Rhabdomyosarcoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shadan Mehraban, M.D.[2]

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.

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.

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).

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.

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.

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.

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.

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.

There is insufficient evidence to recommend routine screening for Rhabdomyosarcoma.

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.

Tissue biopsy is the gold standard test for the diagnosis of rhabdomyosarcoma.

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.

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 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.

The essential laboratory tests for patients with rhabdomyosarcoma are evaluation of CBC, liver function tests, renal function tests, blood electrolytes, and coagulation studies.

Electrocardiography may be used for assessment of cardiac function before starting chemotherapy in patients with rhabdomyosarcoma.

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 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 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 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.

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.

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 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.

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.

There are no primary preventive measures available for rhabdomyosarcoma.

There are no secondary preventive measures available for rhabdomyosarcoma.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shadan Mehraban, M.D.[2]

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.

• Rhabdomyosarcoma is derived from two Greek words, Rhabdo means rod shape and myo means muscle.^[1]
• Rhabdomyosarcoma was firstly described by Weber (German physician) in 1854.
• In 1946, distinct morphology, histology, and classification of rhabdomyosarcoma was understood by Arthur Stout.^[2]
• Stout announced Rhabdomyoblasts as a round, strap, racquet, and spider forms.^[3]
• Intergroup Rhabdomyosarcoma Study Group (IRSG) conducted thirty years of investigation about rhabdomyosarcoma.

• Improvement of knowledge and treatment of rhabdomyosarcoma was mostly came by cooperative group studies because this was not possible for a single institution or regional centers to conduct studies about biology and treatment of rhabdomyosarcoma due to variable nature and uncommon occurrence of tumors.^[4]

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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]

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).

• The international classification of rhabdomyosarcoma (RMS) was created by the Intergroup Rhabdomyosarcoma Study group (IRSG) therapeutic trials (IRS-I to IV).^[1][2]
• The four main subgroups are:
  • Embryonal rhabdomyosarcoma (ERMS)
  • Alveolar rhabdomyosarcoma (ARMS)
  • Botryoid and spindle cell (leiomyomatous) RMS
  • Sclerosing and spindle cell RMS
• Separate categories for other subtypes which do not classify into above groups:^[3]
  • Undifferentiated
  • Pleomorphic/anaplastic
  • Sarcoma, not otherwise specified (NOS)

RMS subtypes	Definition
Embryonal rhabdomyosarcoma (ERMS)	The most common group Contains 59% of all RMS Intermediate prognosis Mostly occurs in head, neck, and genitourinary system[4] Larger peak between age of 0-5 years and smaller peak among adolescents Specific translocation is not yet designated[5] Loss of heterozygosity (LOH) at the 11p15 locus, the site of the IGF-2 gene
Alveolar rhabdomyosarcoma (ARMS)	Determined by FOXO1 rearrangement, t (1;13) or t (2;13)[6] Poorer prognosis Contains 21% of all RMS More likely among adolescents Mostly occur in the trunk and extremities
Botryoid and spindle cell RMS	Botryoid RMS contain 6% of all RMS Spindle cell RMS contains 3% of all RMS Less common variants of ERMS Accompanied with more favorable prognosis Botryoid name related to grape-like appearance of tumor Botryoid RMS occur within bladder wall and vagina Spindle cell is prevalent among infants and neonates under age of 1 years old Spindle cell RMS occurs in paratesticular location
Sclerosing RMS	Less common variants of ERMS Poor outcome Mostly occurs after age of 1 years old Could also be seen among adults Accompanied with MyoD1 mutation
Anaplastic RMS	Mostly seen in patients with Li-Fraumeni syndrome[7] Contain 1% of all cases Defined as a large hyperchromatic nuclei

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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]

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.

• The origin of rhabdomyosarcoma is straited muscle cells.^[1]
• The presentation sites of rhabdomyosarcoma are:
  • Head and neck (28%)
  • Extremities (24%)
  • Genitourinary tract (18%)
  • Trunk (11%)
  • Orbit (7%)
  • Retroperitoneum (6%)
  • Other sites such as bladder, vagina, nasopharynx, and middle ear (3%)
• Round or spindle-shaped muscle cells are present in embryonal rhabdomyosarcoma (ERMS).^[2]
• Alveolar architecture with small round undifferentiated cells which are separated by dense hyalinized fibrous septa are present in alveolar rhabdomyosarcoma (ARMS).
• Despite all muscle differentiation markers expression in ARMS, mature muscle characteristics is not seen in ARMS histology.

• The exact pathogenesis of rhabdomyosarcoma is unclear.^[3]
• Distruption of skeletal muscle progenitor cell growth and related differentiation may cause rhabdomyosarcoma.^[3]
• There is causal association between MET proto-oncogene and macrophage migration inhibitory factor (MIF).^[4]
• It is thought that P53 is related to oncogenic transformation and tumor progression.^[5]

• According to microarray and targeted sequencing, following genomic characteristics are attributed to Rhabdomyosarcoma (RMS):^{[6][7][8][9][10][11]}
  • Loss of heterozygosity of 11p15.
  • Mutations in TP53
  • Mutations in NRAS
  • Mutations in KRAS
  • Mutations in HRAS
  • Mutations in PIK3CA
  • Mutations in CTNNB1
  • Mutations in FGFR4
  • Translocations in PAX3 or PAX7 genes with FOXO1
• Specific genetic changes in different types of rhabdomyosarcoma:
• Alveolar rhabdomyosarcoma:^[12][13]
  • Translocation of FKHR gene on chromosome 13 with the PAX3 gene on chromosome 2 or the PAX7 gene on chromosome 1
  • PAX7 translocation occur in younger patients with longer event-free survival rate
• Embryonal rhabdomyosarcoma:^[14]
  • Particular gene changes are not clear
  • Loss of heterozygosity from the 11p15 region
  • Hyperdiploid gene
  • Lack of gene amplification

• Through immunohistochemistry, muscle specific proteins can be identified in RMS.^[2]
• RMS stains positive for following proteins:
  • Polyclonal desmin (99%)
  • Muscle-specific actin (95%)
  • Myogenin or myogenic differentiation 1 ( MyoD1) (95%)
    • Expressed more in ARMS rather than ERMS
    • Associated with poorer prognosis
  • Myoglobin (78%)

• Transmission electron microscopy (TEM) can be used for poorly differentiated or undifferentiated tumors.^[15][16]
• Presence of following proteins are associated with TEM features of RMS:
  • Myofilaments
  • Desmin and actin filaments
  • Myotubular intermediate filaments
  • Rudimentary Z-band material

• By using RT-PCR and FISH, features of fusion protein are identified in ARMS.^[17]

Gross findings	Gross pathology
Clusters of edematous and grape-like masses Protrusion into lumen of hollow organs
Poorly circumscribed mass white and infiltrative soft or firm mass
Fleshy tumor Tan gray color tumor

Pathologic findings	Microscopic pathology
The microscopic features of ARMS are:[18] Ovoid to round tumor cells are packed with fibrovascular septae Tumor cells have club-shaped appearance Tumor cells are divided by pseudo-alveolar spaces, slightly like pulmonary alveoli Rhabdomyoblasts are shed into pseudo-alveolar areas Presence of more than 50% alveolar components
The microscopic features of ERMS are:[14][19] Rhabdomyoblasts arranged in sheets and large nests Different stages of cell morphogenesis Positive stains are desmin, actin, myogenin, and MyoD1 Infrequent intermixed fusiform cells No alveolar architectural pattern Typical rhabdomyoblast has eosinophilic cytoplasm with poorly formed myofilaments
The microscopic features of botryoid rhabdomyosarcoma:[20] Botryoid rhabdomyosarcoma grows beneath an epithelial surface Rhabdomyoblasts adhere to dense subepithelial which is called cambrium layer Malignant cells are found in myoxid stroma
The microscopic features of anaplastic rhabdomyosarcoma are:[21] Presence of large hyperchromatic nuclei Atypical bizarre mitotic features Threefold larger nuclear size

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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]

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.

• The particular cause of rhabdomyosarcoma is not clear.^[1][2]
• Some of genetic disorders may be related to higher prevalence of rhabdomyosarcoma:
  • Li-Fraumeni syndrome
  • Nevoid basal cell carcinoma syndrome
  • Neurofibromatosis
  • Costello syndrome
  • Rubinstein-Taybi syndrome
  • Beckwith-Wiedemann syndrome
• It is thought that some environmental factors may be associated to rhabdomyosarcoma such as:^[3][4]
  • Positive history of exposure to alkylating agent
  • Parental x ray exposure
  • Parental usage of recreational drugs (marijuana)
• It is thought that some maternal history and birth characteristics may be associated to rhabdomyosarcoma such as:^[5][6]
  • Maternal history of stillbirths
  • High maternal age at childbirth
  • High birth weight

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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]

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.

• Rhabdomyosarcoma must be differentiated from following diseases:

Disease	History/demography	Symptoms			Physical examination		Diagnosis
		Palpable mass	Pain	Others	Mass tenderness	Others	Genetics	Imaging	Histology
Rhabdomyosarcoma[1][2][3][4]	Most common soft tissue cancer among children and adolescents The third most common extracranial solid tumors Two-third of all cases happen under 6 years old	+	+	Skin changes Respiratory difficulties Vomitting Hematuria	+/-	Fever Erythmatous skin Proptosis Ophtalmoplasia Dysconjugate gaze	Loss of heterozygosity of 11p15. Mutations in: TP53 NRAS KRAS HRAS PIK3CA CTNNB1 FGFR4 Translocations in PAX3 or PAX7 genes with FOXO1	CT scan: Soft tissue density Enhancement with contrast Bone destruction Ultrasound: Well-defined and irregular mass Low to medium echogenicity MRI: T1: Low to intermediate intensity Hemorrhage areas are present in alveolar rhabdomyosarcoma T2: Hyperintense Prominent flow voids are present in extremity lesions of rhabdomyosarcoma T1 C+(Gd): Enhancement	An appearance of round blue cell tumors Myogenesis pathway has various types of differentiation Positive immunohistochemical results for: myoglobin actin desmin Myogenin
Wilms tumor[5][6][7][8][9]	Also called nephroblastoma The most common childhood abdominal malignancy Average age of 3.5 years old	+	+	Hematuria Respiratory symptoms ( due to lung metastases)	+/-	Fever Hypertension/ hypotension	Present mutations of: WT1 P53 FWT1 FWT2 11p15.5 loci	Ultrasound: The best initial diagnostic study. Distinguish tumor mass from other causes of renal swelling like hydronephrosis. Doppler ultrasonography can help to detect invasion of renal vein and IVC by the tumor. CT scan: Heterogeneous soft-tissue density mass Areas of calcification and fat density regions Lymph node metastasis Surrounding organs invasion Thrombus in renal vein or inferior vena cava	Arises from mesodermal precursors of the renal parenchyma Well-circumscribed/ macrolobulated lesion Hemorrhage/ central necrosis may be present It is comprised of 3 types of cells: Stromal Epithelial Blastemal The stroma may include: Striated muscle cartilage bone Fat tissue Fibrous tissue.
Ewing sarcoma[10][11][12][13]	Include ewing sarcoma, askin tumor, and peripheral neuroectodermal tumors primitive The second most common childhood malignant primary bone tumors Usually arises in the long bones of the extremities Common age between 10-20 years old	+	+	Weight loss Fatigue	+	Fever Pathologic fractures Petechiae/ purpura	Reciprocal translocation between chromosomes 11 and 22	Radiographic of region: Poorly marginated destructive lesion Permeative or “moth-eaten” appearance CT scan: Cortical destruction Demonstrate soft tissue disease MRI: Considered as a preferred diagnostic study Better shows tumor size/ intraosseous/extraosseous extent	Small/ round/ blue cell tumors May be undifferentiated or differentiated Regular sized primitive appearing cells
Pediatric neuroblastoma [14][15][16][17]	Most common extracranial solid tumor of infancy Arising from pluripotent sympathetic cells Age distribution: < 1 years old ( 40%) 1-2 years old (35%) > 2 years old (25%)	+ (Abdominal)	+	Constipation Weakness Diarrhea	+(Abdominal)	Proptosis Periorbital ecchymosis Horner syndrome Opsoclonus myoclonus syndrome	Chromosome 1p deletion N-myc amplification	CT scan: Heterogeneous mass Calcification Necrotic areas MRI: T1: heterogeneous mass T2: Heterogeneous/ hyperintense Cystic/ necrotic areas C+ (Gd): Heterogeneous mass	Well defined/ infiltrative mass Homer wright rosettes Secretion of vanillylmandelic acid (VMA) and homovanillic acid (HVA)
Pediatric pheochromocytoma[18][19][20][21]	Rare catecholamine-secreting tumor Occur in both children and adults Average age of 11 years old Associated with neurofibromatosis, von Hippel-Lindau disease, tuberous sclerosis, sturge-weber syndrome, and multiple endocrine neoplasia (MEN) syndromes	–	+/-	Headache Sweating Weakness Convulsion	–	Hypertension Tachycardia Pallor face	Genetic mutation in: NF1 RET VHL SDHD SDHC EGLN1 EGLN2 KIF1B SDHAF2 TMEM127 SDHA IDH1 SDHB MAX HIF2A FH	Ultrasound: Different appearance from solid to mixed cystic or solid to cystic CT scan: Large and heterogenous Calcification Necrosis Cystic changes MRI (in extra adrenal tumors): T1: Heterogenous enhancement Hypointense T2: Hyperintense T1 C+ (Gd): Heterogenous enhancement	Zellballen pattern on microscopy Well-defined clusters Eosinophilic cytoplasm Positive stains for: Chromogranin for zellballlen cells Neurospecific enolase markers for neuronal cells S-100 protein for sustentacular cells
Pediatric osteosarcoma[22][23][24]	The second most common primary bone tumor The third most common tumor among adolescents Can be primary or secondary Primary osteosarcoma occurs in age of 10-20 years old Secondary osteosarcoma occurs in older patients and is secondary to paget disease and bone infarcts Accompanied with positive history of trauma	+	+	Soft tissue swelling Fracture Night sweating	+	Mass swelling Fever Arthritis Decreased joint range of motion Lymphadenopathy	Alteration in retinoblastoma gene (Rb)	Radiography: Osteolytic/ osteoblastic feature Periosteum reaction Calcification or ossification CT scan: Primary lesion and chest CT are required Demonstrate tumor location and extension MRI: Exact assessment of tumor extension Involving joint to joint findings	Contain various cellular pleomorphism and mitoses Poorly trabecular bone formation Fibrocystic and chondroblastic features
Pediatric liposarcoma[25][26][27][28]	Considered as a nonrhabdomyosarcoma soft tissue sarcomas One of the least frequent tumors during childhood Rarely seen in adolescents and age of < 8 years old Average age is 50 years among adults Occur mostly in lower extremities, retroperitoneal region, and shoulder	+	+/-	Weight loss Fatigue	–	N/A	Amplification of 12q13–15 region in MDM2 and CDK4 genes Translocation of t (12;16) (q13;p11.2) in myxoid liposarcoma	CT scan: Inhomogenous fatty structure Tumor mineralization Cortical bone erosion Calcification Infiltration to mediastinum MRI: Adipose content mass Thin irregular septa Hemorrhage Necrosis areas	Divided into following subtypes: Well-differentiated Dedifferentiated, Myxoid/ round cell Pleomorphic Common findings: Lipoblasts presence Cytoplasmic lipid vacuoles Chromatin spikes
Pediatric acute myelocytic leukemia[29][30][31][32]	Replacement of normal bone marrow cells with abnormal cells Myeloblast is malignant cell Wide distribution among childhood to adults Survival rate of 60% Common in down syndrome	+/- ( Abdominal mass, mediastinal mass)	+ (bone pain, joint pain)	Bleeding Infectious	+/-	Lymphadenopathy Hepatosplenomegaly Bruising Petechiae Pallor face Anemia Fever	Genetic translocations include: t (8;21) t (3;21) t (15;17)	Radiography: Chest radiography: Diagnosis of mediastinal mass Extremities radiography: Metaphyseal bands Lytic lesions New periosteal bone formation Pathologic fractures CT scan/ MRI: Thickening/ edema of the bowel wall in presence of abdominal pain or bowel infection Detection of early sinusitis Intracranial hemorrhage in presence of neurological symptoms Radionuclide imaging: Detection of occult infection	Hyperplastic bone marrow with leukemia cells replacement Megaloblastic feature Decrease in normal hematopoietic cell
Pediatric acute lymphoblastic leukemia[33][34]	The most common malignancy among children Few cases may associated with down syndrome, wiskott- aldrich syndrome, and ataxia-telangiectasia Peak age of 2-5 years old Previous history of cancer/ drug exposure Bone marrow replaced with malignant lymphoblasts	+/-( Extramedullary mass in abdomen/ head/ neck)	+/- (Musculoskeletal pain)	Weakness Fatigue Weight loss Bleeding	–	Fever Lymphadenopathy Hepatosplenomegaly Pallor Papilledema Nuchal rigidity Cranial nerve palsy Dyspnea	Chromosomal translocations: t (9;22) t (12;21) t (5;14) t (1;19)	Radiography: Chest x ray: Nodular mass Central lymphadenopathy Bone x ray: Radiolucent metaphyseal bands Coarse trabeculation Periosteal reaction Osteopenia Brain MRI: Leukoencephalopathy Glial cell hyperplasia Meningitis	Divided into 3 subgroups: L1: Small lymphoblast cells Scant cytoplasm Invisible nucleoli L2: Larger lymphoblast cells Abundant cytoplasm Prominent nucleoli L3: Large lymphoblast cells Deep cytoplasmic basophilia Similar to Burkitt lymphoma
Pediatric non-hodgkin lymphoma[35][36][37]	Cancer derives from lymphocytes Diverse age of incidence Associated with autoimmune disorders, previous cancer therapy, and infection	+	–	Lymph node swelling Weight loss Anorexia Abdominal pain Nausea/ vomiting	+ (Chest tenderness)	Fever Hepatosplenomegaly Lymphadenopathy Seizure Petechiae	MLL2 MEF2B EZH2 EP300 KMT2D CDKN2A	Radiography: Chest x ray: Central lymphadenopathy Pleural effusion Pericardial effusion CT scan: Presence of enlarged lymph node in chest, abdomen, and pelvis Ultrasound: Hepatosplenomegaly	Histology findings of non-hodgkin lymphoma depend on: Cell differentiation Cell lineage Location of cell origin

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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]

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.

• 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.^[1][2]
• Rhabdomyosarcoma is responsible for 50% of soft tissue tumors during childhood and 5% of all pediatrics cancers.^[3]
• Almost 350 new cases of rhabdomyosarcoma are diagnosed annually.^[1]

• The incidence of rhabdomyosarcoma is about 0.43 per 100,000 annually among children,adolescents, and young adults under 20 years old.^[1]
• The incidence may depend on the histologic subtype of rhabdomyosarcoma:^[4]
  • Embryonal rhabdomyosarcoma: Embryonal rhabdomyosarcoma peaks in 0 to 4 year age group at approximately 0.4 cases per 100,000 children, with a lower rate in adolescents, approximately 0.15 cases per 100,000 adolescents.
  • Alveolar rhabdomyosarcoma: The incidence of alveolar rhabdomyosarcoma does not vary by gender and is constant from ages 0 to 19 years at approximately 0.1 case per 100,000 children and adolescents.

• In patients with localized disease, the estimated 5-year survival rate is greater than 80% after using surgery, radiation therapy, and chemotherapy for treatment.^[5]
• In patients with metastatic lesions, the estimated 5-year event-free survival is less than 30%.^[6]
• The 3-year event-free survival rate for patients with metastatic lesions without high risk factors (bone marrow involvement, unfavorable site, more than 3 sites, and age younger than 1 year or older than 10 years) is approximately 50%.
• The 3-year event-free survival rate for patients with metastatic lesions with 3 high risk factors is about 12% and with 4 high risk factors is 5%.
• The 5-year survival rate is 86% for orbital site, 80% for genitourinary site, 50% for extremities, 52% for retroperitoneum and trunk.^[7]
• The 5-year survival rate is 77% for patients aged 1-4 years, 47% for infants and 48% for adolescents.

• Approximately two-third of all cases happen under 6 years old.^[8]
• The peak incidence of rhabdomyosarcoma is between 2-6 years and 10-18 years.
• Embryonal rhabdomyosarcoma is usually happen in younger ages especially develops in head/neck sites and genitourinary locations.
• Alveolar rhabdomyosarcoma is usually happen in older patients (adolescents) especially develops in trunk and extremities sites.

• The incidence of rhabdomyosarcoma is higher among black patients than white patients particularly between 15-19 years.^[9]

• The incidence of rhabdomyosarcoma is a little more predominant in males than females (about 1.3:1-1.5:1).^[9]

• The incidence of rhabdomyosarcoma is higher among Caucasian population in comparison to Asian population.^[10]

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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]

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.

• The same as all other childhood cancers, the particular risk factors of rhabdomyosarcoma is not exactly known.^[1]
• Higher incidence of rhabdomyosarcoma is reported among following individuals:^[2][3][4]
  • Exposure to radiation in utero
  • Low socio-economic situations
  • Antibiotic therapy soon after birth
  • In children whose parents took recreational drugs such as cocaine and marijuana during pregnancy^[5]
  • Accelerated growth in uterus
• Rhabdomyosarcoma may be associated with following familial syndromes:^[6][7][8]
  • Beckwith-Wiedemann syndrome^[9]
  • Li-Fraumeni syndrome
  • Costello syndrome^[10]
  • Neurofibromatosis^[11]
• Higher risk of embryonal rhabdomyosarcom in uterine, bladder, and cervix in patients with DICER1 gene mutation and lung pleuropulmonary blastoma.^[12][13]

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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]

There is insufficient evidence to recommend routine screening for Rhabdomyosarcoma.

There is insufficient evidence to recommend routine screening for Rhabdomyosarcoma.

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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]

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.

• Rhabdomyosarcoma may cause metastasis to other organs.^[1]
  • Less than 25% of patients present with distant metastases at he time of diagnosis.^[2]
  • The most common metastatic site is lung.
  • The other metastatic sites are as following:^[3][4]
    • Bone marrow (30%)
    • Bone (30%)
    • Omentum and ascites (16%)
    • Pleura (13%)
    • Visceral involvement
    • Brain metastases
• Patients may develop with some complications after treatment such as:^[5][6]
  • Cardiomyopathy
    • Regarding anthracycline and cyclophosphamide use
  • Pulmonary failure
  • Renal electrolyte wasting
    • Regarding ifosfamide use
  • Acute myelogenous leukemia
    • Regarding etoposide use
  • Secondary malignancies
    • Skin and bone tumors regarding radiotherapy
• Recurrent rhabdomyosarcoma is prevalent among patients with following criteria:^[7]
  • Presence of gross residual disease after initial surgery located in unfavorable sites
  • Lymph node involvement (N1)
  • Tumor size > 5cm
  • Age < 10 years
  • Alveolar rhabdomyosarcoma
  • Distant metastatic at diagnosis
• Long-term complications after treatment regarding to different organs are listed below:

Affected organs	Long-term complications
Head and neck problems[8][9][10]	Short stature ( due to growth hormone deficiency after radiotherapy to hypothalamic–pituitary area) Facial asymmetry Poor dentition Impaired hearing, vision, and learning
Bladder and bowel problems [11][12]	Bladder: Incontinency Frequency Nocturia Bowel: Hemorrhagic cystitis Primary hypogonadism
Eye problems[13]	Cataract Orbital hypoplasia
Dental and facial problems[14][15]	Bony hypoplasia Tooth and root agenesis Trismus Microdontia Enamel defects Osteonecrosis

• Rhabdomyosarcoma prognosis are considered as a favorable one in presence of following criteria:^[16][17][18]
  • No distant metastases at diagnosis
  • Primary tumors sites:
    • Orbit tumors
    • Nonparameningeal head and neck tumors
    • Genitourinary tumors (non-bladder or prostate tumors)
  • Complete surgical removal of the localized tumor at the time of diagnosis
  • Embyonal rhabdomyosarcoma or botryoid on histology
  • Tumor size ≤5 cm
  • Patient’s age between 1 to 10 years old
• Adults and adolescents have worse outcome rather than children.^[19][20]
  • The overall 5-year survival rate is 27% in adults while it is 61% in children.
    • This difference is regarding to unfavorable tumor sites, metastatic recurrence, lymph nodes involvement, and pleomorphic and NOS (not otherwise specified) rhabdomyosarcoma.^[19][21]
• The survival rate and event-free survival rate of nonmetastatic tumors are as following:^[22]

Tumors location	Overall survival rate	Event-free survival rate
Head and neck tumors	64%	35%
Orbit	85%	53%
Paramenigeal tumors	In age < 3 years: 59% In age ≥ 3 years: 65%	In age < 3 years: 33% In age ≥ 3 year:62%
Genitourinary tumors ( non-bladder and prostate)	94%	82%
Genitourinary tumors ( bladder and prostate)	80%	64%
Extremities	46%	35%
Other sites	63%	54%

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