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Fine-needle aspiration of the prostate has recently gained popularity as a reliable technique in the evaluation of prostatic nodules for malignancy. The cytologic features of adenocarcinoma have been described, but the features of other more unusual tumors have not been widely publicized. We report a case of embryonal rhabdomyosarcoma of the prostate gland with epithelioid cytologic features.
We describe the cytopathological picture of a cutaneous rhabdomyosarcoma located in the left nasal furrow of a 4-mo-old girl, some of whose close relatives have died or suffered from different types of neoplasias (Li-Fraumeni syndrome). We believe that the cytological picture is highly characteristic and rules out other round cell tumours of childhood. We underline the usefulness of FNAC in dermatology and strongly advocate the introduction of this technique into the diagnostic armoury of every dermatologist.
The distinction between rhabdomyosarcoma (RMS) and the other small round blue cell tumors of childhood has therapeutic implications which stress the importance of a correct diagnosis. In attempts to reevaluate the cytologic criteria of this entity, we reviewed a series of 17 fine-needle aspiration biopsies and three touch imprints from soft tissue masses. All cases had been histologically confirmed except for two cases that only had immunocytochemical and ultrastructural confirmation. The features occurring most commonly include a uniform population of tumor cells arranged as single cells and cohesive aggregates. The cells were predominantly round/polygonal, with uniform nuclei and scant to moderate amounts of cytoplasm. The nuclear chromatin was most often finely granular and hyperchromatic, while nucleoli were inconspicuous. Binucleated and multinucleated cells were found in 17 of the 20 smears. Intracytoplasmic vacuoles were present in 17 cases, ranging from occasional in one case, a few in 10 cases, and very numerous in six cases. We conclude that the presence of bi/multinucleated cells is an important clue for the diagnosis of RMS on fine-needle aspiration biopsy.
PTPN11 has been identified as a causative gene in Noonan syndrome (NS), responsible for about 50% of cases of NS. Given the association between NS and an increased risk of some malignancies, notably leukemia and probably some solid tumors including neuroblastoma (NB) and rhabdomyosarcoma (RMS), recent studies have reported that gain-of-function somatic mutations in PTPN11 occur in some hematological malignancies, especially de novo juvenile myelomonocytic leukemia (JMML) and in some solid tumors such as NB, although at a low frequency. In a screen for mutations of PTPN11 in 7 cell lines and 30 fresh tumors of RMS and in 25 cell lines and 40 fresh tumors of NB, we identified a missense mutation (A72T) in an embryonal RMS patient. In the RMS samples, we also detected mutations of NRAS in 1 cell line and 1 patient; both mutations were in embryonal RMSs and had no PTPN11 mutations. No mutations of PTPN11 were detected in NB. In 95 leukemia cell lines and 261 fresh leukemia samples including 22 JMMLs, 9 kinds of missense mutations were detected in 17 leukemia samples, which included 11 (50.0%) mutations in JMML samples and lower frequencies in other hematological malignancies. Furthermore, we identified 4 (18.2%) NRAS mutations and 1 (4.5%) KRAS mutation in 5 JMML samples, 1 of which had a concomitant PTPN11 mutation. Our data suggest that mutations of PTPN11 as well as RAS play a role in the pathogenesis of not only myeloid hematological malignancies but also a subset of RMS malignancies.
We present cytogenetic and molecular genetic analyses of two cases of alveolar rhabdomyosarcoma. The characteristic translocation between chromosomes 2 and 13, t(2;13)(q35;q14), has been identified in both cases. Using cell lines derived from these tumor specimens, we have performed Southern blot analysis to investigate the possibility of rearrangement of 14 candidate genes mapping to the relevant regions of 2q and 13q. These candidate genes can be divided into 5 groups: signal transduction proteins (RB1, inhibin alpha, FLT1, and HOX4B), muscle-specific products [myosin light chain, desmin, and nicotinic cholinergic receptor subunits gamma and delta (CHRNG and CHRND)], extracellular matrix proteins (collagen type VI alpha 3 chain, elastin, and fibronectin), transformation-associated products (intestinal alkaline phosphatase and L-plastin), and other genes (esterase D). Conventional gel electrophoresis followed by Southern blot analysis indicated no evidence of rearrangement within or near these genes except for a rearrangement in the CHRNG-CHRND locus, which occurred only in a subpopulation of the late recurrence tumor cells of one patient. In addition, we employed pulsed-field gel electrophoresis-Southern blot analysis to demonstrate the absence of detectable rearrangements within a larger region around each of these genes.
A characteristic balanced reciprocal chromosomal translocation [t(2;13)(q35;q14)] has been identified in more than 50% of alveolar rhabdomyosarcomas. As the first step in characterization of the genes involved in this translocation, we constructed somatic cell hybrids that retained either the derivative chromosome 2 or the derivative chromosome 13 without a normal chromosome 13 homologue. Ten linked DNA probes known to be located within bands 13q13-q14 were mapped relative to the breakpoint on chromosome 13, allowing localization of the breakpoint region between two loci separated by 5.5 cM. A long-range restriction map extending approximately 2,300 kb around these loci failed to provide evidence of rearrangement. Additionally, we confirmed that the FMS-like tyrosine kinase gene (FLT), previously localized to 13q12 by in situ hybridization, is located proximal to the breakpoint, and we demonstrated that FLT is not a target for disruption by this tumor-specific translocation.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and accounts for 10% of all solid tumors in children. There are three different histologic forms of this tumor: embryonal (RMS-E), alveolar (RMS-A), and primitive (RMS-P). Among these, the embryonal form has responded well to chemotherapy. Identification of the correct subtype is important for both the management and treatment of this malignancy. However, the histopathologic classification of RMS is sometimes difficult and distinguishing between the embryonic and primitive forms can present a diagnostic dilemma. Chromosomal abnormalities have been observed in all subtypes. We present the cytogenetic findings in six cases of RMS or related sarcoma. All four cases with RMS-A had both numerical and structural abnormalities in the tumor and involved bone marrow specimens. Three patients had a common marker, t(2;13)(q37;q14), and one patient had a variant marker involving 13q14, t(1;13) (p36;q14), and double minutes (dmin). The single embryonal RMS patient had modal chromosome numbers in the hypertriploid range and extensive structural abnormalities; the t(2;13) was not present, but translocation of 13q to both 1q and 2p was observed, der(1)t(1;13)(q21;q14) and der(2)t(2;13)(p25;q14). The patient with primitive type RMS had a hypodiploid line with several markers, including a complex translocation involving chromosomes 5 and 13 with a breakpoint at 13q14, and t(11;12)(q24;q12), a chromosome marker heretofore found only in Ewing's sarcoma and related tumors. This patient had atypical RMS with mixed neural and myogenic elements. The significance of these chromosomal markers and their importance in the characterization of childhood tumors are discussed, along with a review of the literature.
Rhabdomyosarcoma (RMS) is an uncommon malignant soft tissue sarcoma whose cause is largely unknown. Reported risk factors include genetic alterations (e.g., p53 mutations, a defective gene at 11p15.5, or specific chromosomal translocation of t(2:13)), and parents' use of drugs around the time of conception. We present results from a national, case-control study of 249 RMS cases (170 males and 79 females) and 302 controls (196 males and 106 females). The cases, aged 0-20 years at diagnosis, were identified via the Intergroup RMS Study-III during 1982-1988. Controls were selected by random digit telephone dialing. As a supplement to the original study, information on genetic diseases and birth defects (BD) was collected from the subjects' parents by telephone interview. Fifty-six (22.5%) cases and 55 (18.2%) controls were reported to have genetic diseases or BD (odds ratio [OR] = 1.30,95% confidence interval [CI] = 0.85-2.02, P = .21). The case group had a significantly higher frequency of neurofibromatosis type I (NF1) than did the control group, i.e., five cases (2.0%) had NF1 vs. zero controls (P = .02). The case group also had a higher frequency of major BDs than did the control group (6.0% vs. 2.6%, OR = 2.36, 95% CI = 0.92-6.52, P = .05). However, this excess was only observed in males (7.6% vs. 2.6%, OR = 3.16, 95% CI = 1.02-10.41, P = .02). Among the 15 cases having both RMS and major BDs, six (40.0%) had both conditions in the same regional anatomic site: Two (13.3%) had both in the extremities, two (13.3%) in the genitourinary system, and two in the head and neck. These findings suggest that common genetic mechanisms or in utero exposures may be involved in the development of many childhood tumors and congenital abnormalities.
BACKGROUND: Ninety pediatric patients with parameningeal rhabdomyosarcoma (PM-RMS) were treated between 1970 and 2002 at the Istituto Nazionale Tumori, Milan. METHODS: Combined treatment was implemented in high-risk patients with whole-brain irradiation and intrathecal chemotherapy between 1978 and 1981 and intrathecal methotrexate alone between 1982 and 1987. Radiotherapy was given with conventional fractionation until 1988 and hyperfractionated accelerated radiotherapy (HART) thereafter. RESULTS: The 5-year disease-free survival was 41.3%, increasing from 15.4% (1970-1977) to 55.9% (1989-2002) for localized cases. Local failure rates were 41% and 24% with conventional fractionation and HART, respectively. In patients treated with HART, acute toxicities were more pronounced, but the treatment compliance was better. Severe radiation-related late sequelae were observed. CONCLUSIONS: The outcome for patients with PM-RMS has improved over the years but is still not as satisfactory as that for patients with RMS of other sites. Thanks to improvements in radiotherapy techniques and chemotherapy efficacy, meningeal prophylaxis is no longer necessary. Although more evidence is needed to confirm our data, the results obtained with twice-daily HART seem promising.
BACKGROUND: The AMORE protocol is a local treatment for patients with nonorbital pediatric head and neck rhabdomyosarcoma (HNRMS). The objectives of this study were: (1) to assess the adequacy of the concept, and (2) to identify factors associated with relapse. METHODS: We performed a retrospective multidisciplinary review of 22 children primarily treated according to the AMORE protocol, excluding two children with inadequate imaging data. RESULTS: Seven patients had a local relapse, six within and one outside the residual tumor area. Five of the six patients with relapse in the residual area had gross total or debulking (incomplete) surgery, suboptimal position of the mold for brachytherapy, or both. In the 15 nonrecurrent cases, four patients had either incomplete surgery or suboptimal mold position. Both surgical and brachytherapeutic factors seem to be associated with relapse. CONCLUSIONS: AMORE is an adequate concept. More rigid preoperative imaging and intraoperative verification of the brachytherapy mold position might lead to a reduction in the number of local failures.
Rhabdomyosarcoma (RMS) is a relatively frequent tumor in children. Judicious combinations have markedly improved treatment results in recent years. Orbital localizations are treated with chemotherapy and radiotherapy. It has been advocated that radiotherapy be limited to the original tumor bed. This case report illustrates the danger of shielding part of the orbit: in a clinically tumor-free region before chemotherapy, which was shielded during radiotherapy, a local recurrence was seen while the original tumor bed remained controlled. Therefore, the whole content of the orbit should be irradiated in orbital RMS.
Rhabdomyosarcoma represents the most common soft-tissue neoplasm of the head and neck found in children. The tumor is most commonly seen in Caucasian children under the age of 12, usually presenting as a painless mass. Distant metastases are frequently present, especially in regional lymph nodes, lung, and bone marrow. All patients suspected of having this disorder should have a thorough examination of the head and neck, as well as a complete radiographic evaluation of the primary region. Histologic disagnosis should be made as rapidly as possible. Once this has been accomplished, a thorough search for metastatic disease can be undertaken. Therapy must be individualized, and a team approach is advocated. The roles of surgery, radiation therapy, and chemotherapy are discussed. A staging system and a treatment-therapy plan are outlined.
Inherited mutations of the human tumor suppressor gene Patched (PTCH) lead to an autosomal dominant disorder known as Nevoid Basal Cell Carcinoma Syndrome (NBCCS). The syndrome is characterized by a combination of developmental abnormalities and a predisposition to tumor formation. Tumors in patients with NBCCS include basal cell carcinoma, medulloblastoma, fibroma and rhabdomyosarcoma (RMS). RMS are also present in 15 % of mice haplodeficient for Ptch. To investigate whether mutations in PTCH are a general feature in rhabdomyosarcomagenesis we sequenced the protein-coding region in sporadic human cases of these tumors. For this purpose we first determined the distribution and frequency of polymorphisms in 23 exons of PTCH in 48 healthy caucasians. Ten new polymorphisms were identified (IVS11 + 15-17del AAA; IVS14 + 25T>C; 2485G>A; IVS15 + 9G>C; IVS17 + 21A>G; 3033T>C; 3149T>C; 3387T>C; 3617G>A; 4080C>T). Next, the PTCH coding region in 14 RMS was sequenced. Whereas one case with LOH at the PTCH locus was detected, none of the cases showed nonsense or missense mutations in the coding region of PTCH. These data do not support the existence of frequent mutations in the protein-coding region of PTCH in RMS.
Using Affymetrix oligonucleotide microarrays, we analyzed mRNA gene expression patterns of 12 primary pediatric rhabdomyosarcomas (RMS) and 11 Ewing's sarcomas (EWS), which belong to the small round blue cell tumors (SRBCTs). Diagnostic classification of these cancers is frequently complicated by the highly similar appearance in routine histology, and additional molecular markers could significantly improve tumor classification. A combination of three independent statistical approaches (t-test, SAM, k-nearest neighborhood analysis) resulted in 101 highly significant probe sets that clearly discriminate between EWS and RMS. We identified novel marker transcripts that have not been previously associated with either RMS or EWS yet, including CITED2, glypican 3 (GPC3), and cyclin D1 (CCND1). Expression levels for selected candidate genes were validated by quantitative real-time reverse-transcription PCR. Furthermore, to identify biologically meaningful trends, functional annotations were assigned to 946 genes differentially expressed between EWS and RMS (t-test). Genes involved in protein biosynthesis (n = 28) and complex assembly (n = 9), lipid metabolism (n = 23), energy generation (n = 22), and mRNA processing (n = 11) were expressed significantly higher in EWS. Thus, functional annotation of tumor-specific genes reveals detailed insights into tumor biology and differentiation-specific expression patterns and gives important clues related to the possible cellular origin of these pediatric tumors. Supplementary material for this article is available at the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.
We analyzed the expression signatures of 14 tumor biopsies from children affected by alveolar rhabdomyosarcoma (ARMS) to identify genes correlating to biological features of this tumor. Seven of these patients were positive for the PAX3-FKHR fusion gene and 7 were negative. We used a cDNA platform containing a large majority of probes derived from muscle tissues. The comparison of transcription profiles of tumor samples with fetal skeletal muscle identified 171 differentially expressed genes common to all ARMS patients. The functional classification analysis of altered genes led to the identification of a group of transcripts (LGALS1, BIN1) that may be relevant for the tumorigenic processes. The muscle-specific microarray platform was able to distinguish PAX3-FKHR positive and negative ARMS through the expression pattern of a limited number of genes (RAC1, CFL1, CCND1, IGFBP2) that might be biologically relevant for the different clinical behavior and aggressiveness of the 2 ARMS subtypes. Expression levels for selected candidate genes were validated by quantitative real-time reverse-transcription PCR.
High levels of PDGFR expression in primary rhabdomyosarcoma (RMS) have been associated with disease progression. To date however, there are no reports on the activity of imatinib mesylate, a selective PDGFR inhibitor, in RMS preclinical models. A panel of 5 RMS cell lines was used to investigate the expression of PDGFRalpha and PDGFRbeta, c-Kit and the multidrug transporter ABCG2 (also inhibited by imatinib). In vitro and in vivo experiments were performed using RD (embryonal) and RH30 (alveolar) cell lines to determine the efficacy of imatinib as single agent and in combination with topotecan (TPT). PDGFRbeta was significantly expressed in all cell lines, with the highest levels in RD, while PDGFR alpha and ABCG2 were significantly expressed only in RH30 and RMZ-RC2. c-Kit was not detected. PDGFRbeta signaling was active in RD but not in RH30, whilst PDGFRalpha signaling was not active in either cell lines. Significant ABCG2-mediated extrusion of Hoechst 33342 was demonstrated in RH30 but not in RD, and was inhibited by imatinib and the specific ABCG2 inhibitor Ko143. In vitro, imatinib was not active as a single agent at therapeutic concentrations, but significantly potentiated TPT antitumor activity in both cell lines. In vivo experiments using tumor xenografts confirmed the synergistic interaction in both cell lines. These results suggest that at least 2 different mechanisms--inhibition of ABCG2 and/or PDGFRbeta--are involved in the synergistic interaction between imatinib and TPT, and support the use of this combination for the treatment of high-risk RMS patients.
A cell line of childhood rhabdomyosarcoma (RD) has been grown as a xenograft in immune-deprived mice. The tumor responded to vincristine (VCR), but not to vinblastine, doxorubicin or actinomycin D. The rate and frequency at which resistance developed from administration of VCR once weekly was investigated. Tumor growth could be inhibited for 6 weeks, after which time 11 or 16 xenografts grew progressively despite continued treatment. That this was a tumor-acquired resistance was confirmed by growing both parent and "resistant" lines in the same host. Under these conditions VCR completely inhibited growth of the parent tumor, but not growth of the resistant for 6 weeks, after which time 11 or 16 xenografts grew progressively despite continued treatment. That this was a tumor-acquired resistance was confirmed by growing both parent and "resistant" lines in the same host. Under these conditions VCR completely inhibited growth of the parent tumor, but not growth of the resistant for 6 weeks, after which time 11 or 16 xenografts grew progressively despite continued treatment. That this was a tumor-acquired resistance was confirmed by growing both parent and "resistant" lines in the same host. Under these conditions VCR completely inhibited growth of the parent tumor, but not growth of the resistant line. Continued passage of the resistant line for 10 months in mice either treated with VCR (1.5 mg/kg/wk) or untreated, demonstrated that resistance to VCR was stable in the absence of selection pressure. In addition, the VCR-resistant line acquired a stable change in karyotype with the addition of a number 9 chromosome and an additional, unknown marker.
A transforming N-ras allele was molecularly cloned from the RD human rhabdomyosarcoma cell line, and the nature of its activation studied. Construction of chimeric recombinants between the RD-transforming allele and a normal human allele enabled us to localize the alteration responsible for the activation to the second exon of the N-ras gene. The nucleotide sequence of this exon, when compared to that of the normal allele, revealed a single difference at the 61st amino acid position of the encoded protein; the CAA codon for glutamine in the normal allele was mutated to a CAT codon for histidine in the RD-transforming allele. This result is the first description of a histidine replacing glutamine in the 61st position and provides further evidence that the 61st amino acid is one of the preferential sites for N-ras activation.