Peripheral Primitive Neuroectodermal Tumor Research Articles

An Atypical Etiology of Mediastinal Lymphadenopathy: Extraskeletal Ewing Sarcoma

Background: Ewing's sarcomas and peripheral primitive neuroectodermal tumors are high grade malignant neoplasms, arising from bone and soft tissues and are grouped in the Ewing family of tumors. Primary localization in the mediastinum is extremely rare and was treated in only a few case reports. Lymphatic localization has never been reported. We present a case of an extraskeletal Ewing sarcoma arising from lymphadenopathy in the hilar and anterior mediastinal regions with literature review. Case presentation: A 24 year old man was admitted to our institution for persistent cough, nocturnal diaphoresis, and weight loss of 6 kg. The chest X-ray displayed opacity of the left hilum at polycyclic contours. Chest Computed tomography scan confirmed supradiaphragmatic lymphadenopathy in the hilar and anterior mediastinal. Biopsy was performed. Histological and immunohistochemical analysis showed small and round cells tumor with positive staining for CD99 and vimentin, and negative staining of desmine, myogenine, actine muscle lisse, Proteine S-100, Chromogranine, CD56, pancytokeratin, myeloperoxidase and TTF1. Young age, morphological and immunohistological characters argued in favor of a tumor of Ewing group .We could not perform molecular cytogenetic analysis, because of the lack of technical structure. The staging was negative for any other metastatic disease or primitive bone tumor, and final diagnosis was primary localized Ewing sarcoma in mediastinal nodes. The patient received Ewing’s sarcoma chemotherapy regimen. Complete response was achieved after six courses. Radiotherapy was prescribed, and the same chemotherapy regimen was continued totaling a period of one year. The patient was well with no evidence of local relapse or metastasis three years after diagnosis. Conclusion: Extraskeletal Ewing sarcoma should be contemplated in the differential diagnosis of mediastinal lymphadenopathy. With multimodal treatment, the patients are potentially curable.

Primary extraskeletal peripheral primitive neuroectodermal tumor of subcutaneous tissue neck in a young adult: A rare case report

Primitive neuroectodermal tumors (PNETs) are poorly differentiated small round cell neoplasms which primarily affect childhood age and very rarely seen in adults. Peripheral PNET (pPNET) cases are very rare compared to central PNET, and most of them originate from neural crest cells located outside the central nervous system. We report a case of large extraosseous pPNET arising from subcutaneous tissue of left side neck in a young male patient. Despite aggressive inherent nature of histology, structural complexity of neck area and poor predictors like tumor size >6 cm, extraosseous nature, this case advocate that complete resolution is possible with aggressive multimodal treatment including surgery, radiation therapy, and chemotherapy. Other major concerns in such cases of pPNET are difficulty in diagnosis due to low incidence, unpredictable site involvement, histological similarity with other round cell tumors and lack of established treatment guidelines.

Maksilladaki Primitif Nöroektodermal Tümörün Görüntüleme Bulguları: Olgu Sunumu ve Literatür Derlemesi

Primitive neuroectodermal tumor (PNET) is a term used to describe a group of highly malignant neoplasms composed of undifferentiated round cell tumors of neuroectodermal origin with variable cell differentiation. PNET generally occurs in the central nervous system (CNS), but peripheral PNET occurring outside the CNS has also been reported. The most common location of PNET in head and neck region is the orbit, followed by the neck and the parotid gland. PNET of the maxilla is rare. The aims of this report are to present the case of a 41-year-old female diagnosed with PNET tumor of the maxilla after detailed clinical, radiological, and histopathological examinations and to review the previously reported cases of PNET of the maxilla in the literature.

Comparison of Primary Spinal Central and Peripheral Primitive Neuroectodermal Tumors in Clinical and Imaging Characteristics and Long-Term Outcome

ObjectivePrimary spinal primitive neuroectodermal tumors are extremely rare entities. The purpose of this study was to analyze the differences in clinical and imaging characteristics and outcomes between primary spinal central PNETs (cPNETs) and peripheral PNETs (pPNETs). MethodsThere were 25 consecutive patients with primary spinal primitive neuroectodermal tumors enrolled. The diagnosis was cPNET in 6 patients with negative CD99 expression and pPNET in 19 patients with positive CD99 expression. Gross total resection (GTR) was achieved in 12 patients, subtotal resection was performed in 9 patients, and partial resection was performed in 4 patients. Postoperative chemotherapy was given to 14 patients, and radiotherapy was given to 16 patients. ResultsThe age at diagnosis was significantly younger in the cPNET group (mean 12.8 years) compared with the pPNET group (mean 22.5 years) (P = 0.040); the 2 pathologies did not show a significant difference in prognosis. GTR (P = 0.041), radiotherapy (P = 0.008), and GTR with radiotherapy (P = 0.009) were significant factors leading to a higher 2-year survival rate. Kaplan-Meier analysis showed that radiotherapy (P < 0.001) and GTR with radiotherapy (P = 0.040) resulted in a longer median survival time. Patients who underwent GTR, chemotherapy, and radiotherapy all together had the highest 1-year (100.0%) and 2-year (71.4%) survival rates and the longest median survival time (32 months). ConclusionsPatients with spinal cPNETs were younger compared with patients with pPNETs. The prognosis of spinal cPNETs and pPNETs was poor with no significant difference between the entities. The most beneficial treatment modality is GTR combined with adjuvant radiotherapy and chemotherapy.

A peripheral primitive neuroectodermal tumor in the larynx: A case report and literature review.

Primitive neuroectodermal tumors (PNETs) are malignant tumors comprised of small round cells of neuroectodermal origin. Current evidence indicates that peripheral PNETs (pPNETs), which arise in the non-central nervous system, possess histological similarity to Ewing's sarcoma. Though the occurrence of pPNETs in the head and neck region is rare, these are aggressive malignant tumors, and long-term survival rates following diagnosis remain poor. The current report presents a case of pPNET and evaluates its significance with regard to previous studies. In the present case, a tumor was located in the larynx of the patient, and was diagnosed as pPNET. Immunohistochemical analysis indicated that tumor cells were positive for cluster of differentiation 99. The patient was treated with surgery, multiagent chemotherapy and radiotherapy. Five years subsequent to treatment, the patient had survived and demonstrated no evidence of disease recurrence. In existing literature concerning pPNET located outside the head and neck region, it is recommended that patients are treated with a combination of resection with a wide surgical margin, multiagent chemotherapy and radiotherapy. The present case report concluded that the combination of surgery, systematic chemotherapy and radiotherapy, offers an improved outcome for pPNET localized to the head and neck region, compared with any of these therapies alone.

Clinical analysis of primitive neuroectodermal tumors in the female genital tract: A report of three cases

Primitive neuroectodermal tumors (PNETs) in the genital tract are very rarely encountered by gynecologists. They are a member of the Ewing sarcoma family. Primitive neuroectodermal tumors encompass a group of embryonic tumors with varying degrees of neuronal differentiation. Peripheral PNETs are small round blue cell tumors with a neuroectodermal origin [1]. Most PNETs of the genital tract occur in the ovary, and more rarely in the vulva, vagina, cervix, and uterus. The literature has only a few case reports and small case series on PNET of the genital tract. In this correspondence, we report three rare cases of PNET with genital tract origin that arose from the vulva, uterus, and ovary, and we assess the clinical characteristics of these neoplasms. We have diagnosed three cases of PNET of the genital tract, the clinical features of which are described in Table 1. The PNETs had a wide range of age distribution and clinical presentation. The tumors ranged in size from 4 cm to 35 cm. Medical histories and imaging studies alone are inadequate for a definitive diagnosis of PNET. Primitive neuroectodermal tumors can be diagnosed via histological investigation of a sample. It is characterized as small round cells with the formation of pseudo-rosettes and HomereWright rosettes [2].

Incidences of Primary Soft Tissue Sarcoma Diagnosed on Extremities and Trunk Wall: A Population-Based Study in Taiwan.

Most epidemiological studies of soft tissue sarcoma (STS) were performed in the Western countries, and only limited data highlighting that in the Asian population. The aim of this study is to conduct a comprehensive analysis for the incidence rates of STS in Taiwan.This was a population-based study analyzing the incidence rates and trends of the primary STS over extremities and trunk wall during 2003 to 2011 by using the nationwide Taiwan Cancer Registry. More specific analyses were conducted for subtypes. Incidence rates of overall STS by cities and counties were also investigated.A total of 3843 cases were diagnosed with STS during the study period, giving an age-standardized rate (ASR) of 1.63 per 100,000 person-years. Liposarcoma was the most frequent subtype, followed by undifferentiated pleomorphic sarcoma and leiomyosarcoma. STS was more frequently diagnosed in males and angiosarcoma was the most prominent sex-specific type. ASR increased with age in most of the STS subtypes and varied by histologic subtype. The incidence of peripheral primitive neuroectodermal tumor was highest in children, whereas rhabdomyosarcoma revealed a bimodal age distribution. Annual percent change (APC) of STS was 2.2%, and significant change in trend was only in males (APC, 3.5%, P < 0.05). Geographical variations indicated that New Taipei City had a significantly higher rate compared with the rest areas. Significantly lower rates were observed in 1 major offshore island.Incidence variations of STS by sexes, ages, histologic subtypes, and geographic regions were observed in Taiwanese population. The emerging factors associated STS incidence rates deserve further studies to verify.

A peripheral primitive neuroectodermal tumor originating from the pancreas: a case report and review of the literature.

A peripheral primitive neuroectodermal tumor (pPNET) is a small round cell tumor occurring mostly in children or young adults and categorized into the Ewing sarcoma family of tumors. pPNETs originating from the pancreas are especially rare, and only 25 cases have been reported in the literature. We report a case of a 22-year-old man who had a giant expansive tumor located in the uncinate process of the pancreas, 80 mm in diameter resulting in obstruction in the duodenum. The patient underwent a pancreaticoduodenectomy. The histological examination showed that the pancreatic tumor was composed of atypical small round cells. Immunohistochemical findings were positive for CD99. An Ewing sarcoma breakpoint region 1 gene 22q12 rearrangement was proven by a two-color fluorescence in situ hybridization assay. We diagnosed the tumor as a pPNET of the pancreas, which, according to the literature, is highly aggressive with poor prognosis. A multidisciplinary approach to treat these neoplasms should improve the prognoses.

Peripheral Primitive Neuroectodermal Tumor (pPNET) of the Penis: A Case Report and Literature Review

Primitive neuroectodermal tumors are derived from primitive neuroectodermal cells and belong to a highly malignant subgroup of round-cell tumors. Peripheral primitive neuroectodermal tumors of the penis are an extremely rare malignant form among penile neoplasms. These tumors are often difficult to diagnose due to atypical symptoms. Here, we report a case of a 24-year-old patient in China with a neoplasm localized at the base of his penis. The initial symptom was dysuria without any inducement. The results of blood and urine examinations indicated no abnormalities. The imaging examination results indicated a firm mass near the base of the penis. The hematoxylin and eosin (H&amp;E) staining revealed round, small tumor cells with heterotypical darkened nuclei. In addition, immunohistochemistry (IHC) revealed strong and diffuse positive staining for CD99 (mic-2), VIM (vimentin), and NCAM1/CD56 (neural cell adhesion molecule 1). In addition, 60% of cells were positive for the cell proliferation marker Ki-67. Based on the above results, the case was diagnosed with peripheral primitive neuroectodermal tumor (pPENT). We reviewed the literature from 1999 to 2013 and identified reports of pPENT with a low incidence and atypical symptoms. Accurate diagnosis with multiple detection technologies, including laboratory diagnostic tests, imaging, morphologic and immunologic examinations, is very important to reduce the misdiagnosis rate.

Clinical presentation and long-term outcome of primary spinal peripheral primitive neuroectodermal tumors.

Primary spinal peripheral primitive neuroectodermal tumors (pPNETs) are extremely rare entities that predominantly occur in children and young adults. Few studies have reported more than three cases. There are no current optimum treatment strategies due to the paucity of data. Here, we present 13 patients (nine females and four males) with primary intraspinal pPNETs who were surgically treated from April 2008 to February 2014. Histopathologic findings revealed the expression of CD99 in all cases. Limb weakness was the most common initial symptom (11/13, 85%). The tumors were located mainly at the cervical level (6/13, 46%) and in the epidural space (10/13, 77%). The radiological diagnosis was neurinoma or meningioma in most cases (10/13, 77%). Gross total resection was achieved in 77% (10/13) of patients. During a mean follow-up of 25.5months, local relapse occurred in 8 (61.5%) patients and distant metastases occurred in 8 (61.5%) patients. The overall 1-year survival rate was 77% (10/13), and the overall 2-year survival rate was 54% (7/13). The 2-year survival rate was 57.1% in patients with adjuvant chemotherapy and 50% in those without chemotherapy. Gross total resection and adjuvant radiotherapy with or without chemotherapy demonstrated a longer survival period (1-year survival rate: 100%; 2-year survival rate: 86%). Our data showed that primary spinal pPNETs are extremely rare and aggressive tumors with a poor prognosis. Radical resection is advocated. Gross total resection combined with adjuvant radiation may help to significantly improve patient survival period. Chemotherapy may also help to slightly prolong patient life.

Radiologic and clinicopathologic findings of peripheral primitive neuroectodermal tumors.

Primitive neuroectodermal tumors (PNETs) constitute a rare type of malignant neuroectodermal tumors that have chromosomal translocations identical to Ewing's sarcoma (ES), and the characteristics of this disease remain unclear. To describe the clinical, radiological, and pathological features of peripheral PNETs (pPNETs) to enhance their recognition. The clinical, imaging, and pathologic findings of 35 patients with pPNETs were retrospectively reviewed, all being confirmed by biopsy or surgical pathology. All 35 patients had preoperative computed tomography (CT) examinations; 10 patients had preoperative magnetic resonance imaging (MRI) studies. Of 35 pPNET patients, 54.3% had a primary tumor in soft tissue, the others in bone. On plain CT images, 33 lesions demonstrated heterogeneous hypodense masses with multiple lamellar lower density, and with osteolytic destruction if the tumor originated in bone. Calcification was only found in five lesions arising in soft tissue. All lesions enhanced heterogeneously with varying areas of cystic changes, and all lesions in bone and 52.6% of lesions in soft tissue showed ill-defined margins after contrast administration. On MRI, these tumors appeared in conjunction with osteolytic bone destruction and irregular soft tissue masses iso- to hypointense to skeletal muscle on T1-weighted images and showed heterogeneously high intensity on T2-weighted images. All lesions enhanced heterogeneously with cystic changes. Homer-Wright rosettes were observed in 15 lesions, and 97.1% lesions were positive for CD99 in histopathological results. pPNETs can involve any part of the body, and a large, ill-defined, aggressive soft tissue mass and heterogeneous enhancement with or without osteolytic bone destruction on CT or MR images could suggest the diagnosis.

Protective, elective lung irradiation in non-metastatic Ewing's sarcoma.

Ewing's sarcoma in childhood is a disease from family of the peripheral primitive neuroectodermal tumours. For a period of 16 y (1984-2000), 34 children with Ewing's sarcoma were treated and followed in our department. Twenty-seven of these patients were without distant metastases. Complex treatment was applied to all these patients-chemotherapy VACA (vincristine, actinomycin D, cyclophosphamide, adriamycin), local radiotherapy to a total dose of 50-56 Gy +/- surgery. After, a local tumour control was achieved in 11 children with non-metastatic Ewing's sarcoma, elective whole lung irradiation to a total dose of 12-15 Gy was applied. Our experience in these 11 patients with non-metastatic Ewing's sarcoma, in whom elective lung irradiation was applied, showed significant reduction in the lung metastases, improved free of disease survival and overall survival. The achieved good treatment results necessitate extending this treatment approach through defining the risk groups of patients, suitable for elective lung radiotherapy combined with chemotherapy in non-metastatic Ewing's sarcoma.

Radiological and clinical findings of osseous peripheral primitive neuroectodermal tumors.

Peripheral primitive neuroectodermal tumor (pPNET) is a rare and highly malignant undifferentiated type of tumor. The aim of the present study was to analyze the computed tomography (CT), magnetic resonance imaging (MRI) and clinical findings of osseous pPNET. The present study retrospectively analyzed the clinical data and CT findings from 15 patients with osseous pPNET; the MRI findings from 11 of these 15 patients were confirmed by histopathological examination. The 15 patients included 9 men and 6 women. The mean patient age was 29 years (range, 16-64 years) and 11 cases were aged <30 years. A CT scan was performed in 15 cases and the findings included a lytic lesion (13 cases), a lytic lesion with irregular sclerosis and dilation (2 cases), a soft tissue mass (15 cases), calcification (2 cases) and periosteal reaction (5 cases). A total of 9 cases of soft tissue mass were heterogeneous, with different sizes of lower-density necrotic areas. An enhanced MRI scan was performed in 11 cases. On T1-weighted images (WI), the soft tissue mass was isointense (8 cases) and marginally hyperintense (3 cases). On T2WI, aggressive soft tissue masses were heterogeneous iso- or hyperintense (11 cases). On contrast-enhanced T1WI, marked heterogeneous enhancement was present in 10 cases and intermediate heterogeneous enhancement in 1 case. The results indicated that osseous pPNET mainly affects male adolescents and young adults. The CT findings of osseous pPNET were destructive lesions with a soft tissue mass and, occasionally, with periosteal reaction. The tumor was often isodense, with patchy hypodense areas. Tumor calcification was uncommon. The MRI findings were those of an aggressive soft tissue mass exhibiting isointensity on T1WI and iso- or hyperintensity on T2WI, with marked heterogeneous enhancement. Although the imaging characteristics of pPNETs may be non-specific, CT and MRI may be useful in delineating the extent of the tumor, identifying distant metastases, predicting resectability and monitoring treatment.

Cyclin D1 is a useful marker for soft tissue Ewing's sarcoma/peripheral Primitive Neuroectodermal Tumor in children and adolescents: A comparative immunohistochemical study with rhabdomyosarcoma

Cyclin D1 amplification and/or overexpression contribute to the loss of the regulatory circuits that govern G1–S transition phase of the cell cycle, playing pivotal roles in different human malignant tumors, including breast, colon, prostate cancer, lymphoma, melanoma and neuroblastoma. In vitro studies have shown that cyclin D1 is overexpressed in Ewing's sarcoma (EWS)/peripheral Primitive Neuroectodermal Tumor (pPNET), but not in rhabdomyosarcoma cell lines. Only a few immunohistochemical studies are available on cyclin D1 expression in EWS/pPNET, which confirmed its expression only in a limited number of cases. The aim of the present study was a comparative immunohistochemical analysis of the expression and distribution of cyclin D1 in a large series of pediatric/adolescent soft tissue EWS/pPNETs and rhabdomyosarcomas (both embryonal and alveolar subtypes) to assess its potential usefulness in their differential diagnosis. Notably cyclin D1 was strongly and diffusely expressed in all cases (20/20) of EWS/pPNET, while it was lacked in all cases (15/15) of rhabdomyosarcomas. Immunohistochemical overexpression of cyclin D1 in EWS/pPNET is a novel finding which could be exploitable as a diagnostic immunomarker for this tumor. Although highly sensitive, cyclin D1 is not specific for EWS/pPNET, and thus it should not be evaluated alone but in the context of a wide immunohistochemical panel. Accordingly, we first emphasize that when pathologists are dealing with a small round blue cell tumor of soft tissues in pediatric/adolescent patients, a strong and diffuse nuclear expression of cyclin D1 is of complementary diagnostic value to CD99 and FLI-1 in confirming diagnosis of EWS/pPNET and in ruling out rhabdomyosarcoma.

Peripheral neuroectodermal tumour of the kidney (Ewing's sarcoma): Restaging with (18)F-fluorodeoxyglucose (FDG)-PET/CT.

Primitive peripheral neuroectodermal tumour and Ewing's sarcoma (PNET/EWS) were originally described as two distinct pathologic entities, although both share common stem-cell precursor and unique chromosomal abnormality. Although its incidence has increased recently, its share in all sarcomas is 1%. It is usually seen in men and women in their twenties. We present a case of a 38-year-old woman with a left renal mass detected incidentally. Magnetic resonance imaging revealed a centrally located hypervascular renal mass with diameter of 6 cm with non-homogenous contrast enhancement containing necrotic and calcific areas. The patient was diagnosed as having PNET/EWS by histopathological examination following radical nephrectomy. Para-aortic lymph node metastasis was found on imaging by (18)F-fluorodeoxyglucose (FDG)-positron-emission tomography/computed tomography (PET/CT).

The Rare Presentation of Extraskeletal Ewing's Sarcoma on the Forehead.

The Rare Presentation of Extraskeletal Ewing's Sarcoma on the Forehead.

Peripheral primitive neuroectodermal tumor of the small bowel mesentery: Report of a case

Primitive neuroectodermal tumor or Ewing's sarcoma is a tumor of undifferentiated small round cells that arise from the soft tissues, and is believed to be of neural origin. It occurs most often in children, followed by adolescents and young adults. A case of a 24-year-old patient with ulcerostenosans Ewing's sarcoma of the initial part of the small intestine is presented in our paper. Reviewing the literature and using as an example the case of a female patient with signs of sideropenic anemia caused by primitive neuroectodermal tumor of the small intestine, an attempt was made to clarify the etiology, clinical presentation, diagnosis and therapy with the aim of its rapid detection and treatment. Mesenteric primitive neuroectodermal tumor is a rare neoplasm in adults, while it usually occurs in children and young adults. Surgical resection of the lesions with the application of chemotherapy is the main form of treatment of patients suffering from this disease.

Clinical outcomes of 36 children with peripheral primitive neuroectodermal tumor receiving comprehensive therapy

Objective: To investigate the clinical features of children with peripheral primitive neuroectodermal tumor (pPNET) and the efficacy of comprehensive therapy in these patients. Methods: The medical records and the follow-up information of 36 children with pPNET were collected and reviewed. All these patients received surgery, chemotherapy and radiotherapy between January 2002 and January 2013 in Tianjin Medical University Cancer Institute and Hospital. The therapeutic effect, recurrence rate and 1-, 3- and 5-year overall survival rates were analyzed. Results: At the end of the comprehensive therapy, 30 cases achieved complete remission, 2 cases achieved partial remission, 2 cases were in stable disease, one case had progressive disease, and one died of pPNET; the response rate reached 94.4%. By the end of the follow up, 14 (46.7%) cases had tumor recurrence; sixteen cases had a disease-free survival, 4 cases survived with tumor, while 12 cases died of recurrence and 4 cases died of tumor progression. The median survival time was 29 months. The 1-, 3- and 5-year overall survival rate of all 36 cases were 94.4%, 50.0% and 30.6%, respectively. The median survival time of cases who were initialy diagnosed of metastatic pPNET was poorer than that of the cases who were initialy diagnosed of pPNET without metastasis (10 months vs 33 months, P = 0.001). Conclusion: Children with pPNET have very poor prognosis. Those who are initialy diagnosed of pPNET without metastasis have a better clinical outcome, while those who develop the recurrence or metastasis have a poor prognosis. DOI:10.3781/j.issn.1000-7431.2014.33.536

Peripheral primitive neuroectodermal tumor of the kidney in a 51-year-old female following breast cancer: A case report and review of the literature.

Peripheral primitive neuroectodermal tumor/Ewing’s sarcoma (pPNET/EWS) is an aggressive type of sarcoma that is rarely observed in the kidney. pPNET of the kidney principally occurs in young patients (<50 years old) and is very rare in older patients (≥50 years old). Additionally, only six cases of pPNET of the kidney have been reported in the literature in older patients (≥50 years old), and pPNET as a secondary primary tumor has rarely been reported. The current study presents a case of renal pPNET in a 51-year-old female who had been surgically treated for breast carcinoma and administered with adjuvant chemotherapy five years prior to hospitalization for pPNET. A computed tomography scan identified a tumor in the lower pole of the right kidney, which was treated by nephrectomy. Immunohistochemistry demonstrated diffuse, strong membranous positivity for cluster of differentiation (CD)99, positive nuclear staining for friend leukemia integration 1, and negative staining for Wilms’ tumor 1 and other markers. Fluorescence in situ hybridization (FISH) analysis of the EWS breakpoint region 1 (EWSR1) demonstrated the characteristic EWSR1 translocation. The patient declined chemotherapy or radiotherapy but accepted traditional Chinese medicine. No evidence of recurrence was observed eight months after diagnosis. Only two cases of renal pPNET with a history of an earlier or synchronous primary cancer were reported in the literature from the USA and Germany, respectively. To the best of our knowledge, the present case is the first FISH-confirmed renal pPNET in an older patient following breast adenocarcinoma.

Abstract A19: Epigenetic drug combination induces genome-wide demethylation and altered gene expression in neuro-ectodermal tumor-derived cell lines

Abstract Background: Epigenetic alterations are inherent to cancer cells, and epigenetic drugs are currently primarily used to treat hematological malignancies. Pediatric neuro-ectodermal tumors originate from neural crest cells and also exhibit epigenetic alterations involving e.g. apoptotic pathways, which suggests that also these tumors may be sensitive to epigenetic drugs. This notion prompted us to assess molecular and functional effects of low dosage epigenetic drugs in neuro-ectodermal tumor-derived cell lines of pediatric origin. Results: In 17 neuroblastoma (NBL) and 5 peripheral primitive neuro-ectodermal tumor (PNET) cell lines a combination treatment of 5-aza-2′-deoxycytidine (DAC) and Trichostatin A (TSA) at nanomolar dosages was found to reduce proliferation and to induce wide-spread DNA demethylation, accompanied by major changes in gene expression profiles. Approximately half of the genes that were significantly up-regulated upon treatment exhibited a significant demethylation in their promoter regions. In the NBL cell lines, almost every cellular pathway (193/200) investigated showed expression alterations after treatment, especially a marked up-regulation of genes in the p53 pathway. The combination treatment also resulted in up-regulation of known epigenetically regulated genes such as X-chromosomal genes, tissue-specific genes and a limited number of imprinted genes, as well as known tumor suppressor genes and oncogenes. Conclusions: Nanomolar dosages of epigenetic drugs have a dramatic impact on the genomes of neuro-ectodermal tumor derived cell lines, including alterations in DNA methylation and concomitant alterations in gene expression. Citation Format: Max M. van Noesel, Floor A M Duijkers, Renee X. de Menezes, Dominique J. P. M. Stumpel, Pieter Admiraal, Rob Pieters, Jules P P Meijerink. Epigenetic drug combination induces genome-wide demethylation and altered gene expression in neuro-ectodermal tumor-derived cell lines. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A19.