Central nervous system (CNS) tumors are the second most common group of malignancies among children; leukemias as a group are the most common. However, CNS tumors are the most common form of solid tumors in children. The overall average annual incidence rate for pediatric CNS tumors (ages 0–19 years) is 5.26 per 100,000 . Embryonal tumors are the most common CNS neoplasms in infants less than 36 months of age and are described by the World Health Organization (WHO) classification scheme as undifferentiated small round cell tumors with divergent patterns of differentiation . Embryonal Tumors include primitive neuroectodermal tumor (PNET), medulloblastoma (MB), atypical teratoid/rhabdoid tumor, and several other histology types. Though those tumors in this category are histologically similar, they have different patterns of incidence and survival, so it is important to look at them individually.
In USA (United States of America), the incident rate of CNS embryonal tumors under 14 years old is 0.8 per 100,000 and the median age is 9. In the age 0 ~ 4, the embryonal tumors are the most common histology, and between age 5 ~ 14, the embryonal tumors are still the third most common subtype compared with pilocytic astrocytoma . Conversely, there were few reports related with the large-scale follow-up or prognostic analysis of pediatrics CNS embryonal tumors in china.
MB comprises up to 20% of all pediatric brain tumors and is currently treated with surgical resection, radiation therapy, and chemotherapy . Molecular genetic parameters, being associated with poorer prognosis of MB, include overexpressed ERBB-2, high MYCC expression, and possibly p53 accumulation . The single most-predictive clinical factor is extent of disease at the time of diagnosis, patients with disseminated disease fare less well . Especially ERBB-2, belonging to the human epidermal growth factor receptor (EGFR) family, is overexpressed in 40% of MBs and its expression correlates with poor outcome . However, ERBB-2 expression in PNET is unclear and should be invested. PNET is histologically similar to classic MB and constitutes 2% of all childhood brain tumors. The most common sites of PNET onset are the cerebrum, suprasellar, or pineal region of children in their first decade of life . Because MB and PNET share the aggressive biological behavior, it is crucial to determine the prognostic factors for guiding the individual treatment.
Glioblastoma multiforme (GBM) is the second most frequently reported malignancy in CNS, which account for 15.6% of all primary brain tumors in adults. GBMs are more common in older adults and are uncommon in children . GBM is frustratingly chemoresistant and follows a highly aggressive course, with an average survival of roughly 1 year. Although small cells are common in GBM, they are predominant or exclusive in a subset known as small cell GBM . Small cell GBM is a histological subtype of GBM with characteristic features of highly proliferative, monotonous small glial cells with high nuclear cytoplasm ratio. In this study, we also focused on the prognostic research for small cell astrocytoma/GBM for the reason that it shares some similar features with embryonal tumors. The cytogenetical investigations for IDH1/2 mutation, 1p/19q loss, and PTEN alteration are strongly supportive methods for the differential diagnosis of small cell GBM . PTEN also represents a putative tumor suppressor gene in MB because loss of PTEN function would contribute to an over-activation of the PI3K/AKT signaling pathway, which is activated in MB . Mutations in the IDH1/2 genes are similarly detected in patients with non-glial tumors with the exception of PNET, which suggesting the unique mechanism of PNET shared with small cell GBM . Therefore, small cell GBM shares the similar genetics and histopathology features with MB and PNET, and we group them together as pediatrics CNS small cell tumors in this study.
The members of the EGFR family have been linked to the astrocytic tumors malignant transformation. This receptor family consists of four tyrosine kinase receptors, ERBB1-4, and seems to be involved in tumor cell proliferation, differentiation and cell survival . Due to overexpression of the ERBB1-4 proteins on the surface of neoplastic astrocytes, they are candidates for targeted therapy . Such treatment, however, requires reliable detection systems for these receptor proteins in tumor tissue. EGFR gene amplification can now simply be evaluated by means of fluorescence in situ hybridization (FISH) . Several studies have shown a varying degree amplification of the EGFR (ERBB1) gene, located on chromosome 7, in GBM . EGFR gene amplification distinguishes small cell GBM from anaplastic oligodendrogliomas , nevertheless the spectrum of clinicopathologic and prognostic features has not been explored fully in small cell GBM. And the other members of EGFR family expression levels and their correlation with prognosis are also unclear.
In china, according our investigation, most hospitals even only offer patient surgical resection without radiation or chemotherapy. It is important to raise the neurosurgeons and oncologic doctors attention for combining various forms treatment to increase young patients disease-free survival time and improve the quality of life. For pathologists’ responsibility, finding the prognostic factors of pediatrics CNS small cell tumors becomes the important task to give the physicians suggestion. This study was also designed to investigate the clinical features and the extent of ERBB-1 ~ 4 gene expression in the small cell GBM, PNET and MB. Further and most importantly, we assumed to explore the prognosis factors in children small cell CNS tumors.