Signs and symptoms in the child with suspected cancer

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Signs and symptoms in the child
with suspected cancer

• Maryna Krawczuk - Rybak
• Department of Pediatric Oncology

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Incidence

• 1 - 2 of total incidence of cancers
• every year 130- 140 children lt16y per million are
  diagnosed with childhood cancer
• survival probability 70 -80
• the incidence within the first 5 years of life is
  twice as high as from 6 to 15 years of age
• Highest incidence in Nigeria, Los Angeles
  (white), Brasil (San
  Paulo), New Zealand, Sweden, Australia
  lowest Fiji, India, Kuwait, China
  (Taipei)

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Distribution of cancer in children lt15 years of
age

• ALL - 23.3
• CNS tumors -20.7
• Neuroblastoma - 7.3
• Non-Hodgkin lymphoma - 6.3
• Wilms tumor - 6.1
• Hodgkin lymphoma - 5.0
• Rhabdomyosarcoma - 3.4
• Retinoblastoma - 2.9
• osteosarcoma - 2.6
• Ewings sarcoma - 2.1
• other - 16.4

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Hereditary component of pediatric malignancies

• Tumor type Approximate
• 
  hereditary component ()
• Optic gliomas 45
• Retinoblastoma 40
• Pheochromocytoma 25
• Wilms tumor 3 5
• CNS neoplasms 1 3
• Leukemia 2.5 - 5

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Differences between children and adults cancer

• 
  children
  adults
• Primary location tissues
  organs
• Histopatology non-epithelial gt90
  epithelial gt80
• mesenchymal
  or
• embryonal
  origin
• Staging 80 disseminate
  local or regional
• Screening neuroblastoma
  mammography
• 
  (catecholamines,usg) colonoscopy
• 
  cytology
• Response drug and radio-
  less sensive
• on treatment sensive
• Prognosis 70 80
  40-50
• curable
  curable

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Dependence of age

• 1 year - neuroblastoma,
  retinoblastoma,
• hepatoblastoma,
  nephroblastoma
• 2 5 y -ALL, CNS tumors,
• Adolescence -Hodgkin lymphoma, osteosarcoma,
  sarcoma
  Ewing,
• soft tissue sarcoma
• Infancy and puberty gonadal tumors (boys)
• Puberty- gonadal tumors (girls)

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Dependence of age

• gt80 neuroblastoma - in the first 3 y
• 80 nephroblastoma - in the first 5 y
• 70 bone tumors - in the age 10 15 y

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Dependence of sex

• More often in male 43
• More often in male lymphomas, leukemias, CNS
  tumors, neuroblastoma, osteosarcoma, RMS
• The same proportion nephroblastoma,
  retinoblastoma
• More often in female germ cell tumors
  (adolescent), thyroid cancer, adrenal
  cancer

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Common chief complaints given by parents
that suggest a
pediatric cancer

• Chief complaints

• Suggest cancer

• Chronic drainage from ear
• Recurrent fever with bone pain
• Morning headache with vomiting
• Lump in neck that does not respond to antibiotics
• White dot in eye
• Proptosis

• RMS, LCH
• Ewings sarcoma, leukemia
• Brain tumor
• Hodgkin lymphoma, NHL
• Retinoblastoma
• Leukemia, neuroblastoma histiocytosis, RMS

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• Swollen face and neck
• Mass in abdomen
• Paleness and fatigue
• Limping
• Bone pain
• Bleeding from vagina
• Weight loss

• NHL, leukemia
• Wilms tumor, neuroblastoma, NHL,
  hepatoblastoma/ hepatoma
• Leukemia, lymphoma
• Osteosarcoma, bone tumors, leukemia
• Leukemia, Ewings sarcoma, NBL
• Yolk sac tumor, RMS
• Hodgkins lymphoma

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Presenting signs and symptoms of some common
pediatric cancers and their differential
diagnosis
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Lymphadenopathy

• Transient proliferative response to local or
  generalized infection
• Sign of malignancy

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History

• Duration of lymphadenopathy
• Previous cat scratches, rodent bites, tick bites
• Previous tonsillitis, skin lesions, infections
  in the lymphatic region drained
• Significant weight loss
• Night sweats
• Fever

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Location size

• Tonsillar and inguinal lymph nodes secondary to
  localized infection
• Supraclavicular, infraclavicular, axillary
  serious nature -left supraclavicular node
  gt malignant disease arising in the abdomen
  (lymphoma, RMS) and spreading via the thoracic
  duct
  -right
  supraclavicular node gt thoracic lesions (this
  node drains the superior areas of the lungs and
  mediastinum)
• Nodes gt2.5 cm - pathologic

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Character

• Nodes
• -firm, rubbery, matted -gt malignant
• -warm, tender, fluctuant -gtinfection
• -localized vs. generalized

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Causes of lymphadenopathy

• Infection
  
  -bacterial ( skin infection, staphylococcus,
  streptococcus, septicemia, tuberculosis,
  brucellosis)
  -viral ( mononucleosis, cytomegalovirus,
  rubella, varicella, HIV, adenovirus, herpes
  simplex, cat- scratch disease)
  
  -protozoal ( toxoplasmosis, trypanosomiasis)
  -spirochetal (syphilis,
  rat-bite-fever)
  -fungal (histoplasmosis,
  dermatophytosis, coccidioidomycosis)
  
  -Kawasakis disease
  -

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• Connective tissue disorders
  -rheumatoid
  arthritis
  -systemic lupus
  erythromatosus
• Storage disease
  -
  Niemann- Pick disease
  - cystinosis
• Granulomatous disease
  -sarcoidosis
  
  -chronic granulomatous
  disease

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• Lymphoproliferative disorders
  -autoimmune
  lymphoproliferative syndrome
  -angioimmunoblastic lymphadenopathy with
  dysproteinemia
  -X-linked
  lymphoproliferative syndrome
  -Castelmans disease
• Neoplastic diseases
  -lymphoma
  
  -leukemia
  
  -metastases from solid
  tumors
  -histiocytoses

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Investigations

• Erythrocyte sedimentation, leukocytosis, CRP
• Serologic tests (toxo, CMV, Epstein-Barr virus,
  HIV)
• Chest radiograph, CT scan
• Abdominal sonogram (or CT)
• Lymph node biopsy
• Bone marrow examination

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Headaches

• Complaints of repeated headaches signs of
  increased intracranial pressure brain tumor
• In supratentorial tumors
  vomiting occured
  in 46
  headaches in 43
• In infratentorial tumors
• coordination difficulties - 60
• vomiting 76
• headaches 56

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• The best method of screening for brain tumor in
  patient with headaches is a careful neurologic
  examination, because approximately 95 of
  children with headache had abnormal neurologic
  findings in clinical examination!
• Good clinical history
  -
  duration of symptoms and their location
  
  - timing, severity precipitating events
• - mode of onset
  

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• Following symptoms suggest a brain tumor
• Recurrent morning headaches
• Headaches that awaken the child
• Intense and incapacitating headaches
• Changes in the quality, frequency and pattern of
  the headaches

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Condition suggesting the need for CT
in children
with headaches

• Presence or onset of neurologic abnormality
• Ocular findings such as papilledema, decreased
  visual acuity, or loss of vision
• Vomiting that is persistent, increasing in
  frequency, or preceded by recurrent headaches
• Change in character of headaches, such as
  increased severity and frequency
• Recurrent morning headaches or headaches that
  repeatedly awaken child from sleep
• Short stature or deceleration of linear growth

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• Diabetes insipidus
• Age of 3 years or less
• Neurofibromatosis
• Cured of ALL with irradiation of CNS as a part of
  initial treatment

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Bone and joint pain

• Is most common in children with
• Ewings sarcoma 90 (intermittent at first gt
  increases in severity with time
• Osteogenic sarcoma in 80
• The time between the onset of symptoms and
  the diagnosis can be as long as 8 to 12 months

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• Arthralgias or bone pain may be prominent
  presenting features of acute lymphoblastic
  leukemia - in 27 33.
  Can
  be mistaken for various rheumatic disease!
• Persistent bone or joint pain, especially if
  associated with swelling, mass, limitation of
  motion -
  made a radiograph!

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Abdominal masses

• Is the most common presenting finding of
  malignant solid tumors in children
• In newborn/ infant - Wilms tumor or
  neuroblastoma
• In older children is more likely to be
  secondary to leukemic or lymphomatous involvement
  of the liver or spleen
• Kidney abnomalities
• Faeces mass

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• Abdominal examination is frequently not easy gt
  the child has to be
  relaxed before palpating the abdomen
• Radiological examination radiograph,
  ultrasonograph, CT
• Urianalysis
• Stool specimen
• Tumor markers

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Mediastinal masses

• Benign and malignant tumors
• Anterior mediastinum lymphomas, masses of
  thymic origin, teratomas, angiomas, lipomas,
  thyroid tumors
• Middle mediastinum lymphomas, metastatic or
  infection-related lesions involving lymph nodes,
  pericardial cysts, bronchogenic cysts, esophageal
  lesions, hernias through the foramen Morgani
• Posterior mediastinum neurogenic tumors and
  cysts (neuroblastoma, ganglioneuroblastoma,
  neurilemomas, ganglioneuromas, pheochromocytomas,
  thoracic meningocele, Ewings sarcomas,
  lymphoma, RMS

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• Patients may be asymptomatic or may present with
  symptoms secondary to compression or erosion of
  adjacent organs such as respiratory tract
  e.g. cough, stridor, hemoptysis
• Mass is discovered during rutine chest
  radiographs
• CT, ultrasound, MRI
• Histologic examination

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Pancytopenia and leukocytosis

• Anemia, leukopenia, thrombocytopenia occur
  alone or in combination as a common presenting
  sign in acute leukemia
  
  - 50 present hemoglobin
  concentration lt 7.5 g/L - 70 -
  platelet counts lt 150.000/mm3
  - 30 - WBC lt 5.000/mm3
• Lymphomas, NBL, Ewings sarcoma, RMS

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Leukocytosis

• Acute leukemia
  -
  gt40.000/mm3 in 45 children with ALL
  gt 100.000/mm3 - in 10
  children with ALL
  
  in 20 with AML
• Nonmalignant causes
  -
  infections (staphylococcal, pneumococcal,
  Haemophilus, meningococcus, Salmonella)
  
  - lymphoid leukemoid reaction infectious
  lymphocytosis, mumps, varicella, adenovirus,
  cytomegalovirus, pertussis infections
  
  - eosinophilia parasitic
  infections, visceral larval migrans,
  hypereosinophilic syndrome, allergy

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Central nervous system malignancies
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Epidemiology

• Commonest malignant solid tumors in childhood
• 20 of cancers in age lt 15 years
• Annually 20 26/ 1 million children below the
  age of 16 years
• Age stratified incidence is
  lt1year
  - 27/ 1 million
  
  1 4 - 31/ 1
  million
  5 9
  - 27/ 1 million
  10 14
  - 20/ 1 million
• Slightly higher frequency in boys 1.251
  (especially for medulloblastoma and germinoma)

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Etiology and pathogenesis

• Association between primary CNS tumors and
  following conditions/ genetic disorders
  
  1. Neurofibromatosis
  (NF) type 1 and 2
  2. Tuberous sclerosis
  3. Von
  Hippel- Lindau syndrome
  4. Gordlins, Cowdens,
  Turcots syndromes
  5. Li-Fraumeni syndrome (mutation of
  suppressor oncogene p53)
• Deletion of chromosome 17 or 20 (medulloblastoma)
• Exposition of the brain to ionizing radiation
  i.e. after cranial radiotherapy in leukemia

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Pathology

• Supratentorial lesions (30 40)
  1.
  Cerebral hemisphere ( astrocytoma, ependymoma,
  glioblastoma, meningioma)
  2. Sella or
  chiasm ( craniopharyngioma, pituitary adenoma,
  optic nerve glioma)
• Infratentorial lesions (60 70)
  1. Cerebellum
  (medulloblastoma, astrocytoma, meningioma)
  
  2. Brain stem (
  astrocytoma, ependymoma, glioblastoma)

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Classification

• Based on histogenesis and predominance of cell
  type
• Degree of malignancy is defined by grading system
  e.i. WHO grade based on cellular morphology,
  mitotic index, anaplasia and necrosis
  
  grades I and II represent benign tumors
  grades III and IV -
  malignant tumors

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Clinical presentation

• Depends on
  - age
  
  -anatomical site
  -tumor type
• -raised intracranial pressure (ICP)
  -localizing neurological deficits

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Signs of increased IPC

• Direct tumor infiltration
• Compression of normal structures
• Secondary to obstruction of the cerebrospinal
  fluid (CSF)

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• Older children
  
  -inilially behavioural changes and declining
  school performance prior to development of the
  more classical features of headache, nausea and
  vomiting , headaches start as generalized and
  intermittent gt increase
  in both intensity and frequency with time -
  the child may awake with headache at night,
  with the pain generally being worse in the
  morning and improving during the day with an
  upright posture
  -School-age children complain of visual
  disturbances

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• Infants and younger children
  plasticity of the
  developing skull and inability to communicate
  symptoms gt
  -infant may be irratable, with
  failure to thrive, associated with anorexia and
  vomiting
  -regression of developmental
  milestones
  -increase head circumference with widened
  sutures and a tense anterior fontanelle
  
  sun-setting sign

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Symptoms and signs according to anatomical site
of CNS tumors

• Supratentorial (30-40)
  
  Cerebral hemisphere- hemiparesis, spasticity,
  seizures (focal or generalized)
  
  -
  para/suprasellar endocrinopathy (growth
  failure, diabetes insipidus, pubertal
  abnormality)
  
  - hypothalamus diencephalic syndrome
  (infants), developmental and behavioural
  abnormalities
  - optic
  pathway visual field, acuity, color vision
  deficits, optic atrophy, nystagmus, head tilt
  
  - pineal - Parinauds
  syndrome, sleep abnormalities
  - thalamus, basal ganglia pain,
  sensory loss, memory disturbances
• - intraventicular
  
  - meningeal
  

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• Infratentorial (60 70)
  
  - posterior fossa ataxia, nystagmus,
  dysmetria (presents as clumsiness or worse
  handwriting)
  - brainstem multiple
  cranial nerve palsies, hemiparesis, spasticity,
  mood changes
• Spinal (2 5)
  
  - primary intramedullary pain (local
  back and root pain), motor and sensory
  disturbance
  -
  spinal metastases scoliosis, sphincter (bowel,
  bladder) disturbances, reflex changes

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Diagnostic evaluation

• Magnetic resonance and computed tomography
  basic imaging techniques for brain tumors
• Positron emission tomography help to
  distinguish tumors or lesions with a volume
  greater than 1 cm3
• Conventional radiography of the skull bone
  structure, separating off sutures ( due to ICP),
  calcification within the brain
• Special methods (for special indications)
  
  - brain scintigraphy
  
  - angiography
  
  -ultrasonography
  
  
  -myelography

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Additional diagnosis

• Cerebral fluid analysis ( to determine spread of
  the tumor to the spinal fluid)
• Electroencephalography
• Stereotactic biopsy

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Therapy

• Neurosurgery for maximum tumor removal and low
  morbidity depending on the location and extent of
  the tumor
  
  -often preoperative relief of intracranial
  pressure by ventriculoperitoneal or
  ventriculoarterial shunt
  - preoperative reduction of
  tumor edema by corticosteroids
  
  - in patients with seizures -
  anticonvulsive therapy

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• Radiotherapy extension and volume of
  irradiation depend on the biology and histology
  of the tumor, age of the child and combination
  with chemotherapy and neurosurgery
  
  - irradiation in children lt 3
  years of life only in special cases
• Chemotherapy depends on tumor type, location
  and age -efficacy and penetration depend on
  vascularization of the tumor

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MR spectra and MR images of medulloblastoma
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8-year-old girl with juvenile pilocytic
astrocytoma
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2-year-old boy with atypical teratoid-rhabdoid
tumor
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• Neuroblastoma

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• Malignant, embryonal tumor derived from precursor
  cells of sympathetic ganglia and adrenal medulla
• Other types of tumors derived from sympathetic
  nervous system
  
  -ganglioneuroblastoma
  -ganglioneuroma
  
  -pheochromocytoma
• Possibility to spontaneous regression and
  differentiation to benign tumor in infants less
  1 year of age
  
  extremely malignant in older children

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Epidemiology

• 8 of all neoplasms in children
• Most frequent malignant neoplasm in infants
• Mean age at diagnosis 2 5 years

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Pathology

• Two distinct entities
  1.
  possibility of spontaneous regression (apoptosis
  or differentiation into ganglioneuroblastoma)
  2.
  chemosensitive, chemocurable
  3. chemoresistant malignancies

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Molecular cytogenetics

• MYCN oncogene amplification.
  
  MYCN is located on chromosome 2p.
  
  
  Independent prognostic factor
  in
  stage III EFS for patients with a single copy
  is 80
  for those with amplification MYCN 20
• DNA ploidy hyperploidy good prognosis
• Nerve growth factor receptor ligands for high
  affinity tyrosine kinase receptors TRKA, TRKB,
  TRKC
  -TRKA expression
  is associated with MYCN single copy, low stage
  and good prognosis
  
  - TRKA (-) MYCN amplification very poor
  survival
• Structural and numerical abnormalities of
  chromosome 1
  

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Clinical manifestation

• Occurence in any area with sympathetic nervous
  system
  
  Primary location
  
  -abdomen
  65
  -adrenal medulla
  or sympathetic ganglia 46
  -posterior
  mediastinum 15
  -pelvic
  4
  -head and neck
  3
  -others
  8
  

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2-year-old-girl with abdominal neuroblastoma
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Horners syndrome
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Cancer cachexia
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Common symptoms

• Weight loss
• Fever
• Abdominal disturbances
• Irratability
• pain of bones and joints
• Child not stand up, not walk
• Pallor
• Lassitude

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Symptoms associated
with catecholamine
production

• Paroxysmal attacks of sweating, flushing, pallor
• Headache
• Hypertension
• Palpitation

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Paraneoplastic syndromes

• VIP syndrome untreatable diarrhea,with low level
  of potassium
• Opsoclonus
• Anemia, trombocytopenia, leukopenia( in bone
  marrow infiltration or massive hemorrhage)

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Local symptoms

• Abdomen
  
  -intra-abdominal tumor retroperitoneal
  locationparavertebral and presacral
  -neurological dysfunction -abdominal distension
• Liver
  
  -hepatomegaly
• Chest, posterior mediastinum, vertebrae
  -compression of
  trachea gt coughing, dyspnea
  -infiltration in vertebral foramina
  gt dumbbell tumor
  -compression of nerves gtdisturbances of gait,
  muscle weakness, parasthesia, bladder
  dysfunction, constipation

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• Eyes
  
  -periorbital edema, swelling, yellow- brown
  ecchymoses
  -proptosis and
  exophthalmos, strabismus, opsoclonus
  
  -papillary edema, bleeding of the retina,
  atrophy of the optic nerve
• Neck
  
  -cervical lymphadenopathy
  
  -supraclavicular tumor
  -Horner syndrome
  enophthalmos, miosis, ptosis, anhydrosis

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• Skin
  
  -subcutaneous
  nodules of blue color gt reddish gt white
  owing to vasoconstriction from release of
  catecholamines after palpation
  
  - nodules are mainly observed in
  neonates or infants with disseminated NBL
• Bone
  
  -pain
  
  involvement mainly in the skull
  and long bones
  - in X-rays lytic defects
  with irregular margins and periosteal reaction
• Bone marrow
  
  -trombocytopenia, anemia

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Metastases

• Lymphatic and/or hematogenous spread
• Often initially present in children
  (40 50 children lt
  1 year and 70 children gt 1 year)
• Metastatic spread mostly in bone marrow, bone,
  liver, skin

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International Staging System for NBL(INSS)

• 1 - localized tumor with complete
  excision,lymph nodes negative
• 2a - localized tumor without incomplete gross
  excision, representative, ipsilateral nonadherent
  lymph nodes negative for tumor microscopically
• 2b ipsilateral nonadherent lymph nodes positive
  for tumor. Enlarged contralateral lymph nodes
  negative microscopically
• 3 unresectable unilateral tumor infiltrating
  across the midline,with or without regional lymph
  node involvement or localized unilateral tumor
  with contralateral regional lymph node
  involvement or midline tumor with bilateral
  extension by infiltration or by lymph node
  involvement
• 4 any primary tumor with dissemination to
  distant lymph nodes, bone, bone marrow, liver,
  skin or other organs (except as defined for stage
  4S
• 4s localized primary tumor (as defined for
  stages 1, 2a, 2b) with dissemination limited to
  skin, liver or bone marrow limited to infants
  aged less than 1 year)

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Laboratory findings

• Tumor markers
  
  -catecholamines
  
  vanillylmandelic acid (VMA), homovanillic acid
  (HVA) dopamine in urine/ plasma
  
  adrenaline, noradrenaline
  
  -neuron-specific enolase (glycolitic enzyme of
  brain and neuroendocrine tissues) -NSE
• Ferritin
• Lactate dehydrogenease (LDH)
• Bone marrow (aspiration and biopsy)
  

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Locoregional involvement

• Computed tomography scan and/or
• Ultrasound and/or
• magnetic resonance imaging gt localize the mass,
  provide measurements, give anatomical information
  about intra- and extraperitoneal structures,
  differentiate cystic from solid tumors, define
  the extent of a primary tumor and its
  relationship with other structures, detect small
  calcification

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Evaluation of metastases

• Bone marrow metastases bone marrow aspiration
  and trephine biopsy
• Skeletal metastases - X-ray, Tc-99 scintigraphy,
  
• mIBG scintigraphy demonstrates primary, residual
  tumor masses,diffuse bone marrow infiltration,
  skeletal, lymph node and soft tissue metastases
• FDG-PET scanning

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Infant with neuroblastoma(stage 4S)
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Therapy

• Depends on age, stage, localization and
  molecular features at diagnosis
• Surgery
• Chemotherapy
• Radiotherapy
• Target radiotherapy (I-131-mIBG)
• Differentiation therapy(retinoids 13-cis and
  all-trans)
• Immunotherapy anti-GD2 antibodies

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Prognosis

• Depends on
  
  -age (favorable if less than 18 months of age at
  diagnosis), -stage and localization (favorable in
  primary NBL of thorax, presacral and cervical)
  
  -involvement of lymph nodes (poor prognosis)
• Low-risk group - 90 long-term survival
• Intermediate and high-risk groups
  -response to initial
  treatment 60-70 of children with complete or
  partial remission
  -after consolidation therapy
  (high-dose chemotherapy autologous stem cell
  support) EFS after 3 years is 40-60

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CT image with large abdominal neuroblastoma
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Neuroblastoma FDG-PET scans
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123-MIBG scintscan