NeuroblastomaSYMPATHETIC EMBRYONAL NEUROBLASTOMA

NBL

Epidemiology of neoplasms in

children

Neoplasms of early childhood constitute

about 0,5- 2% of all neoplasms

Second most common cause of death in

children

Type and age stratification of neoplasms in

children different than in adults

Remember!!!

Diffrent course of development

Biology

Genetic differences

Neuroblastoma

Malignant cancer arising from neural crest

cells

One of the most common neoplasms in

children

30- 50% of all the tumours in infants

Proportion of neuroblastoma incidence in

boys to incidence in girls: 1,2:1

Epidemiology

60 - 70 new cases are diagnosed in Poland

each year

50% of tumours before the age of 2

90% before the age of 5

2/3 of infants with neuroblastoma have no

deviation in PE from the norm

!!! 60- 70% of cases are diagnosed in stage IV

Histologic division of tumours

arising from sympathetic nervous

system

Neuroblastoma

Ganglioneuroblastoma

Ganglioneuroma

Neurofibroma

Pheochromocytoma

Shaded areas represent neuroblasts, white areas are ganglioneuroma component

Three main types

of neuroblastoma

Histopathological examination

Neuroblastoma is a so called small round blue cell tumour

Histopathological view shows characteristic groups of small primitive cells with round or oval hypochromatic nuclei and small amount of cytoplasm.

Grainy chromatin is compared with grains of salt and pepper

.

Homer Wright rosettes

Clearly visible stages of mitotic divisions with apoptotic cells - Homer Wright rosettes, consisting of neoplasm cells organised in a ring-shape surrounding pale pink fibre material of their thin cytoplasmatic projections

Under the microscope

Ganglioneuroblastoma Neuroblastoma

Characteristic biological features

of a neuroblastoma

Possibility of a spontaneous remission, even

at advanced stages

In 85- 90% of cases tumour secreting

hormones

90% of patients show an increase in

neurospecific enolasis

Occurrence

It can develop where embryonal cells of the

sympathetic nervous system can be found

Most common place of primary

tumour

40% adrenal glands

25% abdominal ganglia

15% chest

2-5% neck

2-5% pelvis

Higher risk of incidence in children of mothers who*:

take fenytoin during gestation

often imbibe alcohol during gestation

use hair dye

take hormones

undergo diuretic treatment

There is no correlation between neuroblastoma incidence and smoking or drinking coffee by the mother or exposure to medical sources of ionising radiation.

Neoplasm is not more common in children with congenital defects, immunodeficiency syndromes and chromosome aberrations.

*Kramer S, Ward E, Meadows AT, Malone KE. Medical and drug risk factors associated with neuroblastoma: a case-control study. J Natl

Cancer Inst. 78. 5: 797-804 (1987)

Cytogenetic disorders

Amplification of N- myc (25- 50%)

protooncogene

DNA (ploidy) in tumour cells

In 25-35% of cases there is genetic

aberration of deletion in chromosome 1

(1p35-36)*.

*Presence of this chromosome aberration is related to unfavourable prognosis

Patient with a neuroblastoma

Neurofibromatosis

Hirschsprung disease

Heterochromy

Symptoms?

Drowsiness

Lack of apetite

Abdominal pain

Palness

Weakeness Irritability

Losing weight

Clinical symptoms of a number of diseases neoplastic and non-neoplastic!

Clinical symptoms

Atypical

Polimorphism resulting form various primary

tumour location, metabolic disorders and

various symptoms related to

metastases

Head and neck:

Head and neck:

Palpable tumour

Horner’s syndrome if tumour is located in the

cervical ganglia of the sympathetic system

Eye socket and eye:

Eye socket and eye:

Effusions and bruising around eyesocket

(periorbital ecchymoses = raccoon eyes), endophthalmos

Swelling of eyelids

and conjunctiva

Papilledema

Degeneration of optic nerve

Bleeding in retina

Strabismus

„ raccoon eyes”

Gabrysia

Chest

(mediastinum posterior):

Chest

(mediastinum posterior):

dyspnoea, cough, stridor

lung infections

chest pains

difficulty swallowing

neck swelling, CVSS

Lack of symptoms (tumours located in lower

part of chest)

Abdomen:

Abdomen:

growing paplable tumour, pushing kidney forward to the side and down

lack of apetite

vomiting

abdominal pains

loss of body mass

hypertension caused by tumour pressing on kidney vessels hepatomaegalia in case of metastasis to liver

sudden growth of tumour, pain, paleness, hypotonia in case of bleeding to tumour

CT

Spinal area:

Spinal area:

Localised back pain

Neurological disorders caused by pressure on spinal nerves

Paraplegy

Cauda equina syndrome

Cerebellum ataxia

Oversensitiveness

Muscle atrophy

Scoliosis

Bladder disorders

Sphincter disorders

Pelvis

constipation

anxiety while passing urine

urine retention

tumour palpable in per rectum examination

Skeleton:

anaemia resulting from bone marrow

infilitration

bone pain

anxiety (in younger children)

Skin and subcutaneous tissue:

Numerous subcutaneous nodules (characteristic of IV Stage neuroblastoma in infants, rarely after early childhood).

Numerous papular or nodular exanthema 2–20 mm in diameter, with bluish tinge (sometimes described in literature as blueberry muffins).

Exanthema has a tendency to become paler towards the middle and form erythemic halo after 2–3 minutes from rubbing the exanthema

These symptoms are related to blood vessels

contracting catecholamine released by

neoplasma cells.

Changes on skin occur on all body, but are

most common on torso and extremities.

Metastases

Bones

Bone marrow

Distant lymph nodes

Subcutaneous tissue, skin

other (lungs, CNS)

Paraneoplastic syndromes

General symptoms caused by

excessive production of

catecholamine

hypertension

occasional face reddening, sweating

heart palpitation

"mirror syndrome” *

*Newton ER, Louis F, Dalton ME, Feingold M. Fetal neuroblastoma and catecholamine-induced maternal hypertension. Obstet Gynecol. 65. 3

Suppl: 49S-52S (1985)

General symptoms caused by

excessive production of the VIP

Watery diarrhoea

Abdominal pain

Intestianal atonia

intense hipocalemia

Cerebral encefalopathy

(opsoclony mioclony syndrome)

Concerns 2-4% patients with neuroblastoma,

Etiology is not known.

Consists of:

sudden, chaotic eyeball movements,

progressive ataxia

irregular, myoclonic muscle spasms

Symptoms usually subside after removal of the primary tumour, but 70-80% of patients retain long-term neurologic defficiencies.

Internationa Neuroblastoma

Staging System (INSS)

· Stage 1: Localised confined tumour, completely removable, without mkicroscopic residual. Lymph nodes negative for tumour,

· Stage 2A: Localised tumour with incomplete gross excision representative ipsilateral nonadherent lymph nodes negative for tumor microscopically,

· Stage 2B: Localized tumor infiltrating across the midline with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive or negative for tumor. Enlarged contralateral lymph nodes must be negative microscopically.

·Stage 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 ,

· Stage 4: Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs, except as defined for stage 4S,

· Stage 4s: Localized primary tumor, as defined for stage 1, 2A, or 2B, with dissemination limited to skin, liver, and/or bone marrow (limited to infants younger than 1 year)

Diagnostics

Diagnosis on the basis of histopathological

confirmation of a neuroblastoma in the biopsy

of the tumour or bone marrow biopsy and

elevated level of catecholamine in plasma or

their metabolites in the urine (DA, A, NA,

VMA)

Evaluating the size of primary

tumour location and possible

metastases with imaging

abdominal US and CT

Chest X-ray/ CT

MR in uncertain cases

head X-ray/ CT

X-ray of long bones, scintigraphy

bone marrow biopsy, trepanobiopsy

Genetic evaluation

N-myc amplification

Deletion of the short arm of chromosome 1

Immunohistochemical

examination:

Positive reaction of neoplasm cells to:

synaptophisin,

chromogranin,

neurofilaments

Neuron-specific enolase (NSE)

Treatment

Depends on the stage and prognosis

Combined treatment

Prognosis:

General survival rate is 55%:

almost 100% at Stage I,

75% at II,

43% at III,

15% at IV (children before 1 year - 60 -70%)

70–80% at IVS

Patients with tumour localised in adrenal

glands have smaller chance of being cured.

Spontaneous remission*

spontaneous (idopathic) and complete

remission of tumour in metastatic stage was

described.

Ocurrence observed only in infant

neuroblastoma (diagnosed before the age of

1).

Type 4S constitutes around 5% of

neuroblastoma incidence.

*Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet. 369. 9579: 2106-20 (2007)

Developments in treatment

Immunotherapy

GD2 is a disialoganglioside present at the

tumour cells surface

anti-GD2 therapies are in clinical trials

* Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet. 369. 9579: 2106-20 (2007).

Topoisomerase 1 inhibitors

Topotecan and irinotecan achieve good results, especially

combined with cyklofosphamid.

Retinoids

Randomised research into the effectiveness of all-trans

retinoic acid after ablational chemiotherapy shows

potential effectiveness of retinoids in therapy of high-risk

patients

Angiogenesis inhibitors

Vascularisation of tumour correlates with the fenotype aggressiveness. Angiogenesis inhibitors are an attractive therapeutic alternative. Pre-clinical trials have so far been inconclusive.

Tyrosine kinases inhibitors

Small molecue kinasis inhibitor Trk, CEP-701 (KT-6587) demonstrated high effectiveness in suppressing the neuroblastoma cells growth in vivo. Clinical trials are in progress.

Radiotherapy:

Attempts at applying radiotherapy selectively

to neuboalstoma cells