Continuing Education Activity

Rhabdomyosarcoma (RMS) is a malignant soft tissue sarcoma that is believed to originate from primitive mesenchymal cells that typically differentiate into skeletal tissue. However, these tumors can also arise in other types of tissue and any anatomic area. RMS is the most common soft tissue sarcoma diagnosed in children; only 1% to 2% of these cancers are found in adults. The etiology and risk factors remain largely unknown. Most cases of rhabdomyosarcoma are sporadic; however, the disease can be associated with familial syndromes. Rhabdomyosarcoma is classified into histologic subtypes: embryonal, alveolar, pleomorphic, spindle, and mixed-type. Embryonal is the most commonly occurring subtype and also has the best prognosis. The management approach is tailored to a patient's risk stratification. Two systems are used to characterize risk stratification for RMS: the Clinical Group or the Stage. Each system uses different factors to categorize patients according to risk, and most authorities use both to determine the most appropriate therapeutic approach. Currently, treatment is multimodal, combining surgery, when feasible, to completely remove the primary tumor and chemotherapy to control disease spread, even if no evidence of metastasis is present on imaging because most patients have been found to have micrometastasis in studies. Radiotherapy is used to treat most high and intermediate-risk patients as well. The survival of rhabdomyosarcoma patients has improved due to interprofessional collaboration, leading to advancements in diagnosis and management approaches. This activity for healthcare professionals is designed to enhance the learner's competence when managing rhabdomyosarcoma, equipping them with updated knowledge, skills, and strategies for timely diagnosis and effective interventions, as well as highlighting the role of interprofessional coordination of care, leading to better outcomes for patients and reduced morbidity.

Objectives:

• Identify the known histopathologies of rhabdomyosarcoma.

• Delineate the recommended evaluation and diagnosis of rhabdomyosarcoma.

• Differentiate the treatment options for each rhabdomyosarcoma risk group.

• Outline the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by rhabdomyosarcoma.

Introduction

Rhabdomyosarcoma (RMS) is a malignant soft tissue sarcoma that is believed to originate from primitive mesenchymal cells that typically differentiate into skeletal tissue. However, these tumors can also arise in other types of tissue and any anatomic area. RMS is the most common soft tissue sarcoma diagnosed in children; only 1% of these cancers are found in adults.[1] The etiology and risk factors remain largely unknown. Most cases of rhabdomyosarcoma are sporadic; however, the disease can be associated with familial syndromes.[2]

Rhabdomyosarcoma is classified into histologic subtypes: embryonal, alveolar, pleomorphic, spindle, and mixed-type. Embryonal is the most commonly occurring subtype and also has the best prognosis.[1] The management approach is tailored to a patient's risk stratification. Two systems are used to characterize risk stratification for RMS: the Clinical Group or the Stage. Each system uses different factors to categorize patients according to risk, and most authorities use both to determine the most appropriate therapeutic approach. Currently, treatment is multimodal, combining surgery, when feasible, to completely remove the primary tumor and chemotherapy to control disease spread, even if no evidence of metastasis is present on imaging because most patients have been found to have micrometastasis in studies. Radiotherapy is used to treat most high and intermediate-risk patients as well.[3][4] The survival of rhabdomyosarcoma patients has improved due to interprofessional collaboration, leading to advancements in diagnosis and management approaches. Healthcare professionals should seek to enhance their competence when managing rhabdomyosarcoma. Furthermore, they should have updated knowledge, skills, and strategies for timely diagnosis and effective interventions to improve patient outcomes and reduce morbidity.

Etiology

Although the etiology of rhabdomyosarcoma is largely unknown, there is evidence of an underlying genetic component because a chromosomal translocation has been identified in many RMS tumors, and RMS has been associated with several inherited cancer syndromes (eg, Noonan, Li-Fraumeni, Beckwith-Wiedemann, and Costello.[5][6]

Risk Factors

An increased risk of developing RMS is also seen with other factors, including:

• Fetal radiation exposure
• Parental drug use
• Family history of RMS in a first-degree relative
• Preterm birth 
• Fertility drug use
• History of congenital defects [4]

Epidemiology

Rhabdomyosarcoma (RMS) is a rare condition making up 3% of all pediatric cancers. However, RMS is the most common childhood and adolescent soft tissue sarcoma, comprising 50% of soft tissue sarcomas in individuals younger than 20.[1] In the US, there are approximately 350 newly diagnosed patients each year.[4] All histological subtypes of RMS have also been shown to be significantly more prevalent in males. RMS has a much lower incidence in adults, accounting for approximately 1% of solid cancers.[1]

Although the various subtypes of RMS can arise anywhere in the body, the embryonal histological type is the most common, and the head and neck is the most frequently involved area. RMS involving the extremities is more frequently observed with the alveolar subtype. The pleomorphic and alveolar subtypes have the highest rates of metastases and, consequently, the poorest prognosis compared to other histologic types. The most common metastatic sites include the lungs, bone marrow, and lymph nodes.[1] 

Histopathology

Gross Pathology

Macroscopically, these tumors usually appear as white to purplish black, necrotic, polypoid infiltrative masses that can be soft or firm to palpation. Tumors may be localized or have metastatic spread; frequently, tumors >5 cm at the time of diagnosis have an increased risk for metastasis.[7][8][9] Pleomorphic tumors usually are large, well-circumscribed tumors that have minimal to large amounts of necrosis.[10]

Histologic Pathology

Myogenesis is the normal process of embryonic cell differentiation into skeletal cells. However, RMS is the result of the abnormal repetition of this process. Therefore, RMS is typically identified when histologic evidence of primitive myogenesis is observed in tumor biopsies. RMS cells demonstrate little myogenesis, including undifferentiated mesenchymal cells, elongated myoblasts, and poorly differentiated myofibers.[11][12] Formerly, RMS was divided into 2 primary groups: embryonal and alveolar subtypes due to the histological variation between them. The most recent 2020 WHO classification classifies RMS into 4 main histological subtypes: embryonal, alveolar, spindle or sclerosing cell, and pleomorphic. Some additional variants that had unspecified classifications were included as well.[10][1]

Characteristic histologic findings of RMS tumors include undifferentiated embryonic skeletal cells. Each histologic subtype can usually be differentiated by cell morphology, though there may be some mixed types.[1][11] Sheets of medium-sized cells arranged in large clusters separated by fibrovascular septa are commonly seen in alveolar rhabdomyosarcoma. Scattered giant cells are often seen also. Embryonal subtypes typically have small round blue cells and loosely packed rhabdomyoblasts within a myxoid matrix. Spindle cell types are usually arranged in a pseudovascular pattern and are more differentiated than the other subtypes. Pleomorphic subtypes can often be identified due to having undifferentiated cells with a variety of shapes with enlarged hyperchromatic nuclei.[13][10]

The identification of rhabdomyosarcoma is sometimes difficult due to the histologic similarity of the tumor to the other small, blue, round-cell pediatric bone and soft tissue tumors (eg, Wilms tumor, lymphoma, small-cell osteosarcoma, and Ewing sarcoma). Therefore, specific immunohistochemistry stains, indicative of skeletal tissue, are usually used to differentiate RMS from other tumor pathologies. Differential diagnoses can be narrowed for tumors with cells with characteristic RMS findings, including positive staining for skeletal markers (eg, myogenin, demin, and Myo-D1) and no differentiation. However, biopsy interpretation can be further complicated because other neoplasms may also exhibit positive marker staining. Therefore, molecular analysis is often used for diagnostic confirmation.[11][10][4]

History and Physical

Rhabdomyosarcoma (RMS) is typically asymptomatic, but depending on tumor features (eg, the site of origin, size, and metastases), patients may present with various symptoms. The most common RMS tumor site is the head, neck, and genitourinary areas. Patients with tumors arising in the head and neck area (eg, orbital, nasopharyngeal, and paranasal sinuses) may present with mucopurulent nasal drainage, sinus congestion, or proptosis. Additionally, symptoms caused by the mass effect of enlarging tumors can occur, including proptosis, dizziness, nausea, or headache.[4] RMS tumors within the genitourinary area frequently cause symptoms such as vaginal bleeding, pelvic pain, dysuria, hematuria, and urinary frequency. Patients with RMS tumors involving the extremities are typically painless, although patients with pleiomorphic RMS commonly have rapidly growing, painful masses.[10] Physical findings noted on examination also vary according to the anatomical area involved, including cranial nerve palsies, uterine or scrotal enlargement, and bulging vaginal masses. Enlarged lymphatic nodes may be palpated as well if regional spread occurs.[14][8][15][4]

Evaluation

Clinicians should perform initial diagnostic studies following clinical evaluation to identify the underlying etiology of the patient's symptoms or, if present, the visible mass. As with most neoplasms, additional diagnostic evaluation through imaging and tissue biopsy is typically needed for diagnostic confirmation and to determine the extent of spread and prognosis.[10]

Imaging Studies

MRI imaging of the involved area should initially be used to diagnose patients with a musculoskeletal tumor and is preferred over CT due to better visualization. Additional imaging studies (eg, CT or PET) can be performed based on possible sites of spread. Although ultrasound imaging may be acceptable for localized subcutaneous tumors, MRI and CT imaging modalities better characterize soft tissue tumors.[16] Imaging is integral in all patients with musculoskeletal neoplasms because they are typically staged with the TNM system, comprised of physical and radiologic examination findings. Furthermore, imaging studies can be used to assess tumor response to treatment and recurrence. Clinicians also require tumor assessments by imaging studies to direct biopsies for histological analysis. Therefore, experts recommend imaging studies should be performed before guided biopsies are obtained because resection of the biopsy tract and the tumor is recommended. Consequently, radiology clinicians, surgeons, and oncologists need close collaboration to evaluate a patient well; pediatric subspecialists should be consulted for pediatric patients.[16][17]

Neoplasm characteristics that are assessed through imaging include size diameters, extent of tissue and lymph node involvement, and distant metastasis. Furthermore, accurate assessment of all the anatomical areas involved is essential as surgeons require this information to perform extensive tumor debulking and prevent recurrent disease.[17][16]

Histological and Molecular Analysis Studies

Initial diagnostic studies of RMS involve histological analysis of the mass that assists in identifying the pathology. Biopsies are also essential for staging if a malignancy is diagnosed. The tissue sample may be obtained through an excisional or core needle biopsy. A fine needle biopsy is not recommended because adequate amounts of tissue are unlikely.[10] Because biopsy interpretation can be complicated by other neoplasms that exhibit similar immunohistologic staining, genetic testing, including molecular analysis and fluorescence-in-situ-hybridization testing, is recommended in all patients for diagnostic confirmation and identification of RMS subtypes.[4][10]

Embryonal RMS has been associated with aneuploidies of the RAS and TP53 genes, while alveolar RMS was found in studies to have two distinguishing chromosomal translocations, t(2;13)(q35;q14), which is more common, and t(1;13)(p36;q14).[18][10] Furthermore, genetic analysis has found the genetic fusions PAX3::FOXO1 and PAX7::FOXO1 to be associated with these chromosomal translocations. Therefore, alveolar RMS can be more accurately diagnosed using molecular analysis. Spindle cell and sclerosing subtypes have been found to have various gene fusions involving NCOA2 and VGLL2. Some genetic mutations of MYOD1 have also been identified.[10] Pleomorphic RMS, primarily seen in adults, has been found to have a wide range of genetic alterations.[10] Histologic and genetic identification of RMS subtypes also assists clinicians with determining a patient's prognosis. For instance, sclerosing and spindle cell types typically have an excellent prognosis; however, some mutations of this subtype and all pleomorphic types have a poor prognosis.[4][10]

Treatment / Management

In the US, the management approach is tailored to a patient's risk stratification. Two systems are used to characterize risk stratification for RMS: the Clinical Group or the Stage. Each system uses different factors to categorize patients according to risk, and most authorities use both to determine the most appropriate therapeutic approach. The RMS Stage utilizes categories 1 to 4 with risk stratification determined by tumor characteristics (eg, size, extension, and location), lymph node involvement, and distant metastasis (TMN).[4] Clinical Group utilizes 4 categories, from I to IV, and differentiates risk by surgical pathology, including:[4]

• Completeness of resection
• Presence or absence of residual disease at the margins
• Evidence of distant metastasis

Based on these factors, patients are placed into one of the following risk groups: low, intermediate, or high. In Europe, slightly different features are used to determine risk stratification.[3] Currently, treatment is multimodal, combining surgery, when feasible, to completely remove the primary tumor and chemotherapy to control disease spread, even if no evidence of metastasis is present on imaging because most patients have been found to have micrometastasis in studies. Radiotherapy is used to treat most high and intermediate-risk patients as well.[3][4]

The chemotherapy regimen used in the US for the treatment of RMS is comprised of vincristine, actinomycin D, and cyclophosphamide (VAC), usually in 3-week cycles; in Europe, a different regimen is used, consisting of ifosfamide, vincristine, and actinomycin D (IVA). Studies have shown both regimens to have comparable outcomes.[3][4] For high- to intermediate-risk patients, chemotherapy is typically given for 6 to 9 months; in low-risk patients, chemotherapy is shortened to approximately 24 months, and dosages may also be reduced.[3][4] Some experts recommend repeat imaging to assess tumor response to chemotherapy after 3 cycles.[16]

Recommendations concerning continued surveillance imaging for recurrent disease also vary between Europe and the US. Current guidelines in Europe recommend surveillance imaging every 4 months for 2 years. In the US, there are no set guidelines; however, most clinicians follow current Children's Oncology Group recommendations to repeat imaging every 4 months for 4 years. Due to known complications from radiation exposure, particularly in children, many experts have recently advocated for US clinicians to adopt European surveillance guidelines as both protocols have similar outcomes. The management of patients with RMS is continuously evolving as new, evidence-based results emerge from clinical trials of treatment advancements.[19]

Differential Diagnosis

Other musculoskeletal neoplasms that should be excluded include:

• Ewing sarcoma
• Li-Fraumeni syndrome
• Lipomas
• Liposarcoma
• Lymphadenopathy
• Lymphoproliferative disorders
• Neurofibromatosis type 1
• Osteosarcoma
• Wilms tumor [11][10][4]

Surgical Oncology

Surgical Resection

Surgical treatment of RMS is primarily used for histologic diagnosis and risk stratification.[20] However, because complete tumor removal is an integral part of risk stratification, surgery in combination with chemotherapy and radiation remains an essential aspect of multimodal RMS treatment for many patients. In general, surgical excision of the primary tumor site is recommended if complete excision without disfigurement or decreased function is possible. However, for some sites, tumor resection is difficult due to the risk of causing mutilation of surrounding tissue. With the introduction of effective chemotherapeutic regimens, modern surgical techniques are less radical and emphasize long-term functional preservation. For some patients, definitive surgical excision is frequently performed after several cycles of chemotherapy to decrease the need for extensive or disfiguring surgery, termed delayed primary excision.[18] Adequate margins are defined as a 5mm ring of normal tissue surrounding the tumor.[21] Patients with clear margins following primary tumor resection have higher survival rates than those with grossly positive margins (ie, group 3 or 4) after resection.[4] Other than for RMS tumors in the head and neck area, lymph node sampling as part of initial surgical resection is recommended to determine risk stratification.[4][22]

• Head and neck: RMS of the head and neck, particularly in the parameningeal areas (eg, the nasal cavity, nasopharynx, and paranasal sinus), are typically considered unfavorable sites for resection. Currently, treatment primarily utilizes chemotherapy, with surgery only performed for biopsies or recurrent disease.[23] There are limited studies of localized RMS in nonparameningeal areas that showed beneficial results with using surgical excision and radiotherapy; however, these studies were too small to reach any conclusions.[24] 

• Extremities: RMS of the extremities carries a poorer prognosis than other disease sites. Resection should be done to preserve limb function and ensure complete resection. As with other tumor locations, incomplete resections portend a poorer outcome and require more intensive treatment. Therefore, if complete resection can be performed without functional or cosmetic impairment, then excision should be performed before chemotherapy; however, if complete resection is not possible, chemotherapy followed by excision is recommended. As it has a prognostic and therapeutic role, regional and sentinel lymph nodes should be assessed by imaging and histologic analysis.[25] 

• Paratesticular area: Radical surgical resection via an inguinal orchiectomy, including the entire spermatic cord, is the standard of care for paratesticular RMS. Testicular preservation is not recommended. As with other testicular tumors, a trans-scrotal resection is strongly discouraged due to difficulty achieving complete excision with that approach. Patients with microscopically positive cord margins after the initial resection should undergo repeated excision before chemotherapy. Furthermore, due to the risk of nodal metastasis, retroperitoneal lymph node dissection (RPLND) is recommended for patients with paratesticuar RMS and any of the following:[26]
  • Older than the age of 10
  • Alveolar RMS on histology
  • Lymph nodes >1 cm on imaging

• Genitourinary area: Typically, RMS tumors of the bladder and prostate have a poorer prognosis than other RMS sites due to being unfavorable for complete resection. However, RMS tumors involving the female pelvic organs (eg, vagina, uterus, and vulva) are more favorable for complete resection and have a better prognosis.[7][27] Generally, genitourinary RMS tumors are biopsy-confirmed, initially treated with chemotherapy to reduce tumor size, and then surgically excised.[28][22] In some patients, brachytherapy may be beneficial as well.[29]

Metastatic Disease

Distant metastatic disease is identified in approximately 20% of children at their initial diagnosis. Metastasis is a common finding secondary to lymphatic and hematogenous spread of RMS, with the most frequent areas of space being the lungs, bones, and bone marrow.[4] The overall survival of patients with metastatic rhabdomyosarcoma is meager, reported to be <20%.[5] Treatment of metastase sites has not proved to be beneficial. However, some European studies have demonstrated improved survival in patients who underwent a combination of resection and radiotherapy to aggressively treat the primary tumor despite metastasis.[5]

Second-Look Surgery

Second-look surgeries are controversial but may be used to assess tumor response and determine candidacy for reduced dose radiation. Studies have not demonstrated any benefits to overall survival; however, outcomes have been improved secondary to radiotherapy adjustments. Therefore, many experts recommend interprofessional communication and collaboration to tailor management decisions to each patient.[30][31]

Radiation Oncology

Radiation Therapy Indications

In the US, most patients with RMS are treated with a multimodal approach that combines chemotherapy, surgical excision, and radiation therapy (RT). Some patients classified as low-risk and with clear margins following resection may not require radiation; most others do, though the dose required is adjusted according to their risk group and the residual disease present following initial resection.[32] In Europe, RT was historically avoided due to associated risks, particularly in children who are more likely to experience adverse effects on growth. However, due to the significantly improved survival, clinicians have increasingly utilized this modality.[20]

RT is primarily indicated for localized disease control, which significantly impacts survival. Additionally, RT is preferred by some experts for any involved lymph nodes, as therapeutic lymph node dissection is not recommended. Radiotherapy can be delivered with various methods, including external beam radiation, intensity-modulated radiation, proton therapy, and brachytherapy. Brachytherapy may be preferred in select circumstances, including gynecologic and head and neck tumors, due to the ability to target treatment on the tumor without damaging the surrounding normal tissue as much.[18] Because of the various factors that need to be considered when deciding on the approach to RT, the treatment strategy employed is usually decided upon by the radiation oncologist in collaboration with the multidisciplinary team.[4][18]

Radiation Therapy Planning and Dosing

The tumor volume to be treated and the RT dosage are typically determined by CT imaging in slices with a 2 to 3 mm thick standard thickness. However, other imaging modalities (eg, MRI or PET) may be utilized.[20] Generally, the planned tumor volume to be treated is obtained from CT or MRI imaging of the RMS tumor before any surgical resection or chemotherapy and involves all gross primary and nodal diseases called the gross target volume (GTV). The clinical target volume (CTV) comprises the GTV and an additional 1 cm of tissue surrounding the tumor in case of marginal microscopic disease. The CTV is used to calculate the RT dosage needed.[20] RT guidelines recommend giving RT in fractionated doses of 1.8 Gy daily until the maximum total amount is reached.[33] Table 1 shows the standard RT doses the Children's Oncology Group (COG) used.[20]

Table 1. Standard Radiation Therapy Dosages Utilized by the Children's Oncology Group [20]

Timing of Therapy

In all patients receiving RT, the Children's Oncology Group (COG) recommends beginning treatment after 4 cycles (ie, 12 weeks) of chemotherapy. Most localized recurrence of RMS has been observed in patients who did not receive RT or treatment was delayed past 24 weeks after starting chemotherapy. RT is typically only omitted for low-risk patients with completely resected fusion-negative tumors. However, the optimal time to initiate RT has yet to be determined.[20] Some European guidelines recommend repeated CT or MRI imaging for RT planning after 6 cycles of chemotherapy have been completed. However, as there is no consensus on the optimal RT treatment strategy, radiation treatment is usually determined by the radiation oncologist in collaboration with the multidisciplinary team.[18]

Radiation Therapy Complications 

While acute toxicities can be problematic, late radiation toxicities can have long-lasting effects on a patient's quality of life. As a result, there have been several studies to minimize radiation dose or omit radiation altogether. Late effects, which can vary according to location and dose of RT, are a significant consideration in children and adolescents due to longer life expectancies. Furthermore, younger children have the greatest risk for late-onset adverse effects, with some studies demonstrating the dose effect to be the most pronounced in children ages 2 to 10. Because the mitotically active growth plate region in children is susceptible to radiation, alterations in stature, fibrosis, and limb atrophy can be seen in 80% of children. However, late effects may take up to 10 years to become evident.[34][35] As a result, RT doses >10 Gy should be avoided in children.[36] Late sequelae secondary to RT include:

• Neurocognitive impairment 
• Facial disfigurement (eg, facial bone hypoplasia)
• Endocrinopathies (eg, growth hormone deficiency, diabetes, central hypothyroidism, and ACTH deficiency)
• Ocular impairment (eg, cataracts, amblyopia, retinopathy, and decreased visual acuity)
• Nasal and oral complications (eg, odynophagia, chronic sinusitis, epistaxis, mucositis, and delayed tooth eruption)
• Dermatitis
• Intestinal obstruction
• Chronic otitis and hearing loss
• Urinary incontinence and frequency
• Vaginal stenosis
• Erectile dysfunction
• Joint stiffness and impaired mobility
• Skeletal growth impairment and pathological fractures
• Secondary malignancy [4][32][37][36][35]

Medical Oncology

Chemotherapy Indications

Chemotherapy is indicated for all patients with RMS of any risk category. Frequently, micrometastasis is found in low-risk patients; therefore, chemotherapy is recommended for all patients, even when imaging appears normal.[18] Treatment with chemotherapy has increased overall survival to >70%.[20] Additionally, chemotherapy has been found to decrease the risk of disease progression by 48%.[24] Therefore, multiagent chemotherapy's effectiveness in treating RMS in all patients is well established.

Chemotherapy Timing and Duration

 For the vast majority of patients, chemotherapy is given as the first line of treatment for multiple cycles, which is then paused for interval treatment with surgery and/or RT, followed by the resumption of chemotherapy. The specific agents used in the standard protocols vary between the US and Europe, although clinical outcomes are similar. In the US, the multiagent chemotherapy most commonly utilized is vincristine, actinomycin D, and cyclophosphamide (VAC) for 9 to 12 cycles initially.[32][20] Vincristine inhibits microtubule polymerization. Actinomycin D inhibits DNA transcription, and cyclophosphamide is an alkylating agent.[38] Europe, however, commonly uses 4 cycles of ifosfamide, vincristine, and actinomycin D (IVA) followed by 5 cycles of vincristine and actinomycin D for intermediate-risk patients initially, while 9 cycles of IVA are recommended in high-risk patients. In low-risk patients, 8 cycles of vincristine and actinomycin D are typically recommended.[20]

The total duration of chemotherapy varies depending on a patient's risk stratification and which protocol their clinician is following.[20] Currently, the total duration used by the COG in the US is 24 to 48 weeks; in Europe, the duration is much less, totaling 22 to 27 weeks. There is no consensus on dosage recommendation either, with various studies using an alkylating agent dose ranging from 1 g/m² per course to 2.2 g/m² per course.[3] 

Recurrent Disease

The majority of deaths related to RMS occur within the first 2 years. Outcomes are generally poor, with a median survival time of 9.6 months and a 5-year overall survival of 28%.[39][40]  At present, there is no established standard treatment for RMS relapse because patient survival remains poor even after chemotherapy treatment.[4]

Chemotherapy Complications

• Secondary malignancies: The risk of secondary malignancies increases with certain chemotherapies and radiotherapy compared to surgery alone.[41] Alkylating agents (eg, cyclophosphamide) may contribute to the development of hematologic malignancies such as acute myeloid leukemia.[42] The addition of etoposide appears to increase this risk significantly.[42]

• Hemorrhagic cystitis: The use of cyclophosphamide and ifosfamide is the primary cause of hemorrhagic cystitis in patients treated with those agents. Acrolein, a metabolite of both cyclophosphamide and ifosfamide, is thought to accumulate in the bladder, generating a reactive oxygen species that damages and destroys cells.[43] The relative risk corresponds with the total cumulative dose received. Mesna is typically given prophylactically to reduce the risk of hemorrhagic cystitis by binding to acrolein, allowing the harmless byproduct to be excreted in the urine. Other methods, including hyperhydration, may be equally effective.[44][45]

• Infertility: Alkylating agents such as cyclophosphamide can also lead to infertility in men due to dose-dependent adverse effects on seminiferous tubules. Testosterone production may also be impaired, leading to reduced fertility.[46] Exposure before puberty is not protective.[47] For females, ovarian failure appears to be dose and age-dependent, with only higher doses inducing ovarian failure in younger women.[48]

• Neurotoxicity: Peripheral neuropathy is one of the most common adverse effects associated with vincristine, though the severity appears to vary with dose, age, drug clearance, and race.[49]

Staging

The 2 classification systems utilized in managing rhabdomyosarcoma are the TNM (tumor, nodes, metastasis) Staging system and the Clinical Group (CG) system. These systems complement each other and are used to assess prognosis and guide treatment for patients with rhabdomyosarcoma. The RMS prognostic stratification classifies patients based on these systems as low, intermediate, or high risk. 

The Rhabdomyosarcoma Risk Stratification Systems

In general, the RMS Clinical Group (CG) system (see Table 2. RMS Clinical Group Classification) differentiates risk by surgical pathology, including:[4]

• Completeness of resection
• Presence or absence of residual disease at the margins
• Evidence of distant metastasis

 Table 2. RMS Clinical Group Classification [7][20]

The RMS Stage classification (see Table 3. RMS Staging) is primarily based on the following factors:[4]

• Tumor characteristics (eg, size and extension)
• Lymph nodes involvement
• Distant metastases
• Favorable or unfavorable location
  • Favorable sites: biliary tract, orbit, nonparameningeal head and neck, and genitourinary areas other than the prostate and bladder
  • Unfavorable sites: parameningeal areas, prostate, bladder, and extremities

Table 3. RMS Staging [20][7]

Rhabdomyosarcoma Risk Groups

Risk stratification is essential to determine a patient's prognosis and direct treatment. The risk stratification that is used in Europe was developed by the European Paediatric Soft Tissue Sarcoma Group. Though similar to the risk groups used in the US, the European also incorporates patient age and tumor histology to stratify patients into 4 categories: low, standard, high, and very high risk. In the US, clinicians primarily use the Children's Oncology Group (COG) risk stratification, which integrates FOXO1::PAX fusion status and the RMS grouping and staging systems to stratify patients into 3 main groups with the low-risk group made up of 2 subsets.[20]

Low-risk subset 1

• Stage 1 or 2, CG I to III, fusion-negative 
• Stage 1, CG III, orbital site only, fusion-negative

Low-risk subset 2

• Stage 1, CG III, nonorbital site, fusion-negative
• Stage 3, CG I or II, fusion negative

Intermediate-risk

• Stage 2 or 3, CG III, fusion negative
• Stage 4, CG IV, patient age <10 years, fusion-negative
• Stage 1 to 3, CG I to III, fusion-positive

High-risk

• Stage IV, CG IV, any fusion status

Prognosis

RMS prognosis depends on multiple factors that include clinical and histopathologic characteristics. Localized favorable site disease tends to have the best 5-year overall survival of approximately 90%.[50] The overall survival of patients with metastatic RMS is very low, reported to be <20%.[5] Adults have a much poorer 5-year overall survival when compared with children (27% versus 61%). Parameningeal RMS and RMS of the extremities tend to have a poor prognosis compared to other sites.[51] The prognosis for recurrent RMS is also very poor, and optimal management is still being studied. Similar to an initial diagnosis of RMS, the overall survival with recurrent RMS is based on various factors, including the original tumor stage and the tumor recurrence site and histology.[4]

Complications

There is little research into the quality of life patients have following successful treatment for RMS. The limited studies available have demonstrated that survivors of genitourinary RMS, in particular, may have ongoing issues such as urinary incontinence, urinary frequency, and erectile dysfunction.[4] Chemotherapy and radiotherapy, particularly in children, may cause complications at RMS treatment sites that clinicians should be aware of, including:[16] 

• Neurocognitive impairment 
• Facial disfigurement (eg, facial bone hypoplasia)
• Endocrinopathies (eg, growth hormone deficiency, diabetes, central hypothyroidism, and ACTH deficiency)
• Ocular impairment (eg, cataracts, amblyopia, retinopathy, and decreased visual acuity)
• Nasal and oral complications (eg, odynophagia, chronic sinusitis, epistaxis, mucositis, and delayed tooth eruption)
• Dermatitis
• Intestinal obstruction
• Chronic otitis and hearing loss
• Urinary incontinence and frequency
• Vaginal stenosis
• Erectile dysfunction
• Joint stiffness and impaired mobility
• Skeletal growth impairment and pathological fractures
• Secondary malignancy [4][32][37][36][35]

Consultations

The diagnosis and management of RMS require the involvement of a multidisciplinary team. Radiology clinicians must be consulted to obtain imaging studies that provide the primary care clinicians and oncology physicians with the necessary information to stage a patient with RMS correctly. Oncology clinicians then may collaborate with the other health team members to determine a patient's prognosis and specific treatment protocol. Orthopedic oncologists and neurosurgeons may also need to be consulted if the bone, spine, or brain are involved.[10] 

Deterrence and Patient Education

Since the etiology of RMS is mostly unknown, optimal prevention strategies have yet to be determined. However, because the association between RMS and cancer syndromes has been demonstrated, some experts have proposed that laboratory and imaging studies may be used to monitor individuals with RMS-associated cancers (eg, Li-Fraumeni syndrome) to attempt to diagnose RMS earlier.[4]

Enhancing Healthcare Team Outcomes

Early diagnosis is critical to reducing the mortality of rhabdomyosarcoma. Individuals with delayed diagnoses were found to have a much higher incidence of advanced-stage cancers and increasingly poor outcomes. Therefore, interprofessional collaboration that increases access to diagnostic and treatment resources, improves communication, and advances clinician expertise will significantly reduce diagnostic delays and improve patient outcomes.[4]

Furthermore, diagnosis and management of RMS require the involvement of a multidisciplinary team. When the primary care provider, nurse practitioner, or internist has a patient diagnosed with rhabdomyosarcoma, referral to an oncologist is vital to developing an effective treatment protocol. Radiology clinicians must be consulted to obtain imaging studies that provide the primary care clinicians and oncology physicians with the necessary information to stage a patient with RMS correctly. The management of these malignant lesions is complex and requires an interprofessional team that includes oncology, pathology, radiology, and surgery clinicians, including medical assistants and technicians. Only through collaboration of the entire healthcare team can clinicians determine the optimal care plan for each patient, administer the necessary therapies, and monitor treatment response.[17]