Rhabdomyosarcoma

What is Rhabdomyosarcoma?

Rhabdomyosarcoma (RMS): The term "Rhabdomyosarcoma" is derived from the Greek words "rhabdo," meaning rod shape, and "myo," meaning muscle-neoplacia.

Characteristics:

• It is the most common soft tissue sarcoma in children, originating from muscle tissues.
• RMS arises from primitive muscle cells known as Rhabdomyoblasts.

Historical Background:

• First described in 1854 by Weber, and subsequently studied by various researchers.
• In 1946, Stout characterized rhabdomyoblasts by their appearance in different shapes such as round, strap, racquet, and spider forms.

Cell Characteristics:

• The cells of RMS typically show positivity for intermediate filaments and various proteins commonly found in differentiated muscle cells.
• These include proteins like desmin, vimentin, myoglobin, actin, and the transcription factor myoD.

Genetic Syndromes and Environmental Factors: The causes of Rhabdomyosarcoma (RMS) remain unknown, although genetic syndromes and environmental factors are associated with an increased prevalence.

Genetic Syndromes:

• Neurofibromatosis: Individuals with neurofibromatosis have a 4-5% risk of developing various malignancies, including RMS.
• Li-Fraumeni Syndrome: This syndrome involves a germline mutation of the tumor suppressor gene TP53, contributing to cancer predisposition.
• Rubinstein-Taybi Syndrome
• Gorlin Basal Cell Nevus Syndrome
• Beckwith-Wiedemann Syndrome

Higher Prevalence of Congenital Anomalies:

Patients who later develop RMS often exhibit a higher prevalence of congenital anomalies, including:

• Genitourinary tract anomalies
• Gastrointestinal tract anomalies
• Cardiovascular system anomalies
• Central nervous system anomalies, such as Arnold-Chiari malformation

Environmental Factors:

Environmental factors are believed to influence the development of RMS. Some notable factors include:

• Parental use of marijuana and cocaine
• Intrauterine radiograph exposure
• Prior exposure to alkylating agents

• Most common soft tissue sarcoma in children
• 3% to 4% of all cases of childhood cancer
• More common in Caucasians
• Two-thirds of cases occur in patients under the age of 10 years
• Median age at diagnosis of 5 years
• Approximately 87% of patients are younger than 15 years, and 13% of patients are aged 15-21 years. RMS rarely affects adults. Age-related differences exist for the different sites of primary disease.
• The male-to-female ratio is 1.2-1.4:1.
• Differences exist according to the site of primary disease:
• Genitourinary tract: The male-to-female ratio is 3.3:1 in patients with bladder or prostate involvement and 2.1:1 in GU tract RMS without bladder or prostate involvement.
• Extremity: The male-to-female ratio is 0.79:1.
• Orbit: The male-to-female ratio is 0.88:1.

Tumors can occur anywhere in the body except bone, to which it can metastasize.

Commonest sites:

• Head and neck (28%)
• Extremities (24%)
• Genitourinary (GU) tract (18%)
• The trunk (11%)
• Orbit (7%)
• Retroperitoneum (6%)

RMS occurs at other sites in fewer than 3% of patients.

Classification

International Classification of RMS:

1. Superior prognosis (variants of embryonal):

   • Botryoid: This variant exhibits a grape-like or polypoid appearance and often occurs in mucosal-lined spaces like the vagina or bladder.
   • Spindle cell: This subtype is characterized by elongated spindle-shaped cells and typically presents in the paratesticular region or the orbit.

2. Intermediate prognosis:

   • Embryonal rhabdomyosarcoma: The most common subtype, often found in the head and neck, genitourinary tract, or extremities.

3. Poorer prognosis:

   • Alveolar rhabdomyosarcoma: Characterized by small, round cells forming clusters resembling lung alveoli, typically occurring in the trunk or extremities.
   • Undifferentiated sarcoma/pleomorphic: This subtype lacks the characteristic features of the other types and generally has a more aggressive clinical course.

TNM Staging System

Tumor: Confined to the site of origin (T1); extends beyond the site of origin (T2)

Node: No regional node involvement (N0); regional node involvement (N1); nodes unknown (NX)

Metastasis: No metastasis (M0); metastases present at diagnosis (M1)

RMS staging system:

• Stage 1: Orbit, head/neck (not parameningeal), and GU tract (not bladder/prostate)
• Stage 2: Other locations, N0, or NX
• Stage 3: Other locations, N1 if tumor less than 5 cm, N0 or NX (if tumor >5 cm)
• Stage 4: Any site with distant metastases

Low-risk patients are those with embryonal histology:

• Stages 1-3 in groups I-II (or III for orbit only)
• Stage 1 in group III

Intermediate-risk patients are those with embryonal histology:

• Stages 2-3 in clinical group III (non-orbit)
• Stage 4 in clinical group IV if patient is younger than 14 years

RMS is typically characterized by the presence of an expanding mass. The presentation and symptoms can vary based on the location of the tumor within the body.

If metastatic disease exists, symptoms of bone pain, respiratory difficulty (secondary either to lung nodules or to pleural effusion), anemia, thrombocytopenia, and neutropenia may be present.

Disseminated rhabdomyoblasts in the bone marrow may mimic leukemia, both in symptoms and light microscopy findings.

Important Questions to Ask when Taking History:

• Onset and Duration: When did the symptoms first start? Has the mass been present for a short or extended period?
• Location and Size: Where is the mass located? How has its size changed over time?
• Pain: Is there any pain associated with the mass? Inquire about the nature, intensity, and duration of pain.
• Other Symptoms: Apart from pain, ask about any associated symptoms such as swelling, tenderness, or changes in skin color over the mass.
• Metastatic Symptoms: Do you notice any bone pain, difficulty breathing, persistent cough, fatigue, unexplained weight loss, or changes in blood counts like anemia, thrombocytopenia, or neutropenia?
• General Health: Ask about the child's overall health, energy levels, and any recent changes in their physical well-being.
• Previous Medical History: Have there been any past illnesses, surgeries, or medical conditions? Are there any known genetic syndromes or family history of cancer?
• Medications and Allergies: Inquire about current medications, supplements, and allergies to medications or substances.
• Developmental Milestones: For pediatric patients, ask about developmental milestones and growth patterns.
• Social and Environmental Factors: Explore the child's living environment, exposure to potential toxins or carcinogens, and any history of radiation or chemotherapy.
• Impact on Daily Life: How has the mass affected the child's daily activities, mobility, and overall quality of life?
• Family Support: Discuss the family's understanding of the situation, emotional well-being, and availability of a support system.
• Imaging and Tests: Have any imaging scans, biopsies, or laboratory tests been performed? If so, what were the results?
• Emotional and Psychological Factors: Inquire about the child's emotional response to the symptoms, any fears, anxieties, or questions they may have.

Two age peaks tend to be associated with different tumor locations:

• (2-6 years): Head and neck or GU tract primary tumors.
• Adolescents (14-18 years): Extremity, truncal, or paratesticular primaries.

Some typical presentations by location of nonmetastatic disease are as follows:

• Orbit: Proptosis or dysconjugate gaze.
• Paratesticular: Painless scrotal mass.
• Prostate: Bladder or bowel difficulties.
• Uterus, cervix, bladder: Menorrhagia or metrorrhagia.
• Vagina: Protruding polypoid mass (botryoid, meaning a grapelike cluster).
• Extremity: Painless mass.
• Parameningeal (ear, mastoid, nasal cavity, paranasal sinuses, infratemporal fossa, pterygopalatine fossa): Upper respiratory symptoms or pain.
• Head and neck tumors (one-third of all cases): Proptosis, ophthalmoplegia, nasal drainage and obstruction, headache, cranial nerve palsies, dysphonia, dysphagia, and palpable adenopathy.
• Genitourinary tumors (25% of cases): Hematuria, dysuria, hydronephrosis, palpable abdominal mass, vaginal discharge, and palpable painless masses.
• Extremities (20% of cases): Swelling, palpable adenopathy, and pain.
• Tumors on the Trunk, pelvis, and abdomen can present with: Nerve root compression, palpable mass or adenopathy, jaundice (biliary tract tumors), and perirectal pain and swelling.

Plain Radiograph Films:

Plain radiograph films of the primary site and chest are helpful to determine the presence of calcifications and bone involvement of the primary tumor. They are also used to search for metastatic lung lesions.

CT Scanning:

• Obtain a chest CT scan to evaluate lung metastases. This is usually done preoperatively to distinguish metastases from atelectasis.
• A CT scan of the primary site can assess bone erosion and monitor treatment response.
• In patients with abdominal or pelvic primary tumors, obtain a CT scan of the liver to assess metastatic spread. Ultrasound is an alternative option.

MRI:

MRI provides better definition of the mass and its invasion of adjacent organs, particularly in paraspinal or parameningeal regions. An MRI of the head is useful for symptomatic patients at diagnosis.

Bone Scanning:

Perform bone scanning to detect metastases to the bones.

Ultrasound:

Ultrasound images of the liver are recommended for patients with abdominal or pelvic tumors. CT scanning is an alternative option.

Echocardiography:

Echocardiography is used to assess cardiac function before initiating chemotherapy.

Complete Blood Count (CBC):

Anemia may be present due to inflammation, while pancytopenia might result from bone marrow involvement.

Liver Function Tests:

These include lactic acid dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and bilirubin levels. Metastatic liver disease can influence these protein levels. It's crucial to assess liver function before chemotherapy.

Renal Function Tests:

Renal function, assessed through blood urea nitrogen (BUN) and creatinine levels, must be evaluated before starting chemotherapy.

Urinalysis (UA):

Hematuria, or the presence of blood in the urine, could indicate genitourinary tract involvement.

Blood Electrolyte and Chemistry:

Measurements of sodium, potassium, chlorine, carbon dioxide, calcium, phosphorus, and albumin values help identify any abnormalities in electrolyte and chemistry levels before commencing chemotherapy.

Procedures

Open Biopsy:

An open biopsy is recommended as it provides an ample tissue sample for accurate diagnosis and subsequent molecular studies. Alternatively, a core needle biopsy can be considered.

Cytogenetics and Fluorescent In Situ Hybridization (FISH):

Cytogenetic analysis and FISH are valuable tools to identify the presence of translocations like t(1;13) or t(2;13), often associated with the alveolar subtype of rhabdomyosarcoma. FISH aids in both diagnosing these translocations and in distinguishing them from similar translocations seen in other tumor types. FISH is especially sensitive for these translocations and can assist in assessing residual disease.

Reverse Transcriptase–Polymerase Chain Reaction (RT-PCR) Testing:

If cytogenetics testing is unavailable, or in cases of culture failure, RT-PCR testing can be employed. This method identifies the characteristic translocations linked to alveolar rhabdomyosarcoma (ARMS) and other small, round, blue cell tumors seen in childhood.

Bone Marrow Aspirate and Biopsy:

Performing a bone marrow aspirate and biopsy is important to evaluate the possible metastatic spread of the disease to the bone marrow.

Rhabdomyosarcoma (RMS) Characteristics:

• RMS belongs to the category of small, round, blue cell tumors frequently observed in childhood.
• RMS cells demonstrate varying degrees of differentiation along the myogenesis pathway and may appear as strap cells or myotubes, often displaying muscle cross-striations.
• RMS cells typically exhibit positive immunohistochemistry results for muscle-specific markers, such as myoglobin, actin, and desmin.

RMS Subtypes and Their Distinctive Features:

• Botryoid/Embryonal: Characterized by the presence of a cambium layer, containing loosely arranged tumor cells beneath an epithelial surface. Common in mucosal cavities like the bladder, vagina, nasopharynx, and middle ear.
• Alveolar: Tumor cells align along membranes that resemble lung alveoli. More aggressive and often associated with metastatic disease in the lungs, bone marrow, bones, lymph nodes, breasts, testes, and brain.
• Undifferentiated: Typically lacks evidence of myogenesis differentiation.

Additional Details for Subtypes:

• EMBRYONAL: Presents favorable clinical outcomes and affects younger males. Commonly arises in the head, neck, and genitourinary regions. It involves loss of heterozygosity at the 11p15 locus, resulting in the duplication of the paternal allele that encodes the IGF-2 growth factor.
• ALVEOLAR: Represents 20-25% of RMS cases and is more aggressive, with a higher prevalence in adolescents and involving the extremities, trunk, perianal, and perineal regions. It shows a characteristic fibrous septa arrangement with clusters of rounded cells.
• SPINDLE CELL: A subtype of embryonal RMS, often found in the paratesticular region, characterized by a whorled spindly appearance with relatively differentiated spindle cells, similar to smooth muscle tumors.
• Botryoid Histology: Represents 10% of childhood RMS cases and is commonly found in hollow visceral organs of the genitourinary tract, displaying polypoid, grape-like tumor masses with scattered malignant cells in a myxoid stroma.
• UNDIFFERENTIATED: Diagnosed by exclusion, previously referred to as pleomorphic RMS. More common in adults, displaying marked pleomorphism, irregularly arranged cells, and multinucleated giant cells. Rare in children, it primarily affects older individuals' skeletal muscles.

Embryonal Tumors:

• High background mutation rate, involving single-nucleotide variants and multiple chromosomal gains and losses.
• Common chromosome 8 gains (74% of cases), as well as gains of chromosomes 2, 7, 11, 12, 13q21, and 20, with losses of 1p36, 6, 9q22, 14q21, and 17.
• Activating RAS pathway mutations (42%) involving KRAS, NRAS, and HRAS, along with mutations in genes like FGFR4, ALK, BRAF, CTNNB1, PIK3CA, and PTPN11.
• MDM2 amplification, loss of PTEN, BCL2L1 amplification, homozygous deletions of CDKN2B, increased GLI expression, NF1 deletions, and ALK copy number gains.

Alveolar Tumors:

• Associated with worse clinical outcomes and commonly arise in the trunk and extremities.
• Characterized by t(2;13) or t(1;13) translocations, resulting in PAX3 or PAX7 fusion with FOXO1 genes on chromosome 13.
• ALK gene copy number gains, copy number gains, and overexpression of MYCN.
• Approximately 18% of cases lack FOXO1 rearrangements, known as fusion-negative alveolar RMS.
• Fusion-negative alveolar RMS behaves more similarly to embryonal tumors, emphasizing the importance of PAX/FOXO1 fusion in clinical behavior determination.

Treatment for RMS involves a comprehensive approach, including a combination of surgery, chemotherapy, and radiotherapy.

Patients with RMS are categorized based on risk assessment, considering factors like tumor location, histology results, and surgical outcomes.

Categorization of Patients:

Patients are assigned to a surgicopathologic clinical group (Roman numeral) and a stage (Arabic numeral) to create meaningful categories:

• All patients with metastatic disease (group IV, stage 4) are considered high risk, except for children under 14 years with embryonal rhabdomyosarcoma (ERMS), who tend to fare better for reasons that remain unknown.

Surgical Pathologic (Clinical) Group

• Group I: Tumor completely removed
• Group II: Microscopic residual tumor, involved regional nodes, or both
• Group III: Gross residual tumor
• Group IV: Distant metastatic disease

Treatment for RMS typically involves a comprehensive approach combining surgery, chemotherapy, and radiotherapy.

Risk Categorization:

Patient categorization is based on risk assessment, considering tumor location, histology results, and surgical outcomes:

• Low-risk patients: These individuals have the most favorable prognosis.
• Intermediate-risk or high-risk patients: These groups have a higher likelihood of relapse and incurable disease.

Categorization:

Patient categorization involves assigning them to both a surgicopathologic clinical group (Roman numeral) and a stage (Arabic numeral) to effectively categorize their features:

• Metastatic Disease (Group IV, Stage 4): All patients with metastatic disease are considered high risk, except children under 14 years with ERMS, who tend to have better outcomes for reasons not yet fully understood.

Treatment Approaches:

Chemotherapy is a cornerstone of treatment for all patients with RMS. However, specific regimens may vary depending on the patient's stage and group classification.

Further management may include:

• Surgery: Often an essential component to remove the tumor and assess its extent.
• Radiotherapy: Administered in cases where surgical removal is not feasible or to target remaining tumor cells.

Note:

The treatment plan is personalized for each patient, considering their unique clinical presentation and response to therapy. Regular monitoring and follow-up are crucial to track progress and adjust the treatment approach if needed.

Surgical Management of Rhabdomyosarcoma (RMS):

Surgical care for RMS varies based on the tumor's location. The primary goal is to remove tumors promptly while preserving function and minimizing disfiguration.

Primary Tumor:

• If feasible, prompt tumor removal is recommended, balancing the need for complete excision with preserving function and appearance.
• Surgical excision of the primary site is advised even if metastatic disease is present, if possible.
• The surgical outcome helps determine the clinical grouping used for treatment planning.
• Local control is crucial due to the potential for relapses at the original primary tumor site.
• In some cases, chemotherapy alone may achieve adequate local control for patients with a complete response of the primary tumor. However, residual disease often requires surgery and/or radiation.
• For optimal local control, complete excision of the lesion is preferred, leaving a wide margin (about 2 cm) of healthy tissue.
• Wide margins may not be feasible in certain areas like the head and neck.
• If margins are narrow, multiple biopsy specimens from surrounding tissue can help assess the presence of residual local disease.
• In cases where immediate excision is not possible, a second-look procedure might be considered after a period of chemotherapy (usually around 12 weeks).

Lymph Nodes:

Sampling of involved regional lymph nodes is important to determine the clinical group and assess the potential need for radiation therapy later on.

Radiotherapy for Rhabdomyosarcoma (RMS):

Radiotherapy plays a crucial role in the treatment of RMS, with dosage and timing varying based on the extent and location of the disease.

Dosage:

• Doses for node-negative microscopic residual disease:
• 36 Gy
• 41.4 Gy for those with microscopic disease and pathologically proven but grossly negative nodal disease.
• For gross residual tumors:
• 45 Gy for orbital primary sites
• 50.4 Gy for nonorbital primary sites

Reduced Doses:

The D9602 trial supports reduced doses of radiotherapy for patients with orbital sites of involvement. In patients with embryonal group IIA and orbital group III tumors, reduced doses of radiation without an alkylating agent did not compromise local control rates (approximately 15% local failure).

Treatment Volumes:

• Treatment volumes include:
• All areas of gross disease
• Areas initially infiltrated by the tumor at diagnosis

Timing:

Radiation therapy is typically administered after the initial 12 or 18 weeks of chemotherapy, depending on the patient's specific treatment plan.

Chemotherapy for Rhabdomyosarcoma (RMS):

RMS treatment often involves systemic chemotherapy to target the disease throughout the body. The most common regimen consists of vincristine, actinomycin D, and cyclophosphamide (VAC), along with Ifosfamide.

Follow-Up:

Regular follow-up is crucial to monitor the patient's progress and ensure the effectiveness of the treatment. The follow-up schedule typically includes:

• Every 3 months for the 1st year
• Every 6 months for the 2nd and 3rd years
• Yearly thereafter

Consultations:

The care of patients with RMS involves multiple aspects, requiring a collaborative approach. Consultations with various specialists are essential:

• Initial evaluation and treatment planning at a comprehensive pediatric cancer center
• Radiotherapist for radiation treatment planning
• Psychosocial team to address emotional and psychological needs
• Dentist to manage oral health during treatment
• Pediatric therapists to assist with physical and occupational therapy
• Dietitians to manage nutritional needs, including nasogastric feedings or parenteral nutrition if required

Mortality and Morbidity:

In patients with limited disease, the utilization of a comprehensive treatment approach involving surgery, radiation therapy, and chemotherapy has led to improved overall survival rates.

However, for patients with metastatic disease, achieving significant progress in survival rates has proven challenging. Even after high-dose myeloablative therapy with autologous stem cell rescue, the 5-year event-free survival rate remains below 30%.

While advancements have been made in treating limited disease, addressing metastatic cases remains a complex and ongoing challenge in improving survival rates.