Paediatric Pathology Online
Pathology of Neuroblastoma
Peripheral neuroblastic tumors (neuroblastoma, ganglioneuroblastoma,and ganglioneuroma) are among the most common solid tumours in childhood
Neuroblastoma is a malignant tumour arising from the developing sympathetic nervous system.
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It accounts for 7% of paediatric malignancies, and has a bimodal age distribution with peaks in the first year of life and between 2 and 4 years.
It has several interesting clinical associations including Hirschsprung’s disease and Ondine’s curse.
The tumour itself may have unusual manifestations such as opsomyoclonus or achlorhydria and watery diarrhoea (due to secretion of VIP).
It is the childhood cancer that most often shows spontaneous regression. Small adrenal lesions exactly resembling neuroblastoma ("in situ neuroblastoma") are found in incidentally in about 0.5% of perinatal autopsies presumably reflecting this tendency for regression.
The tumour may be congenital when it can cause hydrops fetalis, and may present in the newborn with massive liver involvement (Pepper's syndrome) and skin metastases (blueberry muffin baby).
The usual presentation is with a mass in the neck, thorax or abdomen.
Urinary catecholamine metabolites (Vanillylmandelic acid -VMA and Homovanillic acid - HVA) are raised in the urine, and calcification is often present radiologically.
The diagnosis is seldom difficult except in undifferentiated cases.
Neuroblasts with salt and pepper nuclei are interspersed with differentiating pre-ganglion cells, neuropil, rosettes and in some cases Schwannian stroma.
The difficulty is in classification and clinically meaningful grading.
Composed of neuroblasts , naked neutropil (ie. without Schwann cells) with or without rosettes.
May be undifferentiated , poorly differentiated (<5% of cells showing differentiation towards ganglion cells) or differentiating (>5% of cells showing tendency to differentiate).
Composed exclusively of mature ganglion cells, Schwann cells, neuritic processes and fibrous tissue.
A ganglioneuroblastoma (GNB) contains both elements, but is more than 50% ganglioneuroma.
The two components may be arranged in various ways.
In nodular GNB there are nodules of neuroblastoma, and the tumour behaves according to the grade of this less differentiated element.
Intermixed ganglioneuroblastoma shows unencapsulated groups of neuroblasts recognizable only on microscopy.
In borderline ganglioneuroblastoma the neuroblastomatous element is less conspicuous and shows more ganglion cell differentiation.
Shimada devised an elaborate scheme which uses a combination of age, presence of Schwannian stroma, ganglion cell differentiation and the mitotic-karyorrhexis index counted on 5000 tumour cells. This grading system is only valid when there are 4 large sections of untreated tumour available for assessment. It is prognostically useful in comparison to other grading systems.
Joshi developed a simpler system using only the presence or absence of calcification, and the mitotic count per 10 high power fields.
Pathologists also help with staging. Bilateral bone marrow trephines have been shown to be more sensitive than marrow aspirates. Their sensitivity is further increased by the use of immunohistochemical markers such as neurone specific enolase.
Care should be taken not to overlook foci of abnormal stroma which may represent regressed or matured neuroblastoma. These foci often mark for S-100 protein.
Prognosis is also affected by other biological markers which correlate to some extent with histological grade.
30% of cases show a deletion of the short arm of chromosome 1 which confers a poorer outlook.
Survival correlates with the degree of amplification of the N-myc oncogene (18 month progression free survival for tumours with 1 copy, 2-10 copies and >10 copies of N-myc is 70%, 30% and 5% respectively).
The presence of high levels of trk-A (part of the nerve growth factor receptor) predicts a good outcome. Triploid tumours do better than "diploid" tumours.
The progress is also inversely related to age at diagnosis.
This has prompted screening programmes using tests for urinary catecholamine metabolites in the first six months of life in some countries.
These programmes recognize preclinical neuroblastomas, but tend to pick up favourable prognosis tumours (low stage, low N-myc copy number, no del 1p) that perhaps would never have come to medical attention.
They miss many poor prognosis tumours that present at high stage in older children.
Expressions of Somatostatin Receptor Subtypes (SSTR-1, 2, 3, 4 and 5) in Neuroblastic Tumors; Special Reference to Clinicopathological Correlations with International Neuroblastoma Pathology Classification and Outcomes.
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