antibodies specific for different intermediate filament types. The tumor cells in the rhabdomyosarcomas and the undifferentiated tumor were stained clearly by antibodies to desmin, the intermediate filament type characteristic of muscle. The staining of tumor cell by antibodies to vimentin, the intermediate filament type characteristic of certain cell types of mesenchymal origin including myoblasts, was different in these 5 cases. In one case of embryonal rhabdomyosarcoma nearly all tumor cells were stained, but in the remaining cases few or no tumor cells were positive with the vimentin antibody. In these rhabdomyosarcomas not only the large rhabdomyoblasts, but also the small undifferentiated cells were labeled by antibodies to desmin. In the latter cell type the desmin filaments were arranged typically in coils. In contrast, tumor cells in the non-muscular mesenchymal sarcomas were stained only by antibodies to vimentin but not by antibodies to desmin or prekeratin. The retention of the desmin marker characteristic of normal muscle in cases of rhabdomyosarcoma not only allowed the undifferentiated desmin-positive sarcoma to be classified as rhabdomyosarcoma but also suggests that the use of antibodies to desmin could be very helpful in the future for the diagnosis of undifferentiated rhabdomyosarcomas.

Adult↗

PubMed2005

Myogenic markers in the evaluation of embryonal botryoid rhabdomyosarcoma of the female genital tract.

Rhabdomyosarcoma presents special diagnostic problems when it involves the uterine cervix in young children because tumor cells may lack marked atypia and may blend with the normal, immature, condensed, cellular stroma, rendering diagnosis difficult. Myogenic makers are a valuable ancillary technique for establishing a diagnosis of rhabdomyosarcoma. However, desmin positivity has been reported in cervical stromal cells, which can confound diagnosis. To determine whether immunohistochemical markers of skeletal muscle differentiation are helpful in the diagnosis of uterine botryoid rhabdomyosarcoma, we compared the immunohistochemical staining pattern of cervical rhabdomyosarcoma from 3 patients with that of normal uteri from age-matched autopsy controls by using antibodies for desmin, smooth muscle actin, muscle-specific actin, myoD1, myogenin, and WT-1. All tumors demonstrated at least focal immunopositivity for desmin, muscle-specific actin, smooth muscle actin, myoD1, and WT-1, and 1 tumor was also positive for myogenin. Autopsy controls showed only scattered subepithelial stromal immunoreactivity for desmin, muscle-specific actin, smooth muscle actin, and WT-1 and showed cytoplasmic, but not nuclear, immunopositivity for myoD1 and myogenin. Myometrium was diffusely positive for desmin and muscle-specific actin. We conclude that desmin, muscle-specific actin, smooth muscle actin, and WT1 are not specific for discriminating embryonal rhabdomyosarcoma from normal subepithelial cells in the female genital tract of children, although the number of immunopositive cells is consistently larger in rhabdomyosarcoma. Nuclear staining for myoD1 and myogenin appears not to occur in normal tissue, but it may be absent or sparse in embryonal rhabdomyosarcoma. Our findings indicate that, in this anatomic site, the diagnosis of rhabdomyosarcoma and in particular determination of tumor margins remain very reliant on histomorphology.

Biomarkers, Tumor↗

PubMed2005

Myogenic markers in the evaluation of embryonal botryoid rhabdomyosarcoma of the female genital tract.

Biomarkers, Tumor↗

PubMed1983

Genitourinary rhabdomyosarcoma.

Rhabdomyosarcoma is the most common soft tissue malignant neoplasm involving the pelvis of children. Debate still exists over whether the best treatment is pelvic exenteration, radiation and chemotherapy or chemotherapy as the cornerstone to treatment, with diminished needs for extensive surgery and prolonged radiotherapy. Contrariwise, there is little debate over the combined treatment modality for paratesticular rhabdomyosarcoma. We have evaluated and treated 19 children with rhabdomyosarcoma, including 17 with pelvic rhabdomyosarcoma and 2 with paratesticular rhabdomyosarcoma. This retrospective study was done to evaluate treatment regimens for patients with genitourinary rhabdomyosarcoma. For patients with pelvic rhabdomyosarcoma the study was divided into 2 series. In an early series 6 of 7 children had a pelvic exenteration with or without chemotherapy. Of these 7 children 3 are well 15 to 27 years following diagnosis. In a later series of 10 children, when chemotherapy was used more commonly, none underwent pelvic exenteration. Of these 10 patients 7 had chemotherapy or chemotherapy and biopsy only. Only 1 child, who presented with stage IV disease, died in this series. Another child with stage III disease had progressive disease despite chemotherapy and subsequent cystoprostatectomy. Thus, of 9 remaining patients 8 are well from 1 to 8 years. It appears that pelvic rhabdomyosarcoma can be treated effectively with chemotherapy, and limited surgery and radiation. Fortunately, pelvic exenteration can now be limited to a select few.

Antineoplastic Agents↗

PubMed2002

Rhabdomyosarcoma of the head and neck in children.

OBJECTIVE: The purpose of this study was to determine the rhabdomyosarcoma types involving the head and neck (H&N) region in children and their immunophenotype. DESIGN: Anatomic pathology archives at Texas Children's Hospital were searched for all rhabdomyosarcoma cases over a 20-year period. One-hundred and thirty-seven cases were identified, with 50 being H&N cases. The cases were typed according to the Intergroup Rhabdomyosarcoma Study (IRS) criteria. Immunocytochemistry for myogenic and non-myogenic markers was performed on all H&N cases. Electron micrographs from cases (n=32) where ultrastructural examination had been performed at the time of original diagnosis were reviewed. RESULTS: Children with H&N rhabdomyosarcomas had a mean age of 5.3 years (median 4 years). There was a male predilection (1.7M:1.0F). Primary tumor sites were: face NOS (18%), orbit/periorbital (16%), nasal cavity/nose (14%), lymph nodes (12%), paranasal sinuses (10%), parameningeal (10%), parotid gland (6%), neck (6%), infratemporal fossa/zygoma (2%), buccal mucosa (2%), palate (2%), and larynx (2%). Metastatic disease at diagnosis (33% of all cases) occurred in the bone marrow (11%), cerebrospinal fluid (6%), peritoneal fluid (6%), lung (4%), parietal pleura (2%), pleural fluid (2%) and pericardial fluid (2%). Rhabdomyosarcoma types (IRS criteria) were: embryonal (60%), alveolar (classic and solid subtypes, 28%), botryoid (4%), undifferentiated (4%), spindle cell (2%) and anaplastic (2%). Immunocytochemical findings were: polyclonal desmin (96%); myogenin (96%); muscle-specific actin (74%), smooth muscle actin (12%). Nonmyogenic markers included: vimentin (100%), CD99 (16%), p53 (16%), pancytokeratin (10%), NSE (8%), LCA (6%), CD20 (6%), EMA (2%), and NB-84 (0%, neuroblastoma). Undifferentiated sarcoma expressed only vimentin. By ultrastructural examination, 44% had readily identified z-bands and myofilaments, 37% had infrequent to rare myofilaments and z-bands, and 19% had myotubular intermediate filaments. CONCLUSIONS: Distribution of H&N rhabdomyosarcoma IRS types is similar to that for all primary sites, with the exception that embryonal types are modestly increased while alveolar type is mildly decreased. There are many non-myogenic immunocytochemical markers that cross-react with rhabdomyosarcoma. Differentiation between favorable and unfavorable rhabdomyosarcoma types is important for appropriate therapy, and predicting prognosis and survival.

Adolescent↗