Pineoblastomas in Pediatric Patients: A Single Institutional Experience

Background/Aims: Medulloblastomas (MBs), atypical teratoid rhabdoid tumors (AT/RTs) and central nervous system primitive neuroectodermal tumors (PNETs) are aggressive embryonal brain neoplasms in children with overlapping histological features but with different pathogenetic pathways. We set out to evaluate the role of epidermal growth factor receptor (EGFR), HER-2, Ki-67 and p53 in embryonal tumors. Material and Methods: We retrospectively evaluated 36 children with embryonic tumors (27 MBs, 7 AT/RTs and 2 supratentorial PNETs). The immunohistochemical expression of EGFR and HER-2 was correlated to histology, expression of the Ki-67/MIB-1 proliferative index, p53 tumor suppressor oncoprotein and prognosis. Results: High expression of Ki-67 was observed in all MBs being particularly increased (>50%) in 8 cases, while p53 protein was detected in 25/27 MBs showing a high expression in 16 cases. EGFR and HER-2 expression was observed in 10/27 and 17/27 MBs, respectively. High Ki-67/MIB-1 and p53 expression was revealed in all AT/RTs and PNETs, while EGFR and HER-2 were detected in 3/7 and 6/7 AT/RTs, respectively. The 5-year progression-free survival and overall survival were 55.5 and 69.2%, respectively. In MBs, the univariate analysis revealed that the Ki-67 index and male gender were both at a significant level related to the survival of the patient. In multivariate analysis, the Ki-67 index was the only independent predictive variable. Conclusions: The Ki-67 index was identified as a factor with independent prognostic power. EGFR and HER-2 expression is variable in embryonal tumors. HER-2 expression, in a considerable number of MBs and AT/RTs, suggests that HER-2 may be implicated in their pathogenesis representing a potential target for novel therapies.

Immunohistochemical lack of nuclear INI1 protein expression has been recently described as characteristic finding in atypical teratoid/rhabdoid tumors (AT/RTs), and has been suggested as useful marker to distinguish AT/RTs from other malignant pediatric central nervous system (CNS) tumors. In this study, we examined a large series of malignant pediatric CNS tumors to determine the immunohistochemical expression of INI1 protein in different malignant pediatric tumor entities. Archival paraffin-embedded biopsy specimens of 289 malignant pediatric CNS tumors including medulloblastomas, supratentorial primitive neuroectodermal tumors, glioblastomas, anaplastic astrocytomas, anaplastic ependymomas, choroid plexus carcinomas, germ cell tumors, and AT/RTs were analyzed immunohistochemically for expression of nuclear INI1 protein. Positive INI1 staining was observed in 263 tumors. Lack of INI1 protein was detectable in 26 tumors. Seventeen of the 26 tumors showed morphologically characteristic features of AT/RTs, whereas 9 embryonal tumors did not display rhabdoid features. Tumors without rhabdoid phenotype but lack of INI1 showed an aggressive clinical course and poor response to conventional treatment regimens. In summary, immunohistochemical expression of INI1 protein is lacking in tumors displaying characteristic morphologic features of AT/RT. Furthermore, a certain number of embryonal tumors without rhabdoid features but lack of INI1 protein and aggressive biologic behavior can be detected. We conclude that INI1 protein analysis should be routinely performed in all malignant pediatric embryonal CNS tumors to detect cases with lack of INI1 protein, because patients with these tumors are likely to benefit from intensified treatment.

<p> </p><p> </p><p>Central nervous system (CNS) embryonal tumours are a heterogeneous and aggressive group of neoplasms that predominantly affect children and adolescents. These tumours have historically posed significant diagnostic and therapeutic challenges due to their overlapping morphological features and variable biological behaviour. Traditionally, CNS embryonal tumours were classified into medulloblastomas and supratentorial primitive neuroectodermal tumours (PNETs) based on histological appearance. However, the designation “PNET” lacked biological specificity and reproducibility resulting in diagnostic ambiguity and limited clinical utility.</p><p> </p><p>The 2016 World Health Organisation (WHO) classification marked a paradigm shift by eliminating the term “PNET” and introducing molecular parameters into diagnostic frameworks. This change reflected the recognition that morphology alone was insufficient to define biologically relevant entities and highlighted the importance of molecularly informed classification. Building on this foundation, the 2021 WHO classification emphasizes integrated diagnostics, combining histopathology, immunohistochemistry and increasingly DNA methylation profiling. This approach has enabled the recognition of multiple molecularly defined embryonal tumour entities, each associated with distinct biological behaviour, prognostic implications and therapeutic opportunities. This review provides a comprehensive overview of the 2021 WHO classification of CNS embryonal tumours with emphasis on the integration of molecular and histopathological features. </p><p> </p>

BACKGROUNDImprovement of molecular diagnostics has led to significant changes in the categorization of paediatric brain tumours, unveiling novel tumour entities in the latest 2021 WHO classification of central nervous system (CNS) tumours (5th edition), particularly within the group of rare tumours of the CNS (encompassing rare embryonal and sarcomatous tumours (REST) and gliomas). However, treatment recommendations are currently based on small patient cohorts lacking standardized protocols, with even more limited options for progressive or relapsed disease. METHODSPatients from specialized European oncologic centres diagnosed or reclassified as REST receiving anti-angiogenic therapy after relapse (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial - MEMMAT) will be analysed. RESULTS So far, 14 patients from Austria, Czech Republic, Denmark and France were identified, with molecularly reclassified 4 CNS tumours with BCOR/BCORL1 alteration (CNS BCOR/BCORL1), 4 CNS astroblastomas, MN1-altered (ABM_MN1), 3 embryonal tumours with multi-layered rosettes (ETMR) and 1 DICER1-mutated intracranial sarcoma (CNS DICER1) as well as 2 primitive neuroectodermal tumours (PNETs, reclassification ongoing). Initial histological classifications ranged from ependymoma group 3, ETMR, malignant peripheral nerve sheath tumour (MPNST) to EGFR-positive glioblastoma. In 2 cases categorization was unclear with either anaplastic ependymoma, plexus carcinoma or ETMR. 10 patients received standard MEMMAT protocol (biweekly intravenous Bevacizumab with oral drugs: Celebrex, Thalidomide, Fenofibrate, Cyclophosphamide/Etoposide alternating and intrathecal Etoposide and Cytarabine). In 4 cases therapy was modified with an individualized metronomic treatment regimen. CONCLUSION Therapy at initial diagnosis, duration of relapse-treatment, clinical as well as radiological response, overall survival, progression-free survival and molecular hallmarks will be presented.

Embryonal central nervous system (CNS) tumors are currently classified into three types: medulloblastoma, atypical rhabdoid/teratoid tumors, and primitive neuroectodermal tumor (PNET). A distinctive subtype of PNET called "embryonal tumor with abundant neuropil and true rosettes" (ETANTR) was reported in 2000. ETANTR is a recently described variety of PNET that combines microscopic features of neuroblastoma and ependymoblastoma, demonstrating areas of fine fibrillary neuropil intermingled with cellular zones and ependymoblastic rosettes. It has been suggested that this neoplasm should be considered as a separate entity. ETANTR is an eminently pediatric tumor that has been reported exclusively in children younger than 4 years. A 9-month-old girl underwent subtotal resection of a brainstem neoplasm. A 23-month-old girl was submitted to surgery for a frontoparietal tumor. In both instances, the histopathological diagnosis confirmed ETANTR. Both children were treated with chemotherapy and one with radiotherapy. Death in both patients occurred after a mean period of 10 months. By reporting these two new instances of ETANTR, we want to contribute to the knowledge of this highly malignant CNS embryonal neoplasm that occurs only in young children, given its present lethal prognosis, the scarcity of reported cases, and the lack of treatment guidelines.

Embryonal tumors constitute the most common malignant brain tumor group in children. Although patient prognosis has been substantially improved over recent decades, identification of prognostic markers would be of obvious significance. In the present study we evaluated the prognostic significance of cyclin A and B1 in correlation with Ki-67 index in pediatric embryonal tumors. We retrospectively evaluated 53 children with embryonic tumors who were treated surgically in our institute. All patients had regular follow-up examinations. The streptavidin-biotin-horseradish peroxidase (HRP) method was performed on paraffin sections for detection of Ki-67/MIB-1, and cyclin A and B1. There were 42 cases of medulloblastoma (MB), 9 cases of atypical teratoid/rhabdoid tumor (AT/RT), and 2 cases of supratentorial primitive neuroectodermal tumor (PNET). In MB patients, Ki-67 index >50% was associated with worse survival (P = 0.003). Cyclin A index >40% was associated with significantly poorer survival (P = 0.023). Patients with cyclin B1 index >15% exhibited a trend towards poorer survival (P = 0.068). On multivariate analysis, only Ki-67 index was identified as a factor with independent prognostic power. In AT/RT and PNET, there was high expression of Ki-67 and variable expression of cyclin A and B1. Apart from Ki-67 index, cyclin A may have a prognostic role. Study of the above indices at diagnosis could alter or intensify treatment methods, so as to improve disease outcome. There is obviously a need for future studies with larger number of patients to confirm our preliminary observations.

Background: The pineal gland, a small, pinecone-shaped organ deep within the brain, is responsible for producing melatonin. The gland consists of pineal parenchymal cells and glial cells that can form neoplasms. Pineal region neoplasms can also arise from germ cells and adjacent structures. This review focuses on detection of serum and cerebrospinal fluid (CSF) biomarkers of germ cell tumors and pineal parenchymal cell tumors, as these types comprise most neoplasms specific to the pineal region. Methods: For this review, we searched PubMed using the following keywords: biomarkers, germ cell tumor, germinoma, melatonin, pineal, pineal gland, pineal neoplasm, pinealoma, pineal parenchymal cell tumor, pineal region, and pineal tumor. We limited our search to full-text English articles and identified other relevant sources from the reference lists of identified articles. Results: Serum and CSF biomarker assays have a role in cases of suspected pineal germ cell or parenchymal neoplasms. Biomarkers including alpha-fetoprotein, beta-human chorionic gonadotropin, and placental alkaline phosphatase inform diagnosis and treatment and are important for monitoring germ cell tumor response to treatment. No biomarkers are currently available that inform diagnosis or treatment of pineal parenchymal tumors, although melatonin assays may have a role in monitoring response to treatment. Conclusion: Serum and CSF biomarkers in conjunction with clinical and radiographic evidence of a pineal region mass can inform the decision whether to undertake stereotactic biopsy or surgical excision or whether to proceed straight to medical treatment.

Tumors of the pineal region comprise several different entities with distinct clinical and histopathological features. Whereas some entities predominantly affect adults, pineoblastoma (PB) constitutes a highly aggressive malignancy of childhood with a poor outcome. PBs mainly arise sporadically, but may also occur in the context of cancer predisposition syndromes including DICER1 and RB1 germline mutation. With this study, we investigate clinico-pathological subgroups of pineal tumors and further characterize their biological features. We performed genome-wide DNA methylation analysis in 195 tumors of the pineal region and 20 normal pineal gland controls. Copy-number profiles were obtained from DNA methylation data; gene panel sequencing was added for 93 tumors and analysis was further complemented by miRNA sequencing for 22 tumor samples. Unsupervised clustering based on DNA methylation profiling separated known subgroups, like pineocytoma, pineal parenchymal tumor of intermediate differentiation, papillary tumor of the pineal region and PB, and further distinct subtypes within these groups, including three subtypes within the core PB subgroup. The novel molecular subgroup Pin-RB includes cases of trilateral retinoblastoma as well as sporadic pineal tumors with RB1 alterations, and displays similarities with retinoblastoma. Distinct clinical associations discriminate the second novel molecular subgroup PB-MYC from other PB cases. Alterations within the miRNA processing pathway (affecting DROSHA, DGCR8 or DICER1) are found in about two thirds of cases in the three core PB subtypes. Methylation profiling revealed biologically distinct groups of pineal tumors with specific clinical and molecular features. Our findings provide a foundation for further clinical as well as molecular and functional characterization of PB and other pineal tumors, including the role of miRNA processing defects in oncogenesis.

Pineal tumors are rare neoplasms that are categorized into pineoblastomas, pineocytomas, and pineal parenchymal tumors of intermediate differentiation. Pineal anlage tumors are primary pineal tumors with neuroepithelial and ectomesenchymal differentiation and without endodermal differentiation. The authors review the literature and report the case of a 5-month-old boy with a pineal anlage tumor. This is only the sixth case of a pineal anlage tumor reported in the English-language literature adding to the understanding of this tumor's presentation, immunomorphological and molecular characteristics, embryological origin, radiological appearance, treatment outcome, and prognosis.

We have read with great interest the comments made by Benesch and Urban on our recent description of the distinctive features of primitive neuroectodermal tumor (PNET) of the kidney.1 We agree that PNET of the kidney should be considered part of the Ewing's sarcoma family of tumors (ESFT), sharing the same histologic, cytochemical, cytogenetic, and molecular features.2, 3 Our purpose in describing these patients was twofold: first, we wished to inform oncologists and pathologists that PNET may present as a primary renal tumor; and second, we suggested that PNET arising in the kidney may have an aggressive clinical course. PNET arising primarily in the kidney is rare. As our series illustrates, this entity must be included in the differential diagnosis of primary renal tumors, particularly in children and young adults. Furman et al.4 noted that lymphoma, carcinoid tumors, small cell neuroendocrine carcinoma, and rhabdomyosarcoma may present as primary small cell tumors of the kidney. As we discussed, Wilms' tumor of blastemic type, renal neuroblastoma, and malignant rhabdoid tumor may share histologic features with PNET. Benesch and Urban reiterate our recommendation that immunohistochemistry for CD99 is mandatory in such cases, and we agree that molecular characterization of these tumors should be performed when tissue is available. Four other recent case reports also note the rarity of this tumor and the importance of considering renal PNET a distinct clinical entity.4-7 Of the 11 cases described (8 with metastatic disease at diagnosis), 1 patient died after surgery, 7 patients died of disease progression at a median of 5 months after diagnosis, and the 3 survivors were still receiving treatment at the time the reports were made.1, 4-10 Given the small number of cases of PNET of the kidney, statistically significant comparisons of the outcomes of patients with ESFT by this primary site are not possible. Nevertheless, PNET of the kidney appears to represent a subgroup with very aggressive behavior. We agree that patients with advanced local or metastatic disease are at higher risk of overall treatment failure; however, PNET, arising at other sites typically respond well to initial therapeutic interventions. Kushner et al.11 reported a 20-year retrospective series that excluded a number of long term survivors with PNET "because their small tumors were inadequate for confirming the diagnosis." In that report, 9 of 11 patients who received more that 1200 mg/m2/course of cyclophosphamide initially responded to chemotherapy. Using very aggressive short term therapy, this group recently reported initial responses in all 32 evaluable patients with peripheral PNET, 77% event free survival in 24 patients with locoregional disease, and 5 of 6 patients with lung metastases progression free.12 This report suggests that patients with metastatic peripheral PNET may be curable with aggressive therapy. In other reports, 13 of 14 patients13 and 16 of 17 patients14 with peripheral PNET responded to initial combination chemotherapy. Although we previously reported poor outcome for patients with PNET of soft tissues,15 we have recently updated these data.16 In our recent group of 17 patients with soft tissue PNET treated since 1988, all 9 patients evaluable for initial response to chemotherapy responded. The 5-year progression free survival is 62 ± 16% for the entire group, including 8 patients with tumors >8 cm and 3 with metastatic disease at diagnosis. In contrast, 2 of our patients with renal PNET, all diagnosed after 1990 and receiving modern, aggressive therapy, showed primary resistance to agents that are very active against the ESFT, dying 1 and 4 months after diagnosis. The patients described by Scheaff et al.,6 Chan and Llewellyn,8 and Mor et al.,9 2 with localized disease and 1 with disease spread only to retroperitoneal lymph nodes, all died within 10 months of diagnosis. Our series and the four other new case reports4-7 suggest that PNET of the kidney is a distinct clinical entity that must be distinguished from other primary renal tumors. Therapeutic approaches for this tumor should be the same as for other sites of ESFT, but may be less successful. Carlos Rodriguez-Galindo M.D.*, Neyssa M. Marina M.D. , David M. Parham M.D. , William H. Meyer M.D.?

Patients with pineal tumors are often asymptomatic and the symptoms depend on the location of the mass. In fact, around 3%-8% of pediatric brain tumor cases are pineal tumors. Children with pineal tumors may present with dizziness and vertigo as early signs. These symptoms are common conditions among 5-15 years old children and could probably lead to misdiagnoses. We present a case of 14-year-old who came to the emergency room of DR. Soetomo Hospital Surabaya with neurotologic symptoms. After a series of radiographic and laboratory examinations, he was diagnosed with germinoma. A ventriculoperitoneal shunt was performed in the emergency room and intravenous dexamethasone was administered.

Primary central nervous system (CNS) neuroblastoma, FOXR2-activated (CNS-NB-FOXR2), is a rare embryonal tumor characterized by neuroblastic differentiation and structural rearrangement of the FOXR2 gene. Previously grouped under CNS primitive neuroectodermal tumors (PNET), this entity has been reclassified based on genome-wide DNA methylation profiling. In this study, we present the detailed clinicopathological and immunohistochemical features of two pediatric cases diagnosed at our center. The first case involved a six-year-old with a left frontal mass; the second was a one-year-old with a large bifrontal lesion. Radiologically, both cases mimicked other embryonal tumors or high-grade gliomas. Histologically, tumors displayed small round blue cell morphology with neuroblastic features, including Homer-Wright rosettes and ganglionic differentiation. Immunohistochemistry demonstrated diffuse positivity for OLIG2, synaptophysin, and L1CAM, with negative expression for GFAP, EMA, and IDH1 R132H. FOXR2 showed nuclear positivity in both cases, supporting the diagnosis. Both cases exhibited diffuse L1CAM positivity-a rare finding with limited evidence in the existing literature. Although DNA methylation profiling could not be performed, the diagnosis was supported by characteristic morphology and immunohistochemistry profile. This report highlights key diagnostic features and potential mimics of CNS neuroblastoma, FOXR2-activated, and underscores the utility of immunohistochemistry in low-resource settings. Recognizing this entity is essential for accurate classification and appropriate therapeutic planning. Further studies are warranted to explore targeted therapies, including MEK inhibitors, which may hold promise based on emerging molecular data.

Primitive neuroectodermal tumor (PNET) is a prototypic malignant small round cell tumor of childhood that is characterized in most cases by t(11;22) resulting in an EWS-FLI1 gene fusion. Once thought to be uncommon, PNET now accounts for almost 20% of malignant soft tissue tumors in children. Increased recognition of PNET is partly due to advances in immunohistochemistry and molecular diagnostics, which have led to the identification of the tumor in non-classical sites. We report the clinical, histologic, immunohistochemical, and molecular findings of two visceral PNETs of the digestive system--one involving the small intestine and the other involving the hepatic duct. Histologically, each tumor was composed of malignant small cells growing in sheets, nests, and lobules; the tumor cells of both cases showed characteristic immunoreactivity for vimentin and O13 (CD99). Reverse transcription-polymerase chain reaction (RT-PCR) analysis for t(11;22) using nested primers was performed with RNA extracted from paraffin-embedded, formalin-fixed tissue and demonstrated an EWS exon 7 to FLI1 exon 5 fusion in both cases, confirmed by Southern blot hybridization and DNA sequence analysis. These results illustrate the expanded clinicopathologic profile of PNET, and demonstrate that visceral PNETs, despite their unusual sites of presentation, maintain the characteristic immunohistochemical and genetic features of PNETs at more conventional sites.

Pineal tumors are quite rare and are fairly aggressive tumors seen in young adults and children. These tumors arise from the pineal region or recess from various types of cells in the gland and structures located in close propinquity to the gland. Pineal gland tumors have a heterogeneous spectrum that includes pineal parenchymal tumors (PPTs) and papillary tumors of the pineal region (PTPR). The PPTs are further subclassified into pineocytomas (Grade 1), PPTs of intermediate differentiation (grade 2 or 3), and pineoblastomas (grade 4) based on the World Health Organization (WHO) grades and histopathological features. We discuss the case of an 11-year-old male child who presented with complaints of headache for 15 days, vomiting for seven days, and diplopia for four days. On magnetic resonance imaging (MRI), a soft tissue density lesion was noticed in the posterior third ventricle region. Based on the location and the MRI findings, the differential diagnosis considered were a pineal lesion, a choroid plexus papilloma, or a meningioma. He underwent a right occipital ventriculoperitoneal shunt followed by total excision of the tumor, and the resected specimen was sent for histopathological examination. After pathologic examination, the diagnosis of pineoblastoma (grade 4) with features of a PPT of intermediate differentiation (grades 2-3) was revealed, and the same was confirmed on immunohistochemistry.

Objective To investigate the clinical and pathological features,therapy and prognosis of primitive neuroectodermal tumors(PNET) in children.Methods The clinical data of 16 children with PNET were analyzed retrospectively.The survival rate was calculated by Kaplan-Meier.Results Among the 16 children,14 children died.The median survival time was 22 months.The median survival time was 13 months for group S (surgical resection alone) and 28 months for group S + R + C (chemotherapy plus radiotherapy after surgery),respectively.There were significant differences between the two groups (P ＜ 0.05).Conclusions PNET,a highly malignant tumor,most often occurs in young people,and the prognosis is poor.The combined therapy is the main treatment for PNET,and the survival time of the combined therapy group is longer than that of the non-combined therapy group. Key words: Primitive neuroectodermal tumors ; Therapy ; Prognosis