Zheng S, Huang KE, Jia J, et al.
Rhabdomyosarcomatous differentiation in gastrointestinal stromal tumors after imatinib resistance: a potential diagnostic pitfall.
Exp Biol Med (Maywood). 2013; 238(1):120-4 [PubMed]

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the digestive tract and characterized by expression of protein-tyrosine kinase (KIT) protein. Treatment of advanced GISTs has been improved dramatically following the development of imatinib. Despite the often long-lasting clinical benefit seen in most patients treated with imatinib, many will eventually suffer disease progression. In general, progressing GISTs retain their typical morphology. In this study, we present a patient with metastatic GISTs, who received more than 16 months of treatment with imatinib and whose tumors changed their morphological and immunohistochemical characteristics after imatinib-resistance. Histological, immunohistochemical and mutational analysis was performed on the prior and post-imatinib treatment GIST samples. The imatinib-resistant tumor cells in the progressing metastases showed marked pleomorphism which proved to be rhabdomyoblastic differentiation with Desmin and Myogenin immunopositivity. However, there was no secondary mutation of KIT, PDGFRA, KRAS and BRAF genes found in the imatinib-resistant lesion, except primary KIT V559D mutation. To our knowledge, this case represents the few reports on this unusual type of transdifferentiation in GISTs under imatinib therapy. Awareness of this phenomenon would help to avoid diagnostic confusion when evaluating post-imatinib samples from GISTs.

Kuru TH, Roethke MC, Nyarangi-Dix J, et al.
Pediatric case report on magnetic resonance imaging/transrectal ultrasound-fusion biopsy of rhabdomyosarcoma of the bladder/prostate: a new tool to reduce therapy-associated morbidity?
Urology. 2013; 81(2):417-20 [PubMed]

Rhabdomyosarcomas are the most common soft tissue sarcomas in children. Here we present management of an 18-month-old boy with metastatic rhabdomyosarcoma of the bladder/prostate. After radiochemotherapy, high-spatial-resolution 3-Tesla multiparametric magnetic resonance imaging (MRI) showed regressive systemic disease but a residual mass at the right seminal vesicle. For histologic re-evaluation, 3-dimensional-controlled stereotactic MRI/transrectal ultrasound (TRUS)-fusion biopsy specimens were taken. Because histologic analysis showed nonvital tissue, a decision could be made against adjuvant radical cystoprostatectomy. Advanced 3-Tesla imaging and MRI/TRUS-fusion biopsies in children are feasible and represent an effective tool to examine suspicious pelvic lesions. Depending on histology, this can lead to a significant reduction of therapy-associated morbidity.

Hemida R, Goda H, Abdel-Hady el-S, El-Ashry R
Embryonal rhabdomyosarcoma of the female genital tract: 5 years' experience.
J Exp Ther Oncol. 2012; 10(2):135-7 [PubMed]

OBJECTIVES: To present our single institution experience with 10 cases of embryonal rhabdomyosarcoma diagnosed over 5 years.
METHODS: Retrospective analysis of the medical records of 10 patients. The initial presenting data as age, complains and staging were analyzed. Surgical interference of all cases was studied. The follow up data regarding survival and recurrences were analyzed.
RESULTS: The mean age at diagnosis was 4.3 years (range: 2-12). Six cases (60%) were subjected to "True Cut" biopsy and 4 cases (40%) were subjected to complete surgical excision of the tumor. All cases received chemotherapy. "Vincristine, Actinomycin D, Cyclophosphamide" combination was the most commonly used. Radiation therapy was used in 3 patients (30%) in the form of external beam radiation. The 5-year overall survival of our studied cases were 80%.
CONCLUSION: The recurrence rate of our retrospectively studied 10 cases of embryonal rhabdomyosarcoma of vagina and cervix was high (70%). However, five-year survival was 80%. Combined modality treatment is essential to improve prognosis.

Li RF, Gupta M, McCluggage WG, Ronnett BM
Embryonal rhabdomyosarcoma (botryoid type) of the uterine corpus and cervix in adult women: report of a case series and review of the literature.
Am J Surg Pathol. 2013; 37(3):344-55 [PubMed]

In its classical form, embryonal rhabdomyosarcoma (ERMS, botryoid type) is a vaginal neoplasm occurring in infants and young girls and is often not considered in the differential diagnosis of uterine corpus and cervical spindle cell tumors in adult women. Clinicopathologic and immunohistochemical features of 25 cases of ERMS in women 20 years of age or older were analyzed. Patient age ranged from 20 to 89 years (mean, 44.4 y; median, 46 y), with 8 patients aged 20 to 39 years, 14 patients aged 40 to 59 years, and 3 patients older than 60 years of age. Tumors originated in the cervix in 20 cases and in the uterine corpus in 5. They were characterized by an edematous hypocellular spindle cell proliferation, typically with cellular condensation beneath epithelial surfaces (cambium layer), in which tightly packed hypercellular foci were scattered. Neoplastic cells had hyperchromatic nuclei and minimal cytoplasm, usually with delicate cytoplasmic processes. Occasionally, elongated or globular cells with eosinophilic cytoplasm (rhabdomyoblasts) were evident, but cytoplasmic cross-striations were only rarely identified. Apoptotic bodies and mitotic figures were usually identified in the hypercellular foci. Hemorrhage was common, often making recognition of the hypercellular foci difficult. Desmin and myogenin were coexpressed in 22 of 23 (95.6%) tumors evaluated. Proliferative activity, as assessed by Ki-67 expression, was notably elevated in all tumors evaluated, typically concentrated in the hypercellular foci. Estrogen and progesterone receptors were expressed focally in only 3 of 12 (25%) and 1 of 8 (12.5%) tumors evaluated, respectively. Follow-up was available in 7 cases. Five patients were alive without evidence of disease with follow-up of 3 to 8 years, and 1 patient was alive with disease at 5 months. One patient died at 5 months with pulmonary nodules, but it was not determined whether this was due to metastatic ERMS or the patient's known ductal breast carcinoma. ERMS has a broader clinical profile than classically expected and should be considered in the differential diagnosis of a uterine corpus or cervical spindle cell tumor, regardless of patient age. Recognition can be rendered difficult by the hypocellular background, which can suggest a benign polyp or low-grade tumor, and hemorrhage, which can obscure the characteristic hypercellular foci. Identification of hypercellular foci in which mitotic activity and apoptotic bodies are found, desmin and myogenin are coexpressed, proliferative activity is notably elevated, and hormone receptor expression is usually absent is very useful for establishing the diagnosis.

Cate F, Bridge JA, Crispens MA, et al.
Composite uterine neoplasm with embryonal rhabdomyosarcoma and primitive neuroectodermal tumor components: rhabdomyosarcoma with divergent differentiation, variant of primitive neuroectodermal tumor, or unique entity?
Hum Pathol. 2013; 44(4):656-63 [PubMed]

Three cases of composite uterine neoplasms comprised of primitive neuroectodermal tumor (PNET) and rhabdomyosarcoma (RMS) have previously been described, including only one wherein the rhabdomyosarcomatous component was of the embryonal subtype. Whether such composite neoplasms are a variant of RMS, a variant of PNET, or a unique entity is unknown. We report the clinicopathologic, immunohistochemical, and molecular cytogenetic findings in a case of uterine embryonal RMS with coexisting PNET that was diagnosed in a 25-year-old female. The tumor broadly involved the cervix and corpus uteri and resulted in uterine inversion. The 2 distinct components each showed classic morphologic features, including cartilage in the RMS component. The unique combination of histologic, immunohistochemical and molecular findings in composite neoplasms of this type raises a question of whether they should be classified and treated as RMS, PNET, or a unique high-grade sarcoma. A variety of clinicopathologic arguments are presented that support the notion that the current neoplasm is an embryonal rhabdomyosarcoma with divergent neuroectodermal and cartilaginous differentiation.

Peregud-Pogorzelski J, Wawrykow P, Wozniak S, et al.
Highly effective unconventional management of aspergillosis of the left maxillary sinus in an 11-year-old girl with rhabdomyosarcoma embryonale of the frontal sinus.
J Med Microbiol. 2013; 62(Pt 4):652-4 [PubMed]

Invasive fungal infections are common causes of death in children treated for malignancies, and therefore present an important and growing clinical problem. Fungal invasion usually affects immunocompromised patients, but increased incidences are also associated with intensification of antineoplastic therapy and increased numbers of organ and bone marrow transplantations. Fungal infections in parameningeal and cerebral locations carry high risks of treatment failure. We describe the case of an 11-year-old female patient with rhabdomyosarcoma embryonale of the frontal sinuses with metastases to the neck lymph nodes, treated according to the CWS 2002 protocol for high-risk patients. Left maxillary sinus aspergillosis was diagnosed during chemotherapy following radiotherapy, and 56 days after surgical excision of the tumour. No effect was achieved by use of amphotericin B. Further treatment included intravenous voriconazole at 6 mg per kg body weight every 12 h for 2 weeks, followed by oral voriconazole at 4 mg per kg body weight twice daily for 6 months. Simultaneous excision of necrotic tissues from the nasal cavity, ethmoid bone, maxillary sinus and frontal recess was performed. The sinus was kept open for 3 weeks to allow voriconazole lavage every 12 h for 3 weeks. This unconventional treatment resulted in eradication of sinus aspergillosis and allowed intensive chemotherapy to be continued with no recurrence of aspergillosis.

MacQuarrie KL, Yao Z, Fong AP, et al.
Comparison of genome-wide binding of MyoD in normal human myogenic cells and rhabdomyosarcomas identifies regional and local suppression of promyogenic transcription factors.
Mol Cell Biol. 2013; 33(4):773-84 [PubMed] Article available free on PMC after 01/08/2013

Rhabdomyosarcoma is a pediatric tumor of skeletal muscle that expresses the myogenic basic helix-loop-helix protein MyoD but fails to undergo terminal differentiation. Prior work has determined that DNA binding by MyoD occurs in the tumor cells, but myogenic targets fail to activate. Using MyoD chromatin immunoprecipitation coupled to high-throughput sequencing and gene expression analysis in both primary human muscle cells and RD rhabdomyosarcoma cells, we demonstrate that MyoD binds in a similar genome-wide pattern in both tumor and normal cells but binds poorly at a subset of myogenic genes that fail to activate in the tumor cells. Binding differences are found both across genomic regions and locally at specific sites that are associated with binding motifs for RUNX1, MEF2C, JDP2, and NFIC. These factors are expressed at lower levels in RD cells than muscle cells and rescue myogenesis when expressed in RD cells. MEF2C is located in a genomic region that exhibits poor MyoD binding in RD cells, whereas JDP2 exhibits local DNA hypermethylation in its promoter in both RD cells and primary tumor samples. These results demonstrate that regional and local silencing of differentiation factors contributes to the differentiation defect in rhabdomyosarcomas.

Saboo SS, Krajewski KM, Zukotynski K, et al.
Imaging features of primary and secondary adult rhabdomyosarcoma.
AJR Am J Roentgenol. 2012; 199(6):W694-703 [PubMed]

OBJECTIVE: Rhabdomyosarcomas are rare and aggressive soft-tissue sarcomas in adults. The purpose of this article is to describe the imaging features of primary and secondary adult rhabdomyosarcomas utilizing MRI, CT, and (18)F-FDG PET/CT.
CONCLUSION: MRI is the imaging technique of choice for the evaluation of primary rhabdomyosarcoma involving most body sites (extremity, pelvis, head, and neck), with the added advantages of diffusion-weighted imaging and whole-body MRI for staging. CT and FDG PET/CT play major roles in the evaluation of metastatic disease. Because the imaging features of adult rhabdomyosarcoma are nonspecific, other parameters, such as clinical findings, age, site, lymphadenopathy, and metastatic disease, should be combined to narrow the differential diagnosis.

Wood R, Lazarus J, Davidson A, et al.
Genitourinary rhabdomyosarcoma: lessons from a developing-world series.
J Pediatr Surg. 2012; 47(11):2083-6 [PubMed]

OBJECTIVE: The objective was to retrospectively review a large series of pediatric patients with genitourinary rhabdomyosarcoma from a developing country.
METHODS: A total of 49 children were treated over a 47-year period (1961-2008). Analysis of the clinical presentation, demographics, surgical records, histological results, and oncological management was performed. The patients were analyzed as a whole and also in 2 separate groups (pre- and post-1992).
RESULTS: The median age at clinical presentation was 3½ years. The majority (59%) of patients were Intergroup Rhabdomyosarcoma Study group 3, with locally advanced disease at presentation. Twenty (41%) of the 49 patients presented with primary tumors greater than 10 cm in diameter. Sixteen (33%) of the 49 patients had positive regional lymph nodes at presentation. The overall survival of the series was 30 (65%) of 46. The survival for those treated after 1992 in Intergroup Rhabdomyosarcoma Study group 3 was superior (P = .04) to those treated before 1992 (80% vs 56%).
CONCLUSION: Children in this large African series of genitourinary rhabdomyosarcoma present with greater locally advanced disease (node positive and bulky disease) when compared with the developed world. Improvements in the last 2 decades in local surgical and oncological care have led to an improvement in survival in children with locally advanced disease.

Hatley ME, Tang W, Garcia MR, et al.
A mouse model of rhabdomyosarcoma originating from the adipocyte lineage.
Cancer Cell. 2012; 22(4):536-46 [PubMed] Article available free on PMC after 16/10/2013

Rhabdomyosarcoma (RMS) is an aggressive skeletal muscle-lineage tumor composed of malignant myoblasts that fail to exit the cell cycle and are blocked from fusing into syncytial muscle. Rhabdomyosarcoma includes two histolopathologic subtypes: alveolar rhabdomyosarcoma, driven by the fusion protein PAX3-FOXO1 or PAX7-FOXO1, and embryonal rhabdomyosarcoma (ERMS), which is genetically heterogeneous. Here, we show that adipocyte-restricted activation of Sonic hedgehog signaling through expression of a constitutively active Smoothened allele in mice gives rise to aggressive skeletal muscle tumors that display the histologic and molecular characteristics of human ERMS with high penetrance. Our findings suggest that adipocyte progenitors can be a cell of origin for Sonic hedgehog-driven ERMS, showing that RMS can originate from nonskeletal muscle precursors.

de Souza RR, Oliveira ID, Caran EM, et al.
Investigation of PAX3/7-FKHR fusion genes and IGF2 gene expression in rhabdomyosarcoma tumors.
Growth Horm IGF Res. 2012; 22(6):245-9 [PubMed]

The purpose of our study was to investigate the prevalence of the PAX3/7-FKHR fusion genes and quantify the IGF2 gene expression in rhabdomyosarcoma (RMS) samples. Soft tissue sarcomas account 5% of childhood cancers and 50% of them are RMS. Morphological evaluation of pediatric RMS has defined two histological subtypes, embryonal (ERMS) and alveolar (ARMS). Chromosomal analyses have demonstrated two translocations associated with ARMS, resulting in the PAX3/7-FKHR rearrangements. Reverse transcriptase-polymerase chain reaction (RT-PCR) is extremely useful in the diagnosis of ARMS positive for these rearrangements. Additionally, several studies have shown a significant involvement of IGF pathway in the pathogenesis of RMS. The presence of PAX3/7-FKHR gene fusions was studied in 25 RMS samples from patients attending the IOP-GRAACC/UNIFESP and three RMS cell lines by RT-PCR. IGF2 gene expression was quantified by qPCR and related with clinic pathological parameters. Of the 25 samples, nine (36%) were ARMS and 16 (64%) were ERMS. PAX3/7-FKHR gene fusions expression was detected in 56% of ARMS tumor samples. IGF2 overexpression was observed in 80% of samples and could indicate an important role of this pathway in RMS biology.

Van Gaal JC, Van Der Graaf WT, Rikhof B, et al.
The impact of age on outcome of embryonal and alveolar rhabdomyosarcoma patients. A multicenter study.
Anticancer Res. 2012; 32(10):4485-97 [PubMed]

BACKGROUND: The prognosis of rhabdomyosarcoma (RMS) in children and adolescents has improved since the introduction of multi-agent chemotherapy. However, outcome data of adults with RMS are scarce. This multicenter retrospective study investigated the effect of age on outcome of RMS.
PATIENTS AND METHODS: Data were collected from three Dutch University Medical Centers between 1977-2009. The effect of age and clinical prognostic factors on relapse-free and disease-specific survival (DSS) were analyzed.
RESULTS: Age as a continuous variable predicted poor survival in multivariate analysis. Five-year DSS was highest for non-metastatic embryonal RMS, followed by non-metastatic alveolar RMS and was poor in metastatic disease. Higher age correlated with unfavorable histological subtype (alveolar RMS) and with metastatic disease at presentation in embryonal RMS. In non-metastatic embryonal RMS and in all alveolar RMS, higher age was an adverse prognostic factor of outcome.
CONCLUSION: This study indicates that age is a negative predictor of survival in patients with embryonal and alveolar RMS.

Gosiengfiao Y, Reichek J, Walterhouse D
What is new in rhabdomyosarcoma management in children?
Paediatr Drugs. 2012; 14(6):389-400 [PubMed]

Optimal management of rhabdomyosarcoma requires establishing the correct pathologic diagnosis, histologic sub-type, primary site, extent of disease (Stage), and extent of resection (Group). Based on these features, cooperative groups in North America and Europe have defined risk-adapted treatments that include surgery, chemotherapy, and usually radiotherapy. This article focuses on recent findings that can impact or have already impacted rhabdomyosarcoma treatment guidelines and highlights controversies that should be addressed in order to improve outcome for children with rhabdomyosarcoma. Rhabdomyosarcoma is currently sub-classified in children based on histology into the favorable embryonal/botryoid/spindle cell types and the unfavorable alveolar form. Risk group assignment depends in part on histologic sub-type. Alveolar rhabdomyosarcoma is sometimes associated with chromosomal translocations, which impact clinical behavior. An important ongoing debate is whether molecular diagnostic tools to identify chromosomal translocations and/or define gene expression profiles should be used to sub-classify rhabdomyosarcoma rather than histology. Clinical trials continue to evaluate retrospective as well as prospective cohorts in order to carefully determine the impact of histology versus biologic features on outcome in the context of specific therapeutic regimens. Most rhabdomyosarcoma recurrences involve the primary site or adjacent region. Cooperative groups continue to investigate new approaches to local control in order to reduce local recurrences and sequelae associated with local therapy. Delaying primary resection until after chemotherapy has started appears to increase the number of tumors that can be completely resected with acceptable morbidity in some primary sites. Radiation dose reductions following delayed primary resection have been investigated. Although outcomes appear similar to the conventional approach of full-dose radiotherapy without delayed primary resection, long-term effects of the two approaches have not been rigorously compared. Early evidence suggests that newer methods of delivering radiotherapy, including intensity-modulated radiotherapy (IMRT), proton beam radiotherapy, and brachytherapy maintain efficacy but may reduce long-term sequelae compared with 3-dimensional conformal radiotherapy. Chemotherapy regimens defined by the cooperative groups vary by risk group. The most commonly used regimens include vincristine and dactinomycin in combination with an alkylating agent, either cyclophosphamide or ifosfamide. In order to improve outcomes, recent clinical trials have introduced new chemotherapeutic agents (e.g. topotecan, carboplatin, or epirubicin) into the treatment regimens. However, outcomes have not been significantly impacted. Novel chemotherapy administration schedules have been tested in patients with metastatic rhabdomyosarcoma, including interval compressed dosing or maintenance therapy, and may be promising. Molecularly targeted agents are currently under investigation in combination with chemotherapy for patients with recurrent or metastatic rhabdomyosarcoma. It is hoped that these novel agents will benefit all patients with rhabdomyosarcoma in the future.

Yang JC, Wexler LH, Meyers PA, Wolden SL
Parameningeal rhabdomyosarcoma: outcomes and opportunities.
Int J Radiat Oncol Biol Phys. 2013; 85(1):e61-6 [PubMed]

PURPOSE: To examine patterns of failure in patients with parameningeal rhabdomyosarcoma (PM-RMS) treated with intensity modulated radiation therapy (IMRT).
METHODS AND MATERIALS: Forty-seven patients with PM-RMS received chemotherapy and IMRT for definitive treatment. The median age was 9 years (range, 0.5-35 years). The high-risk features were as follows: 40% alveolar histology, 72% group III and 26% group IV disease, 57% either intracranial extension (ICE) (n=25) or cranial neuropathy (n=21). The median time to RT from the start of chemotherapy was 15 weeks (range, 2-54 weeks). Patients received 50.4 Gy in 1.8-Gy fractions to the primary tumor by use of IMRT. Thirteen patients aged≥14 years with alveolar histology received 36 Gy prophylactic nodal irradiation (PNI) to bilateral cervical nodes. Events were defined as local, regional (nodal), central nervous system (CNS), or distant failures.
RESULTS: With a median follow-up time of 3.3 years (range, 0.5-12.8 years), 18 patients experienced failure: 5 local, 2 regional, 6 distant, and 7 CNS. The 5-year local failure-free survival was 86%. Age, histology, and time to RT did not influence the risk of local failure. The 5-year regional failure-free survival was 92%: 100% for embryonal and 74% for alveolar (P=.03). However, there were no lymph node failures in patients with alveolar histology who were given PNI. The 5-year CNS failure-free survival was 83%: 100% without and 70% with ICE (P=.01); 95% without and 69% with cranial neuropathy (P=.02). The estimated 5-year event-free survival and overall survival were 61% for group III and 58% for group IV patients.
CONCLUSIONS: Distant failure was the most common type of failure among group IV patients. Patients with alveolar histology seem to benefit from PNI. The presence of ICE or cranial neuropathy portends a high risk of CNS failure, the most common pattern of failure among non-group IV patients. These patients may benefit from the addition of novel CNS-directed therapy.

Wan X, Yeung C, Kim SY, et al.
Identification of FoxM1/Bub1b signaling pathway as a required component for growth and survival of rhabdomyosarcoma.
Cancer Res. 2012; 72(22):5889-99 [PubMed] Article available free on PMC after 15/11/2013

We identified Bub1b as an essential element for the growth and survival of rhabdomyosarcoma (RMS) cells using a bar-coded, tetracycline-inducible short hairpin RNA (shRNA) library screen. Knockdown of Bub1b resulted in suppression of tumor growth in vivo, including the regression of established tumors. The mechanism by which this occurs is via postmitotic endoreduplication checkpoint and mitotic catastrophe. Furthermore, using a chromatin immunoprecipitation assay, we found that Bub1b is a direct transcriptional target of Forkhead Box M1 (FoxM1). Suppression of FoxM1 either by shRNA or the inhibitor siomycin A resulted in reduction of Bub1b expression and inhibition of cell growth and survival. These results show the important role of the Bub1b/FoxM1 pathway in RMS and provide potential therapeutic targets.

Armeanu-Ebinger S, Herrmann D, Bonin M, et al.
Differential expression of miRNAs in rhabdomyosarcoma and malignant rhabdoid tumor.
Exp Cell Res. 2012; 318(20):2567-77 [PubMed]

Alveolar rhabdomyosarcoma (RMA) and malignant rhabdoid tumor (MRT) have a frequent metastatic spread and a poor prognosis. Aberrant miRNA expression is often found in metastatic tumors. The aim of this study was to identify specific miRNA expression patterns in these tumors. We analyzed the expression of miRNAs in RMA and MRT in tissue samples and in the rhabdomyosarcoma (RMS) cell lines (Rh30 and RD). Selected target miRNAs were modulated with mimic or inhibitor oligonucleotides. Functional analysis was monitored by flow cytometry and migration assays. A set of 107 differentially expressed miRNAs showed tissue-specific clustering of RMA and MRT. Comparison with the Sarcoma microRNA Expression Database revealed RMA- and MRT-specific miRNAs. Metastatic invasion associated miRNA miR-9 was overexpressed in RMA. miR-200c-inhibiting migration-was lower expressed in RMA than in MRT. Transient transfection of RMS cells with a miR-200c mimic and miR-9( inhibitor did neither increase the expression of the known target E-cadherin nor decrease migration. Expression of E-cadherin could be induced in RD cells using decitabine, but demethylation did not influence cell migration. Despite a comparable high rate of metastatic invasion pediatric RMA and MRT show a different pattern of miRNA expression possibly allowing risk stratification.

Marburger TB, Gardner JM, Prieto VG, Billings SD
Primary cutaneous rhabdomyosarcoma: a clinicopathologic review of 11 cases.
J Cutan Pathol. 2012; 39(11):987-95 [PubMed]

BACKGROUND: Rhabdomyosarcoma is a malignant mesenchymal tumor with skeletal muscle differentiation. Primary cutaneous rhabdomyosarcoma is rare. We report a series of 11 cases of primary cutaneous rhabdomyosarcoma.
METHODS: Cases diagnosed as rhabdomyosarcoma arising in the dermis/subcutis with no identified primary tumor elsewhere were retrospectively reviewed. Follow-up was obtained.
RESULTS: The tumors occurred in five children and six adults. The adult subset consisted of pleomorphic, epithelioid and not otherwise specified (NOS) subtypes while the pediatric subset showed alveolar and embryonal subtypes. All cases showed immunohistochemical staining consistent with the diagnosis of rhabdomyosarcoma. Three adult cases showed immunoreactivity for cytokeratins (one pleomorphic, one epithelioid and one NOS.
CONCLUSIONS: Primary cutaneous rhabdomyosarcoma shows a bimodal age distribution and male predominance, correlating with rhabdomyosarcoma in deep soft tissue. Follow-up, available on all patients, showed aggressive behavior in both children and adults. Primary cutaneous rhabdomyosarcoma should be considered in the differential diagnosis of tumors with abundant eosinophilic cytoplasm and those with "small round blue cell" morphology. Desmin, myogenin and MYOD1 are a trio of markers with high sensitivity and specificity for primary cutaneous rhabdomyosarcoma. Cytokeratin immunoreactivity in primary cutaneous rhabdomyosarcoma represents a potential diagnostic pitfall in the differential diagnosis with sarcomatoid carcinoma.

Marchesi I, Fiorentino FP, Rizzolio F, et al.
The ablation of EZH2 uncovers its crucial role in rhabdomyosarcoma formation.
Cell Cycle. 2012; 11(20):3828-36 [PubMed] Article available free on PMC after 15/10/2013

Rhabdomyosarcoma (RMS) is a pediatric tumor that arises from muscle precursor cells. RMS cells express several markers of early myogenic differentiation, but they fail to complete both differentiation program and cell cycle arrest, resulting in uncontrolled proliferation and incomplete myogenesis. Previous studies showed that EZH2, which is involved in both differentiation and cancer progression, is overexpressed in RMS, but a functional binding between its expression and its functional role in tumor formation or progression has not yet been demonstrated. We hypothesized that EZH2 is a key regulator of muscular differentiation program in RMS cells. In this study, we demonstrated that EZH2 directly binds muscle specific genes in RD cells. Silencing of EZH2 promotes the recruitment of a multiprotein complex at muscle-specific promoters, their transcriptional activation and protein expression. Moreover, we demonstrated that EZH2 is directly involved in transcriptional repression of MyoD, the main factor promoting myogenesis. EZH2 ablation induces MyoD activation the recovery of its binding on muscle-specific genes.

Wickramasinghe CM, Domaschenz R, Amagase Y, et al.
HES6 enhances the motility of alveolar rhabdomyosarcoma cells.
Exp Cell Res. 2013; 319(1):103-12 [PubMed]

HES6, a member of the hairy-enhancer-of-split family of transcription factors, plays multiple roles in myogenesis. It is a direct target of the myogenic transcription factor MyoD and has been shown to regulate the formation of the myotome in development, myoblast cell cycle exit and the organization of the actin cytoskeleton during terminal differentiation. Here we investigate the expression and function of HES6 in rhabdomyosarcoma, a soft tissue tumor which expresses myogenic genes but fails to differentiate into muscle. We show that HES6 is expressed at high levels in the subset of alveolar rhabdomyosarcomas expressing PAX/FOXO1 fusion genes (ARMSp). Knockdown of HES6 mRNA in the ARMSp cell line RH30 reduces proliferation and cell motility. This phenotype is rescued by expression of mouse Hes6 which is insensitive to HES6 siRNA. Furthermore, expression microarray analysis indicates that the HES6 knockdown is associated with a decrease in the levels of Transgelin, (TAGLN), a regulator of the actin cytoskeleton. Knockdown of TAGLN decreases cell motility, whilst TAGLN overexpression rescues the motility defect resulting from HES6 knockdown. These findings indicate HES6 contributes to the pathogenesis of ARMSp by enhancing both proliferation and cell motility.

Ahn SJ, Kim IO
Spinal cord glioblastoma induced by radiation therapy of nasopharyngeal rhabdomyosarcoma with MRI findings: case report.
Korean J Radiol. 2012 Sep-Oct; 13(5):652-7 [PubMed] Article available free on PMC after 15/10/2013

Radiation-induced spinal cord gliomas are extremely rare. Since the first case was reported in 1980, only six additional cases have been reported.; The radiation-induced gliomas were related to the treatment of Hodgkin's lymphoma, thyroid cancer, and medullomyoblastoma, and to multiple chest fluoroscopic examinations in pulmonary tuberculosis patient. We report a case of radiation-induced spinal cord glioblastoma developed in a 17-year-old girl after a 13-year latency period following radiotherapy for nasopharyngeal rhabdomyosarcoma. MRI findings of our case are described.

Masià A, Almazán-Moga A, Velasco P, et al.
Notch-mediated induction of N-cadherin and α9-integrin confers higher invasive phenotype on rhabdomyosarcoma cells.
Br J Cancer. 2012; 107(8):1374-83 [PubMed] Article available free on PMC after 09/10/2013

BACKGROUND: Rhabdomyosarcoma (RMS) is the commonest type of soft-tissue sarcoma in children. Patients with metastatic RMS continue to have very poor prognosis. Recently, several works have demonstrated a connection between Notch pathway activation and the regulation of cell motility and invasiveness. However, the molecular mechanisms of this possible relationship remain unclear.
METHODS: The Notch pathway was manipulated pharmacologically and genetically. The mRNA changes were analysed by quantitative PCR and protein variations by western blot and immunofluorescence. Finally, the capabilities of RMS cells to adhere, heal a wound and invade were assessed in the presence of neuronal cadherin (N-cadherin)- and α9-integrin-blocking antibodies.
RESULTS: Cells treated with γ-secretase inhibitor showed lower adhesion capability and downregulation of N-cadherin and α9-integrin. Genetic manipulation of the Notch pathway led to concomitant variations in N-cadherin and α9-integrin. Treatment with anti-N-cadherin-blocking antibody rendered marked inhibition of cell adhesion and motility, while anti-α9-integrin-blocking antibody exerted a remarkable effect on cell adhesion and invasiveness.
CONCLUSION: Neuronal cadherin and α9-integrin are postulated as leading actors in the association between the Notch pathway and promotion of cell adhesion, motility and invasion, pointing to these proteins and the Notch pathway itself as interesting putative targets for new molecular therapies against metastases in RMS.

Bektaş-Kayhan K, Karagöz G, Bayrak Ö, et al.
Implant-assisted dental rehabilitation of a patient with maxillary rhabdomyosarcoma.
J Craniofac Surg. 2012; 23(5):e384-6 [PubMed]

Rhabdomyosarcoma is a malignant, soft tissue neoplasm consisting of cells derived from the primitive mesenchyme that exhibit a profound tendency to undergo myogenesis. Multimodality therapy for tumors in the head and neck regions has a significant effect on maxillofacial skeletal growth, dental development, and the whole ecologic system of the oral cavity. Here we aimed to discuss the influence of head-neck cancer therapy in pediatric patients with long-term follow-up and present a case with implant-assisted dental rehabilitation and also functional and aesthetic outcomes.

Kim NK, Kim HS, Suh CO, et al.
Clinical results of high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation in children with advanced stage rhabdomyosarcoma.
J Korean Med Sci. 2012; 27(9):1066-72 [PubMed] Article available free on PMC after 09/10/2013

Regardless of improvement in cure of Rhabdomyosarcoma (RMS), the results in treatment of advanced stage of RMS in children are still dismal. Recently, high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (HDC/APBSCT) has been tried to manage the advanced high-risk RMS patients. We investigated the effectiveness of HDC/APBSCT by reviewing the clinical records of high-risk pediatric RMS patients in single institute database. Over twenty years, 37 patients were diagnosed as RMS with high-risk at the time of first diagnosis. These patients were classified as two groups according to treatment method. The first group was HDC/APBSCT and the other was conventional multi-agent chemotherapy group. Differences of clinical results between the two groups were analyzed. The median age of patients was 5 yr, ranging from 6 months to 15 yr. The 5-yr event free survival rate (EFS) of all patients was 24.8% ± 4.8%. HDC/APBSCT group and conventional multi-agent chemotherapy group were 41.3% ± 17.8% and 16.7% ± 7.6% for 5-yr EFS, respectively (P = 0.023). There was a significant difference in the result of HDC/APBSCT between complete remission or very good partial response group and poor response group (50% ± 20.4% vs 37.5% ± 28.6%, P = 0.018). HDC/APBSCT can be a promising treatment modality in high-risk RMS patients.

Sarkar D, Ray S, Saha M, et al.
Alveolar rhabdomyosarcoma with multiple distal metastases. A case report and review of literature.
BMJ Case Rep. 2012; 2012 [PubMed]

An 18-year-old boy, presented with a history of right hip pain with movement restriction and proptosis of right eye. There was severe anaemia, febrile neutropaenia and bleeding manifestations. CT scan of right orbit documented a retro orbital mass. MRI revealed a mass on right side of the pelvis with metastatic deposits in spine. Biopsy from that mass revealed alveolar rhabdomyosarcoma. Bone marrow biopsy showed sarcomatous involvement with decrease in all three cell lineages. Chemotherapy was started according to standard protocol. We lost the patient after 3 weeks of initiation of chemotherapy. In our case, the unusual primary site and presentation with multiple distal metastases makes this case stand apart and therefore worth reporting.

Eugene T, Corradini N, Carlier T, et al.
¹⁸F-FDG-PET/CT in initial staging and assessment of early response to chemotherapy of pediatric rhabdomyosarcomas.
Nucl Med Commun. 2012; 33(10):1089-95 [PubMed]

PURPOSE: The objective of this retrospective study was to compare positron emission tomography/computed tomography using fluorine-18-fluorodeoxyglucose (18F-FDG-PET/CT) and conventional imaging modalities (CIM) in initial staging and early assessment of response to chemotherapy in children and young adults treated for rhabdomyosarcoma (RMS).
PATIENTS AND METHODS: At initial staging, 23 patients (9 months to 21 years) with histologically proven RMS underwent 18F-FDG-PET/CT in addition to CIM (MRI of the primary site, whole-body CT, and bone scintigraphy). After three courses of chemotherapy, 13 patients underwent 18F-FDG-PET/CT in addition to CIM. RECIST criteria and visual analysis of 18F-FDG uptake were used for assessment of response. The standard of reference was determined by an interdisciplinary tumor board on the basis of imaging material, histopathology, and follow-up data (median = 5 years).
RESULTS: 18F-FDG-PET/CT sensitivity was superior to that of CIM for determination of lymph node involvement (100 vs. 75%) and detection of metastases (100 vs. 66%). 18F-FDG-PET/CT results changed therapeutic management in 13% of cases. After three courses of chemotherapy 18F-FDG-PET/CT was able to detect 92% of objective responses compared with 84% by CIM. The rate of complete response was 69% with 18F-FDG-PET/CT compared with 8% with CIM.
CONCLUSION: This study confirms that 18F-FDG-PET/CT reveals important additional information at initial staging of pediatric RMS, which suggests a superior prognostic value of 18F-FDG-PET/CT in early response to chemotherapy assessment.

Basit F, Humphreys R, Fulda S
RIP1 protein-dependent assembly of a cytosolic cell death complex is required for inhibitor of apoptosis (IAP) inhibitor-mediated sensitization to lexatumumab-induced apoptosis.
J Biol Chem. 2012; 287(46):38767-77 [PubMed] Article available free on PMC after 09/11/2013

Searching for new strategies to trigger apoptosis in rhabdomyosarcoma (RMS), we investigated the effect of two novel classes of apoptosis-targeting agents, i.e. monoclonal antibodies against TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 (mapatumumab) and TRAIL receptor 2 (lexatumumab) and small-molecule inhibitors of inhibitor of apoptosis (IAP) proteins. Here, we report that IAP inhibitors synergized with lexatumumab, but not with mapatumumab, to reduce cell viability and to induce apoptosis in several RMS cell lines in a highly synergistic manner (combination index <0.1). Cotreatment-induced apoptosis was accompanied by enhanced activation of caspase-8, -9, and -3; loss of mitochondrial membrane potential; and caspase-dependent apoptosis. In addition, IAP inhibitor and lexatumumab cooperated to stimulate the assembly of a cytosolic complex containing RIP1, FADD, and caspase-8. Importantly, knockdown of RIP1 by RNA interference prevented the formation of the RIP1·FADD·caspase-8 complex and inhibited subsequent activation of caspase-8, -9, and -3; loss of mitochondrial membrane potential; and apoptosis upon treatment with IAP inhibitor and lexatumumab. In addition, RIP1 silencing rescued clonogenic survival of cells treated with the combination of lexatumumab and IAP inhibitor, thus underscoring the critical role of RIP1 in cotreatment-induced apoptosis. By comparison, the TNFα-blocking antibody Enbrel had no effect on IAP inhibitor/lexatumumab-induced apoptosis, indicating that an autocrine TNFα loop is dispensable. By demonstrating that IAP inhibitors and lexatumumab synergistically trigger apoptosis in a RIP1-dependent but TNFα-independent manner in RMS cells, our findings substantially advance our understanding of IAP inhibitor-mediated regulation of TRAIL-induced cell death.

Alghamdi S, Castellano-Sanchez A, Brathwaite C, et al.
Strong desmin expression in a congenital desmoplastic infantile ganglioglioma mimicking pleomorphic rhadomyosarcoma: a case report including ultrastructural and cytogenetic evaluation and review of the literature.
Childs Nerv Syst. 2012; 28(12):2157-62 [PubMed]

PURPOSE: Desmoplastic infantile gangliogliomas (DIGs) are rare tumors of infancy. Herein, we describe an unusual case of DIG diagnosed by prenatal ultrasound.
METHODS: This 5-day-old newborn was delivered after a prenatal ultrasound revealed a large cystic mass in the left cerebral hemisphere along with an echogenic solid component.
RESULTS: The tumor revealed a glial and neuronal proliferation in a background of desmoplasia more typical of DIG and a minor component with a more primitive, immature appearance to the glioneuronal elements. A significant component of the tumor was composed of pleomorphic eosinophilic spindle cells in whorls and interlacing fascicles that showed a strong, sharp, and diffuse positivity for desmin, thus mimicking rhabdomyosarcoma. However, the tumor cells were GFAP (+), INI-1 (+), and myogenin (-). Mitoses were seen both in the more spindle cell astroglial areas as well as the more primitive neuroepithelial cells. The MIB-1 proliferation index was brisk, exceeding 15 %, and in areas it was estimated to be as high as 30 %. Such high proliferation index has been described and accepted in the more primitive neuroepithelial areas, but not in the terminally differentiated, spindle cell astroglial areas as in our case. Our patient was incidentally diagnosed prenatally. To our knowledge, this case is the first documented congenital DIG diagnosed prenatally.
CONCLUSIONS: This case highlights the pitfalls in diagnosing DIG, which can mimic a rhabdomyosarcoma. Furthermore, it underscores the importance of re-evaluating the grading of these tumors or at least segregating the variants where the prognosis may be more guarded.

Exley R, Bernstein JM, Brennan B, Rothera MP
Rhabdomyosarcoma of the trachea: first reported case treated with proton beam therapy.
J Laryngol Otol. 2012; 126(9):966-9 [PubMed]

OBJECTIVE: We report a case of rhabdomyosarcoma of the trachea in a 14-month-old child, and we present the first reported use of proton beam therapy for this tumour.
CASE REPORT: A 14-month-old girl presented acutely with a seven-day history of biphasic stridor. Emergency endoscopic debulking of a posterior tracheal mass was undertaken. Histological examination revealed an embryonal rhabdomyosarcoma with anaplasia. Multimodality therapy with surgery and chemotherapy was administered in the UK, and proton beam therapy in the USA.
CONCLUSION: Only three cases of rhabdomyosarcoma of the trachea have previously been reported in the world literature. This is the first reported case of treatment of this tumour with proton beam therapy. Compared with conventional radiotherapy, proton beam therapy may confer improved long-term outcome in children, with benefits including reduced irradiation of the spinal cord.

Li DL, Zhou RJ, Yang WT, et al.
Rhabdomyosarcoma of the breast: a clinicopathologic study and review of the literature.
Chin Med J (Engl). 2012; 125(14):2618-22 [PubMed]

BACKGROUND: Rhabdomyosarcoma (RMS) is an uncommon malignancy of the breast. The aim of this study was to summarize its clinicopathologic features and biological behavior.
METHODS: Five primary or secondary breast RMSs were collected. Their clinicopathological characteristics and all published literature about breast RMS were reviewed. Immunohistochemical study of desmin, myogenic differentiation 1 (MyoD1), myogenin, leukocyte common antigen (LCA), vimentin, cytokeratin (AE1/AE3), E-cadherin, neuron specific enolase (NSE), CD99, chorioallantoic membrane 5.2 (CAM5.2) and epithelial membrane antigen (EMA) expression were performed.
RESULTS: The five patients were all female with ages ranging from 16 to 46 years old (mean, 30 years). Three were metastatic breast RMSs, two embryonal and one solid variant alveolar, with the primary tumor sites the right labium majus, left nasal meatus and nasopharynx, respectively. The other two, one embryonal and one alveolar, were primaries. Grossly, the surgical specimens revealed round or oval, well-demarcated but nonencapsulated masses. Their cut surfaces consisted of homogeneous grayish yellow or white tissue. Microscopically, most tumor cells were poorly differentiated small round, oval or small polygons with eosinophilic cytoplasm. All cases were positive for vimentin, desmin, MyoD1 and myogenin. One embryonal RMS also had a few cells with perinuclear staining of AE1/AE3. The other markers were negative.
CONCLUSIONS: Although primary or metastatic RMS in breast was almost confined to young adolescent females, our cases suggested that it can also happen to the middle-aged women. Embryonal RMS has a certain metastatic potential. MyoD1 and myogenin are two useful markers when making differential diagnosis. Axillary lymph node status and age may play a role in the prognosis of primary breast RMS patients.

Palermo M, Mastronardi LM, García RH, et al.
Primary gastric rhabdomyosarcoma. Case report.
Acta Gastroenterol Latinoam. 2012; 42(2):131-4 [PubMed]

Rhabdomyosarcomas are rare and malignant tumors. There have been reported two histological types of gastric rhabdomyosarcomas, the pleomorphic and embryonal cell types. We report the case of a 53-year-old male with endoscopic diagnosis of a Bormann type III ulcer which revealed a gastric primary rhabdomyosarcoma. Ultrasound showed two liver lesions, two hepatic pedicle lymph nodes and a huge primary gastric tumor. CT scan revealed a primary gastric tumor. The patient is submitted to a distal gastrectomy with a Billroth II reconstruction and a resection of the distal liver metastases at segment IV The patient was discharged uneventfully on the eighth postoperative day. The gold standard for a final diagnoses is the immuno-histochemical staining of the endoscopic biopsy. There is very little information on the results of chemotherapy and the surgical treatment is the best choice.