What Is RMS Disease in Adults and How Does It Affect Health?

Rhabdomyosarcoma (RMS) is a rare and aggressive cancer that primarily affects skeletal muscle tissue. While more common in children, adults can develop it, often facing different challenges in diagnosis and treatment. Due to its rarity in adults, RMS is frequently misdiagnosed or detected late, affecting prognosis and therapeutic options.

Understanding its biological mechanisms, clinical presentation, subtypes, diagnostic methods, and prognostic factors is crucial for improving patient care.

Biological Basis

RMS originates from mesenchymal cells capable of differentiating into skeletal muscle. Myogenic progenitors, regulated by factors like MYOD1, MYF5, and MYOG, typically follow a structured developmental path. In RMS, genetic and epigenetic disruptions interfere with this process, leading to uncontrolled proliferation and impaired differentiation. Unlike normal muscle development, where cells exit the cell cycle to form mature fibers, RMS cells remain undifferentiated or partially differentiated, fueling tumor growth.

Distinct genetic abnormalities define RMS subtypes. Alveolar RMS often involves chromosomal translocations, particularly PAX3-FOXO1 or PAX7-FOXO1 fusions, which create oncogenic transcription factors that disrupt gene expression and promote tumor survival. Embryonal RMS, more common in adults, frequently exhibits loss of heterozygosity at chromosome 11p15 and mutations in TP53, NRAS, and FGFR4, driving tumor growth through PI3K/AKT/mTOR and RAS/MAPK pathways.

Epigenetic modifications further complicate RMS biology. Aberrant DNA methylation and histone changes silence tumor suppressor genes and activate oncogenic pathways. For example, hypermethylation of the CDKN2A locus leads to unchecked cell cycle progression, while dysregulated microRNAs, such as miR-206, impair muscle differentiation, allowing tumor cells to evade normal growth constraints.

Clinical Characteristics

RMS in adults often has a subtle onset, delaying diagnosis. Symptoms depend on tumor location, with common sites including the head and neck, genitourinary tract, and extremities. Patients may initially notice a painless mass that enlarges over time, though discomfort can arise as the tumor compresses surrounding structures. Retroperitoneal or deep soft tissue tumors may remain asymptomatic until they reach a significant size, potentially causing organ dysfunction or neuropathic pain.

RMS is aggressive, with a high likelihood of local invasion and distant metastasis. Unlike pediatric cases, adults more frequently present with metastatic disease, especially in the lungs, bone marrow, and lymph nodes. Pulmonary involvement can cause persistent cough or breathing difficulties, while bone metastases may lead to skeletal pain or fractures. Alveolar RMS has a greater tendency for lymphatic spread, whereas embryonal RMS often extends directly into adjacent tissues. The presence of metastases at diagnosis significantly impacts treatment strategies and survival.

Histopathology helps differentiate RMS subtypes and assess tumor behavior. Less differentiated tumors tend to be more aggressive. Immunohistochemical staining for markers like desmin, myogenin, and MyoD1 confirms diagnosis. Imaging techniques, including MRI and PET-CT, assess tumor extent and metastasis. Given its rarity in adults, RMS is often misdiagnosed as other soft tissue sarcomas or benign lesions, underscoring the need for thorough histological and molecular evaluation.

Subtypes Of RMS

RMS is classified into embryonal, alveolar, and pleomorphic subtypes, each with distinct pathological and clinical characteristics.

Embryonal

Embryonal RMS (ERMS) is the most common subtype in adults, typically arising in the head and neck, genitourinary tract, or retroperitoneum. Histologically, ERMS consists of spindle-shaped and round cells resembling early skeletal muscle development. Genetic alterations often include loss of heterozygosity at chromosome 11p15, disrupting growth-regulating genes like IGF2. Mutations in TP53, NRAS, and FGFR4 contribute to abnormal cell proliferation.

ERMS generally has a better prognosis than other subtypes, particularly when diagnosed early. However, in adults, it often presents at an advanced stage, reducing treatment effectiveness. Standard therapy includes surgery, chemotherapy, and radiation, with vincristine, actinomycin D, and cyclophosphamide (VAC) as the primary regimen.

Alveolar

Alveolar RMS (ARMS) is more aggressive and linked to chromosomal translocations involving PAX3-FOXO1 or PAX7-FOXO1 fusion genes. These genetic changes drive tumor survival, proliferation, and metastasis. ARMS typically affects the extremities and trunk, presenting as a rapidly growing mass.

Unlike ERMS, ARMS has a higher risk of early metastasis, particularly to the lungs, bone marrow, and lymph nodes. Histologically, it features small, round cells arranged in alveolar-like spaces. Due to its aggressive nature, ARMS in adults has worse outcomes, requiring intensive treatment, including high-dose chemotherapy, radiation, and targeted therapies aimed at disrupting PAX-FOXO1 signaling.

Pleomorphic

Pleomorphic RMS (PRMS) is rare and almost exclusively seen in adults. Unlike ERMS and ARMS, PRMS lacks characteristic genetic translocations and instead exhibits complex chromosomal abnormalities. It primarily affects deep soft tissues in the extremities, presenting as an infiltrative mass.

Histologically, PRMS consists of highly pleomorphic, multinucleated tumor cells resembling undifferentiated pleomorphic sarcoma. It is resistant to conventional chemotherapy and has a poor prognosis due to high recurrence and metastasis rates. Surgery with wide margins is the primary treatment, often supplemented by radiation. Unlike other RMS subtypes, PRMS does not respond well to standard chemotherapy, prompting research into novel therapies, including immune checkpoint inhibitors.

Diagnostic Approaches

Diagnosing RMS in adults is challenging due to its rarity and diverse presentation. Many cases are initially misdiagnosed as benign tumors or other sarcomas, delaying treatment. A comprehensive diagnostic process combining imaging, histopathology, and molecular analysis is essential.

Imaging studies assess tumor size, location, and metastasis. MRI is preferred for soft tissue evaluation, while CT is used for detecting lung metastases. PET-CT enhances staging accuracy by identifying metabolically active tumor sites. However, imaging alone cannot confirm RMS, necessitating histopathological examination.

A core needle biopsy provides tissue samples for histological and immunohistochemical analysis. RMS cells express myogenic markers like desmin, MyoD1, and myogenin, distinguishing them from other sarcomas. Molecular testing, particularly for alveolar RMS, detects PAX-FOXO1 fusion genes via fluorescence in situ hybridization (FISH) or reverse transcription-polymerase chain reaction (RT-PCR). These genetic markers confirm the subtype and provide prognostic information. When genetic alterations are unclear, next-generation sequencing (NGS) can identify additional mutations influencing treatment decisions.

Prognostic Factors

RMS prognosis in adults depends on tumor histology, genetic alterations, disease stage at diagnosis, and treatment response. Compared to pediatric cases, adult RMS has a lower survival rate, often due to delayed diagnosis and differences in tumor biology. The five-year survival rate in adults is approximately 30–40%, compared to 70–80% in children. This disparity is partly due to the higher prevalence of aggressive subtypes, such as pleomorphic and alveolar RMS, in adults.

Molecular markers play a crucial role in prognosis. Patients with alveolar RMS harboring the PAX3-FOXO1 fusion gene have worse outcomes than those with PAX7-FOXO1 fusion or fusion-negative tumors. In contrast, embryonal RMS, which lacks these translocations, is associated with better survival, especially when localized. Tumor size and location also influence outcomes, with smaller tumors and those in surgically accessible sites having better prognoses. Patients achieving complete remission after initial therapy have significantly improved survival rates. Prognostic models integrating clinical, histopathological, and molecular data are increasingly used to tailor treatments.

Supportive Measures

Managing RMS in adults requires more than tumor-directed therapy. A comprehensive approach addresses treatment-related complications, maintains quality of life, and optimizes long-term outcomes. Supportive care includes pain management, nutritional support, and rehabilitation services.

Chemotherapy and radiation can cause significant side effects, such as myelosuppression, mucositis, and neuropathy. Growth factor support, including granulocyte colony-stimulating factor (G-CSF), helps mitigate chemotherapy-induced neutropenia. Antiemetic regimens incorporating 5-HT3 receptor antagonists and NK1 receptor blockers control nausea and vomiting, improving treatment adherence.

Psychosocial support is essential, as many patients experience anxiety, depression, or financial strain. Counseling and support groups provide coping mechanisms. Physical rehabilitation helps restore function, particularly after limb-sparing surgeries or radiation-induced fibrosis. Long-term survivorship programs monitor for late effects, such as cardiotoxicity from anthracyclines or secondary malignancies, ensuring early intervention. A multidisciplinary approach enhances patient outcomes and overall well-being.