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Pure testicular rhabdomyosarcoma is a very rare tumor and 7 cases have been reported in literature. A 20-year-old male patient presented with a painless right testicular swelling who underwent inguinal orchiectomy with suspicion of testicular malignancy. The case was regarded as an embryonal rhabdomyosarcoma according to histopathologic and immunohistochemical findings. The case is presented and the relevant literature is reviewed and discussed.
Primary cardiac tumours are rare, with only one quarter of the patients being malignant. The vast majority of malignant neoplasms of the heart are sarcomas. We describe a patient of primary cardiac rhabdomyosarcoma presented as coronary artery disease and recurrent myocardial infarction. Histopathologic finding of the excised native heart revealed a high grade pleomorphic rhabdomyosarcoma in the myoepicardial portion of the anterior wall with rupture. The accompanying unusual feature was myocardial infarction because of tumour emboli of the left anterior descending and left circumflex coronary arteries. After transplantation, the patient developed mild to moderate acute cellular rejection of the transplanted heart on post-transplantation day 1, 8, and 44, respectively. Unfortunately, he expired on the post-transplantation day 47 because of acute rejection, presenting as concomitant intramyocardial and epicardial lymphocytic vasculitis and multifocal myocardial ischaemia. We found that this uncommon medial lymphocytic vasculitis lesion was mediated by T cells and also by antibody directly against smooth muscle cells of small arteries. The consequence of such immune response would be compromised myocardial oxygenation resulting in allograft failure.
Rat, mouse, pig and chicken alphafoetoproteins (AFP), rat serum albumin and egg albumin, or their fluoresceinated conjugates were added to cultures of several cloned cell lines isolated from a nickel-induced rat rhabdomyosarcoma. The intracellular uptake of assayed proteins was revealed by the indirect immunoperoxidase technique and/or by direct fluorescence microscopy. All the clones examined bound AFP, and all but one internalized the protein. The protein localized in the membrane and the cytoplasm, as well as along straight processes interconnecting cells. Nuclei were always AFP negative. The protein uptake of fluoresceinated conjugates of AFP and serumalbumin was already visible 15 min after incubation and progressed with time to reach a plateau 4-5 h later. Ultrastructural radioautographs of cells incubated with [3H]-AFP (rat) showed protein accumulation in several organelles and particularly in lipid droplets. Parallel to these observations, the intracellular presence of AFP within myofibrillar structures was demonstrated in tongue sections of rat foetuses and neonates. The results presented here provide experimental evidence of the reappearance in cloned cell lines derived from a primary rhabdomyosarcoma of a property pertaining to foetal striated muscle.
An increasing number of reports highlight the fact that tumour cells are able to give rise in vitro to immunogenic variants, which are defined in vivo as being non tumorigenic, tum-. We have observed the emergence of immunogenic variants, derived from a primary nickel-induced rat rhabdomyosarcoma established in culture (RMS 9-4/0), resistant to treatment with the chloronitrosourea, chlorozotocin (CZT) (R-lines). They were separated from the whole population of cells by a cloning procedure. Furthermore, we demonstrate that the cloning procedure by itself allows the isolation of tum- variant designated as C-lines. In both cases, the tum- phenotype was observed after s.c. injection of cells into syngeneic rats with a broad range of R9 or C8 cells (10(4) to 10(7). This characteristic was inherited in a stable manner. Athymic mice developed tumours of rat rhabdomyosarcoma origin when grafted with 10(5) cells. Immunization of rats with one R variant (R9) tum- protected the rats grafted with the parental RMS 9-4/0 cells against metastatic invasion of the lungs, but not against local tumour growth, and rats grafted with a CZT-resistant tum+ cell variant S4T (in vivo-derived) against its hepatic and pulmonary metastases, while the local tumour progressed as usual. Immunization of rats with one C variant (C8) tum- cells did not protect them against either metastases or local growth of the implanted tumours. Both R and C lines cells became progressively resistant to NK- and macrophage-induced cytotoxicity. Splenic lymphocyte transfer from immune rats into nude mice, i.e., the Winn test, showed a complete degree of protection against C8 or R9 tumour growth. We conclude that two different antigenicities were revealed, one common to R9 and C8 cells in relation with their selection procedure by repeated cloning. Another antigenicity appeared in the R9 line, selected by CZT-resistance. The anti R9 cell immunization against CZT-resistant tum+ S4T could argue in favour of CZT action in the acquisition of R9 cell antigenicity. More likely, an amplification of antigens rather than induction of a new antigen could explain the protection of anti R9 immunized rats against parental tumour metastases.
A human tumour cell line, designated RMS-YM, was established from a childhood rhabdomyosarcoma. The monolayer cells were polygonal, round or spindle-shaped. The cells became multilayered and formed many focal piles when confluent. RMS-YM became stable with a doubling time of about 30 h and has been maintained for 104 passages to date. Tumourigenicity of the cells was confirmed by heterotransplantation into nude mice. Morphological features were similar to those of the primary tumour, and myofibrils were found by electron microscopy. The expression of desmin and human myoglobin, and high levels of striated muscle system specific enzymes were recognised. Chromosomal analysis revealed possible gene amplification in the form of homogeneously staining regions. Oncogene analysis was performed on the primary tumour and the cell line, but neither N-myc nor N-ras genes were amplified, nor were Ki-ras, Ha-ras or N-ras genes mutated at the 12th, 13th and 61st codons. The RMS-YM cell line may provide a system to identify novel genes which are amplified in rhabdomyosarcoma.
Eleven survivors of pelvic rhabdomyosarcoma underwent bladder function studies and upper urinary tract evaluation at a mean of 6.6 years after completion of therapy, which included a conservative, bladder-sparing surgical policy. Primary tumour sites were: bladder base/prostate, 6; bladder dome, 1; vagina, 2; and pelvic side wall, 2. Seven children (five bladder base/prostate, one vagina and one pelvic side wall tumours) had received irradiation to the pelvis with external beam alone, brachytherapy or both. All seven of these patients had markedly reduced functional bladder capacity (11-48% of mean expected value for age) and abnormal voiding patterns, though bladder compliance was not reduced and bladder emptying was almost complete in five cases. Four of these children also had upper tract dilatation and two required reconstructive bladder surgery because of severe bilateral hydronephrosis. By contrast, each of four children treated without radiotherapy had a normal functional bladder capacity and a normal voiding pattern. all survivors of pelvic rhabdomyosarcoma, especially those who have received radiotherapy, should be carefully monitored for dysfunction of both lower and upper urinary tracts. The frequency-volume voiding chart is a sensitive and easily accomplished method of assessing bladder function in these patients.
Twenty-six previously untreated children, median age 3.4 years, with pelvic rhabdomyosarcoma (RMS) were seen between 1983 and 1988. Fourteen were girls. The planned strategy was to conserve pelvic organs, especially the bladder, by using primary chemotherapy, conservative surgery and, in most cases, radiotherapy. With a median follow-up of 71 months (range 34-103 months) overall survival was 73%, with no treatment-related death. The bladder salvage rate of 88% in survivors with bladder base/prostate primaries was much higher than that reported by the United States Intergroup Rhabdomyosarcoma Studies (IRS), though many of the preserved bladders did not function normally. We identified problems with both radiological and histological off-treatment monitoring. The overall accuracy of computerised tomographic (CT) scanning for prediction of tumour recurrence was only 81%, and endoscopic biopsies proved misleading in four of the ten bladder base/prostate patients monitored by serial cystoscopy. We conclude that a higher cure rate can be achieved by using intensive chemotherapy/radiotherapy and conservative surgery to treat children with pelvic RMS. Factors that might contribute to our favourable bladder salvage results, compared with those of the IRS, include (a) the fact that one of two specialist surgeons monitored and operated on all these patients and (b) our increasing awareness, during the study, that post-chemotherapy/radiotherapy histopathology and pelvic CT scan appearances may be misleading. Referral to paediatric centres with special experience of pelvic RMS may help raise the rate of bladder salvage in these children.
Pleomorphic rhabdomyosarcoma (PRMS) is a rare and controversial tumor of skeletal muscle phenotype. Diagnostic criteria for PRMS by combined histology and currently available immunohistochemistry have not been clearly defined. We report 38 pleomorphic rhabdomyosarcomas in adults, explore morphologic variants, and discuss our experience with both specific and nonspecific skeletal muscle markers in these tumors. Clinical data, morphology, and immunohistochemistry were reviewed. Electron microscopy was performed. Of 38 cases, there were 28 males and 10 females. Patient ages ranged from 21 to 81 years (median = 54 y; mean = 51 y). Tumors were located in the lower extremity (n = 18), abdomen/retroperitoneum (n = 6), chest/abdominal wall (n = 5), spermatic cord/testes (n = 4), upper extremity (n = 3), and one each in the mouth and orbit. Tumor sizes ranged from 1.5 to 15.0 cm (mean = 7.3 cm; median = 6.8 cm). The cases were divided into three variants, each with large, atypical, pleomorphic polygonal rhabdomyoblasts (PRMB) with abundant eosinophilic cytoplasm in varying numbers and different morphologic backgrounds of round or spindled rhabdomyoblasts (RMB). 1. Classic PRMS: Predominantly atypical PRMB in sheets (n = 8). 2. Round cell PRMS: Clusters of PRMB throughout the tumor with a background of slightly atypical, medium-sized, round, blue RMB (n = 13). 3. Spindle cell PRMS: Scattered PRMB in a predominance of atypical spindled RMB arranged in a storiform growth pattern (n = 17). Immunohistochemistry revealed the following: myoglobin (37/38), MyoD1 (19/36), skeletal muscle myogenin (myf4; 19/34), fast skeletal muscle myosin (4/5), desmin (36/38), muscle-specific actin (MSA; 25/35), smooth muscle actin (SMA; 15/33), and muscle specific myogenin (myf3; 25/35). Immunohistochemistry was supportive of skeletal muscle differentiation with at least one positive skeletal muscle-specific marker (myoglobin, MyoD1, fast skeletal muscle myosin, or myf4). In addition, all cases had some positivity for nonspecific muscle markers (desmin, MSA, SMA, myf3). Electron microscopy (EM), performed on eight selected cases from all three morphologic groups, demonstrated definitive skeletal muscle differentiation in all cases. Follow-up, available on 30 (79%) cases, revealed that 70% of patients died of disease (mean 20 months, range 1 month-108 months), 3% were alive with disease at 12 months (n = 1); and 27% had no evidence of disease (mean, 83 mo; range, 18 to 108 mo). PRMS, a tumor of predominantly middle-aged adult males in the lower extremity, can be diagnosed by the morphologic presence of scattered PRMB with immunohistochemical evidence of at least one skeletal muscle-specific marker. There are three morphologic variants of PRMS. The appropriate diagnosis of PRMS is significant as it is a high-grade sarcoma, with an aggressive clinical course.
BACKGROUND: A 5-year-old year girl with a medical history of mental retardation, physical abnormalities and a known interstitial deletion of chromosome 9q22-q32 presented with a palpable suprapubic mass. During ultrasound investigation, a left renal mass was also detected. The patient underwent surgical removal of both neoplasms, which were diagnosed as a rhabdomyosarcoma and a Wilms tumor. Seven years later, she presented with macroglossia and a benign mandibular cyst. INVESTIGATIONS: Physical examination, karyotyping, abdominal and pelvic ultrasound, brain CT scan, anatomic pathology analysis with immunohistochemistry, and typing of polymorphic markers in the patched (PTCH) gene region. DIAGNOSIS: Gorlin syndrome with synchronous rhabdomyosarcoma and Wilms tumor. MANAGEMENT: Left nephrectomy, excision of paravesical tumor, excision of mandibular cysts, chemotherapy, and radiotherapy.
We have examined the structure and expression of the products associated with the t(2;13)(q35;q14) translocation associated with alveolar rhabdomyosarcoma. The chromosome 13 gene (FKHR) is identified as a member of the fork head domain family of transcription factors characterized by a conserved DNA binding motif. Polymerase chain reaction analysis demonstrates that a 5'PAX3-3' FKHR chimaeric transcript is expressed in all eight alveolar rhabdomyosarcomas investigated. Immunoprecipitation experiments detect the predicted fusion protein. These findings indicate that the t(2;13) generates a potentially tumorigenic fusion transcription factor consisting of intact PAX3 DNA binding domains, a truncated fork head DNA binding domain and C-terminal FKHR regions.
1 In an effort to identify endogenous, native mammalian urotensin-II (U-II) receptors (UT), a diverse range of human, primate and rodent cell lines (49 in total) were screened for the presence of detectable [125I]hU-II binding sites. 2 UT mRNA (Northern blot, PCR) and protein (immunocytochemistry) were evident in human skeletal muscle tissue and cells. 3 [(125)I]hU-II bound to a homogenous population of high-affinity, saturable (Kd 67.0+/-11.8 pm, Bmax 9687+/-843 sites cell(-1)) receptors in the skeletal muscle (rhabdomyosarcoma) cell line SJRH30. Radiolabel was characteristically slow to dissociate (< or =15% dissociation 90 min). A lower density of high-affinity U-II binding sites was also evident in the rhabdomyosarcoma cell line TE671 (1667+/-165 sites cell(-1), Kd 74+/-8 pm). 4 Consistent with the profile recorded in human recombinant UT-HEK293 cells, [125I]hU-II binding to SJRH30 cells was selectively displaced by both mammalian and fish U-II isopeptides (Kis 0.5+/-0.1-1.2+/-0.3 nm) and related analogues (hU-II[4-11]>[Cys(5,10)]Acm hU-II; Kis 0.4+/-0.1 and 864+/-193 nm, respectively). 5 U-II receptor activation was functionally coupled to phospholipase C-mediated [Ca2+]i mobilization (EC50 6.9+/-2.2 nm) in SJRH30 cells. 6 The present study is the first to identify the presence of 'endogenous' U-II receptors in SJRH30 and TE671 cells. SJRH30 cells, in particular, might prove to be of utility for (a) investigating the pharmacological properties of hU-II and related small molecule antagonists at native human UT and (b) delineating the role of this neuropeptide in the (patho)physiological regulation of mammalian neuromuscular function.
Besides their cholesterol-lowering effect, 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) show antiproliferative behaviour, which has been suggested as a promising anticancer strategy. However, the signalling cascades leading to statin-induced death of cancer cells are poorly characterized. Here we show that statins activate the mitochondrial pathway of apoptosis in rhabdomyosarcoma RD cells via translocation of Bax from the cytosol to mitochondria. The prototypical representative of statins, simvastatin, induced consecutive activation of caspase 9 and 3 in a concentration-dependent manner. The permeability transition pore inhibitor bongkrekic acid was capable of completely preventing simvastatin-induced caspase 9 and 3 activity, corroborating the mitochondrial pathway of apoptosis as the sole mechanism of statin action. Alternative pathways via death receptors, that is, caspase 8 or calpain activation, were not triggered by simvastatin. Simvastatin-treated RD cells could be completely rescued from apoptosis by the co-application of mevalonic acid, indicating that deprivation of cholesterol precursors is essential for statin-induced apoptosis. However, pretreatment with subthreshold concentrations of simvastatin was sufficient to augment doxorubicin toxicity via the mitochondrial apoptotic machinery. Moreover, the presence of doxorubicin increased the potency of simvastatin to trigger caspase activation. Taken together, these data highlight the therapeutic anticancer potential of statins and their additivity and mutual sensitization, in combination with doxorubicin in human rhabdomyosarcoma cells.
Patients with primary metastatic or recurrent rhabdomyosarcoma (RMS) have a very poor prognosis. Since high-dose chemotherapy (HDC) +/- TBI was thought to improve survival, many centers performed this therapy using different types of hematopoietic rescue (auto BM or PBSC, allo BM). This is a retrospective, multi-center analysis of the results of treatment in 36 patients with primary metastatic or relapsed RMS who were given HDC +/- TBI and hematopoietic rescue between 1986 and 1994. The median age was 6 years (< 1-22 years). Primary therapy was given according to either one of the Cooperative German Soft Tissue Sarcoma Studies CWS-81, -86, -91 or the European Study for Stage IV Malignant Mesenchymal Tumors in Childhood. There were 22 alveolar RMS, 13 embryonal RMS and one undifferentiated sarcoma. The indication for HDC was primary metastatic disease (27 patients) or a relapse of a primary localized tumor (nine patients). Thirty-two patients were in 1st or 2nd CR when given HDC and four in VGPR. The median time from last event to HDC was 44 weeks (21-110). HDC consisted of fractionated melphalan ((4 x 30-45 mg/m2), VP16 40-60 mg/kg, carboplatin 3 x 400-500 mg/m2) in 26 patients, 10 of whom received additional FTBI. Seven patients were treated with melphalan alone or in combination with carboplatin. Two patients received cyclophosphamide/busulphan with TLI (total lymphoid irradiation) and one cyclophosphamide with FTBI. Thirty-one patients were given autologous BM or PBSC as hematopoietic rescue and five allogeneic bone marrow from HLA-identical siblings. Fourteen patients received GM-CSF or G-CSF after hematopoietic stem cell transfusion (HSCT). Ten patients received adjuvant IL-2. There was one toxic HDC-related death. Nine patients are alive and free of disease with a median observation time of 57 months (32-108). The median time from HDC to relapse was 4 months (1-17). The tumor recurred in the majority of patients at previously known sites; in three cases new metastatic sites were observed. Patients with primary localized tumors who had been treated with HDC because of relapse did slightly better (four of nine alive with NED) than patients with primary metastatic disease (five of 27 alive with NED). HDC is still of uncertain value in the therapy of poor-risk rhabdomyosarcoma and should be performed only as part of controlled clinical trials.
Rhabdomyosarcomas are characterized by loss of heterozygosity (LOH) at chromosome region 11p15.5, a region known to contain several imprinted genes including insulin-like growth factor 2 (IGF2), H19, and p57(KIP2). We analyzed 48 primary tumour samples and found distinct genetic changes at 11p15.5 in alveolar and embryonal histological subtypes. LOH was a feature of embryonal tumours, but at a lower frequency than previous studies. Loss of imprinting (LOI) of the IGF2 gene was detected in 6 of 13 informative cases, all harbouring PAX3-FKHR or PAX7-FKHR fusion genes characteristic of alveolar histology. In contrast, H19 imprinting was maintained in 14 of 15 informative cases and the case with H19 LOI had maintenance of the IGF2 imprint indicating separate mechanisms controlling imprinting of IGF2 and H19. The adult promoter of IGF2, P1, was used in 5 of 14 tumours and its expression was unrelated to IGF2 imprinting status implying a further mechanism of altered IGF2 regulation. The putative tumour suppressor gene p57(KIP2) was expressed in 15 of 29 tumours and expression was unrelated to allele status. Moreover, in tumours with p57(KIP2) expression, there was no evidence for inactivating mutations, suggesting that p57(KIP2) is not a tumour suppressor in rhabdomyosarcoma.
Rhabdomyosarcomas (RMSs) are one of the most common solid tumor of childhood. Rhabdomyosarcoma (RMS) cells fail to both complete the skeletal muscle differentiation program and irreversibly exit the cell cycle as a consequence of an active repression exerted on the muscle-promoting factor MyoD. Myostatin is a negative regulator of normal muscle growth, we have thus studied its possible role in RMS cells. Here, we present evidence that overexpression of myostatin is a common feature of RMS since both subtypes of RMS (embryonal RD and alveolar Rh30 cells) express high levels of myostatin when compared to nontumoral skeletal muscle cells. Interestingly, we found that inactivation of myostatin through overexpression of antisense myostatin or of follistatin (a myostatin antagonist) constructs enhanced differentiation of RD cells. In addition, RD and Rh30 cells treated with blocking antimyostatin antibodies progress into the myogenic terminal differentiation program. Finally, our results suggest that high levels of myostatin could impair MyoD function in RMS cells. These results show that an autocrine myostatin loop contributes to maintain RMS cells in an undifferentiating stage and suggest that new therapeutic approaches could be exploited for the treatment of RMS based on inactivation of myostatin protein.
AIMS: We report three cases of skeletal muscle regeneration, of which two mimicked a small round cell tumour, especially a rhabdomyosarcoma. METHODS AND RESULTS: One case presented as an intramuscular mass, located in the right quadriceps of a 12-year-old male; the second patient was a 25-year-old football player who complained of painful left peroneus muscles; the third patient was a 22-year-old male who underwent an amputation of the right thigh 5 days after right leg amputation due to limb crush. Histologically, muscle biopsy specimens showed a proliferation of small round cells, either infiltrating the striated muscle in a diffuse manner or growing within and around necrotic myofibres. Immunohistochemically and ultrastructurally, the cellular population was composed of two types of cells: phagocytic cells the nuclei of which occasionally showed a wreathlike arrangement around necrotic myofibres resulting in structures resembling Langhans-type multinucleated giant cells, and proliferating satellite cells showing enlarged nuclei, prominent nucleoli, mitotic figures, myogenic differentiation and fusion features in order to form regenerating myotubes. CONCLUSIONS: Muscle regeneration is a benign process that may occasionally mimic a small round cell proliferation resembling a lymphoma or an alveolar rhabdomyosarcoma with which it should not be confused.
We describe a case of fetal rhabdomyosarcoma detected during the third trimester of pregnancy by prenatal sonography. At 33 weeks' gestation, sonography performed because of suspected polyhydramnios showed a solid mass of 120 x 54 mm arising from the anterior wall of the fetal thoracic cage. Another mass within the left maxillary area which originated from the left orbital floor was also detected. In the abdomen, there were multiple round masses in and around the liver. As the previous scan at 28 weeks had appeared normal, the multiple masses which became visible and enlarged rapidly in different locations led us to believe that there was fetal cancer. The most likely diagnosis was rhabdomyosarcoma (which was later confirmed), because it is the most prevalent soft-tissue tumor in children and may develop within or outside muscle anywhere in the body and at any age. Two other reported cases which were detected by prenatal ultrasound examination are also discussed.
The case history is described of an adolescent girl with alveolar rhabdomyosarcoma of the maxillary sinus, who was treated with radical radiotherapy and adjuvant chemotherapy. She relapsed in the breast and, after incomplete excision, received radical radiotherapy resulting in long-term survival with breast conservation. The characteristics of patients with metastatic rhabdomyosarcoma with breast involvement are discussed. In adolescent girls, the breast is postulated to be a preferential metastatic site.