Metastatic Alveolar Rhabdomyosarcoma Research Articles

Protein kinase C iota as a therapeutic target in alveolar rhabdomyosarcoma

Alveolar rhabdomyosarcoma is an aggressive pediatric cancer exhibiting skeletal muscle differentiation. New therapeutic targets are required to improve the dismal prognosis for invasive or metastatic alveolar rhabdomyosarcoma. Protein kinase C iota (PKCι) has been shown to play an important role in tumorigenesis of many cancers but little is known about its role in rhabdomyosarcoma. Our gene expression studies in human tumor samples revealed overexpression of PRKCI. We confirmed overexpression of PKCι at the mRNA and protein level using our conditional mouse model that authentically recapitulates the progression of rhabdomyosarcoma in humans. Inhibition of Prkci by RNA interference resulted in a dramatic decrease in anchorage-independent colony formation. Interestingly, treatment of primary cell cultures using aurothiomalate (ATM), which is a gold-containing classical anti-rheumatic agent and a PKCι-specific inhibitor, resulted in decreased interaction between PKCι and Par6, decreased Rac1 activity and reduced cell viability at clinically relevant concentrations. Moreover, co-treatment with ATM and vincristine, a microtubule inhibitor currently used in rhabdomyosarcoma treatment regimens, resulted in a combination index (C. I.) of 0.470–0.793 through cooperative accumulation of non-proliferative multinuclear cells in the G2/M phase, indicating that these two drugs synergize. For in vivo tumor growth inhibition studies, ATM demonstrated a trend towards enhanced vincristine sensitivity. Overall, these results suggest that PKCι is functionally important in alveolar rhabdomyosarcoma anchorage-independent growth and tumor cell proliferation and that combination therapy with ATM and microtubule inhibitors holds promise for the treatment of alveolar rhabdomyosarcoma.

Palliative Tumor Control by Trabectedin in Pediatric Advanced Sarcoma

Refractory soft tissue sarcomas carry a poor prognosis and limited treatment options require the use of new chemotherapeutic agents. We report the case of an eight year old boy with non metastatic alveolar rhabdomyosarcoma of the right forearm (Group 3, Stage III). After treatment failure of several chemotherapeutic regimens and progression of his disease, Trabectedin was administered at 1.3 mg/m2/dose intravenously over 24 hours for two cycles. The patients quality of life improved as noted by a significant decrease in opiate requirements and ability to tolerate oral intake. The drug was well tolerated with the exception of transient neutropenia.

Evasion Mechanisms to Igf1r Inhibition in Rhabdomyosarcoma

Inhibition of the insulin-like growth factor 1 receptor (Igf1r) is an approach being taken in clinical trials to overcome the dismal outcome for metastatic alveolar rhabdomyosarcoma (ARMS), an aggressive muscle cancer of children and young adults. In our study, we address the potential mechanism(s) of Igf1r inhibitor resistance that might be anticipated for patients. Using a genetically engineered mouse model of ARMS, validated for active Igf1r signaling, we show that the prototypic Igf1r inhibitor NVP-AEW541 can inhibit cell growth and induce apoptosis in vitro in association with decreased Akt and Mapk phosphorylation. However, drug resistance in vivo is more common and is accompanied by Igf1r overexpression, Mapk reactivation, and Her2 overexpression. Her2 is found to form heterodimers with Igf1r in resistant primary tumor cell cultures, and stimulation with Igf2 leads to Her2 phosphorylation. The Her2 inhibitor lapatinib cooperates with NVP-AEW541 to reduce Igf1r phosphorylation and to inhibit cell growth even though lapatinib alone has little effect on growth. These results point to the potential therapeutic importance of simultaneous targeting of Igf1r and Her2 to abrogate resistance.

Positron Emission Tomography–Computed Tomography Evaluation of Maxillary Rhabdomyosarcoma in an Adult

Rhabdomyosarcoma is a rare primary head/neck tumor. This article illustrates the utility of multimodality imaging techniques in a 34-year-old male with metastatic alveolar rhabdomyosarcoma, including an apparently favorable metabolic response to chemotherapy between baseline and early post-treatment positron emission tomography–computed tomography. Clinical and histopathologic features of the disease are also presented.

Allogeneic Hematopoietic Stem Cell Transplantation Against Recurrent Rhabdomyosarcoma

The prognosis of high-risk rhabdomyosarcoma (RMS) with metastatic or recurrent disease remains poor. We report a 6-year-old girl who successfully underwent allogeneic hematopoietic stem cell transplantation against recurrent metastatic alveolar RMS. The disease recurred at distant lymph node metastasis with bone marrow involvement. After chemotherapy and radiotherapy for the metastatic site, she underwent allogeneic bone marrow transplantation during complete remission from her 5/8 HLA-matched father. She developed acute graft-versus-host disease after preemptive donor lymphocyte infusion and remains in a disease-free condition for 31 months after transplantation. A graft-versus-tumor effect through allogeneic immune cells might produce a beneficial effect for high-risk RMS.

Fine needle aspiration cytology of metastatic alveolar rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is an aggressive malignant soft tissue tumor that arises from primitive striated muscle cells called rhabdomyoblasts. RMS is a rare tumor in adults, and involvement of the sinonasal area is extremely rare, comprising only 1.5% of all reported head and neck RMSs. Alveolar RMS, mainly seen in adults, has the worst prognosis. Incidence of lymph node metastases is more common in this type compared with the other forms. Fine needle aspiration cytology (FNAC) has been used extensively in the diagnosis of metastatic malignancies. However, metastatic soft tissue sarcomas are often overlooked, primarily due to the low frequency with which they occur. Here, we report a rare case of metastatic alveolar RMS in the cervical lymph nodes of an 18-year-old girl that was detected by FNAC. After 6 months, the patient came with a huge mass involving the nasal vestibule and the upper lip. Histology of both the main mass and the lymph nodes revealed alveolar RMS.

Endoscopic ultrasound‐guided fine‐needle aspiration of metastatic alveolar rhabdomyosarcoma to the pancreas with fluorescence in situ hybridization: A case report

Alveolar rhabdomyosarcoma (ARMS) is a rare tumor in adults. Cytologic diagnosis of metastatic ARMS to the pancreas diagnosed by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has been reported rarely in the literature. A 20-year-old male with a history of ARMS in the right maxillary sinus resected one year earlier and pancreatitis treated two months earlier, presented on routine follow-up. Abdominal positron electron tomography-CT scan revealed a mass in the pancreas and fluorodeoxyglucose uptake in the left paraaortic lymph node. Subsequent magnetic resonance imaging of the abdomen showed a 3.6 × 6.4 cm mass in the tail of the pancreas. EUS-FNA was performed using a 22-gauge needle. Cytologic criteria and immunohistochemistry in the smears were analyzed. A diagnosis consistent with metastatic ARMS was rendered. Subsequent FISH analysis of the case and histologic review of the primary tumor supported the final diagnosis. A diagnosis of metastatic ARMS to the pancreas can be made by EUS-FNA. FISH can be used as an ancillary technique in diagnosing the tumor.

Metastatic alveolar rhabdomyosarcoma in multiple endocrine neoplasia type 2A

Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, accounts for 3% of childhood malignancies. Multiple Endocrine Neoplasia (MEN) type 2A is an autosomal dominant syndrome associated with near universal development of medullary thyroid carcinoma. We describe a previously unreported association of MEN-2A with metastatic alveolar RMS and review the literature on associated hereditary cancer predisposition syndromes and current therapeutic options. The high penetrance of malignancy in patients with MEN warrants a heightened suspicion for the development of nonendocrine malignancies. The diagnosis of RMS should prompt consideration of screening for familial genetic syndromes in certain patients.

Aberrant expression of synaptophysin in two metastatic alveolar rhabdomyosarcomas. Pitfalls in fine needle aspiration cytology diagnosis

Aberrant expression of synaptophysin in two metastatic alveolar rhabdomyosarcomas. Pitfalls in fine needle aspiration cytology diagnosis

First Case Report of Bilateral Metastatic Intratesticular Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children. The tumor spreads by local extension, to regional lymph nodes, or by distant metastasis. Only few cases of intratesticular metastatic RMS have been reported in the published data. We present a case of an 18-year-old boy with metastatic alveolar RMS to the testis and the first reported case of bilateral testicular involvement.

UNUSUAL LEPTOMENINGEAL DISSEMINATION IN A CHILD WITH EXTRACRANIAL METASTATIC ALVEOLAR RHABDOMYOSARCOMA

The authors describe a 6-year-old boy diagnosed with alveolar rhabdomyosarcoma located in the thigh, with distal metastases to lungs, bones, and bone marrow. A very good partial response to first-line chemotherapy was obtained, but the child developed fatal leptomeningeal dissemination immediately after complete resection of the primary tumor. This case demonstrates the rapidity with which leptomeningeal spread of extracranial metastatic alveolar rhabdomyosarcoma can occur and underscores the importance of diagnostic lumbar puncture and brain radiological investigations at diagnosis, even when the tumors are not in the parameningeal location.

Aberrant expression of synaptophysin in two metastatic alveolar rhabdomyosarcomas. Pitfalls in fine needle aspiration cytology diagnosis

Aberrant expression of synaptophysin in two metastatic alveolar rhabdomyosarcomas. Pitfalls in fine needle aspiration cytology diagnosis

De novo germline TP53 mutation presenting with synchronous malignancies of the central nervous system

We present a case of a 14-year-old male with a germline TP53 mutation who presented with synchronous primitive neuroectodermal tumor and choroid plexus carcinoma. Identification of synchronous brain tumors prompted genetic testing for predisposition to malignancy. Within 5 months of presentation, the child developed widely metastatic alveolar rhabdomyosarcoma. Patient DNA sequencing showed a TP53 allele with a premature stop codon in the oligomerization/nuclear export signal (NES) domain (R342ter). The child's parents, younger brother, paternal grandparents, and maternal grandmother, are without history of malignancy. The patient's brother tested negative for TP53 mutations. This case identifies a rare, de novo, germline TP53 mutation presenting with synchronous CNS malignancies and exhibiting a more fulminant course than typical cases of Li-Fraumeni syndrome.

WT1 (WILMS TUMOR 1) PEPTIDE IMMUNOTHERAPY FOR CHILDHOOD RHABDOMYOSARCOMA: A Case Report

Immunotherapy using a Wilms tumor (WT1) peptide has been undergoing clinical trials for adulthood leukemia and solid cancer with promising results. In this study, the authors used WT1 peptide vaccination to treat a 6-year-old girl with metastatic alveolar rhabdomyosarcoma. She received weekly intradermal injection with HLA-A*2404-restricted, 9-mer WT1 peptide against residual bone disease. After 3 months her bone disease disappeared, concurrent with an increase in the frequency of WT1-specific cytotoxic T lymphocytes (CTLs). A high proportion of WT1-specific CTLs with effector or effector memory phenotype were detected in peripheral blood of this patient. She is currently still on continued WT1 peptide immunotherapy in a disease-free condition for 22 months. WT1 peptide-based immunotherapy should be a promising option for high-risk rhabdomyosarcoma in childhood.

An in Vitro and in Vivo Evidence That Human Rhabdomyosarcomas (RMS) Express Functional CXCR7 Receptor: Overlapping and Distinct Role of CXCR4-SDF-1 and CXCR7-SDF-1/ITAC Axes in Regulating Metastatic Behavior of RMS Cells

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of adolescents and children that frequently infiltrates the bone marrow (BM). We have demonstrated that the a-chemokine stromal-derived factor (SDF)-1-CXCR4 axis (Blood 2002; 100:2597, Cancer Res . 2003; 63:7926, Cancer Res. 2007; 67:2131) plays an important role in RMS metastases. With the recent description of CXCR7, a new receptor for SDF-1 that also binds the interferon-inducible T cell-alpha chemoattractant (ITAC) chemokine, we become interested in the role of the CXCR7-SDF-1/ITAC axis in RMS metastasis. To address this issue, we evaluated 7 highly metastatic alveolar RMS (ARMS) and 3 less metastatic embryonal RMS (ERMS) cell lines. We found that all RMS cell lines express CXCR7 in contrast to CXCR4, which was expressed by 7 of 10 RMS cell lines only. CXCR4 was expressed at a much higher level by highly metastatic ARMS lines while CXCR7 was expressed at a high level on the less metastatic ERMS lines. More importantly, CXCR7 receptor on RMS cell lines was functional after stimulation with ITAC and SDF-1 as evidenced by MAPKp42/44-, AKT-, and STAT-3 phosphorylation, chemotaxis, cell motility, and adhesion assays. We also noticed that CXCR7 undergoes rapid internalization after stimulation with SDF-1 and ITAC, is a lipid raft-associated receptor, and, surprisingly, has a downregulated expression in response to hypoxia. We also noticed that similarly to CXCR4, signaling from activated CXCR7 was not associated with increased RMS proliferation or cell survival. Thus, we conclude that both CXCR4 and CXCR7 are not affecting proliferation of RMS cells; however they play an important role in both SDF-1- and ITAC-directed metastasis. For the first time, we also identify ITAC as a new regulatory chemokine that is actively involved in this process. In conclusion, since CXCR7 is more important in adhesion and becomes down-regulated during hypoxia, this changes the balance in SDF-1 signaling through both receptors (CXCR7/CXCR4). As a result, SDF-1 activates more robust CXCR4 receptor, which promotes chemotactic responses of RMS cells. As a biological consequence, this switch in SDF-1 receptor signaling increases the metastatic potential of RMS by mobilizing tumor cells to egress from the tumor into the peripheral blood and lymph and migrate to new tissue locations. We also conclude that targeting of the CXCR-SDF-1 axis alone without simultaneous blockage of CXCR7 will be an inefficient strategy to inhibit metastasis of RMS cells. This is currently being tested in our laboratories in immunodeficient mice inoculated with human RMS cells.

Alveolar Rhabdomyosarcoma With Neuroendocrine/Neuronal Differentiation: Report of 3 Cases

The aim of this study is to report the clinicopathologic characteristics of 3 cases of alveolar rhabdomyosarcoma with neuroendocrine/neuronal differentiation. Specimens of 3 cases of alveolar rhabdomyosarcoma were studied using histologic, immunohistochemical, ultrastructural, and molecular genetic techniques. The patients were a 19-year-old man with metastatic alveolar rhabdomyosarcoma in a groin lymph node, a 16-year-old girl with alveolar rhabdomyosarcoma of the perineum, and a 20-year-old man with recurrent orbital alveolar rhabdomyosarcoma. Microscopically, case 1 was composed of compact sheets of medium to large tumor cells. Cases 2 and 3 were small blue round cell tumors. Cases 1 and 3 were solid throughout, whereas case 2 demonstrated alveolar and solid architecture. By immunohistochemistry, the following markers were positive: desmin (3/3), myogenin (3/3), synaptophysin (3/3), and chromogranin (2/3). Ultrastructurally, sarcomeric filaments were seen in all cases, while neuroendocrine granules were detected only in case 1. PAX:FKHR fusion transcript was identified in case 2, case 3 had a variant PAX3 transcript, and case 1 was negative. The data presented expands the known differentiation of alveolar rhabdomyosarcoma.

Emergency Surgery for Left Atrial Metastatic Alveolar Rhabdomyosarcoma Manifesting as a Right Atrial Mass

We report the case of a 43-year-old woman with a history of alveolar rhabdomyosarcoma of the forearm, scalp, and paraspinal region who developed acute shortness of breath owing to a tumor arising from the left atrium and extending through the coronary sinus. This was causing partial obstruction across the tricuspid valve as a result of the ball-valve effect. Emergency resection of the atrial mass was performed, and histologic analysis confirmed the presence of metastatic rhabdomyosarcoma. To our knowledge, this is the first reported case of emergency surgical resection of intracardiac metastatic alveolar rhabdomyosarcoma.

Metastatic alveolar rhabdomyosarcoma to the breast: a case report

To present the unusual occurrence of a Metastatic Alveolar Rhabdomyosarcoma to the right breast in a young woman, six years after the primary in the right thigh had been surgically excised and treated. A search of the literature from this part of the world showed that this is quite rare as no report of a similar case was found. Breast lumpectomy samples submitted were routinely processed to obtain paraffin sections which were then stained routinely with haematoxylin and eosin. Reticulin stain and immunohistochemistry were used to exclude an epithelial lesion. Metastatic Rhabdomyosarcoma to the breast is a rare condition and is almost exclusive to adolescent females. Routine breast examinations should be mandatory for long term female survivors of primary Rhabdomyosarcomas.

Fine-needle aspiration cytology of alveolar rhabdomyosarcoma utilizing ThinPrep® liquid-based sample and cytospin preparations: A case confirmed by FKHR break apart rearrangement by FISH probe

Rhabdomyosarcoma is the most common childhood sarcoma that occurs in the soft tissues of the head and neck, genitourinary system, and extremities. While this tumor may also be seen in young adults, it is distinctly unusual to see this neoplasm beyond the fifth decade. The use of fluorescence in situ hybridization (FISH) probes on fine-needle aspiration material for chromosomal analysis to detect chromosomal translocations are not well established. Herein we present a case of metastatic alveolar rhabdomyosarcoma originating in the nasal sinus and recurring in the neck of an adult man 5 yr after his initial presentation. The ThinPrep smear demonstrated isolated malignant tumor cells similar to his previous histologic material. The cytologic findings of alveolar rhabdomyosarcoma were confirmed utilizing a dual color break apart FISH probe which identified the FKHR translocation on the cytospin preparation prepared from a ThinPrep vial and processed as a cytospin preparation. In addition to routine and immunocytologic staining, we demonstrate that aspirated tumor cells can be analyzed using a FISH probe to identify specific chromosomal abnormalities.

Use of a tissue expander and a polyglactic acid (Vicryl) mesh to reduce radiation enteritis: case report and literature review

Management of stage IV rhabdomyosarcoma comprises systemic chemotherapy with local control by conservative surgery and radiotherapy. Abdominal radiotherapy may lead to radiation enteritis causing such serious morbidity as malabsorption, fistulae or stricture formation. The risk increases with the dose of radiation and length of bowel involved. Various methods have been utilised to displace the bowel from the radiation field. Usually these are applied in patients requiring pelvic irradiation. We report a case of metastatic alveolar rhabdomyosarcoma requiring radiotherapy to the right renal bed. Effective displacement of small bowel from the tumour site was achieved by a combined use of a tissue expander and Vicryl mesh. There were no complications from the surgery. This is the first report discussing combined use of a tissue expander and Vicryl mesh to aid radiotherapy to the renal fossa in a paediatric patient.