Soft tissue sarcomas

Heterogeneous group of neoplasms which stem from muscles, vessels, lymphatic tissue, connective tissue, synovial tissue or primitive mesenchymal cells The most common – rhabdomyosarcoma (RMS) approximately 50% of all sarcomas in children and young adults Incidence: -in childhood 7.5% of all neoplasms -annually new diagnosis in 8/1 million children <16years -ratio of boys: girls 1.4 : 1

Subtypes Mesenchyma Myxoma, mesenchymoma Striated muscle RMS Smooth muscle Fatty tissue Connective tissue Synovial tissue Lymphatic vessels Nerve sheath Blood vessels Myxoma, mesenchymoma RMS Leiomyosarcoma Liposarcoma Fibrosarcoma Synovial sarcoma Lymphoangiosarcoma Neurofibrosarcoma Angiosarcoma, hemangiopericytoma

Rhabdomyosarcoma Age of distribution: Location: <1 year -7% 1 – 4 -35% 5 – 9 -25% 10-14 -20% >15 -13% Location: Head and neck -26% Orbital - 9% Genitourinary -22% Extremities -18% Trunk -7% Retroperitoneal -7% Perineal and anal -2% Others -9%

Histopathology Embryonal : 53-64% of all RMS in childhood location: orbit, head and neck, abdomen, genitourinary tract subtype: sarcoma botryoides(6%) – in genitourinary tract Alveolar: 21% location: mainly extremities Pleomorphic : 1% mainly in adulthood Undifferentiated: 8%

Clinical manifestation Symptoms depend on tumor location Head and neck -35% - location : orbit and parameningeal – middle ear, mastoid, nasal, paranasal area, pharynx, fossa pterygopalatina, fossa infratemporalis, neck -symptoms: orbit- proptosis -middle ear: pain, chronic otitis media, polypoid mass obstructing the ear canal -nasopharyngeal tract:obstruction of airways, sinusitis, pain, epistaxis, difficulty in swallowing, eventually polypoid tumor visible in the pharynx or in nasal area -neck:hoarseness, difficulty in swallowing, visible tumor

RMS

Genitourinary tract: 22% -location:urethra, vagina, uterus, prostate, bladder, testes, paratesticular area, spermatic cord -symptoms: problems of urination, hematuria, vaginal bleeding, sarcoma botryoides Extremities (18%) and trunk (7%): -location: trunk, chest, abdomen, paraspinal area -symptoms: indolent mass, symptoms of spinal compression, dyspnea Retroperitoneal area:7%, -symptoms: large tumor, abdominal pain, ascites

Extermity RMS

RMS of the bladder

Diagnosis Biopsy Radiology diagnosis: usg, CT, MRI Bone scan Bone marrow aspiration and biopsy Lumbar puncture

Staging I A- localized tumor,confined to site origin, completely resected I B - localized tumor infiltrating beyond site of origin, completely resected II A –localized tumor, gross total resection, but microscopic residual disease II B –locally extensive tumor (spread to regional lymph nodes), completely resected II C –extensive tumor (spread to lymph nodes, gross total resection, but with microscopic residual disease) III A- localized or locally extensive tumor, gross residual disease after biopsy only III B- localized or locally extensive tumor, gross residual disease after major resection (50% debulking) IV any size of primary tumor with or without regional lymph node involvement, with distant metastases, irrespective of surgical approach to primary tumor

Metastatic spread -metastases via lymphatic or/and hematogenous spread -CNS, lung, lymph nodes, liver, bone, bone marrow Treatment Surgical procedure (total resection or biopsy) Radiotherapy (II- IV) Chemotherapy (CWS)

Prognosis Depend on: stage, tumor size, extension after surgery, location (favorable: orbit or genitourinary tract), histology (unfavorable: pleomorphic) Age (more favorable in children < 7years old) Survival: EFS 20 – 80 % depending on stage

Bone tumors Osteosarcoma Ewing’s sarcoma = 90% of primary bone tumors occuring in children and adolescents

Osteosarcoma Primary malignant tumor of bone, originates from mesenchymal stem cell capable of differentiating toward bone The most common bone tumor in children and adolescents Rare in first decade of life Most frequent in adolescent during growth spurt Male : female 1.3 – 1.6 :1

Location Approximately 50% in knee region Skeletal regions affected by greatest growth rate, i.e. distal femoral and proximal tibial metaphyses humerus – third most frequently involved bone Pelvis, i.e. ilium approximately 10%

Etiology/ genetics Relation between rapid growth and development of osteosarcoma Ionizing radiation Alkylating agents and anthracyclines →secondary osteosarcoma Association with Paget’s disease Common second malignancy after inherited retinoblastoma –alteraltion in Rb common in sporadic osteosarcoma Common association with a germline TP53 mutation (Li-Fraumeni syndrome)

Clinical presentation Pain originating from involved region for weeks – months – even 1 –1.5 year!!! Delayed diagnosis !!! Loss of function 10-15% of patients metastases when staged Lung metastases predominate

Evaluation Radiology: plain radiographs in two planes – characteristic radiological features: - tumor matrix may be mineralized resulting in variable dense opacities of different sized and shapes - tumor margins may be poorly defined. Destructive growth pattern with lytic and sclerotic areas and normal bone tissue commonly observed - cortex exhibits frequently destructive growth, the tumor is rarely limited to medullary space -extension into soft tissue -periosteal reaction often present, radiating striations called „sunburst signs” or open traingles overlying the diaphyseal side of lesion –Codman’s triangle or in the form of multiple layers – „onion skin”

Magnetic resonance imaging (MRI) of primary site of at least complete involved bone plus adjacent joints. MRI is more appropriate than CT scan Open biopsy Metastases: chest X-ray, CT scan of thorax, skeletal radionuclide scan

Treatment Combined therapy : preoperative chemotherapy + surgery (goal is a wide resection, limb –saving surgery with allograft or prosthesis ) + postsurgical chemotherapy Osteosarcoma is relatively radioresistant Prognosis: 5 -year overall survival –65% (without metastasis at diagnosis– 70%, with metastasis -30%

Ewing sarcoma family of tumors Neuroectodermal histogenesis of tumors Genetics: 95% of patients present translocation t(11;22) >translocation of the EWS gene on chromosome 22q12 with one of the genes of the FLI oncogene family = fusion transcript EWS - FLI Histological subclassification: - classic Ewing sarcoma (ES) -extraskeletal or soft tissues ES -Askin tumor (chest wall) -peripheral primitive neuroectodermal tumor (PNET) of bone or/and soft tissue

Epidemiology Annual incidence 2.7/1million children < 15 years Male : female 1.5 :1 80% of tumors in patient younger than 20 years of age 50% - in second decade of life Mean age at diagnosis 15 years More common in white than black population

Clinical presentation Pain followed by swelling of the overlying affected bone The duration from the onset of first symptoms to diagnosis - many months.Symptoms are frequently explained away as being a result of trauma or „growing pains” Systemic symptoms: fever (20%) Presence of nerve root pain or neuropathies from nerve compression Anemia, leukocytosis, increased sedimentation rate Pathological fracture – in 10% of cases

Location Almost 50% of ES – in the femur or pelvis Mainly lower extremities involved, less frequently – upper extremities Chest wall Less common in the spine, paravertebral region, head and neck

Pathologic fracture mass of Ewing sarcoma

Metastases Hematogenous route is most frequent pattern of spread: lungs, bone, bone marrow Askin tumor may invade the adjacent pleural space with subsequent pleural effusion

Metastases Radionuclide scan of skeleton X-rays or MRI scans of affected areas Chest X-ray Bone marrow aspiration

Evaluation Laboratory findings: -complete blood count -blood sedimentation, C- reactive protein -tumor lysis parameters, electrolites, kidney and liver parameters -lactate dehydrogenase Radiology : x-ray:periosteal reaction(onion-skin phenomenon) MRI (tumor volume) Open biopsy

Treatment Neoadjuvant chemotherapy + surgery + adjuvant chemotherapy + radiotherapy Prognosis Depends on surgical resection, tumor localization, tumor volume, presence of macroscopic metastases, molecular/ biological aspects 5 year EFS approximately 70%

Retinoblastoma

Epidemiology 2% of all neoplasms in childhood Annually 3/ 1 million children < 16 years old diagnosed, 1 in 15000 – 20000 births Median age at diagnosis – 2 years Boys : girls 1:1 Bilateral form 20-40% (more frequent in girls)

Etiology/ genetics/pathogenesis Sporadic form –60% Hereditary form 40%, two mutational event are required for tumor occurence: 1. Mutation in germ cell 2. Mutation in target cell (retina). Autosomal , dominant trait with high penetrance, i.e. nearly 50% of relatives develop a retinoblastoma, mostly bilateral. Chromosomal alteration is located on chromosome 13q14 involving the RB1 retinoblastoma gene ( which is in the chromosomal region linked to the development of osteosarcoma – the most frequent secondary tumor)

Clinical manifestation Leukokoria – „cat’s eye” – in the pupil of the eye is the first sign in majority of patients Strabismus Anisocoria Loss of vision Diagnosis is generally established on fundoscopy

Diagnosis Fundoscopy – a white tumor accompanied by angiomatous dilatation of the vessels. Radiological examinations: ultrasound CT magnetic resonance imaging (MRI)

Therapy Surgical management (enucleation) The objective is to maintain vision without endangering the life of the child. In the advanced stages enucleation is necessary. Chemotherapy Radiotherapy Laser photocoagulation Cryotherapy Brachytherapy Prognosis: survival 80-90% of all patients