Rhabdomyosarcoma differential diagnosis

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

Overview

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.

Differential Diagnosis

• 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	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	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	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	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	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	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	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	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	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	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