Continuing Education Activity

Rhabdomyosarcoma (RMS) is a primitive pediatric malignant soft tissue sarcoma of skeletal muscle phenotype that originates from a primitive mesenchymal cell. Most cases are diagnosed in children under the age of 6. The etiology and risk factors remain largely unknown. Most cases of rhabdomyosarcoma are sporadic; however, the disease is associated with familial syndromes. Rhabdomyosarcoma types include embryonal rhabdomyosarcoma (approximately 60%), alveolar (approximately 20%), pleomorphic (approximately 10%), and spindle/sclerosing (approximately 10%). The survival of rhabdomyosarcoma patients has improved, especially in the last decade, mainly due to interprofessional disease management approaches. This activity highlights the presentation, diagnosis and highlights the role of the interprofessional team in the management of rhabomyosarcoma.

Objectives:

• Describe the histopathology of rhabdomyosarcoma.
• Review the evaluation of a patient with rhabdomyosarcoma.
• Summarize the treatment options for rhabdomyosarcoma.
• Outline the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by rhabdomyosarcoma.

Introduction

Rhabdomyosarcoma (RMS) is a primitive pediatric malignant soft tissue sarcoma of skeletal muscle phenotype that originates from a primitive mesenchymal cell. Most cases are diagnosed in children under the age of 6. The etiology and risk factors remain largely unknown. Most cases of rhabdomyosarcoma are sporadic; however, the disease is associated with familial syndromes. Rhabdomyosarcoma types include embryonal rhabdomyosarcoma (approximately 60%), alveolar (approximately 20%), pleomorphic (approximately 10%),  and spindle/sclerosing (approximately 10%). The survival of rhabdomyosarcoma patients has improved, especially in the last decade, mainly due to interprofessional disease management approaches [1][2].

Etiology

Although the etiology and specific risk factors for rhabdomyosarcoma are largely unknown, there is increased risk of rhabdomyosarcoma secondary to in utero radiation exposure, accelerated in utero growth, low socioeconomic status, and parents using recreational drugs during pregnancy. RMS has been associated with some familial syndromes, such as neurofibromatosis, Noonan, Li-Fraumeni, Beckwith-Wiedemann, and Costello [1][3][2].

Epidemiology

Rhabdomyosarcoma is the most common childhood and adolescent soft tissue sarcoma (3% of childhood tumors, 50% of pediatric soft tissue sarcomas) with slight male predominance (M/F, 1.3:1). RMS accounts for approximately 1% in adulthood tumors. Although rhabdomyosarcoma can arise anywhere in the body, there are distinct age and type involvement patterns. Children and young adolescents have more head and neck involvement which is usually of the embryonal type. Extremity rhabdomyosarcoma is more common in adolescents and usually the alveolar type. Botryoid rhabdomyosarcoma occurs in hollow viscera, usually in children. Pleomorphic rhabdomyosarcoma typically arises in the extremities and mainly affects adults. Common rhabdomyosarcoma metastatic sites include lung, bone marrow, and lymph nodes [4][5][3].

Histopathology

Rhabdomyosarcoma has distinct gross and histopathological features. Grossly these tumors usually present as poorly circumscribed, white, soft or firm, infiltrative masses. The tumor is usually greater than 5 centimeters at the time of diagnosis. The cell of origin of RMS is the rhabdomyoblast. These cells usually show an eccentric eosinophilic granular cytoplasm, rich in thick and thin filaments, and a variable cell shape that may be round or elongated, often referred to as strap cells or tadpole cells respectively. There are several histologic subtypes of rhabdomyosarcoma with important treatment and prognostic implications: embryonal rhabdomyosarcoma, botryoid and spindle cell (leiomyomatous), sclerosing and spindle cell, alveolar rhabdomyosarcoma, and sarcoma not otherwise specified (NOS). The WHO classification for myogenic tumors published in 2013, classifies rhabdomyosarcoma into four categories: (1) embryonal, (2) alveolar, (3) pleomorphic, and (4) spindle/sclerosing. Anaplasia is regarded by many pathologists as an additional factor that leads to adverse prognosis. Anaplasia in RMS is defined as the presence of enlarged hyperchromatic nuclei, three times larger than those of adjacent cells, and multipolar mitoses. The embryonal subtype is the most common, accounting for up to 60% of all rhabdomyosarcoma cases. Embryonal rhabdomyosarcoma morphologically shows variable cellularity of typical rhabdomyoblasts arranged in sheets and large nests within a myxoid matrix. Alveolar rhabdomyosarcoma shows intersecting fibrous septa with rhabdomyoblasts arranged in interseptal nests and discohesive alveolar arrangement and a FOXO1 rearrangement, t (1; 13) (PAX3-FOXO1) or t (2; 13) (PAX7-FOXO1) by genetic testing. The pathological identification of rhabdomyosarcoma is sometimes difficult due to the similarity of this entity to the other small, round, blue, cell tumors of bone and soft tissue in childhood that include, lymphoma, small cell osteosarcoma, mesenchymal chondrosarcoma, and the Ewing sarcoma family of tumors. To confirm the diagnosis of rhabdomyosarcoma immunohistochemical, molecular genetic and/or ultra-structural techniques may be needed. Immunohistochemistry is a very useful tool that is used to establish the diagnosis of rhabdomyosarcoma. Rhabdomyosarcoma is usually positive for myogenin, demin, sarcomeric actin, myogenin, and myoglobin. It is usually negative for NKX2.2, CD99, CD45, CK, S100, and NSE. Pathological classification of rhabdomyosarcoma has been shown to be a prognostic indicator. The botryoid and spindle cell types show superior prognosis, the embryonal cell type shows intermediate prognosis, and the alveolar and undifferentiated sarcoma shows a poor prognosis [1][4][5][6].

History and Physical

The presenting signs and symptoms of rhabdomyosarcoma are variable and depend on multiple factors including the site of origin, the patient’s age, and the presence or absence of distant metastases. When presenting in the head and neck area, the patient may present with a localized, painless, enlarging mass. Rhabdomyosarcoma of the bladder may present with hematuria and urinary obstruction. Rhabdomyosarcoma of the extremities typically presents as a painful mass, with or without associated erythema of the overlying skin [7][8].

Evaluation

The initial evaluation of patients with suspected rhabdomyosarcoma should aim to identify the anatomic boundaries of the tumor because this decision determines the tumor stage, risk stratification, and treatment. The initial workup for patients with suspected rhabdomyosarcoma should include CT or MRI scan of the tumor, CT scan of abdomen and retroperitoneum, CT scan of the chest, bone scan, and bilateral bone marrow aspirate and biopsy. Additional studies can be performed based on possible sites of spread. A biopsy of the lesion is necessary for diagnosis. It is highly recommended that an experienced pediatric pathologist assesses the biopsy. The two major histologic subtypes, embryonal and alveolar rhabdomyosarcoma, show different clinical and molecular characteristics, reflecting differences in biologic mechanisms. Alveolar rhabdomyosarcoma presents throughout childhood in the trunk and extremities and harbors two distinguishing chromosomal translocations; the first and more common is t(2;13), and the second, less common, one is t(1;13)(p36;q14). Embryonal rhabdomyosarcoma usually presents in children, mainly in the head, neck, and genitourinary sites. Embryonal rhabdomyosarcoma does not show specific translocations. However, most embryonal rhabdomyosarcoma shows loss of heterozygosity (LOH) at the 11p15 locus, the site of the IGF-II gene [7][4][9][6].

Treatment / Management

Treatment of rhabdomyosarcoma is based on risk stratification, which includes histologic classification, presurgical stage, and postsurgical clinical group. Treatment modalities include surgery, chemotherapy, and radiotherapy. Local treatment is a crucial part of rhabdomyosarcoma management; however, the pros and cons of radical surgery and/or radiotherapy should be considered. Chemotherapy and, in some cases, radiotherapy can induce partial differentiation in childhood rhabdomyosarcoma. The last decade has shown great improvement in patient outcomes as a result of multimodality therapeutic protocols. Two main chemotherapy regimens used in the treatment of rhabdomyosarcoma include (1) the VAC regimen, which consists of vincristine, actinomycin D, and cyclophosphamide, and (2) the IVA regimen, which consists of ifosfamide, vincristine, and actinomycin D. These drugs are administered in up to 15 cycles, depending on disease stratification. Ionizing radiation (IR) therapy has been shown to be a powerful tool in decreasing disease recurrence rates and is often indicated in higher stage classifications. IR therapy is mainly used to complement patient management, especially when complete resection is not possible. In conclusion, the treatment of patients with rhabdomyosarcoma is undergoing continuous evolution as new, evidence-based results emerge from clinical trials [8][10][4][11][12][13].

Differential Diagnosis

• Ewing sarcoma

• Li-Fraumeni syndrome

• Lipomas

• Liposarcoma

• Lymphadenopathy

• Lymphoproliferative disorders

• Neurofibromatosis type 1

• Osteosarcoma

• Wilms tumour

Staging

The two staging systems utilized in the management of rhabdomyosarcoma are the TNM (tumor, nodes, metastasis) staging system and the clinical grouping (CG) system. The TNM and CG staging systems complement each other and are used to assess prognosis and select treatment for patients with rhabdomyosarcoma. The rhabdomyosarcoma prognostic stratification classifies patients based on the above staging systems as low, intermediate, or high risk. The risk stratification is based on the clinical group, site, size, age, histology, metastases and lymph node status [8][10][11].

The CG of rhabdomyosarcoma by the intergroup rhabdomyosarcoma study group (IRSG) is as follows:

I: Confined to the Site of Origin

• Localized tumor, anatomically confined to the site of origin; the tumor can be completely resected,
• Localized tumor, infiltrating locally into the adjacent structure, the tumor can be completely surgically resected.

II: Local Infiltration         

• Localized tumor, gross total resection is possible; however, microscopic residual disease is possible.
• Locally extensive tumor (may have spread to regional lymph nodes); however, complete surgical resection is possible.
• Locally extensive tumor (may have spread to regional lymph nodes), the tumor can be completely surgically resected; however, microscopic residual disease is possible.

III: Localized Extensive Tumor   

• Localized extensive tumor, gross residual disease after biopsy only.
• Localized extensive tumor, gross residual disease is possible after major resection (greater than or equal to 50% tumor debulking).

IV: Metastatic Rhabdomyosarcoma 

• Any size primary tumor, with or without regional lymph node involvement, with distant metastases.

The TNM Staging

Stage 1

• The tumor presents in a region with favorable prognosis.
• The tumor can be any size and can show local invasion to nearby areas and/or spread to regional lymph nodes.
• The tumor should have distant spread.

Stage 2

• The tumor presents in a region with unfavorable prognosis.
• The tumor should be 5 cm or smaller with no evidence local invasion to nearby areas and/or spread to regional lymph nodes or distant parts of the body.

Stage 3

• The tumor presents in a region with unfavorable prognosis.
• And one of the following: The tumor is 5 cm or smaller but has spread to nearby lymph nodes. The tumor is larger than 5 cm and with/without spread to regional lymph nodes; in either case, the cancer has not shown metastatic spread.

Stage 4

• The tumor may have started anywhere in the body and is of any size.
• The tumor shows metastatic spread.

Favorable sites are the biliary tract, orbit, head and neck (excluding parameningeal), and genitourinary (excluding prostate and bladder); all others are unfavorable.

Risk Group Criteria

Low-risk

• Embryonal rhabdomyosarcoma: Clinical stage 1-3, Clinical group 1-3 
• Alveolar rhabdomyosarcoma should not be categorized as a low-risk group.

Intermediate-risk

• Includes patients with stage I, II, or III disease
• Embryonal rhabdomyosarcoma: Clinical stage I-III, clinical group 3
• Alveolar rhabdomyosarcoma: Clinical stage I-III, clinical group 1-3

High-risk

• Includes patients with stage IV disease
• Embryonal rhabdomyosarcoma: Clinical stage IV, clinical group 4
• Alveolar rhabdomyosarcoma: Clinical stage IV, clinical group 4

Prognosis

Rhabdomyosarcoma prognosis depends on multiple factors that include clinical, biologic, and pathologic characters. In general, adults have poorer 5-year overall survival when compared with children (27% versus 61%). The overall survival of metastatic rhabdomyosarcoma patients is low and typically does not exceed 25%. Parameningeal rhabdomyosarcoma and rhabdomyosarcoma of the extremities tend to have a worse prognosis compared to other sites [14].

Enhancing Healthcare Team Outcomes

When the primary care provider, nurse practitioner, or the internist comes across a new patient with rhabdomyosarcoma it is important to refer these patients to an oncology. The treatment of these malignant lesions is complex and requires an interprofessional team that includes an oncologist, radiation therapist, radiologist, and a surgeon. Rhabdomyosarcomas generally tend to be less responsive to chemotherapy and radiation; surgery is the sole method for cure, but recurrences are common. Patients need to be educated about the different treatments and their pros and cons. The overally survival of patients with rhabdomyosarcoma remain poor.[15][16]