Rhabdomyosarcoma overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shadan Mehraban, M.D.[2]
Overview
Rhabdomyosarcoma is a malignant cancer, specifically a sarcoma (cancer of connective tissues), in which the cancer cells are thought to arise from skeletal muscle progenitors. Rhabdomyosarcoma is considered as the most common malignant soft tissue tumors and the third most common extracranial solid tumors during childhood. The origin of rhabdomyosarcoma is straited muscle cells. The presentation sites of rhabdomyosarcoma are head and neck, extremities, Genitourinary tract, trunk, orbit, retroperitoneum, bladder, vagina, nasopharynx, and middle ear. The microscopic pathology of rhabdomyosarcoma depends on the histological subtype. Development of rhabdomyosarcoma is the result of specific genetic mutations. The four main subgroups are embryonal rhabdomyosarcoma (ERMS), alveolar rhabdomyosarcoma (ARMS), botryoid and spindle cell (leiomyomatous) rhabdomyosarcoma, Sclerosing and spindle cell rhabdomyosarcoma. Its two most common forms are embryonal rhabdomyosarcoma and alveolar rhabdomyosarcoma. There are no established causes or risk factors for rhabdomyosarcoma; however, rhabdomyosarcoma is more prevalent among the patients with beckwith-wiedemann syndrome, li-fraumeni syndrome, Costello syndrome, and neurofibromatosis. Symptoms of rhabdomyosarcoma can vary greatly depending on the size, location and spread of the tumor. General symptoms of rhabdomyosarcoma are palpable mass, pain, erythmatous skin, fever, nasal discharge, headache, vomiting, change in hearing, vision, speech, or swallowing and physical exam's findings depend on the tumor origin and the presence or absence of metastases. The common sites of metastasis include lungs, bone marrow, and bone. Tissue biopsy is the gold standard test for the diagnosis of rhabdomyosarcoma. Rhabdomyosarcoma is associated with a 5 year survival rate of 72%. There are two staging classification for rhabdomyosarcoma including Children group (CG) and tumor, node, and metastasis system (TNM). Treatment for rhabdomyosarcoma may consists of chemotherapy, radiation therapy and surgery and treatments depends on staging classification and risk stratification. Primary resection of tumor is one of the main prognostic factors in rhabdomyosarcoma.
Historical Perspective
Rhabdomyosarcoma is considered as the most common malignant soft tissue tumors and the third most common extracranial solid tumors during childhood. Rhabdomyosarcoma was firstly described by Weber (German physician) in 1854. In 1946, distinct morphology, histology, and classification of rhabdomyosarcoma was understood by Arthur Stout. Stout announced Rhabdomyoblasts as a round, strap, racquet, and spider forms.
Classification
The international classification of rhabdomyosarcoma (RMS) was created by the Intergroup Rhabdomyosarcoma Study group (IRSG). The four main subgroups include: Embryonal rhabdomyosarcoma (ERMS), Alveolar rhabdomyosarcoma (ARMS), botryoid and spindle cell (leiomyomatous) RMS, sclerosing and spindle cell RMS. The other separate categories for subtypes which do not classify into above groups are undifferentiated, Pleomorphic/anaplastic, and Sarcoma, not otherwise specified (NOS).
Pathophysiology
The origin of rhabdomyosarcoma is straited muscle cells.The presentation sites of rhabdomyosarcoma are head and neck, extremities, Genitourinary tract, trunk, orbit, retroperitoneum, bladder, vagina, nasopharynx, and middle ear.The exact pathogenesis of rhabdomyosarcoma is unclear. However, there is causal association between MET proto-oncogene and macrophage migration inhibitory factor (MIF) and it is thought that P53 is related to oncogenic transformation and tumor progression. Multiple gene mutations are related to rhabdomyosarcoma such as loss of heterozygosity of 11p15, TP53, NRAS, KRAS, HRAS, PIK3CA, CTNNB1, FGFR4, and translocation in PAX3 or PAX7 genes with FOXO1. Immunohistochemistry can identify some specific proteins related to rhabdomyosarcoma such as desmin, actin, myogenin, and myoglobin. The other histologic procedure is transmission electron microscopy (TEM) which can be used for poorly differentiated or undifferentiated tumors and myofilaments, actin, desmin, myotubular intermediate filaments, and rudimentary Z-band material. Fusion protein is identified by reverse transcriptase polymerase chain reaction and fluorescent in situ hybridization.
Causes
There are no established causes for rhabdomyosarcoma. Some of genetic disorders may be related to higher prevalence of rhabdomyosarcoma. Also some environmental factors, maternal history and birth characteristics may increase prevalence of rhabdomyosarcoma.
Differentiating Xyz from Other Diseases
Rhabdomyosarcoma must be differentiated from wilms tumor, ewing sarcoma, neuroblastoma, pheochromocytoma, liposarcoma, osteosarcoma, acute myelocytic leukemia, acute lymphoblastic leukemia, and non-hodgkin lymphoma. They mostly differentiated by their signs, symptoms, and imaging findings. The gold standard of diagnosis is usually tissue biopsy.
Epidemiology and Demographics
Rhabdomyosarcoma is considered as a most common soft tissue cancers among children and adolescents and it is the third most common extracranial solid tumors during childhood which comes after neuroblastoma and wilms tumor. Rhabdomyosarcoma is responsible for 50% of soft tissue tumors during childhood and 5% of all pediatrics cancers. Approximately two-third of all cases happen under 6 years old.The incidence of rhabdomyosarcoma is about 0.43 per 100,000 annually among children, adolescents, and young adults under 20 years old. In patients with localized disease, the estimated 5-year survival rate is greater than 80% after using surgery, radiation therapy, and chemotherapy for treatment and in patients with metastatic lesions, the estimated 5-year event-free survival is less than 30%. The incidence of rhabdomyosarcoma is a little more predominant in males than females.
Risk Factors
As all other childhood cancers, the particular risk factors of rhabdomyosarcoma is not exactly known; however, rhabdomyosarcoma is more prevalent among the patients with beckwith-wiedemann syndrome, li-fraumeni syndrome, Costello syndrome, and neurofibromatosis.
Screening
There is insufficient evidence to recommend routine screening for Rhabdomyosarcoma.
Natural History, Complications, and Prognosis
Common complications of rhabdomyosarcoma include metastasis to lung, bone marrow, and bone, cardiomyopathy, pulmonary failure, renal electrolyte wasting, acute myelogenous leukemia, secondary malignancies, and recurrent rhabdomyosarcoma. Rhabdomyosarcoma is associated with a 5 year survival rate of 72%. Adults and adolescents have worse outcome rather than children. The presence of metastasis is associated with a particularly poor prognosis. Histologically, the embryonal rhabdomyosarcoma and anatomically, the orbital and genitourinary tract rhabdomyosarcomas have the most favorable prognosis.
Diagnosis
Diagnostic Study of Choice
Tissue biopsy is the gold standard test for the diagnosis of rhabdomyosarcoma.
Staging
There are two staging classification for rhabdomyosarcoma including Children group (CG) and tumor, node, and metastasis system (TNM). Each of them has four stages of rhabdomyosarcoma based on the location of tumor, size of tumor, involvement of lymph nodes, and metastasis. Also, risk stratification system is used for classification of patients into low, intermediate, and high risk groups.
History and Symptoms
Symptoms of rhabdomyosarcoma can vary greatly depending on the size, location and spread of the tumor. General symptoms of rhabdomyosarcoma are palpable mass, pain, erythmatous skin, fever, nasal discharge, headache, vomiting, change in hearing, vision, speech, or swallowing. Specific symptoms of parameningeal rhabdomyosarcoma are headache and facial asymmetry. Symptoms of rhabdomyosarcoma of orbit are proptosis and vision problems. Symptoms of pelvic or abdominal rhabdomyosarcoma are vomiting, constipation, and abdominal pain.
Physical Examination
Physical examination findings depend on the tumor origin and the presence or absence of metastases. Physical examination of patients with rhabdomyosarcoma is usually remarkable for nontender, palpable mass, fever, and erythematous skin might be present.
Laboratory Findings
The essential laboratory tests for patients with rhabdomyosarcoma are evaluation of CBC, liver function tests, renal function tests, blood electrolytes, and coagulation studies.
Electrocardiogram
Electrocardiography may be used for assessment of cardiac function before starting chemotherapy in patients with rhabdomyosarcoma.
X-ray
Radiography is one of the first steps for evaluation of the patients with rhabdomyosarcoma. Radiography of affected site and chest x ray are considered as essential features for diagnosis and metastases.
CT scan
CT scan is considered as one of the first steps for evaluation of rhabdomyosarcoma. Primary site CT scan, chest CT scan, abdominal and retroperitoneal CT scan are required for evaluation of rhabdomyosarcoma. On CT scan, rhabdomyosarcoma is characterized by soft tissue density, enhancement with contrast, and bone destruction.
MRI
MRI is used for for evaluation of primary tumor and its invasion. MRI is used for diagnosis of primary location of rhabdomyosarcoma located in head and neck, paraspinal, parameningeal regions, extremities, and pelvic tumors. MRI features in rhabdomyosarcoma are characterized by low to intermediate intensity on T1, hyperintense on T2, and considerable contrast enhancement on T1 contrast.
Ultrasound
Ultrasound is beneficial for diagnosis of rhabdomyosarcoma in pelvic and abdominal tumors. Ultrasound findings of rhabdomyosarcoma are in favor of well-defined, irregular mass with low to medium echogenicity.
Other Imaging Findings
Positron emission tomography (PET) scanning and bone scan are usually used for assessment of metastatic lesion in rhabdomyosarcoma. There are no associated findings regarding these studies in rhabdomyosarcoma.
Other Diagnostic Studies
Biopsy considered as the most commonly diagnostic study in rhabdomyosarcoma and it can be done by open surgery, core-needle biopsy, and fine-needle biopsy. Lumbar puncture is an another diagnostic study in parameningeal rhabdomyosarcoma and meningeal involvement cases. Bone marrow aspiration and biopsy are usually performed evaluation of bone marrow involvement due to metastases. Regional and distant lymph nodes need to be assessed clinically and radiologically and lymph nodes that are greater than 1 cm are considered as suspicious ones
Treatment
Medical Therapy
Treatment for rhabdomyosarcoma may consists of chemotherapy, radiation therapy and surgery and treatments depends on staging classification and risk stratification. Rhabdomyosarcoma chemotherapy depends on patient's risk groups. Vincristine, actinomycin D,and cyclophosphamide are the fundamental chemotherapy standard based on Children's Oncology Group. Ifosfamide, vincristine, and actinomycin D are the fundamental chemotherapy standard base on European Soft tissue Sarcoma Group. Patients's response to chemotherapy is classified to five groups as complete response, good response, poor response, objective response, and progressive disease. Radiation therapy may be used as local therapy and is usually initiated after 4 chemotherapy cycles. The only exception for starting radiotherapy from the first day is vision loss and spinal cord compression. Radiotherapy dosage is based on completeness of tumor resection before chemotherapy and completeness of a delayed primary tumor excision after adjuvant chemotherapy.
Surgery
Primary resection of tumor is one of the main prognostic factors in rhabdomyosarcoma. However, surgical resection of the rhabdomyosarcoma is often difficult or impossible because the tumor is usually embedded deep within the tissue, leaving it difficult to reach. Surgical tumor resection must contain complete tumor removal with performing safe margin resection. In case of narrow margins, several biopsies are needed to identify residual disease. If surgical excision could not be performed, 12 weeks chemotherapy is recommended. Assessment of lymph nodes are essential as well such as assessment of axillary and femoral lymph nodes in rhabdomyosarcoma of extremities.
Primary Prevention
There are no primary preventive measures available for rhabdomyosarcoma.
Secondary Prevention
There are no secondary preventive measures available for rhabdomyosarcoma.