Version May 2024
INTRODUCTION — Sarcomas are rare malignant tumors that can arise from mesenchymal tissue at any body site. The histopathologic spectrum of sarcomas is broad, presumably because the embryonic mesenchymal cells from which they originate have the capacity to mature into striated skeletal and smooth muscle, adipose and fibrous tissue, bone, and cartilage.
Rhabdomyosarcomas (RMS) are thought to originate from immature cells that are destined to form striated skeletal muscle; however, these tumors can arise in locations where skeletal muscle is not typically found (eg, the urinary bladder).
Undifferentiated sarcomas derive from mesenchyme that cannot be ascribed to a specific tissue lineage. As such, they are grouped with non-rhabdomyosarcomatous soft tissue sarcomas [1] and will not be discussed further in this review.
The treatment of RMS has evolved considerably over the past several decades. Cure rates have risen, largely due to the increasingly intensive, multimodality therapeutic protocols that have been developed by large international cooperative groups, such as the Intergroup Rhabdomyosarcoma Study Group (IRSG). The IRSG has now become the Soft Tissue Sarcoma Committee of the Children's Oncology Group (COG), and the designation IRS is no longer used for cooperative group trials.
This topic review will cover the clinical presentation, diagnostic evaluation, staging, and risk stratification for purposes of treatment selection among patients with RMS. The epidemiology, pathology, and treatment of RMS are discussed separately.
●(See "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis".)
●(See "Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment".)
CLINICAL PRESENTATION — The presenting signs and symptoms of rhabdomyosarcomas (RMS) are variable and are influenced by the site of origin, the age of the patient, and the presence or absence of distant metastases. In general, the primary lesion has the appearance of a nontender mass, occasionally with overlying skin erythema. A history of antecedent trauma is uncommon, and fever is only rarely present.
Presentation by anatomic site — Any body part can be affected by RMS. However, the most common primary sites are the head and neck region (35 to 40 percent), the genitourinary tract (25 percent), and the extremities (20 percent). The impact of the primary site location on prognosis is illustrated in Table 1 Any body part can be affected by RMS. However, the most common primary sites are the head and neck region (35 to 40 percent), the genitourinary tract (25 percent), and the extremities (20 percent) [2-4]. The location of the primary site impacts prognosis (table 1) [5].
Head and neck — Head and neck primary RMS can arise in the orbit (25 percent), parameningeal sites (middle ear, nasal cavity, paranasal sinuses, nasopharynx, and infratemporal fossa; 50 percent), or other locations (including the scalp, parotid gland, oral cavity, pharynx, thyroid and parathyroid glands, and neck; 25 percent) [6]. RMS involving the head or neck is most commonly of the embryonal subtype and rarely involves regional lymph nodes [7]. (See "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis", section on 'Embryonal RMS'.)
Orbital tumors produce proptosis and, occasionally, ophthalmoplegia, while parameningeal lesions can cause nasal, aural, or sinus obstruction with or without a mucopurulent or sanguineous discharge. Head and neck RMS arising from sites other than these typically present as a localized, painless enlarging mass. (See "Head and neck sarcomas", section on 'Rhabdomyosarcoma'.)
Genitourinary tract — The overwhelming majority of genitourinary tract RMS are of the embryonal type, and many are of the botryoid variant. They can arise from the bladder, prostate, or the male or female genital tracts [8]. (See "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis", section on 'Embryonal RMS'.)
Bladder tumors may be associated with hematuria and urinary obstruction, while prostatic primaries typically present as large pelvic masses causing urinary frequency or constipation from extrinsic compression of the bladder or intestinal tract.
Vaginal tumors tend to develop in very young girls and are accompanied by a mucosanguineous discharge; a polypoid mass may protrude from the vagina (sarcoma botryoides). (See "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis", section on 'Embryonal RMS'.)
Cervical and uterine tumors are more common in older girls. Paratesticular tumors can produce scrotal or inguinal enlargement in prepubertal or postpubertal males.
Extremities — Extremity tumors tend to arise in adolescents, and the typical presentation is that of a painful mass or swelling, with or without erythema of the overlying skin. Between 50 and 75 percent of extremity RMS are of the alveolar type, and they are more likely to spread to regional lymph nodes and along fascial planes.
Other — Less common sites of primary disease include the trunk, chest wall, perineal-perianal region, and biliary tract. Primary RMS of the liver, brain, trachea, heart, breast, and ovary have all been reported.
Regional nodes — The incidence of locoregional lymph node involvement depends upon the primary disease site. Lymphatic spread is unusual with head and neck primaries, particularly in children under the age of 10. In contrast, nodal involvement is present in up to one-half of patients with extremity lesions and in over one-half of males over the age of 10 who present with paratesticular primary sites [9-11].
A retrospective study from the Intergroup Rhabdomyosarcoma Study Group (IRSG), IRS-IV, suggests that the presence of regional nodal metastases negatively impacts the prognosis of patients with otherwise localized alveolar tumors [12], suggesting that more aggressive therapy might be warranted in this subgroup of patients. (See 'Prognostic stratification scheme for risk-adapted therapy' below.)
Distant metastases — Fewer than 25 percent of patients have overt distant metastatic disease at diagnosis, and over one-half of these have only a single site of metastatic involvement, typically the lung [13-16]. Other sites of distant metastatic involvement include bone marrow (approximately 30 percent), bone (30 percent), omentum/ascites (16 percent), and pleura (13 percent); visceral involvement and brain metastases are rare [16].
Despite the small number of patients who have clinically overt metastases at diagnosis, it is presumed that the majority of patients who present with apparently localized disease have subclinical metastatic disease. This is based on the observation that before the routine use of systemic chemotherapy as a component of primary multimodal therapy, a substantial number of patients developed metastases and died of their disease despite achieving local tumor control.
INITIAL DIAGNOSTIC AND STAGING EVALUATION — The entire team of specialists (including the surgeon and radiation oncologist) who will be involved in the care of the child with RMS must have the opportunity to evaluate the patient at the time of initial diagnosis. It is particularly important that the anatomic boundaries of the tumor (which determine the tumor stage, risk stratification, and treatment) be documented prior to starting therapy.
Diagnostic biopsy — If possible, the initial diagnostic biopsy should be performed at a facility with expertise in the evaluation of the child with a soft tissue or bone sarcoma to ensure that the tissue is processed properly and to allow for the special studies that are essential for accurate diagnosis and histologic classification (table 2). Review of the diagnostic material by a pediatric pathologist with special expertise in this area should be strongly considered because of the profound implications of a precise diagnosis on treatment and outcome.
The classification of a tumor as RMS requires the identification of features of skeletal muscle lineage. Typically, this involves light microscopic identification of rhabdomyoblasts or cross-striations that are characteristic of skeletal muscle. For cases that lack these features, immunohistochemical staining (IHC) or electron microscopy may provide evidence supporting myogenic differentiation.
Once RMS diagnosis is confirmed or highly suspected by light microscopic or IHC evaluations, fluorescence in situ hybridization (FISH) or reverse transcriptase polymerase chain reaction (RT-PCR) for FOXO1 rearrangement is performed on all tumors, regardless of the histology. Identification of FOXO1 rearrangement by FISH or RT-PCR is required to provide a diagnosis of alveolar RMS and has replaced the histology variable in all Children's Oncology Group (COG) treatment protocol risk group assignments. This topic is addressed in detail separately. (See "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis", section on 'Histology' and "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis", section on 'Molecular pathogenesis and molecular diagnostic testing'.)
Staging evaluation — A summary of recommended initial staging studies is shown in the table (table 3), and an approach to initial staging is depicted in the algorithm (algorithm 1).
Radiographic imaging of the primary site — The initial radiologic evaluation should include plain radiographs of the affected area, as well as computed tomography (CT) scan or magnetic resonance imaging (MRI) of the primary site and surrounding structures. Children who have a primary tumor below the diaphragm, including all genitourinary primaries, should undergo abdominal CT (thin-cut 5 mm sections) to evaluate retroperitoneal nodal involvement. (See 'Lymph node assessment' below.)
MRI is increasingly considered the imaging method of choice for certain primary locations, such as head and neck, extremity, parameningeal, and pelvic tumors, because of its multiplanar capacity, ability to attenuate bone artifact, and superior soft tissue contrast. Ultrasonography may provide additional information in patients with pelvic tumors (particularly involving the bladder) because the characteristic water density of urine helps in tumor localization.
Metastatic workup — Based on possible sites of spread, the workup can include chest CT without contrast, bilateral bone marrow aspiration and biopsy, radionuclide bone or positron emission tomography (PET-CT) scan. One of the last two imaging modalities is adequate for bone imaging. Sites that appear abnormal on bone scan should be investigated further with plain radiographs and, if findings are equivocal, MRI. If a pleural or peritoneal effusion fluid is present, it should be sampled for cytological evaluation. If tumor cells are found, the patient would be classified having metastatic disease (clinical group IV, stage 4) (table 4).
The metastatic workup should be tailored to the clinical and histologic characteristics. A retrospective analysis of 1687 patients enrolled in Intergroup Rhabdomyosarcoma Study Group (IRSG) studies over a 13-year period suggests that 45 percent of patients with newly diagnosed RMS (particularly those with node-negative, noninvasive tumors) may be spared one or more staging procedures, such as chest CT, staging bone marrow examination, and bone or PET-CT scans [17]. However, a full metastatic workup is indicated for any patient with involved regional lymph nodes (N1 disease) and for those with a node-negative, invasive (T2) tumor of unfavorable histology (alveolar histology or a PAX-FOXO1 [paired box protein-forkhead box protein 01] fusion). National cooperative group protocols recommend a staging workup that is based on clinical and histologic variables, and we agree with this approach (algorithm 1). European cooperative groups and the European Society of Paediatric Radiology guidelines recommend a whole-body PET-CT in all new patients [18], but this approach has not yet been adopted uniformly in the United States.
In general, suspicious findings on the metastatic workup warrant biopsy confirmation. However, some patients with indeterminate pulmonary nodules do not require a confirmatory biopsy. As an example, in a study of 316 patients with localized RMS who were enrolled in the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) 2005 study, 67 had indeterminate pulmonary nodules at diagnosis, defined as ≤4 pulmonary nodules <5 mm or one nodule measuring ≥5 and <10 mm [19]. Clinical outcomes were similar for those without or with indeterminate pulmonary nodules, suggesting that the latter group of patients does not need to be upstaged (ie, to stage IV disease on the basis of the indeterminate pulmonary nodules) or undergo a confirmatory lung biopsy.
Laboratory studies — Initial baseline laboratory studies should include a complete blood count with differential, serum electrolytes, blood urea nitrogen, liver function tests, and serum levels of creatinine, phosphorus, magnesium, uric acid, and calcium. Although uncommon, hypercalcemia can occur in patients with or without bone metastases [20]. Baseline coagulation studies should be obtained, while disseminated intravascular coagulation as a presenting manifestation of RMS is uncommon [21]. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Diagnostic evaluation'.)
Lumbar puncture — Although unnecessary in most patients, pretreatment lumbar puncture is recommended in those with a parameningeal primary RMS (including middle ear, nasal cavity, paranasal sinus, nasopharynx, and infratemporal fossa sites) if there is evidence of intracranial or meningeal invasion on imaging studies. Lumbar puncture is not indicated in patients with orbit/eyelid primaries unless there is evidence of meningeal invasion on MRI. Presence of tumor cells in cerebrospinal fluid cytology or leptomeningeal dissemination can rarely occur and if present, the patient is classified as having metastatic disease and craniospinal irradiation must be administered.
Lymph node assessment — Biopsy of any enlarged lymph nodes is necessary to confirm local metastatic disease. While there is no established definition for an "enlarged" node, a criterion of ≥1 cm has been used in COG protocols for any site. If this is not feasible or not performed for whatever reason, local control with radiotherapy should include those nodes that are clinically presumed to be involved. Biopsy is indicated if there is increased fluorodeoxyglucose uptake on PET-CT in a lymph node that is smaller than 1 cm, but the specific standardized uptake value (SUV) threshold to use is unknown.
In the absence of pathologically enlarged nodes, sentinel node biopsy is indicated for all extremity tumors. Furthermore, all males 10 years of age or older who have a paratesticular RMS and no imaging evidence of metastatic disease in para-aortic lymph nodes should undergo routine ipsilateral nerve-sparing retroperitoneal lymph node (RPLN) sampling. (See "Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment", section on 'Paratesticular'.)
STAGING AND PROGNOSTIC STRATIFICATION — In addition to histology and molecular analysis for FOXO1 rearrangement, there are two classification procedures to appropriately stratify newly diagnosed patients with RMS into risk-based therapy groups: the clinical group (CG) and the tumor, node, metastasis (TNM) system.
Clinical group — The most widely used surgicopathologic staging schema is the CG system developed by the Intergroup Rhabdomyosarcoma Study Group (IRSG) in 1972 [4,22]. Based upon data derived from IRS-I and II on degree of tumor spread at diagnosis and the amount of disease remaining after initial surgery, this system recognizes four disease categories (CG I through IV, Roman numerals) with distinctly different prognoses (table 5).
TNM system — Although the CG system is clinically useful for assigning treatment, it does not take into account other important prognostic factors, such as tumor size and primary site, nodal involvement, histology, cytogenetics, and patient age [22-24]. To address some of these concerns, a pretreatment TNM-type staging system was developed and incorporated into the fourth IRSG protocol (IRS-IV) (table 4) [25].
This modified TNM system assigns one of four disease stages (from 1 through 4, Arabic numerals) based upon the site and size of the primary lesion, regional nodal involvement, and presence or absence of metastatic disease. Favorable disease sites include the orbit and eyelid, other nonparameningeal head and neck locations, and nonbladder, nonprostate genitourinary tumors (eg, paratesticular tumors), while unfavorable sites include the extremities, bladder and prostate, cranial parameningeal sites, trunk, and retroperitoneum.
Prognostic stratification scheme for risk-adapted therapy — The TNM and CG staging systems complement each other, and both are used in contemporary classification schemes to assess prognosis and select treatment for individual patients with RMS [26]. The prognostic stratification schema that was adopted by the IRSG for its study protocol combines information from the CG and TNM staging systems as well as the histologic variant to stratify patients into distinct prognostic groups with very good, good, or poor prognosis [27].
Data indicate that patients who have alveolar tumor histology without one of the two characteristic translocations [t(1;13) and t(2;13)] leading to FOXO1 rearrangement have similar survival rates to patients with embryonal tumors [28]. Therefore, clinical practice has evolved away from using histology to classify these tumors, and has replaced it with an assessment of the presence or absence of the characteristic FOX01 fusion gene [29]. These prognostic categories are then used as the basis for treatment selection, a process referred to as risk-adapted therapy (table 6). (See "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis", section on 'Molecular classification and risk stratification' and "Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment", section on 'Treatment strategies according to risk group'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Soft tissue sarcoma".)
SUMMARY
●Clinical presentation – The presenting signs and symptoms of rhabdomyosarcoma (RMS) are variable and are influenced by site of origin, the age of the patient, and the presence or absence of distant metastases. In general, the primary lesion has the appearance of a nontender mass, occasionally with overlying skin erythema. (See 'Presentation by anatomic site' above.)
•Lymphatic spread is unusual with head and neck primaries, but it is present in up to one-half of patients with extremity lesions and in over one-half of males over the age of 10 who present with paratesticular primary sites. Clinically and radiographically enlarged nodes warrant biopsy. In the absence of enlarged nodes, sentinel lymph node biopsy is indicated for all extremity tumors, and all males 10 years of age or older who have a paratesticular RMS and no imaging evidence of metastatic disease in para-aortic lymph nodes should undergo routine ipsilateral nerve-sparing retroperitoneal lymph node sampling. (See 'Regional nodes' above.)
•Fewer than 25 percent of patients have overt distant metastatic disease at diagnosis, and over one-half of these have only a single site of metastatic involvement, typically the lung. Subclinical metastatic disease is presumed to be present in the majority of patients who present with apparently localized disease. (See 'Distant metastases' above.)
●Initial diagnostic and staging evaluation – Accurate staging requires identification of the primary tumor site and size, extent of disease (nodal, metastases), and histology subtype. (See 'Initial diagnostic and staging evaluation' above.)
•Diagnostic biopsy – The initial diagnostic biopsy should be performed at a facility with expertise in the evaluation of the child with a soft tissue or bone sarcoma to ensure that the tissue is processed properly and to allow for the special studies that are essential for accurate diagnosis and histologic classification. Once RMS diagnosis is confirmed or highly suspected by light microscopic or immunohistochemical evaluations, fluorescence in situ hybridization (FISH) or reverse transcriptase polymerase chain reaction (RT-PCR) for FOXO1 rearrangement is performed on all tumors, regardless of the histology. (See 'Diagnostic biopsy' above.)
•Staging evaluation – The metastatic workup should be tailored to the clinical and histologic characteristics (algorithm 1) using the following initial staging studies (table 3), as indicated. (See 'Staging evaluation' above.)
●Prognostic stratification – In contrast to most other solid tumors, prognosis and treatment recommendations are based upon several factors in addition to disease extent. The prognostic stratification schema adopted for RMS clinical protocols combines information from the clinical group (CG) and tumor, node, metastasis (TNM) staging systems as well as age at diagnosis, histology, and the presence or absence of a characteristic FOX01 fusion gene in alveolar tumors to stratify patients into three distinct prognostic groups with very good, good, or poor prognosis (table 6). These prognostic categories are then used as the basis for treatment selection, a process referred to as risk-adapted therapy. (See 'Prognostic stratification scheme for risk-adapted therapy' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marc Horowitz, MD, and Thomas F DeLaney, MD, who contributed to earlier versions of this topic review.
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