Neuroblastoma

High level expression of Trk A gene is associated with a favourable outcome in neuroblastoma.

Favorable prognostic factors in neuroblastoma are: Age less than 1 year, Stage I and II, hyperdiploid or near diploid tumors.

Ref: Robbins Pathologic Basis of Disease, 6th Edition, Page 485, 487

Neuroblastoma originate from adrenals, peripheral nerves and posterior mediastinum.

Ref: O.P.Ghai 7th Ed Page 590-591,6th Ed page 573,Robbins 8th Ed page 476.

Ans.D all of the above

Neuroblastoma

o Neuroblastoma is a malignant tumor of the autonomic nervous system.

o It has the following peculiarities : –

o Most common abdominal cancer of childhood.

Most common cancer of infancy.

Most common extracranial solid tumor of childhood (most common solid tumor of childhood is brain tumor).

o It is a neuroendocrine tumor, arising from any neural crest element of the sympathetic nervous system.

o The primary tumor is localized in the sympathetic nervous system.

o The common sites of neuroblastoma are : –

(i)       Adrenal (most common)      (iii) Cervical area (Neck)               (v) Paravertebral retroperitoneum

(ii)     Pelvis                                 (iv) Posterior mediastinum

o Metastasis present in 60-70% of children at the time of diagnosis and the most frequent site of metastasis is the skeletal system (bones and bone marrow). Other common sites of metastasis are liver, lymph nodes, and skin. Metastasis to the lung is rare (<3%).

Ans. is ‘a’ i.e., Adrenals; ‘b’ i.e., Mediastinum

The common sites of neuroblastoma are : –                                                  

i)      Adrenal (most common)           iii) Cervical area (Neck)              v) Paravertebral retroperitoneum

ii)     Pelvis                                     iv) Posterior mediastinum

Answer is ‘c’ i.e. Hyperdiploidy

Ans. is ‘c’ i.e., Splenomegaly 

Clinical features-

• MC  site- adrenal medulla
• MC site of metastasis- Lymph node > bone > bone marrow
• Dancing eye syndrome & opsomyoclonus, Racoon’s eye sign.

• Diarrhoea, Proptosis, bone involvement

Ans. is ‘a’, ‘b’  Seen in adrenal glands, TVMA/HVA 

Neuroblastoma

• Neuroblastoma is an embryonal malignancy of the sympathetic nervous system arising from neuroblasts (pluripotent sympathetic cells).
• Neuroblastoma is the most common extracranial solid tumor in infancy and children. It is the third most common pediatric cancer after leukemia/lymphoma and brain tumor.
• Age, stage, and some molecular defects encountered in tumor cells are important prognostic factors and are used for risk stratification and treatment assignment. The differences in outcome for patients with neuroblastoma are striking.
• Infants younger than I year have a good prognosis, even in the presence of metastatic disease, whereas older patients with metastatic disease fare poorly, even when treated with aggressive therapy.
• Pathogenesis: NB includes a spectrum of tumors with variable degrees of neural differentiation, ranging from undifferentiated small round cells (neuroblastoma) to tumors containing mature ganglion cells (ganglioneuroblastoma or gangioneuroma).
• Clinical Manifestation.
• The median age at diagnosis is 2 yr; 90% of cases are diagnosed before 5 yr of age.
• The incidence is slightly higher in males and whites.
• NB may develop at any site of sympathetic nervous system tissue. The signs and symptoms of NB reflect the tumor site and extent of disease. Most cases of NB arise in the abdomen, either in the adrenal gland or in retroperitoneal sympathetic ganglia. This usually presents as a palpable mass in the flank or midline. NB may also originate from cervical, thoracic, or pelvic ganglia.
• NB may metastasize to various sites most common being long bones and skull, bone marrow, liver, lymph nodes,

• and skin. Lung metastasis are rare. Signs and symptoms associated with metastasis are: fever, irritability, failure

  to thrive, bone pain, bluish subcutaneous nodules, orbital proptosis, and periorbital ecchymoses.

  Neurological signs and symptoms seen with NB: Less commonly, NB causes neurological signs and symptoms. Location in the superior cervical ganglion can cause Homer’s syndrome. Paraspinal NB can invade the spinal canal and compress the cord or the nerve roots. NB can also present as a paraneoplastic syndrome of autoimmune origin-ataxia, opsomyoclonus.

• Biochemical marker

• – More than 90% of patients have elevated catecholamines: homovanillic acid (HVA) and/or vanillylmandelic acid (VMA) detectable in urine.

• Prognosis:
• The most important clinical and biologic prognostic factors currently used to determine treatment are the age of the patient at diagnosis , INSS staging, Shimada histology and various chromosomal and molecular markers(mainly MYCN status and ploidy/ DNA index for infants).

• Chromosomal and molecular markers

a)MYCN:

– The most important of these biologic markers is MYCN.

– MYCN is an overexpressed oncogene in neuroblastoma with the amplification of the distal arm of chromosome 2.

Patients whose tumors have MYCN amplification tend to have rapid tumor progression and a poor prognosis, even in the setting of other coexisting favorable factors such as low stage disease or 4S disease.

–  In contrast to MYCN, expression of the H-ras oncogene correlates with lower stages of the disease.

b) Deletion of the short arm of chromosome:

–  Deletion of the short arm of chromosome 1 is the most common chromosomal abnormality present in neuroblastomas, and it confers a poor prognosis. The 1p chromosome region likely harbors tumor suppressor genes or genes that control neuroblast differentiation.

c) DNA index:

–  DNA index is another useful test that correlates with response to therapy in infants. Infants whose neuroblastomas have hyperdiploidy (ie, DNA index >1) have a good therapeutic response to cyclophosphamide and doxorubicin. In contrast, infants whose tumors have a DNA index of 1 are less responsive to the latter combination and require more aggressive therapy.

–  DNA index does not have any prognostic significance in older children

• The survival rate 5 years from diagnosis is approximately 83% for infants, 55% for children aged 1-5 years, and 40% for children older than 5 years.

Answer is C (Lung Metastasis is common) :

Lung metastasis are rare in neuroblastoma – Nelson

Neuroblastoma is the most common extracranial solid tumor in childhood

Neuroblastoma is the second most common solid malignancy of childhood after brain tumors which makes it the most common extracranial solid tumor in childhood

Most common solid tumor in childhood: Brain tumorsQ

Most common extracranial solid tumor in childhood: NeuroblastomaQ Most common intra abdominal solid tumor in childhood: NeuroblastomaQ

Metastasis is present in > 50% of patients at the time of diagnosis

‘Metastasis is present in 60- 70% of patients at the time of diagnosis’ – Ghai 6^th /573

Metastasis to Lungs is Rare (uncommon)

‘Lung metastasis is rare occurring in < 3% of cases’ – Nelson 18^th / 2138

Common sites of metastasis in Neuroblastoma

• Long bones — skull, bone marrow
• Liver
• Lymph nodes
• Skin

Often Encases Aorta and its branches at time of diagnosis

‘Encasement of abdominal aorta and inferior vena cava by tumor is common’-Weuroblastoma’by Pochedly (1990)/154

‘Some neuroblastomas are sharply demarcated with a fibrous pseudocapsule but others are far more infiltrative and invade surrounding strictures including the kidney, renal vein, I V C and envelop the aorta’ – Robbins 7^th / 501

‘Wilm’s tumor does not encase the aorta whereas encasement is characteristic of neuroblastoma’

– Radiology Illustrated (2003) / 209 Note

Although encasement of aorta is likely to occur late in disease neuroblastomas are already metastatic (stage IV disease) at presentation in > 50% of patients. Hence encasement of aorta may be often found at the time of diagnosis.

Remember

Ans. is ‘a’ i.e., Trk-A expression absent 

Intratumoral calcification

DNA ploidy- Hyperdiploid or near-triploid

Trk-A Expression

CD-44 Expression

Ans.B. Chromogranin A

Neuroendocrine markers of neuroblastoma :- i) CD-56     ii) Chromogranin-A     iii) Synaptophysin