Central nervous system malignancies

1
Central nervous system malignancies
2
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)

3
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

4
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)

5
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

6
Clinical presentation

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

7
Signs of increased ICP

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

8

• 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

9

• Infants and younger children
  plasticity of the
  developing skull and inability to communicate
  symptoms gt
  -infant may be irritable, 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

10
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
  

11

• 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

12
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

13
Additional diagnosis

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

14
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

15

• 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

16
MR spectra and MR images of medulloblastoma
17
8-year-old girl with juvenile pilocytic
astrocytoma
18
2-year-old boy with atypical teratoid-rhabdoid
tumor
19

• Neuroblastoma

20

• 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

21
Epidemiology

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

22
Pathology

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

23
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 curable 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
  

24
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
  

25
Common symptoms

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

26
Symptoms associated
with catecholamine
production

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

27
Paraneoplastic syndromes

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

28
Local symptoms

• Abdomen
  
  -intra-abdominal tumor
• paravertebral 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

29

• 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,
• Raccon eyes

30

• 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

31
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

32
2-year-old-girl with abdominal neuroblastoma
33
CT image with large abdominal neuroblastoma
34
123-MIBG scintscan
35
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)

36
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)
  

37
Locoregional involvement

• Computed tomography scan and/or
• Ultrasound and/or
• magnetic resonance imaging ?
  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

38
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

39
Therapy

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

40
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

41
Hepatic tumors
42

• Malignant
  
  -hepatoblastoma 43
  
  -hepatocellular carcinoma 23
  -sarcoma
  6
• Benign
  
  -vascular (haemangioma,haemangioendothelioma)
  13 -hamartoma
  6
  -others 9

43
Incidence (malignant)

• -1.2 5 of all neoplasms in childhood
  
• Boys girls 1.4 2 1
• High incidence in genetically associated
  syndromes
  -Beckwith-Wiedemann syndrome, familial
  adematous polyposis, trisomy 18, glycogen
  storage disease, hereditary tyrosinemia,
  Li-Fraumeni syndrome
• HBL mostly in infants, rarely after the age of
  3 years
• Hepatocellular Ca in older children, in
  adolescents, after hepatitis B

44
Clinical symptoms

• Abdominal mass and/ or abdominal distention
• Anorexia, weight loss
• Lethargy
• Jaundice and ascites
• Abdominal pain
• Pallor
• Precocious puberty (hepatoblastoma), virilization
  (due to gonadotrophin production by the tumor)
• Generalized osteoporosis (HBL)- tumor cells
  secrete osteoclast-activating factor

45
Laboratory diagnosis

• Serum AFP elevated in 80 - 90 of children with
  HBL and in 60-70 with hepatocellular Ca
• B-HCG elevated in both
• Increased bilirubin
• Increased serum aspartate aminotransferase
  (AST), alanine transaminase (ALT) because of
  associated hepatitis or cirrhosis
• Anemia, thrombocytosis, trombocytopenia (rarely)
• biopsy

46
Radiological diagnosis

• Ultrasound liver enlarged, displacement of
  stomach and colon, elevated diaphragm on the
  right side
• CT, MRI
• Liver scintigraphy
• metastases chest X-ray, lung CT
• HBL
  
  
  hepatocellular carcinoma

47
Treatment

• Presurgical chemotherapy (makes HBL resectable)
• Complete resection (initially gt 50 of liver
  tumors are not totally resectable)
• Liver transplantation
• Prognosis
• Depends on stage of the tumor
  
  after complete tumor
  resection and chemotherapy 65-75
  children with HBL
  and 40-60 with
  hepatocellular Ca survive

48
Germ cell tumors (GCT)
49

• Develop from embryonal germ cells
• Represent ectodermal, endodermal and mesodermal
  lineages
• Approximately 3 of childhood malignancies
• Annually 2.4 3.8/ 1 million/per year
• 2/3 GCTs in children occur in extragonadal sites
• The commonest GCT - sacrococcygeal teratoma
• Bimodal age distribution
  
  one peak in children lt 3y ears of age
  (sacrococcygeal tumors, yolk sac tumors of
  testis)
  
  - the later- the later GCT of the ovary,
  testis, and intracranial sites

50
Histological classification of gonadal and
extragonadal tumors

• Germ cell and germinoma/ dysgerminoma and
  embryonal yolk sac tumor (pluripotent cells)
  
  a)extraembryonic
  structures
  - yolk sac
  or endodermal sinus tumor
  -
  choriocarcinoma
  
  b) embryonal ecto-, meso-, endodermal
  origin tissues represented
  -teratoma
  
  c) embryonal carcinoma
• Gonadal germ cells and stroma tumor (Sertoli and
  Leydig cells)
• Epithelial cells (ovarian origin) and granulosa
  cell tumor or mixted form as well as epithelial
  cell tumors more common in adults

51
Clinical symptoms

• Testicular GCT scrotal enlargement,hydrocele
• Ovarian tumors abdominal pain, acute abdomen,
  abdominal mass
• Extragonadal GCT main sites of involvement
  -sacrococcygeal
  
  t.1- (47)
  predominantly external,
  t.2 -both external and
  intrapelvic
  t.3 -external, pelvix and abdominal
  
  t.4 entitely presacral,
  -mediastinal
  (dyspnea, wheezing, thoracic pain, superior vena
  cava syndrome),
  -intracranial (visual
  disturbances, diabetes insipidus,
  hypopituitarism, anorexia, precocious puberty)

52
Ovarian and testicular GCT
53
Sacrococcygeal tumor in newborn
54
Diagnostics

• Radiological diagnosis
  
  ultrasound, computed tomography or
  magnetic resonance imaging
• Tumor markers
  
  alpha-fetoprotein (AFP)- globulin produced in
  the fetal yolk sac, in embryonal hepatocytes and
  in gastrointestinal tract. Increase in malignant
  GCT, hepatoblastoma
• Newborns
  48,000/-34,000IU
• Up to 1 month
  9,000/-12,000
• Up to 2 months 320
  /-280
• Up to 4 months 74
  /-56
• Up to 6 months 12/-10
• Up to 8 months 8/-5
  
  beta -human chorionic gonadotropin (HCG)
  increase in germinoma/ dysgerminoma,
  choriocarcinoma

55
Therapy

• Depend on
• stage, location, tumor markers level
• Surgery in stage I
• Advanced stages chemotherapy, surgery,
  radiotherapy
• Survival
• 95 - sacrococcygeal teratoma
• 80 -yolk sac tumor

56
Wilms tumor

• Nephroblastoma

57

• Malignant embryonal tumor of renal tissue
  consisting of varying proportion of blastema,
  stroma and epithelium
• Epidemiology
  6 of
  all neoplasms in children
  80 of children at
  diagnosis are less than 5 years old
  peak incidence between 2nd and 3rd year of age
  - incidence slightly higher
  in boys

58
Genetics

• Chromosomal association
• Chromosome 11p13 with Wilms tumor suppressor gene
  WT1 in 10-30 of nephroblastoma
• Chromosome 11p15 with Wilms tumor suppressor gene
  WT2
• Chromosome 17q with familial FWT-2
• Association with congenital anomalies
  
  -WAGR syndrome Wilms tumor, aniridia, genital
  malformation, mental retardation)
  
  -DenysDrash syndrome
  pseudohermaphroditism, glomerulopathy, mutation
  on chromosome 11p
  -Beckwith
  Wiedemann syndrome- hemihypertrophy,
  macroglossia, omphalocele, visceromegaly,
  associated with WT2

59
Clinical manifestation

• Abdominal mass- visible and/or palpable - 70.
  Palpation must
  be done with care risk of tumor rupture or
  dissemination!
• Fever
• Vomiting, anorexia
• Hematuria (micro or macro) 20-25
• Hypertension in renin-producing tumors
• Pain 44
• Special symptoms in association with congenital
  anomalies

60
Laboratory diagnosis

• Urine hematuria
• Chemistry high serum calcium in children with
  rhabdoid nephroblastoma
• Acquired von Willebrand coagulopathy in about 8
  of patients
• Differential diagnosis of NBL 24-h urine
  catecholamine analysis
• Biopsy only in children with unclear
  presentation or diagnosis

61
The child with Wilms tumor
62
Radiological diagnosis

• Ultrasound
• Computed tomography
• Magnetic resonance imaging
  anatomy of tumor
  extend of any spread within abdomen
  Metastases
• Chest radiographs (posteroanterior and lateral)
  to exclude pulmonary metastases
• Angiography may be indicated in bilateral
  nephroblastoma
• Radioisotope scans , skeletal survey in patients
  with suspected skeletal metastates
• CNS MRI in clear-cell sarcoma or rhabdoid kidney
  sarcoma and in patients with possible brain
  metastases

63
Wilms tumor pulmonary metastatic disease
64
Wilms tumor intraoperative view
65
Prognostic factors

• Histological appearance favourable,
  unfavourable
• Histology rhabdoid tumor
• Diffuse anaplasia
• Viable malignant cells after preoperative
  chemotherapy
• Infiltration of tumor capsule
• Invasion of tumor cells into vessels
• Nonradical surgical resection of tumor
• Lymph nodes involvement
• Tumor rupture
• Metastatic spread
• Large tumor volume

66
Stage

• National Wilms Tumor Study Group staging system
  I tumor
  confined to the kidney and completely resected
  
  II- tumor extend beyond the kidney but is
  completely resected (none at margins, no lymph
  nodes). At least one of the following has
  occured a)
  penetration of the renal capsule
  
  b) invasion of the renal sinus
  vessels
  c)biopsy of tumor
  before removal
• III- gross or microscopic residual tumor
  remains postoperatively including inoperable
  tumor, tumor at surgical margins, tumor spillage
  involving peritoneal surfaces, regional lymph
  node metastases or transected tumor thrombus
  
  
  IV- hematogenous metastases or
  lymph node metastases outside the abdomen (lung,
  liver, bone, brain)
  
  V bilateral renal Wilmstumor at
  onset

67
Treatment

• Preoperative chemotherapy gt surgerygt
  postoperative chemotherapy with or without
  radiotherapy
• Primary surgery in infants less than 6 months old
  and in adolescents (gt15years)
• Prognosis
• I stage 3year EFS 90
  II
  85
  III
  82
  IV
  58