Rhabdomyosarcoma
Rhabdomyosarcoma is a highly aggressive form of cancer that develops from mesenchymal cells that have failed to fully differentiate into myocytes of skeletal muscle. Cells of the tumor are identified as rhabdomyoblasts.
The four subtypes are embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, and spindle-cell/sclerosing rhabdomyosarcoma. Embryonal and alveolar are the main groups, and these types are the most common soft tissue sarcomas of childhood and adolescence. The pleomorphic type is usually found in adults.
It is generally considered to be a disease of childhood, as the vast majority of cases occur in those below the age of 18. It is commonly described as one of the small-blue-round-cell tumors of childhood due to its appearance on an H&E stain. Despite being relatively rare, it accounts for approximately 40% of all recorded soft-tissue sarcomas.
RMS can occur in any soft-tissue site in the body, but is primarily found in the head, neck, orbit, genitourinary tract, genitals, and extremities. No clear risk factors have been identified, but the disease has been associated with some congenital abnormalities. Signs and symptoms vary according to tumor site, and prognosis is closely tied to the location of the primary tumor. Common sites of metastasis include the lungs, bone marrow, and bones. There are many classification systems for RMS and a variety of defined histological types. Embryonal rhabdomyosarcoma is the most common type and comprises about 60% of cases.
Outcomes vary considerably, with five-year survival rates between 35 and 95%, depending on the type of RMS involved, so clear diagnosis is critical for effective treatment and management.
Treatment usually involves a combination of surgery, chemotherapy, and radiation. 60 to 70% of newly diagnosed patients with nonmetastatic disease can be cured using this combined approach to therapy. Despite aggressive multimodality treatment, less than 20% of patients with metastatic RMS are able to be cured of their disease.
Types
Given the difficulty in diagnosing rhabdomyosarcoma, definitive classification of subtypes has proven difficult. As a result, classification systems vary by institute and organization. Rhabdomyosarcoma in the 2020 WHO classification, though, is listed as four histological subtypes: embryonal, alveolar, pleomorphic, and spindle-cell/sclerosing.Embryonal
is the most common histological variant, comprising about 60–70% of childhood cases. It is most common in children birth to four years old, with a maximum reported incidence of four cases per million children. ERMS is characterized by spindle-shaped cells with a stromal-rich appearance, and the morphology is similar to the developing muscle cells of a 6- to 8-week-old embryo. Tumors often present in the head and neck, as well as the genitourinary tract.Embryonal subtype
is almost always found in mucosal-lined organs, including the vagina, bladder, and nasopharynx. It often presents in infants younger than a year old, as a round, grape-like mass on the affected organ. Histologically, cells of the botryoid variant are defined by a dense tumor layer under an epithelium. This subtype has a good prognosis.Botryoid rhabdomyosarcoma is also sometimes present in adult women, found in the cervix or uterus.
Alveolar
is the second-most common type. ARMS comprises around 20–25% of RMS-related tumors, and it is equally distributed among all age groups with an incidence of about one case per million people ages 0 to 19. For this reason, it is the most common form of RMS observed in young adults and teenagers, who are less prone to the embryonal variant. This type of RMS is characterized by densely packed, round cells that arrange around spaces similar in shape to pulmonary alveoli, although variants have been discovered without these characteristic alveolar spacings. ARMS tends to form more often in the extremities, trunk, and peritoneum. It is also typically more aggressive than ERMS.Pleomorphic
, also known as anaplastic rhabdomyosarcoma, is defined by the presence of pleomorphic cells with large, lobate hyperchromatic nuclei and multipolar mitotic figures. These tumors display high heterogeneity and extremely poor differentiation. The pleomorphic cells may be diffuse or localized, with the diffuse variation correlating to a worse prognosis. It occurs most often in adults, rarely in children, and is often discovered in the extremities. Due to the lack of discernible separation among cancers of this type, clinicians often label undiagnosed sarcomas with little to no discernible features as anaplastic RMS. It is the most aggressive type of RMS, and often requires intensive treatment.Spindle-cell/sclerosing
Spindle-cell/sclerosing rhabdomyosarcoma is an added subtype listed in the 2020 WHO classification of soft-tissue sarcomas.This subtype is very similar to that of leiomyosarcoma, and it has a fascicular, spindled, and leiomyomatous growth pattern with notable rhabdomyoblastic differentiation. It occurs most commonly in the paratesticular region, and the prognosis for this particular form of RMS is excellent with a reported five-year survival rate of 95%. The sclerosing aspect of this subtype has a hyaline sclerosis and pseudovascular development.
Multiple classification systems have been proposed for guiding management and treatment, and the most recent and widely used classification system is the "International Classification of Rhabdomyosarcoma" or ICR. It was created by the IRSG in 1995 after their series of four multi-institutional trials aimed at studying the presentation, histology, epidemiology, and treatment of RMS. The ICR system is based on prognostic indicators identified in IRSG I–IV. Pleomorphic rhabdomyosarcoma usually occurs in adults rather than children, and is therefore not included in this system.
Signs and symptoms
RMS can occur in almost any soft-tissue site in the body; the most common primary sites are genitourinary, parameningeal, extremity, orbit, other head and neck, and miscellaneous other sites. RMS often presents as a mass, but signs and symptoms can vary widely depending on the site of the primary tumor. Genitourinary tumors may present with hematuria, urinary tract obstruction, and/or a scrotal or vaginal mass. Tumors that arise in the retroperitoneum and mediastinum can become quite large before producing signs and symptoms. Parameningeal tumors may present with cranial nerve dysfunction, symptoms of sinusitis, ear discharge, headaches, and facial pain. Orbital tumors often present with orbital swelling and proptosis. Extremity tumors generally present as a rapidly enlarging, firm mass in the relevant tissue. The cancer's prevalence in the head, face, and neck will often allow for earlier signs of the disease simply due to the obvious nature of tumors in these locations. Despite the varying presentation and typically aggressive nature of the disease, RMS has the potential to be diagnosed and treated early. The fourth IRSG study found that 23% of patients were diagnosed in time for a complete resection of their cancer, and 15% had resection with only minimal remnants of the diseased cells.Risk factors
Rhabdomyosarcoma is difficult to diagnose. Risk factors that increase the likelihood of this cancer include inherited disorders such as Li-Fraumeni syndrome, Neurofibromatosis type 1, Beckwith-Wiedemann syndrome, Costello syndrome, Noonan syndrome, and DICER1 syndrome.Genetic
There are multiple genetic lesions associated with rhabdomyosarcoma, but there has been little consistent data demonstrating an association between specific genetic abnormalities and outcome. However, alveolar and embryonal types of RMS can be distinguished cytogenetically, and identification of specific genetic lesions can allow for accurate classification of the ARMS subtype when the histopathological findings are equivocal or unclear. This is valuable for clinical practice as the alveolar type presents a higher risk to the patient and will often require more aggressive treatment than the embryonal type. Thus, ARMS is also referred to as Fusion Positive rhabdomyosarcoma. Up to 90% of alveolar RMS cases present with a translocations of t or, less commonly, t. Both involve the translocation of a DNA binding domain of either PAX3 or PAX7'','' a member of the Paired Box family of transcription factors, to a transactivation site on FOXO1 '', a member of the forkhead/HNF-3 transcription factor family. The t translocation results in a fusion of the PAX3 gene with FOXO1, while the t translocation involves the fusion of PAX7 with FOXO1. PAX3 has a demonstrated role in muscle cell development, which supports its potential role in RMS. The t translocation can result in the PAX3-FKHR fusion product, which is indicative of classic cystic ARMS. Cases of FP-RMS are associated with a poorer prognosis than fusion-negative RMS.The fusion protein presents a potential therapeutic target, and in recent years more research has been conducted to clarify the role of PAX3-FOXO1 in FP-RMS. PAX3-FOXO1 is now known to drive key oncogenes such as MYC and MYCN by creating long-distance genetic interactions by super enhancers. In this context, PAX3-FOXO1 both drives the expression of MYC, MYCN and even MYOD1 but also co-binds with these master transcription factors at super enhancers to support cancer growth. Furthermore, it was demonstrated that FP-RMS subtypes were especially sensitive to inhibitors of a super enhancer bound protein BRD4.
Embryonal RMS usually presents with a loss of heterozygosity in the short arm of chromosome 11. This region is associated with multiple oncogenes, and the potential loss-of-function of this region is likely associated with the loss of a tumor suppressor. However, the specific consequences of this LOH at have yet to be determined. The short arm of chromosome 11 is also the site of the insulin-like growth factor 2 gene, which is often over-expressed in RMS.
The loss-of-function of tumor suppressor p53 is associated with many cancers including rhabdomyosarcoma, and approximately 50% of RMS cases have been shown to carry some form of mutation to the P53 gene. Other oncogenes often associated with rhabdomyosarcoma, albeit with less frequency, include NMYC, NRAS, KRAS, P16, and c-Met. One study showed that 35% of embryonal RMS tumors contained activating mutations in either NRAS or KRAS and it is worth noting that ras activation has been shown to block myogenic differentiation, which could help explain its potential role in rhabdomyosarcogenesis. More recently, a mechanistic and epigenetic link between mutant RAS isoforms and a block of myogenic differentiation has been demonstrated. Furthermore, it has been shown that this differentiation block can be overcome with a clinical stage inhibitor of the MAP kinase pathway known as a MEK inhibitor.