Tumour expressions of hypoxic markers predict the response to neo-adjuvant chemotherapy in children with inoperable rhabdomyosarcoma.

Objective: The study was to assess whether tumour expressions of hypoxia-inducible factor (HIF)-1α, glucose transporter (GLUT)-1, carbonic anhydrase (CA) IX and vascular endothelial growth factor (VEGF) predict response to neo-adjuvant chemotherapy (naCHT) in children with inoperable rhabdomyosarcoma (RMS). Methods: Immunohistochemical expressions of hypoxia markers were determined semi-quantitatively in tumour tissue microarray of 46 patients with embryonal RMS (RME) and 20 with alveolar (RMA), treated with CWS protocols (1992-2013). Results: In paediatric RME, response to naCHT was influenced significantly by tumour expression of CA IX and GLUT-1. Patients with RMA with low expressions of analysed markers responded well to naCHT, while all poor-responders expressed highly hypoxia markers. Only 5.88% of RMA and 11.11% of RME tumours did not express any of the proteins. In both RME and RMA subgroups, most poor-responders demonstrated simultaneous high expression of ≥3 markers, while most patients expressing ≤2 markers responded well to naCHT. In the whole cohort, co-expression of ≥3 markers, was the only independent factor predicting poor-response to chemotherapy (odds ratio 14.706; 95% CI 1.72-125.75; p = 0.014). Conclusions: Immunohistochemical expression pattern of four endogenous markers of hypoxia, in tumour tissue at diagnosis, emerges as a promising tool to predict response to naCHT in children with inoperable RMS.

Immunohistochemical assessment of cyclin D1 and p53 is associated with survival in childhood malignant peripheral nerve sheath tumor.

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is rare, aggressive soft tissue sarcoma which may affect children. OBJECTIVE: We aimed to assess prognostic significance of immunohistochemical (IHC) markers, osteopontin, fibronectin, survivin, cyclin D1 and p53, in pediatric MPNST. METHODS: A total of 26 pediatric MPNST patients were enrolled in the current study with a median follow-up of 51 months. IHC staining using commercially available monoclonal antibodies were employed to detect analyzed antigens on tissue microarrays. Eventually, all markers were subclassified to high (H) and low (L) expression categories in all analyzed tumors. RESULTS: High IHC expressions of survivin, cyclin D1, osteopontin, fibronectin, and p53 were detected in 18 (69.2%), 13 (50%), 16 (61.5%), 16 (61.5%), and 13 (50%) tumors, respectively. A significant correlation was demonstrated between cyclin D1 and osteopontin (p= 0.004). Both markers were associated with neurofibromatosis type 1 (NF1) status (p= 0.041 and p= 0.037, respectively). H-fibronectin was more prevalent in deeply located tumors (p= 0.046). None of the markers was associated with IRS stage, age at diagnosis, and tumor size. Univariate analysis identified IRS stage, regional lymph node metastases, NF1, and cyclin D1 as variables associated with overall survival (OS), whereas tumor depth, osteopontin, and cyclin D1 - for relapse-free survival (RFS). Subsequent multivariate analysis identified cyclin D1 and p53 as independent variables predicting RFS, whereas cyclin D1 and regional lymph nodes status were independent predictors for OS.

Tumor expression of survivin, p53, cyclin D1, osteopontin and fibronectin in predicting the response to neo-adjuvant chemotherapy in children with advanced malignant peripheral nerve sheath tumor.

PURPOSE: Selected cell-cycle regulators and extracellular matrix proteins were found to play roles in malignant peripheral nerve sheath tumor (MPNST) biology. We aimed to analyze whether initial tumor tissue expressions of survivin, p53, cyclin D1, osteopontin (OPN) and fibronectin (FN) correlate with the response to neo-adjuvant CHT (naCHT) in children with advanced inoperable MPNST. METHODS: The study included 26 children with MPNST (M/F 14/12, median age 130 months) treated in Polish centers of pediatric oncology between 1992 and 2013. Tissue expression of markers was studied immunohistochemically in the manually performed tissue microarrays and assessed semi-quantitatively as low and high, based on the rate of positive cells and staining intensity. RESULTS: Good response to naCHT was noted in 47.6%, while poor-in 52.4% of patients. The response to naCHT was influenced negatively by the presence of neurofibromatosis NF1 and high initial tumor tissue expression of OPN, survivin, p53 and cyclin D1. Patients with high tumor expression of either OPN, survivin or p53 and those with simultaneous high expression of ≥ 3 of the markers, responded significantly worse to naCHT, than patients, in whom expression of ≤ 2 markers were detected at diagnosis. Nearly, 85% of patients expressing ≥ 3 markers, responded poor to CHT; while 87.5% of children, expressing ≤ 2 markers, were good responders. CONCLUSION: The initial tumor tissue expression of OPN, survivin, p53 and cyclin D1 may serve as markers to predict response to naCHT in pediatric advanced MPNST. Future studies in more numerous group of patients are needed to confirm these preliminary results.

Osteopontin: its potential role in cancer of children and young adults.

OBJECTIVE: Osteopontin (OPN) is aglyco-phosphoprotein, involved in tissue remodeling, inflammation and boneresorption. In various adult neoplasms OPN was shown to correlate with cancer progression, invasiveness and metastasis. AIM: to define the role of OPN in malignancies of children and young adults. MATERIAL AND METHODS: a structured PubMed and Google Scholar literature analysis based on reports published in English between I'1995 and XII'2015. RESULTS: 14 studies (four on hematological malignancies, four on bone tumors, three on CNS tumors, two on dendritic proliferative diseases and one on renal tumors) were identified. Higher levels of serum and cerebro-spinal fluid OPN protein, and high expressions of OPN mRNA and SPP1 gene were present in more aggressive and advanced childhood malignancies. In children with acute lymphoblastic leukemia with CNS involvement and with atypical teratoid/rhabdoid tumor (AT/RT) and medulloblastoma, the serum and CSF OPN levels reflected tumor bulk and response to therapy, while in children with AT/RT and multisystem Langerhans cell histiocytosis with high-risk organs involvement, high OPN serum levels correlated with poorer survival. To the contrary, in osteosarcoma, high OPN mRNA and SPP1 gene expressions correlated with better survival and good response to chemotherapy. CONCLUSIONS: The literature review suggests that OPN may play important roles in the development and progression of selected cancers of children and young adults, including acute lymphoblastic leukemia, malignant gliomas, AT/RT and Langerhans cell histiocytosis. However, limited number of published studies prevents from definite concluding on the clinical utility of OPN as a marker of diagnosis, prognosis and treatment monitoring in these pediatric cancers. Further studies performed in more numerous groups of patients with particular types of cancers of children and young adults are warranted.

Pulmonary anthracosis mimicking lung metastases in pediatric rhabdomyosarcoma.

Although childhood rhabdomyosarcoma typically metastasizes to lungs, various processes may mimic metastatic etiology. Described herein is the case of an 8½-year-old boy with orbital embryonal rhabdomyosarcoma (RME) in whom three small foci were detected within both lungs on computed tomography. The lesion number and size, however, did not fulfil the Cooperative Weichteilsarkom Study Group 2006 protocol criteria for lung metastasis. Chemotherapy for localized RME produced primary tumor regression and vanishing of the left lung lesion. Two lesions in the right lung remained unchanged. On thoracoscopy multiple minute nodules disseminated in both lungs were detected. Histopathology excluded RME spread but indicated anthracosis in the lung parenchyma and intrapulmonary lymph nodes. Heavy smoking by parents and previous home furnace combustion appeared to be predisposing factors. Uncommon non-malignant intrapulmonary diseases, including anthracosis, should be considered when staging pediatric cancer.