More than 95% of laryngeal tumors in adults are squamous cell carcinoma. Laryngeal rhabdomyosarcomas are very rare, but extremely malignant tumors. Rhabdomyosarcoma must certainly rank close to, if not the least common of the laryngeal sarcomas. Most of reported cases have occurred in children . Rhabdomyosarcoma arises from undifferentiated mesodermal tissue. It accounts for 40% of sarcomas found in the head and neck region. Among sarcomas arising in the larynx, rhabdomyosarcoma is one of the rarest. The first case of rhabdomyosarcoma of the larynx was reported by Glick in 1944 . On gross pathology, rhabdomyosarcomas are soft, reddish-brown and lobulated. There are four principal histological varieties of rhabdomyosarcoma: embryonal, alveolar, pleomorphic and botryoid according to their degree of cellular differentiation and maturity. Adult rhabdomyosarcomas are usually composed of closely packed round cells with peripherally located nuclei. The cells have glycogen-rich, eosinophilic, vacuolated cytoplasm with cross-striations. Nevertheless they may have present cytological variability and resemble different stages of skeletal muscle morphogenesis. Immunostaining reveals positive findings for muscle-specific actin, desmin, and myoglobin and more specifically myogenin and MyoD1 are also positive . Mitoses are typically absent . Adult embryonal rhabdomyosarcoma has possibly unique molecular characteristics, nevertheless it has not been defined yet .
At the same time for oncology and surgery specialists the precise pre-therapeutical staging of tumors of the musculoskeletal system provides important prognostic information and has impact on the entire therapy management. During therapy imaging is extremely important in the follow-up and in diagnosing a possible recurrent disease . Recently, PET and PET/CT have emerged as a functional diagnostic imaging modality for the management of various tumors in adult population and in the case of RMS FDG PET/CT is more accurate than CT regarding clinical staging and re-staging of patients with rhabdomyosarcomas. The overall TNM staging and M staging accuracies of FDG PET/CT was defined as high as 86% . The specificity of PET/CT for the characterization of pulmonary metastases with a diameter > 0.5 cm and lymph node metastases with a diameter of <1 cm was significantly increased over that of CT alone .
Till now only several cases of this laryngeal tumor have been described in world literature in the adult population [9–11]. Although rhabdomyosarcoma of the larynx tends to be less aggressive than rhabdomyosarcoma elsewhere in the head and neck region , adult patients with laryngeal rhabdomyosarcoma often present at a later stage than other laryngeal tumors, mainly squamous cell carcinoma , which negatively influence the prognosis. One needs to remember that although laryngeal involvement by primary and metastatic rhabdomyosarcoma is very rare, however when occurs-it can result in life-threatening upper airway obstruction .
Rhabdomyosarcoma is a solid tumor, resulting from dysregulation of the skeletal myogenesis program. Four histological subtypes occur in RMS-embryonal (ERMS), alveolar (ARMS), pleomorphic and botryoid. The entire spectrum of genetic factors underlying RMS development and progression is unclear until today. While chromosomal rearrangements account for the majority of alveolar tumors, the genetic defects underlying the pathogenesis of embryonal type remain largely undetermined. Cytogenetically ERMS karyotype is disturbed, most frequently hyperdiploid, with extra copies of chromosomes 2, 7, 8, 11, 12, 13, and 20. Aneuploidies typical of sporadic E-RMS include gain of chromosomes 3, 8, 13 and loss of chromosomes 9, 14, X . Although no consistent structural chromosomal alteration has been identified in ERMS , loss of heterozygosity at 11p15.5 is the most frequent genetic alteration in embryonal rhabdomyosarcoma . Multiple changes affecting chromosome arms are being detected in ERMS cases, including gain or loss of specific regions harboring cancer progression-associated genes . Aneuploidy and mitotic chromosomal instability observed in RMS was suggested to be a result of the overexpression of the AURKA (aurora kinase A) gene that is reported in all RMS tumors tested . Other gene associated with RMS development is BUBR1 (budding uninhibited by benzimidazoles 1 homolog beta)-a key protein in the mitotic spindle checkpoint and potent inhibitor of Cdc20. Missense germline mutations of BUB1B were reported in patients with ERMS and supported the link between aneuploidy and cancer development .
Molecular genetics analyses have not only assisted in understanding the molecular mechanism in sarcoma pathogenesis but also demonstrated new relationships within different types of sarcomas leading to a more proper classification of sarcomas .
Multiple signaling pathways seem to be involved in ERMS development and progression. Array-based CGH analysis in primary RMS detected copy number changes of transcription factors such as MYC-related and the cytoskeleton and cell adhesion gene-laminin gamma-2 and also p21-activated kinase-1. In the animal model interaction between HER family genes and the p53 pathway was shown to be involved in the origin of human rhabdomyosarcoma . Moreover the pathogenesis of ERMS was also linked to deregulation of the hedgehog signaling pathway. Recent findings suggest that haploinsufficiency for the two tumor suppressor genes PTCH (patched (Drosophila) homolog (nevoid basal cell carcinoma syndrome)) and SUFU (suppressor of fused homolog)-which are both active in this signaling pathway-is frequent in ERMS development .
In the majority of ERMS cases screened, overexpression of MCL1 (induced myeloid leukemia cell differentiation protein) and MAP2K4 (mitogen-activated protein kinase 4) genes, both involved in cell viability regulation, was reported . At the same time a few studies performed on series of embryonal tumors suggest that dysregulation of RAS function may be relevant to ERMS disease pathogenesis. NRAS (neuroblastoma RAS viral (v-ras) oncogene homolog) mutations are found in as high number as 20% of primary ERMS cases . Another gene of RAS family - HRAS (GTPase HRas also known as transforming protein p21) - was reported to be found in the state of uniparental disomy (UPD) and/or mutated in multiple ERMS cases. It was even subsequently suggested that HRAS germline mutations are the first step in ERMS development and are followed by lost of the other HRAS allele and expression of mutant HRAS only .
Moreover FGFR1 (fibroblast growth factor receptor 1) overexpression was detected in all primary RMS tumors and cell lines tested. A hypomethylation of a CpG island upstream to FGFR1 exon 1 was identified, which suggests a molecular - epigenetic - mechanism of FGFR1 overexpression . Recent studies have also shown a significant involvement of insulin-like growth factor (IGF) signaling components in the pathogenesis of rhabdomyosarcoma. High levels of insulin-like growth factor II mRNA (IGF-II) were detected in ERMS and increased transcriptional activity was confirmed to be result of AP-2 (activating protein 2) transcription factor overexpression. Moreover differential expression of IGF pathway genes can distinguish RMS subtypes, with IGF2 significantly more expressed in ERMS. In such cases it is possible that PAX3/FKHR fusion gene inhibits IGF2 expression . Embryonal rhabdomyosarcoma is also characterized by high expression levels of PAX3 and PAX7. As PAX3 and PAX7 are known to play a role in the regulation of migratory events in embryogenesis, it is possible that the metastatic potential of ERMS is driven by PAX overexpression . Moreover ERMS may overexpress CXCR4 and CXCR7 receptors that bind prometastatic alpha-chemokine stromal-derived factor-1 (SDF-1).
Not only proteins but also microRNAs (miRNA) have been implicated in RMS development and the clinical behavior of RMS. Muscle-specific miRNAs levels are lower in RMS compared with skeletal muscle but generally higher than in other normal tissues. Low miR-206 expression correlates with poor overall survival and is an independent predictor of shorter survival in metastatic embryonal RMS cases without PAX3/7-FOXO1 fusion genes. Low miR-206 expression also significantly correlates with high SIOP stage and the presence of metastases at diagnosis. High miR-206 expression strongly correlated with expression of genes involved in muscle differentiation and low expression is associated with genes linked to MAPkinase and NFKappaB pathway activation . At the same time miR-183 is significantly overexpressed in RMS and is an important contributor to cell migration and has a potential oncogenic role through the regulation of 2 tumor suppressor genes, EGR1 and PTEN . Moreover introduction of miR-1 and miR-133a into an embryonal rhabdomyosarcoma-derived cell line is cytostatic, thereby suggesting a tumor suppressor-like role for these myogenic miRNAs .
All data collected till now suggest the involvement of genes encoding cell adhesion, cytoskeletal signaling as well as transcriptional and cell cycle components in RMS tumorigenesis . It is not possible to indicate specific steps in cell transformation and further research is needed to understand the molecular mechanism underlying RMS carcinogenesis, deregulation of proliferation and differentiation of skeletal myoblasts. We urge reporting of these rare tumors to enhance understanding the genetic component associated with this disease. Understanding of the molecular biology of sarcomas is leading towards development of newer and more effective treatment regimens .