Prognosticating survival of pineal parenchymal tumors of intermediate differentiation (PPTID) by grade.

BACKGROUND: Pineal parenchymal tumors of intermediate differentiation (PPTID) are a rare group of pineal parenchymal tumors classified by histology as either World Health Organization (WHO) Grades 2 or 3. The rarity of these tumors in adults has left a number of clinical management questions open. Correspondingly, the aim of this study was to aggregate a large PPTID cohort with sufficient statistical power from a large national cancer database to analyze prognostic parameters. METHODS: All PPTID patients aged over 18 years in the U.S. National Cancer Database (NCDB) between 2005 and 2016 were retrospectively reviewed. Data were summarized and survival was modeled using Kaplan-Meier and Cox regression analyses. RESULTS: A total of 103 adult PPTID patients were identified in the NCDB with 63 (61%) WHO Grade 2 and 40 (39%) WHO Grade 3 tumors. Overall, mean age was 53 ± 18 years with even gender distribution. A total of 75 (73%) patients underwent surgical resection for diagnosis, with gross total resection (GTR) was the most common resection outcome in 50/75 (67%). Chemotherapy was utilized in 18 (17%) patients, and radiation therapy in 37 (36%) patients. Overall, 5-year survival rate was estimated to be 54% (95% CI 42-64%), with mean survival was 84 (95% CI 69-99) months. Patients with Grade 2 tumors survived statistically longer than Grade 3 tumor counterparts (P < 0.01). Overall, older age (HR 1.09, P < 0.01) was associated with shorter survival, whereas GTR (HR 0.43, P = 0.02) was associated with longer survival. Both these parameters were significant within Grade 2 and Grade 3 subgroup analyses as well. CONCLUSIONS: PPTID are rare tumors with expected mean survival more than 5 years, although Grade 2 tumors are expected to survive longer than Grade 3 tumors. Age and gross total resection are significant independent predictors of survival in PPTID overall, as well as within Grade 2 and Grade 3 subgroups separately. The prognostic role and benefit of adjuvant therapy is yet to be elucidated, mandating more molecular and biologic research be done to further optimize clinical management in the future.

Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: a Rare Brain Tumor Consortium registry study.

Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC sub-group, respectively, characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.

Intracranial Germ Cell Tumors in Adolescents and Young Adults: A 40-Year Multi-Institutional Review of Outcomes.

PURPOSE: The aim of this study was to determine the practice patterns and outcomes of intracranial germ cell tumors (IGCT) in adolescents and young adults according to different therapeutic approaches. METHODS AND MATERIALS: One-hundred twelve patients with IGCT aged 15 to 39 years were managed at either XX or the XY center from 1975 to 2015. The charts were retrospectively reviewed and data collected. RESULTS: Median duration of follow-up was 8.3 years. Ninety-four patients had germinomas, and 18 had nongerminomatous germ cell tumors (NGGCT). The primary disease sites were pineal gland (37 of 94 germinoma, 14 of 18 NGGCT) and suprasellar region (23 of 94 germinoma, 2 of 18 NGGCT). Eleven patients with germinoma (12%) and 2 patients with NGGCT (11%) had radiographic spinal metastases or positive lumbar cerebrospinal fluid cytology. Event-free survival (EFS) was 84% and overall survival (OS) was 90% at 10 years for germinoma; EFS was 71% and OS was 86% at 10 years for NGGCT. For patients with germinoma, 10-year EFS was 100% after craniospinal radiation therapy (CSRT) with chemotherapy (N = 10); 100% after whole-ventricular radiation therapy (WVRT), whole-brain radiation therapy (WBRT), or focal radiation therapy (FRT) with chemotherapy (N = 22); 90% after CSRT alone (N = 46); and 41% after WVRT, WBRT, or FRT alone (N = 16) (P < .0005). Ten-year OS was 100%, 100%, 90%, and 72%, respectively (P = .032). For patients with NGGCT, 10-year EFS was 80% after CSRT, WBRT, or WVRT plus chemotherapy (N = 10) versus 58% after FRT plus chemotherapy (N = 8) (P = .31); 10-year OS was 90% versus 58%, respectively (P = .16). CONCLUSIONS: We report excellent overall outcomes according to treatment approach in the largest study of IGCT in adolescents and young adults to our knowledge. EFS and OS were inferior after non-CSRT without chemotherapy in germinoma.

Extent of Resection and Long-Term Survival of Pineal Region Tumors in Helsinki Neurosurgery.

BACKGROUND: Pineal region tumors represent challenging surgical lesions with wide ranges of survival reported in different surgical series. In this article, we emphasize the role of complete microsurgical resection (CMR) to obtain a favorable long-term outcome of pineal region tumors. METHODS: We report a retrospective study of pineal region tumors operated on in Helsinki Neurosurgery between 1997 and 2015. Information was obtained from the hospital records, and an evaluation of the Finnish population register was conducted in July 2018 to determine the current status of the patients. RESULTS: A total of 76 pineal region tumors were operated on. The survival was 62% at a mean follow-up of 125 ± 105 months (range, 0-588 months), and the disease-related mortality was limited to 14 patients (18.4%). Up to July 2018, 29 patients had died. Two patients died 1 and 3 months after surgery of delayed thalamic infarctions, 12 patients of disease progression, and 15 had non-disease-related deaths. Only 1 patient was lost in the long-term follow-up. Ten of 14 disease-related deaths occurred during the first 5 years of follow-up: 5 diffuse gliomas, 3 germ cell tumors, 1 grade II-III pineal parenchymal tumor of intermediate differentiation, and 1 meningioma. CMR was linked to better tumor-free survival and long-term survival, with the exception of diffuse gliomas. CONCLUSIONS: CMR, in the setting of a multidisciplinary management of pineal region tumors, correlates with favorable survival and with minimal mortality. Surgically treated grade II-IV gliomas constitute a particular group with high mortality within the first 5 years independently of the microsurgical resection.

Pineal Parenchymal Tumors of Intermediate Differentiation: A long-Term Follow-Up Study in Helsinki Neurosurgery.

BACKGROUND: Pineal parenchymal tumors of intermediate differentiation (PPTIDs) are rare lesions with particular features compared with other pineal parenchymal tumors. METHODS: We present a retrospective review of patients with histologically confirmed PPTIDs who were operated on in our department between 1997 and 2015. A demographic analysis and an evaluation of preoperative status, surgical treatment, as well as immediate and long-term clinical and radiologic outcomes were conducted. RESULTS: Fifteen patients with PPTIDs were operated on between 1997 and 2015. Gross total removal was achieved in 11 cases; 2 patients underwent near-total resection, 1 partial resection, and 1 received brachytherapy after an endoscopic biopsy. Nine patients required external radiation therapy (4 due to a pleomorphic histology of their lesion including pineoblastoma features in 3 of them; 3 after a subtotal resection; and 2 for tumor recurrence). No patient received chemotherapy. The survival rate of our patients was 57.1% at a mean follow-up of 137.2 ± 77.6 months (39-248 months). CONCLUSIONS: A proper multidisciplinary management of PPTIDs based on a gross total removal of the lesion, and an adjuvant radiotherapy in selected cases, may improve the overall survival of these aggressive tumors.

Prognosis of Pediatric Patients with Pineoblastoma: A SEER Analysis 1990-2013.

BACKGROUND: Pineoblastomas are rare, malignant embryonal tumors that have a relatively higher incidence and a poorer prognosis in children. Owing to the rarity of these tumors, there is a paucity of data on associated prognostic factors. We used the Surveillance, Epidemiology, and End Results (SEER) database to evaluate prognostic factors for pineoblastomas with the aim of improving tumor management. METHODS: Data from all pediatric patients (age ≤17 years) diagnosed with pineoblastoma between 1990 and 2013 were extracted from the SEER-18 registry database. Survival was described with Kaplan-Meier curves. The Cox proportional hazards model was used for both univariate and multivariate analyses. A nomogram was established for predicting 1-, 3-, and 5-year overall survival (OS) in patients with pineoblastoma. RESULTS: Age >5 years (P = 0.004) and radiotherapy treatment (P = 0.000) were associated with better rates of survival. Gross total resection (P = 0.054) also was correlated with better prognosis, whereas tumor size >30 mm in maximum diameter (P = 0.025) was associated with poorer outcome. A nomogram was established based on the results of the Cox model and was validated by a concordance index (C-index) of 0.767 (95% confidence interval, 0.698-0.836) and calibration plots. CONCLUSIONS: Our results show that the impact of tumor extension is not defined. OS is better in older children treated by radiotherapy, and gross total resection also appears to result in increased survival. A nomogram was built to predict 1-, 3-, and 5-year OS for these patients.

DICER1 syndrome: Approach to testing and management at a large pediatric tertiary care center.

BACKGROUND: To expand the current knowledge of DICER1 syndrome and to propose criteria for genetic testing based on experience at a pediatric tertiary care center. PROCEDURE: This study involved a retrospective chart review of the 78 patients (47 probands and 31 family members) seen in the Cancer Genetics Program at The Hospital for Sick Children (SickKids) who were offered genetic testing for DICER1. RESULTS: Of 47 probands offered genetic testing for DICER1, 46 pursued testing: 11 (23.9%) carried a pathogenic variant and one proband (2.1%) carried a missense variant of uncertain significance with evidence for pathogenicity. Thirty-one family members of variant-positive probands were offered testing: eight of the 25 who agreed to testing carried their familial variant (32.0%). Overall, 20 patients were identified to have a variant in DICER1 (eight males, 12 females). Of these, 13 (65.0%) presented with clinical manifestations associated with the syndrome. The most common lesions were pleuropulmonary blastoma (PPB) (five of 20 patients, 25.0%) and pineoblastoma (three of 20 patients, 15.0%). The average age at which individuals were diagnosed with a primary neoplasm was 5.2 years (range 0.8-20 years, median 3.0). Surveillance at our institution, with a median follow-up time of 23 months, has identified PPB in two asymptomatic individuals. These lesions were identified at early stages, thus potentially reducing treatment-related morbidity and mortality. CONCLUSION: This study further delineates the DICER1 syndrome phenotype and demonstrates the feasibility of a DICER1 syndrome surveillance protocol for the early detection of tumors.

Histology-Stratified Tumor Control and Patient Survival After Stereotactic Radiosurgery for Pineal Region Tumors: A Report From the International Gamma Knife Research Foundation.

BACKGROUND: Pineal region tumors represent a rare and histologically diverse group of lesions. Few studies are available to guide management and the outcomes after stereotactic radiosurgery (SRS). METHODS: Patients who underwent SRS for a pineal region tumor and for whom at least 6 months of imaging follow-up was available were retrospectively assessed in 5 centers. Data were collected from the medical record and histology level analyses were performed, including actuarial tumor control and survival analyses. RESULTS: A total of 70 patients were treated between 1989 and 2014 with a median follow-up of 47 months. Diagnoses were pineocytoma (37%), pineoblastoma (19%), pineal parenchymal tumor of intermediate differentiation (10%), papillary tumor of the pineal region (9%), germinoma (7%), teratoma (3%), embryonal carcinoma (1%), and unknown (14%). Median prescription dose was 15 Gy at the 50% isodose line. Actuarial local control and survival rates were 81% and 76% at 20 years for pineocytoma, 50% and 56% at 5 years for pineal parenchymal tumor of intermediate differentiation, 27% and 48% at 5 years for pineoblastoma, 33% and 100% at 5 years for papillary tumor of the pineal region, 80% and 80% at 20 years for germinoma, and 61% and 67% at 5 years for tumors of unknown histology. New focal neurological deficit, Parinaud syndrome, and hydrocephalus occurred in 9%, 7%, and 3% of cases, respectively. CONCLUSIONS: SRS is a safe modality for the management of pineal region tumors. Its specific role is highly dependent on tumor histology. As such, all efforts should be made to obtain a reliable histologic diagnosis.

Pineoblastoma-The Experience at St. Jude Children's Research Hospital.

BACKGROUND: Pineoblastomas are rare, supratentorial, primitive neuroectodermal tumors. OBJECTIVE: To document outcomes with multimodal therapy and evaluate the impact that the degree of surgical resection has on outcome. METHODS: A departmental brain tumor database was queried to identify all patients with pathologically proven pineoblastoma who were treated from January 1997 to June 2015 at St. Jude Children's Research Hospital. For each patient, we recorded demographic, pathological, radiological, surgical, and clinical follow-up data. The effect of degree of surgical resection on survival outcomes was analyzed. RESULTS: Forty-one patients (21 male, 20 female) treated for pineoblastoma were identified. The median age at diagnosis was 5.5 years (range 0.4-28.1) and the median follow-up was 34.5 months. Nineteen patients experienced tumor relapse with a median progression-free survival of 11.3 months, and 18 ultimately succumbed to their disease. Patients who died or experienced treatment failure were younger (median, 2.69 vs 6.5 years, P = .026) and more likely to have metastatic disease at diagnosis (12 [63.2%] vs 5 [22.7%], P = .012). When analyzing only patients 5 years of age or older with focal disease at presentation, those who had a gross total resection or near-total resection-compared with subtotal resection or biopsy-had greater overall survival (75.18 vs 48.57 months), with no patients dying as a result of their cancer. CONCLUSION: Poor prognostic variables for children with pineoblastoma include young age, metastatic disease at presentation, and tumor relapse. For patients older than 5 years with focal disease, maximal tumor resection should be the goal.

Evaluation of age-dependent treatment strategies for children and young adults with pineoblastoma: analysis of pooled European Society for Paediatric Oncology (SIOP-E) and US Head Start data.

Background: Pineoblastoma is a rare pineal region brain tumor. Treatment strategies have reflected those for other malignant embryonal brain tumors. Patients and Methods: Original prospective treatment and outcome data from international trial groups were pooled. Cox regression models were developed considering treatment elements as time-dependent covariates. Results: Data on 135 patients with pineoblastoma aged 0.01-20.7 (median 4.9) years were analyzed. Median observation time was 7.3 years. Favorable prognostic factors were age ≥4 years (hazard ratio [HR] for progression-free survival [PFS] 0.270, P < .001) and administration of radiotherapy (HR for PFS 0.282, P < .001). Metastatic disease (HR for PFS 2.015, P = .006), but not postoperative residual tumor, was associated with unfavorable prognosis. In 57 patients <4 years old, 5-year PFS/overall survival (OS) were 11 ± 4%/12 ± 4%. Two patients survived after chemotherapy only, while 3 of 16 treated with craniospinal irradiation (CSI) with boost, and 3 of 5 treated with high-dose chemotherapy (HDCT) and local radiotherapy survived. In 78 patients aged ≥4 years, PFS/OS were 72 ± 7%/73 ± 7% for patients without metastases, and 50 ± 10%/55 ± 10% with metastases. Seventy-three patients received radiotherapy (48 conventionally fractionated CSI, median dose 35.0 [18.0-45.0] Gy, 19 hyperfractionated CSI, 6 local radiotherapy), with (n = 68) or without (n = 6) chemotherapy. The treatment sequence had no impact; application of HDCT had weak impact on survival in older patients. Conclusion: Survival is poor in young children treated without radiotherapy. In these patients, combination of HDCT and local radiotherapy may warrant further evaluation in the absence of more specific or targeted treatments. CSI combined with chemotherapy is effective for older non-metastatic patients.

Treatment Results for Pineal Region Tumors: Role of Stereotactic Biopsy Plus Adjuvant Therapy vs. Open Resection.

AIM: Pineal tumors represent uncommon intracranial tumors with highly diverse histologic subtypes. There still exists a controversy in literature about what influences overall survival and outcome. MATERIAL AND METHODS: We present the results of 48 patients with pineal tumor treated either by stereotactic biopsy followed by adjuvant therapy (23 patients) or open surgical resection without (18 patients) or with (7 patients) adjuvant therapy in Shohada Tajrish Hospital, Iran (1993-2008). RESULTS: Unremarkable pathology yield was 3/23 in the biopsy and 1/25 in the surgical group. Perioperative mortality and morbidity were 4.3% and 0% in the biopsy group and 32.0% and 4.0% in the surgical group. Analysis showed that age, gender, cranial nerve deficit, motor deficit, preoperative Karnofsky Performance Score (KPS), midbrain involvement, and brain stem involvement had no effect on neither perioperative mortality nor long-term survival, while local invasion and pineocytoma pathology increased perioperative mortality and presence of hydrocephalus and pineoblastoma pathology significantly decreased long-term survival. Hospitalization length was shorter in the stereotactic biopsy plus adjuvant therapy group. CONCLUSION: The results of the study suggests that although gross total resection is the standard of care in most pineal tumors nowadays, stereotactic biopsy followed by adjuvant therapy may still be a safe and viable option.

Outcomes After Surgery and Radiotherapy for Papillary Tumor of the Pineal Region.

BACKGROUND: Papillary tumor of the pineal region (PTPR) is a rare neuroectodermal tumor that was first described in 2003 and formally codified by the World Health Organization in 2007. Limited reports suggest surgical resection is the mainstay of treatment; however, the role of multimodality therapy is not well defined. We evaluated our institutional experience in the treatment of PTPR. METHODS: A retrospective review of 8 patients with pathologically confirmed PTPR diagnosed between 1999 and 2013 was performed. RESULTS: The median age at diagnosis was 37 years (range, 25-56 years). After a median follow-up period of 60 months (range, 10-170 months), 7 of 8 patients were still living. All patients underwent maximum safe surgical resection; 5 received adjuvant radiation (63%). Overall and progression-free survival 5 years after diagnosis were 100% and 51%, respectively. Progression-free survival 5 years after completion of adjuvant radiotherapy was 64%. Crude recurrence rates for patients receiving adjuvant radiotherapy (n = 5) and patients not receiving adjuvant radiotherapy (n = 3) were 20% and 67%, respectively. Crude recurrence rate after gross total resection (GTR) and no adjuvant radiotherapy (n = 2) was 100% versus 0% when adjuvant radiotherapy was administered after GTR (n = 2). After subtotal resection, 3 patients received adjuvant radiotherapy; 1 of these patients had out-of-field recurrence at 46 months (crude recurrence rate 33%). In all cases, salvage with radiation at the time of recurrence was effective. CONCLUSIONS: Our institutional experience confirms a recent multicenter retrospective series showing excellent survival but high risk of local recurrence for PTPR. Our findings suggest that radiotherapy provides durable local control, particularly when administered in the adjuvant setting after GTR.

The postirradiation incidence of cavernous angioma is higher in patients with childhood pineoblastoma or primitive neuroectodermal tumors than medulloblastoma.

PURPOSE: The purpose of this study is to investigate the incidence of cavernous angioma (CVA) in long-term survivors of childhood embryonal tumors treated by cranial irradiation. MATERIALS AND METHODS: Between 1990 and 2012, we treated 25 patients (13 males, 12 females) with embryonal tumors (17 medulloblastomas, 5 primitive neuroectodermal tumors (PNET), 3 pineoblastomas) with craniospinal irradiation. Follow-up ranged from 15.5 to 289.9 months, the irradiation dose to the whole neural axis from 18 to 36 Gy, and the total local dose from 49.6 to 60 Gy. All patients underwent follow-up magnetic resonance imaging (MRI) studies at least once a year, and the diagnosis of posttreatment CVA was based solely on MRI findings. RESULTS: At the time of this writing, 18 were alive and free of the recurrence of the original disease or the development of secondary neoplasms other than CVA; another 2 were alive with medulloblastoma or diffuse astrocytoma. Posttreatment, 14 patients developed CVAs in the course of a median of 56.7 months; 13 of these presented with multiple CVAs. Patients who underwent radiation therapy (RT) at an age younger than 6 years developed multiple CVAs significantly earlier than those treated at a later age (p = 0.0110). Patients with PNET or pineoblastoma developed Zabramski type 1 and 2 CVA significantly earlier than did medulloblastoma patients (p = 0.0042). CONCLUSION: We attribute the high rate of post-RT CVA in our long-term follow-up study of pediatric patients to the delivery of cranial irradiation for embryonal tumors, especially PNET and pineoblastoma, and recommend the regular, long-term follow-up of patients whose embryonal tumors were treated by cranial irradiation.

The management of pineal tumors as a model for a multidisciplinary approach in neuro-oncology.

The management of pineal tumors is a model for multidisciplinarity. Apart from an emergency situation that requires immediate shunting of cerebrospinal fluid (CSF), the initial discussion should involve at least a radiologist, a surgeon, a neurologist and an oncologist. The initial decision is whether obtaining a histological proof is obligatory. It depends on age and ethnicity, site (mono- or bifocality), presence of markers in serum as well as CSF, and/or of malignant cells in the CSF. In cases of marker elevation indicating a germ cell tumor, front line chemotherapy can avoid dangerous immediate surgery. When histological proof is required, the extent of surgery should be discussed, aiming either only at obtaining tissue or removal. If a germ cell tumor is detected, treatment will include a cisplatin-containing chemotherapy followed by focal or ventricular irradiation. Tumors of the pineal parenchyma will be treated according to grade, either by surgery alone (pinealocytoma) or chemo-radiotherapy (pinealoblastomas). Similarly, gliomas will be treated depending on their grade with several different possible lines in low grade, and usually radio-chemotherapy in high grade. A careful balance between improved survival rates and decreased long-term side effects will guide the decisions of all these specialists.

Treatment of children with central nervous system primitive neuroectodermal tumors/pinealoblastomas in the prospective multicentric trial HIT 2000 using hyperfractionated radiation therapy followed by maintenance chemotherapy.

PURPOSE: The prognosis for children with central nervous system primitive neuroectodermal tumor (CNS-PNET) or pinealoblastoma is still unsatisfactory. Here we report the results of patients between 4 and 21 years of age with nonmetastatic CNS-PNET or pinealoblastoma diagnosed from January 2001 to December 2005 and treated in the prospective GPOH-trial P-HIT 2000-AB4. METHODS AND MATERIALS: After surgery, children received hyperfractionated radiation therapy (36 Gy to the craniospinal axis, 68 Gy to the tumor region, and 72 Gy to any residual tumor, fractionated at 2 × 1 Gy per day 5 days per week) accompanied by weekly intravenous administration of vincristine and followed by 8 cycles of maintenance chemotherapy (lomustine, cisplatin, and vincristine). RESULTS: Twenty-six patients (15 with CNS-PNET; 11 with pinealoblastoma) were included. Median age at diagnosis was 11.5 years old (range, 4.0-20.7 years). Gross total tumor resection was achieved in 6 and partial resection in 16 patients (indistinct, 4 patients). Median follow-up of the 15 surviving patients was 7.0 years (range, 5.2-10.0 years). The combined response rate to postoperative therapy was 17 of 20 (85%). Eleven of 26 patients (42%; 7 of 15 with CNS-PNET; 4 of 11 with pinealoblastoma) showed tumor progression or relapse at a median time of 1.3 years (range, 0.5-1.9 years). Five-year progression-free and overall survival rates (± standard error [SE]) were each 58% (± 10%) for the entire cohort: CNS-PNET was 53% (± 13); pinealoblastoma was 64% (± 15%; P=.524 and P=.627, respectively). CONCLUSIONS: Postoperative hyperfractionated radiation therapy with local dose escalation followed by maintenance chemotherapy was feasible without major acute toxicity. Survival rates are comparable to those of a few other recent studies but superior to those of most other series, including the previous trial, HIT 1991.

Increased mitotic and proliferative activity are associated with worse prognosis in papillary tumors of the pineal region.

Papillary tumors of the pineal region are rare glial tumors located in the vicinity of the third ventricle, the clinical behavior of which is often aggressive. Little is known about the prognostic markers that might aid to identify patients at increased risk for recurrence. Therefore, the prognostic value of histopathologic and clinical features was examined in a series of 21 patients. Median age of the 12 male and 9 female patients was 35 years (range, 10 to 56 y). On histopathologic examination, all tumors were characterized by loose papillary structures and tumor cells forming broad perivascular pseudorosettes showing cytokeratin expression. In addition, tumors showed increased cellularity (n=4; 19%), nuclear pleomorphism (n=4; 19%), solid growth (n=11; 52%), necrosis (n=8; 38%), increased mitotic activity (≥3 mitoses per 10 high-power fields [n=10; 48%]), and increased proliferation (Ki67/MIB1 index ≥10% [n=8/20; 40%]). Gross total resection could be achieved in 13/21 patients (62%). Postoperatively, 13 patients received radiotherapy and 4 patients chemotherapy. Median recurrence-free survival was 66 months in 19 patients, for whom detailed follow-up information was available. Twelve patients (63%) experienced tumor progression. Three patients (16%) died of disease. Among the clinical and histopathologic features examined, only increased mitotic activity (52 [8 to 96] vs. 68 [66 to 70] mo [median [95% confidence interval]]) and proliferative activity (29 [0 to 64] vs. 67 [44 to 90] mo) were significantly associated with recurrence (P<0.05). Tumors of the 3 patients who had succumbed to disease showed increased mitotic and proliferative activity. In conclusion, increased mitotic and proliferative activities are associated with worse prognosis in papillary tumors of the pineal region.

Early response to chemotherapy as an indicator for the management of germinoma-like tumors of the pineal and/or suprasellar regions.

Recent advances in diagnostic imaging and experience with germinomas may allow for the differentiation of central nervous system germinomas from other tumors based on clinical information, without histological verification. We retrospectively analyzed clinically diagnosed germinoma-like tumors of the pineal and/or suprasellar regions. This was done to evaluate the efficacy of our strategy of defining germinoma-compatible tumors based on good responses to initial chemotherapy. The responses to chemotherapy and survival of 34 consecutive patients with germinoma-like tumors who underwent initial treatment from July 2001 to October 2010 were analyzed. The minimum apparent diffusion coefficient (minADC) value and proton magnetic resonance spectroscopy (MRS) were evaluated in recent patients. Twelve patients with histologically verified germinomas and 18 with germinoma-compatible tumors showed early logarithmic decreases in tumor volume in response to initial chemotherapy, typical low minADC values and typical MRS characteristics, including increased choline/creatine ratios, decreased N-acetylasparate/creatine ratios, and large lipid peaks. These patients had good progression-free survival. The other four patients, with histologically verified non-germinomas, showed no response to chemotherapy, and one patient with a pineoblastoma showed a similar minADC value and MRS characteristics to those of patients with germinomas. The response to initial chemotherapy can be used to distinguish germinoma-compatible tumors from non-germinoma in patients with germinoma-like tumors of the pineal and/or suprasellar regions. The evaluation of minADC and proton MRS are useful for distinguishing germinomas from other tumors. However, a subset of non-germinomas may show similar characteristics to germinomas. The benefit of bypassing unnecessary surgical intervention can be achieved, at least in Asian populations with a high incidence of germinomas.

Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era.

PURPOSE: To report on the frequency of cysts and tumors of the pineal gland in patients with retinoblastoma. DESIGN: Observational retrospective case control study. SETTING: Institutional. study population: Four hundred eight patients treated for retinoblastoma from January 2000 to January 2012 at Wills Eye Institute, Philadelphia, Pennsylvania, USA. OBSERVATION PROCEDURE: Magnetic resonance imaging (MRI) features of the pineal gland were evaluated in all patients with retinoblastoma. Characteristics of patients with pineal cysts and pineoblastoma were reviewed. MAIN OUTCOME MEASURES: Comparison of frequency of pineal gland cyst and pineoblastoma in children managed with systemic chemoreduction vs other methods. RESULTS: Of 408 patients, treatment included systemic chemoreduction in 252 (62%) and nonchemoreduction methods in 156 (38%). Overall, 34 patients (8%) manifested pineal gland cyst and 4 (1%) showed pineoblastoma. Of all 408 patients, comparison (chemoreduction vs nonchemoreduction) revealed pineal cyst (20/252 vs 14/156, P = .7) and pineoblastoma (1/252 vs 3/156, P = .1). The pineal cyst (n = 34) (mean diameter 4 mm) was asymptomatic (n = 34), followed conservatively (n = 34), and with minimal enlargement (n = 2, 9%) but without progression to pineoblastoma. The cyst was found in 22 germline and 12 nongermline patients (P = .15). Among the 4 patients with pineoblastoma, all had germline mutation and 2 had family history of retinoblastoma. Among all patients with family history of retinoblastoma (n = 45), 2 (4%) developed pineoblastoma. The pineoblastoma was asymptomatic in 2 patients and symptomatic with vomiting and headache in 2 patients. The mean interval from date of retinoblastoma detection to pineal cyst was 2 months (median 2, range 0-8 months) and to pineoblastoma was 27 months (median 28, range 7-46 months). Management included aggressive chemotherapy and radiotherapy, with 2 survivors. CONCLUSIONS: Pineal gland cyst was incidentally detected in 8% of retinoblastoma patients, causing no symptoms, and without progression to pineoblastoma. Pineoblastoma was detected in 1% of patients and fewer patients who received systemic chemotherapy developed pineoblastoma, possibly indicating a systemic protective effect.

Role of surgery, radiotherapy and chemotherapy in papillary tumors of the pineal region: a multicenter study.

Papillary tumor of the pineal region (PTPR), recently described as a distinct clinicopathological entity, can show aggressive biological behavior. The optimal therapeutic approach of PTPR has not been well defined. The role of surgery, radiotherapy, and chemotherapy in the treatment of PTPR was analyzed in a large multicenter series. In order to determine factors that influence prognosis, outcome data of a series of 44 patients with histopathologically proven PTPR were retrospectively analyzed. Of the 44 patients, 32 were still alive after a median follow-up of 63.1 months. Twelve patients experienced progressive disease, with seven undergoing two relapses and five more than two. Median overall survival (OS) was not achieved. Median progression-free survival (PFS) was 58.1 months. Only gross total resection and younger age were associated with a longer OS, radiotherapy and chemotherapy having no significant impact. PFS was not influenced by gross total resection. Radiotherapy and chemotherapy had no significant effect. This retrospective series confirms the high risk of recurrence in PTPR and emphasizes the importance of gross total resection. However, our data provide no evidence for a role of adjuvant radiotherapy or chemotherapy in the treatment of PTPR.

Treatment of young children with CNS-primitive neuroectodermal tumors/pineoblastomas in the prospective multicenter trial HIT 2000 using different chemotherapy regimens and radiotherapy.

BACKGROUND: Especially in young children, primitive neuroectodermal tumors of the central nervous system (CNS-PNET) and pineoblastomas are associated with an unfavorable outcome, and only a few prospective trials have been conducted thus far. METHODS: From January 2001 through January 2005, 17 eligible children aged <4 years with CNS-PNET not otherwise specified (n = 8), ependymoblastoma (n = 1), or pineoblastoma (n = 8) confirmed by central review were prospectively treated in the trial HIT 2000. In nonmetastatic disease (n = 11), up to 5 postoperative cycles of HIT-SKK systemic multiagent chemotherapy (8 months duration), followed by craniospinal radiotherapy (CSI), were given. In metastatic disease (M1-M3, n = 6), treatment consisted of a shorter induction chemotherapy (2-3 months) with carboplatin and etoposide, followed by tandem high-dose chemotherapy (HDCT) in case of good response to induction. During induction and HDCT, patients received intraventricular methotrexate. CSI was applied to all patients with poor response to induction or residual disease after HDCT and was optional for patients with residual disease before HDCT. RESULTS: Five-year event-free survival and overall survival rates ± standard error for all eligible patients were 24% ± 10% and 40% ± 12%, respectively (median follow-up of survivors: 8.3 years). Only one patient with nonmetastatic disease remained free of relapse/progressive disease during induction. Three of 6 patients with metastatic disease responded to induction and received tandem-HDCT, followed by preventive CSI, and remain in continuous complete remission. CONCLUSIONS: Short intensive induction chemotherapy followed by tandem-HDCT in young children with CNS-PNET/pineoblastomas seems to be superior to the prolonged and less intensive induction regimen.