Retinoblastoma pathophysiology On the Web
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Retinoblastoma is a neoplasm which is caused by the inactivation of RB1 gene, a tumor suppressor gene, located on the long arm of the chromosome 13. Mutation in both alleles of the RB1 gene is necessary for the inactivation of the gene. This disorder may occur in the familial or sporadic form. (Rb) gene product limits the cell progression from the G1 phase to the S phase of the cell cycle. Loss of this active, functional protein (Rb) causes cell cycle dysregulation and subsequent overgrowth and tumor formation.
- Retinoblastoma is a neoplasm which is caused by the inactivation of RB1 gene, a tumor suppressor gene.
- Normally, RB1 gene is necessary for the normal differentiation and growth of retinal stem cells and its mutation results in unregulated growth of these cells and development of the tumor.
- Mutation in both alleles of the RB1 gene is necessary for the inactivation of the gene.
- This disorder may occur in the familial or sporadic form.
- In the familial form (48% of the cases), the first mutation occurs during germ cell division and the second mutation occurs later during the division of somatic cells.
- In the sporadic form, both mutations occur during the lifetime of the individual.
- (Rb) gene product limits the cell progression from the G1 phase to the S phase of the cell cycle.
- Active form of RB protein prevent the interaction of E2F, a transcription factor. Loss of this active, functional protein (Rb) causes transcribing the gene and subsequent cell cycle dysregulation, overgrowth and tumor formation.
- Retinoblastoma occurs due to mutational inactivation of RB1 gene located on the chromosome 13.
- The RB1 gene acts as tumor suppressor gene.
- Two mutational events are needed for the development of retinoblastoma.
- In familial form, with autosomal dominant inheritance, one mutation occurs in the germline and the second one during the somatic division of the retinal cells.
- In the acquired form, both mutations occur during somatic divisions.
- Another gene which has been associated with the pathogenesis of retinoblastoma is MYCN gene.
- Retinoblastoma may also occur as part of 13q deletion syndrome.
- This syndrome is the result of the deletion of the long arm of chromosome 13.
- Symptoms may vary according to the size of the deletion, but it may lead to developmental delay as well.
- Children with chromosome 13q14 deletions may develop retinoblastoma at a later age and they develop a unilateral tumor.
- Mosaicism, presence of RB1 gene mutation in some cells of the affected person, may occur in retinoblastoma.
- Heritable form of this disorder is associated with the development of non-ocular malignancies including:
- Macroscopic appearance of the tumor varies according to the staging of the tumor.
- The tumor is white and has areas of calcification and necrosis.
- The presence of calcium is more noticeable when the tumor is treated via prior chemotherapy or radiotherapy.
- The tumor can be classified into five sub-groups according to its growth pattern:
These growth patterns are described in the table below:
- Microscopically, retinoblastoma is characterized by:
- Retinoblastoma histopathology is a combination of undifferentiated cells and areas of tumor differentiation shown as rosettes and fleurettes.
- The most differentiated part is formed from a bouquet-like aggregates of cells called fleurettes, where mitoses or necrosis are not present.
- The rosettes are composed of cells with varying degrees of differentiation.
- There are two types of rosettes:
- Retinoblastoma may be classified according to the degree of differentiation to well/poor-differentiated.
- There is no specific immunohistochemical marker for the diagnosis of retinoblastoma.
- The most commonly applied marker is neuron specific enolase (NSE).
- Other useful markers are:
- Although there is no specific biomarker for the diagnosis of retinoblastoma, it may be needed for the diagnosis of undifferentiated form of the tumor.
- IHC may be useful for the identification of photoreceptors and glial cells in the retinoblastoma.
- IHC may also be useful in identifying the level of differentiation of the tumor by detecting red and green cones found in the rosettes and fleurettes and blue cones which do not form rosettes and fleurettes.
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