Outcome of multidisciplinary treatment of peripheral primitive neuroectodermal tumor.

Peripheral primitive neuroectodermal tumors (PNETs) constitute very rare and aggressive malignancies. To date, there are no standard guidelines for management of peripheral PNETs due to the paucity of cases arising in various body sites. Therapeutic approach is derived from Ewing sarcoma family, which currently remains multimodal. Our study retrospectively analyzed 86 PNET patients from February 1, 1998 to February 1, 2018 at Peking Union Medical College Hospital with an additional 75 patients from review of literature. The clinicopathologic and treatment plans associated with survival was investigated. Surgery, chemotherapy, female sex, small tumor size, no lymph node metastasis, R0 surgical resection, (vincristine + doxorubicin + cyclophosphamide)/(isophosphamide + etoposide) regimen, and more than 10 cycles of chemotherapy were associated with improved overall survival in univariate analysis. Surgery, more than 10 cycles of chemotherapy, and small tumor size were independent prognostic factors for higher overall survival. Our data indicates that multimodal therapy is the mainstay therapeutic approach for peripheral PNET.

Primitive neuroectodermal tumour of the cervix: a rare diagnosis.

A 48-year-old woman presented with symptoms of lower abdominal pain and vaginal discharge for 6 months. Clinical examination and pelvic ultrasound scan suggested a diagnosis of infected Gartner's cyst, for which she underwent vaginal cystectomy. However, histopathology and immunohistochemistry revealed a diagnosis of primitive neuroectodermal tumour of the cervix. Further investigations revealed the stage to be FIGO IIIB, which was inoperable. She received neoadjuvant chemotherapy (vincristine, adriamycin, cyclophosphamide alternating with ifosfamide, cisplatin and etoposide, every 21 days), but the tumour did not respond to treatment and she was started on radiotherapy with definitive intent (55.8 Gray in 31 fractions over 6.2 weeks). A PET-CT performed 2 months after completion of radiotherapy showed complete response, and she is now receiving adjuvant chemotherapy.

L1-CAM knock-down radiosensitizes neuroblastoma IMR-32 cells by simultaneously decreasing MycN, but increasing PTEN protein expression.

Childhood neuroblastoma is one of the most malignant types of cancers leading to a high mortality rate. These cancerous cells can be highly metastatic and malignant giving rise to disease recurrence and poor prognosis. The proto-oncogene myelocytomatosis neuroblastoma (MycN) is known to be amplified in this type of cancer, thus, promoting high malignancy and resistance. The L1 cell adhesion molecule (L1-CAM) cleavage has been found upregulated in many types of malignant cancers. In the present study, we explored the interplay between L1-CAM, MycN and PTEN as well as the role played by PDGFR and VEGFR on tumorigenicity in neuroblastoma cells. We investigated the effect of L1-CAM knock-down (KD) and PDGFR/VEGFR inhibition with sunitinib malate (Sutent®) treatment on subsequent tumorsphere formation and cellular proliferation and migration in the MycN-amplified IMR-32 neuroblastoma cells. We further examined the effect of combined L1-CAM KD with Sutent treatment or radiotherapy on these cellular functions in our cells. Tumorsphere formation is one of the indicators of aggressiveness in malignant cancers, which was significantly inhibited in IMR-32 cells after L1-CAM KD or Sutent treatment, however, no synergistic effect was observed with dual treatments, rather L1-CAM KD alone showed a greater inhibition on tumorsphere formation compared to Sutent treatment alone. In addition, cellular proliferation and migration were significantly inhibited after L1-CAM KD in the IMR-32 cells with no synergistic effect observed on the rate of cell proliferation when combined with Sutent treatment. Again, L1-CAM KD alone exhibited greater inhibitory effect than Sutent treatment on cell proliferation. L1-CAM KD led to the simultaneous downregulation of MycN, but the upregulation of PTEN protein expression. Notably, radiotherapy (2 Gy) of the IMR-32 cells led to significant upregulation of both L1-CAM and MycN, which was abrogated with L1-CAM KD in our cells. In addition, L1-CAM KD radiosensitized the cells as exhibited by the synergistic effect on the reduction in cell proliferation compared to radiotherapy alone. Taken together, our data show the importance of L1-CAM interplay with MycN and PTEN on the MycN amplified neuroblastoma cell radioresistance, proliferation and motility.

Use of a tissue expander as a radio-protective spacer with a latissimus dorsi flap in the management of a peripheral primitive neuroectodermal tumour (pPNET).

Peripheral primitive neuroectodermal tumours (pPNET) are aggressive neoplasms that require radical surgical resection with adjuvant chemotherapy and radiotherapy. A pPNET of the posterior chest wall was resected with wide soft tissue margins in a 14 year old male. Following tumour excision a spacer device was positioned in the retroperitoneum adjacent to the ipsilateral left kidney displacing it from the planned radiotherapy field. A pedicled latissimus dorsi myocutaneous flap was used to achieve robust soft tissue cover. Ultrasound demonstrated anteromedial displacement of the left kidney with no hydronephrosis and renal function remained normal during subsequent radiotherapy. This report highlights the usefulness of a tissue expander in providing protection for vital structures during radiotherapy.

What's in a name? Intracranial peripheral primitive neuroectodermal tumors and CNS primitive neuroectodermal tumors are not the same.

BACKGROUND: Intracranial peripheral primitive neuroectodermal tumors (P-PNET) are extremely rare. They can be easily misdiagnosed as central nervous system primitive neuroectodermal tumors (CNS-PNET) or meningiomas. Little is known about the optimal treatment and prognosis of these tumors. PATIENTS AND METHODS: We evaluated the treatment and outcome of 17 patients with intracranial, nonmetastatic, genetically confirmed P-PNET. Three patients were treated at our institutions. Thirteen other cases providing sufficient treatment and follow-up information were extracted from the literature. RESULTS: The median age at diagnosis was 17 years. All patients underwent initial surgery. Complete resection was achieved in 9 of the 17 cases (53 %). Combined adjuvant treatment consisting of radiotherapy (focal, n = 10; craniospinal, n = 1) and chemotherapy was administered to 11 of the 17 patients (59 %). The median follow-up time was 1.4 years. In 8 of the 17 patients (47 %), the disease progressed; 4 of the 17 patients (24 %) died. The 2-year progression-free and overall survival rates were 64 % and 76 %, respectively. CONCLUSION: The differential diagnosis for intracranial, meningeal-based, small, round-cell tumors should include P-PNET. It is highly probable that complete resection has a positive impact on survival--as previously reported for extracranial P-PNET--but this cannot be shown by our data. Intensive adjuvant treatment consisting of radiotherapy and chemotherapy seems to be essential. A statistically grounded recommendation for the appropriate target volume and radiation dose is not yet possible. However, in most case reports of primary intracranial P-PNET published to date, patients were treated with focal irradiation. The optimal chemotherapy regimen has yet to be established, with both the Ewing tumor and CNS-PNET protocols being promising candidates for effective treatment.

Primary Ewing's sarcoma/primitive neuroectodermal tumor of the vagina in a 54-year-old woman: a case report.

BACKGROUND: Ewing's sarcoma (ES)/primitive neuroectodermal tumor (PNET) of the genital tract of women is uncommon. Presentation in vagina is exceedingly rare. CASE: A 54-year-old Chinese woman presented with complaints of vaginal bleeding with fragmented bits occasionally. Physical examination revealed two nodules about 4 cm × 3 cm in the vagina. The immunohistochemical stains revealed a rare presentation of a primitive neuroectodermal tumor. The patient was treated with whole-pelvis external beam radiation, vaginal cylinder intracavitary brachytherapy, intracavitary afterloading radiotherapy and bilateral groin area radiotherapy. She died of clinical recurrence after 18 months of treatment. CONCLUSION: This is the oldest but virgin case, treated with radiation completely, of primitive neuroectodermal tumor located in the vagina reported in the literature.

[Efficacy and survival of 92 cases of Ewing's sarcoma family of tumor initially treated with multidisciplinary therapy].

BACKGROUND AND OBJECTIVE: Ewing's sarcoma family of tumor (ESFT) is aggressive. The optimal therapy modality for ESFT is still to be found. This study was to explore the clinical characteristics and therapy for ESFT. METHODS: Ninety-two cases of ESFT were collected from January 1995 to April 2008 in Sun Yat-sen University Cancer Center and analyzed retrospectively. RESULT: Of 92 cases, 23 were Ewing's sarcoma of bone, 21 extraosseous Ewing's sarcoma, 43 peripheral primitive neuroectodermal tumor, and 5 Askin tumor. Median follow-up time was 31.5 months (range, 10-137 months). Thirty-eight patients received multidisciplinary therapy and 19 single model therapy in non-metastasis group. Three-year overall survival (OS) and event-free survival (EFS) were significantly different between non-metastatic multidisciplinary therapy group and non-metastatic single model group (63% vs. 20%, 46% vs. 18%, respectively, P<0.001). The patients who received surgery plus chemotherapy and plus radiation or not had longer survival than those treated with chemotherapy plus radiation in non-metastatic multidisciplinary therapy group (Chi2=7.591, 9.212; P=0.006, 0.002). CAV/IE alternative regimen was superior to other regimens in event-free survival, but not in overall survival (Chi2=6.950, 3.530; P=0.008, 0.06). Cox regression analysis suggested therapy model and response to treatment were independent prognostic factors for ESFT. CONCLUSIONS: Our studying showed multidisciplinary therapy could significantly improve non-metastatic ESFT patients' survival. Chemotherapy plus surgery and plus radiation or not were superior to chemotherapy plus radiation in local control for the non-metastatic ESFT. Therapy model and response were independent prognostic factors.

Primary Ewing's sarcoma of the orbit: case report.

A 22-year-old man presented with tenderness and swelling of the left lateral part of the orbit. Computed tomography revealed a left intraorbital mass measuring 3 cm x 3 cm involving the left lateral wall of the orbit and the greater wing of the left sphenoid bone. Magnetic resonance imaging revealed that the intraorbital mass was extraneuroaxial. During surgery, the tumor was seen to arise from the lateral wall of the orbit and infiltrate into the left temporal muscle. Following the surgery, the patient was administered radiation therapy for the whole cranium and chemotherapy for the residual tumors. However, the tumor recurred, and the patient died about 2 years following the first surgery because the tumor had metastasized to the lung. On light microscopy, the tumor cells were closely packed with uniform, small, and round cells. Immunohistochemical studies showed that the tumor cell membrane stained positive for MIC2. Furthermore, the MIB-1 labeling index was 36.2%. On electron microscopy, small quantities of cytoplasm containing glycogen accumulations without neurosecretory granules and neurofilaments were observed. Based on these results, the tumor was diagnosed to be primary Ewing's sarcoma. Primary orbital Ewing's sarcoma of the skull has been considered to be extremely rare, and a review of the literature was performed.

Multimodality treatment approach in management of primary peripheral primitive neuroectodermal tumor of the orbit.

Primitive neuroectodermal tumor is a small round cell malignancy which rarely involves the orbit. We report a case of a two-year old male child presenting as unilateral eccentric proptosis with extraconal and intraconal mass, diagnosed as primary peripheral primitive neuroectodermal tumor (pPPNET) on histopathology and immunohistochemistry. There is no defined consensus in the management of these tumors due to its rare presentation. We describe its distinguishing features with emphasis on multimodal and aggressive treatment approach which ensures appropriate management of these cases.

[Case report of a subcutaneous peripheral primitive neuroectodermal tumor]. / Tumor subcutáneo neuroectodérmico primitivo periférico. A propósito de un caso.

Peripheral primitive neuroectodermal tumors - also known as Ewing sarcomas - are a rare type of malignant tumor the histology of which characteristically reveals the presence of small round cells. Typically, t(11;22) translocation is observed. We describe the case of a 45-year-old man with a subcutaneous peripheral primitive neuroectodermal tumor in which the t(11;22) translocation was detected. He was satisfactorily treated with surgery and radiotherapy.

Ewing's sarcoma and primitive neuroectodermal tumour in adults: single-centre experience in The Netherlands.

BACKGROUND: Ewing's sarcoma and peripheral primitive neuroectodermal tumours (PNET) are rare tumours and closely related. They occur most often in children and adolescents. Few studies have been published on treatment outcome in adult patients. METHODS: We performed a retrospective analysis of patients aged >16 years who were primarily treated at our university hospital for Ewing's sarcoma or PNET. In general, treatment consisted of long-term multiagent chemotherapy, interrupted by individualised local treatment consisting of surgery and/or radiotherapy. We reviewed clinical features and outcomes to present our experience with Ewing's sarcoma and PNET in adults. RESULTS: From 1979 to 2002, 27 patients with Ewing's sarcoma (20) or PNET (7) were treated. There were 22 men and 5 women, with a median age of 25 years (range 17-49). Ten patients presented with metastases predominantly in lungs (4) or bones (6). Combination therapy consisted of chemotherapy (27), surgery (16) and radiotherapy (16). After a median follow-up of ten years, 14 patients have died (toxicity = 2, progressive disease = 12) and 13 patients are alive and free of disease. Five-year overall survival was 58%. All four patients with bone metastases died, while all five patients presenting with lung metastases are disease-free. CONCLUSION: The five-year overall survival of 58% in this small series on adult patients is in line with paediatric study outcomes. Patients with lung metastases may even be cured by multimodality therapy. We therefore strongly advocate referral of patients with this rare disease to a specialised oncology centre.

Peripheral primitive neuroectodermal tumor with postchemotherapy neuroblastoma-like differentiation.

We report the case of an 11-year-old girl with a retroperitoneal tumor in the left upper quadrant. The girl was admitted to hospital with weight loss and a painless abdominal mass that on biopsy was diagnosed as a peripheral primitive neuroectodermal tumor/Ewing sarcoma (pPNET/EWS) of the soft tissue. The patient underwent chemotherapy followed by surgical resection of the tumor 5 months after diagnosis. The posttreatment residual viable tumor showed a morphologic appearance resembling a neuroblastoma. Interphase and metaphase fluorescent in situ hybridization (FISH) studies performed on the pretreatment and posttreatment samples showed the presence of a t(11;22) rearrangement resulting in EWSR1/FLI1 gene fusion consistent with pPNET/EWS in both specimens. This case is unusual in the sense of showing the typical gene fusion for pPNET/EWS both in the pretherapy sample with the typical morphological appearance of this tumor and in the posttherapy specimen showing neural differentiation suggestive of a neuroblastoma.

Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group.

PURPOSE: To evaluate response rate, event-free survival (EFS), and toxicity of two chemotherapeutic regimens for treatment of children younger than 36 months with malignant brain tumors and to estimate control intervals without irradiation in children with no residual tumor after initial surgery and induction chemotherapy and with delayed irradiation in patients with residual tumor or metastatic disease at diagnosis. PATIENTS AND METHODS: Patients were randomly assigned to one of two regimens of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide v vincristine, carboplatin, ifosfamide, and etoposide). Maintenance chemotherapy began after induction in children without progressive disease. Children with no residual tumors after induction therapy and no metastatic disease at diagnosis were not to receive radiation therapy unless their tumors progressed. RESULTS: Two hundred ninety-nine infants were enrolled. Forty-two percent of patients responded to induction chemotherapy. At 5 years from study entry, the EFS rate was 27% +/- 3%, and the survival rate was 43% +/- 3%. There was no significant difference between the two arms in terms of response rate or EFS. For medulloblastoma, supratentorial primitive neuroectodermal tumor, ependymoma, and rhabdoid tumors, 5-year EFS rates were 32% +/- 5%, 17% +/- 6%, and 32% +/- 6%, and 14% +/- 7%, respectively. Fifty-eight percent of patients who were alive 5 years after study entry had not received radiation therapy. CONCLUSION: Intensified induction chemotherapy resulted in a high response rate of malignant brain tumors in infants. Survival was comparable to that of previous studies, and most patients who survived did not receive radiation therapy.

Definitive irradiation in multidisciplinary management of localized Ewing sarcoma family of tumors in pediatric patients: outcome and prognostic factors.

PURPOSE: To assess the effect of radiation dose on local tumor control of the Ewing sarcoma family of tumors in 79 patients with localized disease treated at a single institution. METHODS AND MATERIALS: Thirty-seven patients received vincristine, actinomycin D, cyclophosphamide, and doxorubicin, and 42 received vincristine, actinomycin D, and cyclophosphamide, with alternating cycles of ifosfamide and etoposide; all underwent definitive radiotherapy (median dose, 37.5 Gy) with either low-dose (<40 Gy) or standard dose (> or =40 Gy) radiation delivered according to the protocol. We calculated the cumulative incidence of local treatment failure, disease recurrence, and overall survival and analyzed the effect of known prognostic factors and radiation dose. RESULTS: The cumulative incidence of local treatment failure at 10 years was 30.4% and that of disease recurrence was 40%. The overall survival rate was 64.5%. Patient age > or =14 years and tumor size > or =8 cm were adverse prognostic factors for local treatment failure; patient age > or =14 years was also associated with worse survival. Although the radiation dose alone did not predict for local treatment failure, the cumulative incidence of local failure at 10 years was 19% when tumors <8 cm were treated with <40 Gy, and no patient treated with standard doses (> or =40 Gy) developed local recurrence (p = 0.084). CONCLUSION: Tumor size and patient age predict for local tumor control in patients with Ewing sarcoma family of tumors treated with systemic therapy and definitive radiotherapy. Patients treated with reduced-dose radiotherapy experienced unacceptably high rates of local recurrence.

Ewing sarcoma: favourable results with combined modality therapy and conservative use of radiotherapy.

BACKGROUND: At the Hospital for Sick Children (HSC), we have treated Ewing sarcoma (ES) with multi-agent chemotherapy, surgery and conservative use of radiotherapy for local control. Our objective was to describe the outcome and prognostic factors associated with this strategy. PROCEDURE: We performed a retrospective chart review of children diagnosed with ES at HSC from Feb 1984 to June 1999. RESULTS: Seventy-two evaluable children were identified. All received chemotherapy. Local control administered was surgery (n = 37), radiation (n = 23), both (n = 10) or neither (n = 2). The 7-year EFS was 66.4%. Recurrence occurred in 23 patients, 7 locally and 16 distantly. Better EFS was associated with male gender (78.5% vs. 52.1%; P = 0.007), localised disease (77.0% vs. 39.4%; P = 0.0004), extremity primary (88.2% vs. 52.8%; P = 0.005) and non-pelvic primary (75.7% vs. 18.2%; P < 0.0001). CONCLUSIONS: Favourable outcomes were seen for patients treated with multi-agent chemotherapy, surgery and conservative use of radiotherapy. Metastatic disease rather than local control was the major cause of failure.

Ewing's sarcoma and peripheral primitive neuroectodermal tumor cells produce large quantities of bioactive tumor necrosis factor-alpha (TNF-alpha) after radiation exposure.

PURPOSE: In the present study, we examined human Ewing's sarcoma (ES) and peripheral primitive neuroectodermal tumor (pPNET) cell lines that are able to produce TNF-alpha as part of the response to irradiation. Radiation-induced tumor cell production of TNF-alpha may enhance irradiation efficacy and improve the effect of local tumor irradiation. On the other hand, radiation-induced tumor cell production of TNF-alpha may adversely affect the normal tissue. METHODS AND MATERIALS: Twelve different ES/pPNET cell lines were investigated in vitro and (after establishment as tumor xenografts in athymic nude mice) in vivo for their TNF-alpha mRNA expression (real-time quantitative reverse transcriptase polymerase chain reaction) and TNF-alpha protein production (in vitro: enhanced amplified sensitivity immunoassay; in vivo: immunohistochemistry) after exposure to different irradiation doses (2, 5, 10, 20, 30, or 40 Gy) and after different time intervals (1, 3, 6, 12, 24, 48, or 72 h after irradiation). The bioactivity of the TNF-alpha protein was evaluated in chromogenic cytotoxicity and neutralization assays. RESULTS: Nine out of 12 ES/pPNET cell lines express constitutively significant quantities of bioactive TNF-alpha in vitro. ES/pPNET cells originating from primary tumors secreted higher TNF-alpha levels than cells derived from metastatic lesions. In 5 of the 9 TNF-alpha-producing cell lines, TNF-alpha mRNA and protein levels were upregulated after irradiation exposure in a time- and dose-dependent manner. After establishment of the ES/pPNET cell lines in athymic nude mice, the radiation-induced TNF-alpha release could be demonstrated also in the xenograft tumors in vivo (analogous to the in vitro experiments). Using the same methods for quantitative analysis, it was determined that the TNF-alpha expression of the radiation-responsive tumor cells was up to 2000-fold higher compared to the maximal radiation-induced TNF-alpha release in normal lung tissue measured during the pneumonic phase. CONCLUSION: Certain ES/pPNET cell lines produce extremely large quantities of bioactive TNF-alpha after radiation exposure in a time- and dose-dependent manner. Radiation-induced TNF-alpha production of tumor cells may be of paramount importance in respect to not only tumor behavior, but also to potential damage to normal tissue and the clinical status of the host.