Advances in the molecular classification of pediatric brain tumors: a guide to the galaxy

Central nervous system (CNS) tumors are the most common solid tumor in pediatrics, accounting for approximately 25% of all childhood cancers, and the second most common pediatric malignancy after leukemia. CNS tumors can be associated with significant morbidity, even those classified as low grade. Mortality from CNS tumors is disproportionately high compared to other childhood malignancies, although surgery, radiation, and chemotherapy have improved outcomes in these patients over the last few decades. Current therapeutic strategies lead to a high risk of side effects, especially in young children. Pediatric brain tumor survivors have unique sequelae compared to age-matched patients who survived other malignancies. They are at greater risk of significant impairment in cognitive, neurological, endocrine, social, and emotional domains, depending on the location and type of the CNS tumor. Next-generation genomics have shed light on the broad molecular heterogeneity of pediatric brain tumors and have identified important genes and signaling pathways that serve to drive tumor proliferation. This insight has impacted the research field by providing potential therapeutic targets for these diseases. In this review, we highlight recent progress in understanding the molecular basis of common pediatric brain tumors, specifically low-grade glioma, high-grade glioma, ependymoma, embryonal tumors, and atypical teratoid/rhabdoid tumor (ATRT). © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Rhabdoid tumor predisposition syndrome with renal tumor 10 years after brain tumor

We report a case of rhabdoid tumor predisposition syndrome with a renal tumor developing 10 years after a brain tumor, which demonstrated an unexpectedly favorable outcome. A 2-year-old boy underwent gross total resection of a brain tumor located in the fourth ventricle, and received adjuvant chemotherapy and radiotherapy. At the age of 11 years, a renal tumor was found and nephrectomy was performed. He is currently alive without evidence of disease over 2 years without postoperative therapy. Histologically, rhabdoid cells were observed in both brain and renal tumors. Loss of SMARCB1 (also known as INI1) expression was found in the nucleus of both tumor cells. Genetic testing revealed pathogenic variants of SMARCB1 exon 5 in the renal tumor and SMARCB1 exon 9 in the brain tumor. In addition, heterozygous deletion of 22q11.21-q11.23 containing the SMARCB1 locus was shared by both tumors and this deletion was identified in normal peripheral blood. Considering the histopathological and genetic findings, our case was considered to be rhabdoid tumor predisposition syndrome with atypical teratoid/rhabdoid tumor and late-onset rhabdoid tumor of the kidney.     

Atypical teratoid rhabdoid tumors (ATRTs): the British Columbia's Children's Hospital's experience, 1986-2006

As "atypical teratoid rhabdoid tumors" (ATRTs) may mimic "small round blue cell tumors" (SRBCT), we reexamined our ATRT experience focusing upon INI-1 immunohistochemistry (IHC). All high-grade pediatric brain tumors occurring from 1986-2006 at our institution underwent INI-1 IHC. Clinicopathologic data from each INI-1 immunonegative case were reviewed. Additional genetic, epigenetic and IHC analyses (including interrogation of INI-1 and CLDN6) were performed on a subset of the INI-1 immunonegative cases. Twelve INI-1 IHC negative tumors were identified retrospectively, of which only two previously carried the diagnosis of ATRT. Overall, the clinicopathologic and genetic data supported the assertion that all 12 cases represented ATRT. Unexpectedly, three long-term survivors (4.2, 7.0 and 8.5 years) were identified. As hypothesized, "teratoid" and "rhabdoid" histologic features were relatively infrequent despite gross total resections in some cases. Methylation specific polymer chain reaction (PCR) (MSP) revealed a uniform methylation pattern across all cases and gene promoters tested (ie, MGMT, HIC1, MLH3 and RASSF1); notably, all cases demonstrated unmethylated MGMT promoters. Our data demonstate that a primitive non-rhabdoid histophenotype is common among ATRTs and highlights the diagnostic importance of INI-1 IHC. Epigenetically, the MGMT promoter is usually unmethylated in ATRT, suggesting that potential temozolomide-based chemotherapy may be of limited efficacy.     

Adult variant of atypical teratoid/rhabdoid tumor: Immunohistochemical and ultrastructural confirmation of a rare tumor in the sella tursica

Atypical teratoid/rhabdoid tumor (AT/RT) is a distinctive neoplasm of young children characterized by diverse histology and fatal course. Adult presentation is rare. We describe the diagnostic problems associated with an AT/RT arising in the sellar region in a 46-year-old female.     

脑电地形图对脑肿瘤的诊断价值

目的：通过观察脑肿瘤病人的脑电图及脑电地形图特点，以探讨脑电地形图对于脑肿瘤的诊断价值。方法：对85例脑肿瘤的病人进行常规脑电图、脑电地形图检查，研究θ、δ、α、β各频带相对能量在各部位脑肿瘤的分布情况及其对脑肿瘤定位、定性的价值，并将脑电图与脑电地形图对于脑肿瘤的定位准确率进行比较。结果：85例脑肿瘤病人中有45例可以观察到病灶，对所有85例脑肿瘤的病人的脑电图和脑电地形图在脑肿瘤定位方面作了比较，有统计学意义。结论：脑电地形图能比常规脑电图提供更为明确的脑损伤局灶性改变的图象，对于提高脑肿瘤的阳性检出率，区分不同性质的肿瘤及定位提供一定的参考价值。     

Primary atypical teratoid/rhabdoid tumor of central nervous system in children: a clinicopathological analysis and review of literature in China

Atypical teratoid/rhabdoid tumor (AT/RT) is a very rare and highly malignant embryonal tumor in the central nervous system (CNS). Five patients (4 girls and 1 boy) with AT/RT were treated in our hospital. The clinical histories, symptoms, neuroimaging aspects, therapies, histological and immunohistochemical findings and follow-up information were reviewed. The patients ranged from 8 to 40 months with a mean age of 20.6 months. One tumor was located in the spinal cord, two in cerebellum and two in the pineal region. The imagings of the tumors resemble medulloblastomas. Pathological examinations showed that one patient had medulloblastoma differentiation, one had choroid plexus carcinoma differentiation, and one had mesenchymal components. Immunohistochemical staining showed that all of the tumors lost the nuclear expression of integrase interactor 1 (INI1), and were positive for Vimentin, S-100 protein and epithelial membrane antigen. One case with no recurrence after 24 months may have benefited from radical excision and postoperative radiotherapy. The other 4 patients died 8, 4, 1 and 1-month respectively after operation without radiotherapy. The diagnosis of AT/RT depends on full sampling, careful observation the morphological characteristics and INI1 examination, even when the tumor are presented in uncommon sites, such as the spinal cord and the pineal region.     

Epithelial differentiation in medulloblastoma: comparison with other embryonal tumors of neuroectodermal origin

Three cases of medulloblastoma characterized by epithelial differentiation are described in patients 6-months-, 1-month- and 8-years-old. Histologically, tumors from the two infant patients showed a perivascular arrangement without apparent radiated cytoplasmic processes from the vessels. Tumor cells displayed round and/or pleomorphic vesicular nuclei and a more abundant eosinophilic cytoplasm than that found in classic medulloblastoma. Neither Homer-Wright rosettes nor ependymal or ependymoblastic rosettes were noted in these tumors. The tumor in the 8-year-old patient exhibited a classic medulloblastoma component intermingled with abundant eosinophilic cytoplasm forming a tubular structure. Immunohistochemically, tumor cells in all cases were positive for cytokeratin, synaptophysin, and vimentin. In the third case involving the 8-year-old patient, epithelial tumor cells were positive for cytokeratin, whereas classic medulloblastoma components were negative for cytokeratin. Positive staining for melanoma-specific antigen was seen only in the third case, where strong reactivity of tumor cells formed a tubulus. However, the classic medulloblastoma component was negative for melanoma-specific antigen. Ultrastructurally, basal laminae were observed around tumor cells in the 6-month-old patient. These morphological and immunohistochemical features suggest that medulloblastoma with epithelial differentiation is a rare but distinct variant of medulloblastoma, and that some of these tumors should show differentiation in ocular pigment epithelium.     

Claudin-6 is of limited sensitivity and specificity for the diagnosis of atypical teratoid/rhabdoid tumors

Recent gene expression microarray analyses have indicated that claudin-6 is specifically expressed in atypical teratoid rhabdoid tumors (AT/RTs), suggesting a role as a positive diagnostic marker in addition to SMARCB1 (INI1) loss, which is encountered in the majority of AT/RTs. In order to investigate the potential of claudin-6 as a diagnostic marker, expression was investigated in 59 AT/RTs and 60 other primary central nervous system (CNS) tumors, including primitive neuroectodermal tumors, medulloblastomas, choroid plexus tumors, and both pediatric and adult low- and high-grade gliomas using immunohistochemistry. Claudin-6 was expressed in 17/59 AT/RTs (29%), but also in a variety of other primary CNS tumors, including 60% of medulloblastomas and 21% of malignant gliomas. Even though high staining scores (2+ or 3+) were more often encountered in AT/RTs (Chi-square 4.177; P=0.041), the overall frequency of claudin-6 staining was not significantly higher in AT/RTs as compared with the other tumors (17/59 vs. 16/60; Chi-square=0.328; P=0.567). In a subgroup of 43 AT/RT patients, of which follow-up data were available, claudin-6 expression did not show any correlation with survival. In conclusion, claudin-6 immunohistochemistry is of limited sensitivity and specificity for the diagnosis of AT/RT and does not correlate with clinical behavior.     

Epidermal growth factor receptor abnormalities in atypical teratoid/rhabdoid tumors and an unusual case with gene amplification

Atypical teratoid/rhabdoid tumor (AT/RT) is a rhabdoid tumor of the central nervous system comprising a mixture of small round cells and mesenchymal and/or epithelial elements, showing mutation of the SMARCB1 gene or SMARCA4 gene. The epidermal growth factor receptor (EGFR) is one of the tyrosine kinase receptors whose overexpressed protein plays important roles in the malignant characteristics of various tumors. We analyzed 8 Japanese cases of AT/RT for EGFR protein overexpression and egfr gene amplification using immunohistochemistry and fluorescence in situ hybridization. The patients included 7 boys and 1 girl (age range 13 days to 2 years), and the tumors were localized in the frontal lobe (1 case), lateral ventricle (1 case), third ventricle (1 case), fourth ventricle (3 cases), and cerebellum (2 cases). We found that all (100%) of them partially expressed a high level of EGFR protein, and that one case showed amplification of egfr, the amplified area being localized and limited to a specific area within the tumor. We speculate that AT/RT is a tumor with heterogeneous egfr amplification, and that the frequency of amplification may depend on loss of function of the specific chromatin-remodeling member.     

Cytomorphological features of atypical teratoid/rhabdoid tumor: An account of 12 years' experience

Atypical teratoid rhabdoid tumor (AT/RT), an aggressive neoplasm mostly affecting young children, is characterized by rhabdoid cells together with epithelial, mesenchymal and primitive differentiation. Diagnosing AT/RT in intraoperative consultation and cerebrospinal fluid (CSF) samples may therefore pose problems. Fourteen immunohistochemically proven AT/RTs diagnosed between 2000 and 2012 were collected. Material consisted of squash smears prepared during intraoperative consultation (thirteen) and CSF smears (three). MGG‐stained CSF smears and H&E stained squash smears were reviewed by a neuropathologist and a cytopathologist. The intraoperative diagnoses were based on squash preparations and 3 out of 13 were consistent with AT/RT, 4 were considered medulloblastoma/primitive neuroectodermal tumors (PNET), 3 were deferred to paraffin section for tumor typing, and another 3 were misdiagnosed as ependymoma, germinoma and malignant glioma. Morphological assessment of intraoperative squash preparations showed that AT/RTs can have a mixture of pseudopapillary and diffuse smearing patterns. Cytomorphologic features consisted of characteristic rhabdoid cells (8/9); primitive appearing cells with a high nuclear to cytoplasmic ratio (7/9); bi‐/multinucleated cells (3/9); rare necrosis/apoptosis and mitoses. Three CSF smears showed high cellularity and inclusion‐bearing large cells. These cells are characterized by reniform/oval, eccentrically placed nuclei with cytoplasmic perinuclear light stained areas which are not seen in intraoperative squash preparations. Differential diagnosis of AT/RT in cytology involves medulloblastoma/PNET, ependymoma, glioma and germinoma among all others. Overlapping features of AT/RT with entities in differential diagnosis are discussed with a special emphasis of rhabdoid cells being the strongest feature to aid in reaching the diagnosis of AT/RT. Diagn. Cytopathol. 2014;42:856–862. © 2014 Wiley Periodicals, Inc.     

中枢神经系统非典型畸胎瘤样/横纹肌样瘤10例临床病理分析

目的 探讨中枢神经系统非典型畸胎瘤样/横纹肌样瘤(atypical teratoid/rhabdoid tumor,AT/RT)的临床病理学特征、诊断、鉴别诊断及预后.方法 回顾性分析2016年～2019年中南大学湘雅医院诊治的10例AT/RT的临床、影像学及病理学特征,并对其进行随访及相关文献复习.结果 10例患者发...     

Cytological diagnosis of cystic brain tumors: a retrospective study of 88 cases

The stereotaxic aspiration of cystic brain tumors is performed to provide cyst decompression and/or to facilitate surgical resection. The purpose of our study was to determine the diagnostic value of brain cyst fluid cytology, especially in clinically suspected recurrent tumors with no histological follow-up (HF), when a diagnosis is most needed. We reviewed the cytological diagnoses of 88 aspirates from 70 patients with cystic brain tumors between 1995 and 2001, of which 31 had a prior known malignancy including 18 primary brain tumors (PBTs) and 13 adenocarcinomas (ACAs). Sixty-nine of 88 aspirates were obtained intraoperatively. Nineteen of 88 aspirates were obtained from 10 patients with recurrent or persistent cystic brain tumors (8 patients with PBT and 2 patients with ACA), with available clinicoradiological correlation (magnetic resonance imaging/computed tomography [MRI/CT] scans) in 13 of them. The 88 aspirates were classified in three categories: 28 positive (32%), 15 atypical (17%), and 45 negative (51%). Eight of 28 positive cases (5 case of PBT, 2 cases of ACA, and 1 case of melanoma) were given a nonspecific diagnosis of malignant neoplasm (9% of all cases). Fifteen of 28 positive cases (6 cases of PBT, 8 cases of ACA, and 1 case of melanoma) were diagnosed correctly and confirmed by HF (17% of all cases). Four of 28 cases were ACA diagnosed solely by cytology (<4% of all cases). One neurocytoma (1/28) case was mistaken for an oligodendroglioma despite cell blocks (CBs) and immunophenotyping (IPT) (<1% of all cases). Eleven of 15 atypical cases were 8 cases of PBT, 2 cases of ACA, and 1 case of postoperative change (PC). Four of 15 atypical cases (from three patients with suspected PBT recurrence) could not be further characterized by CB/IPT and had no HF. Twenty-seven of 45 negative cases were falsely negative (23 cases of PBT, 3 cases of ACA, and 1 case of malignant neoplasm); 11/45 cases were PC, and 7/45 (from five patients with clinically suspected tumor recurrence) cases had no HF. Cytological evaluation of brain cyst fluid is not a reliable means of diagnosing cystic brain neoplasms (including recurrences) due to a high false negative rate and a low sensitivity. Most of the negative or atypical cases (68% of all cases) were recurrent PBT of glial origin that may not be prone to exfoliate. These cytological specimens consisted of lysed blood, obscuring inflammatory cells, and degenerated diagnostic cells if any, yielding inconclusive results.     

Pediatric brain tumors: a histologic and genetic update on commonly encountered entities

As our understanding of pediatric brain neoplasia flourishes, so does the development of diagnostic, prognostic, and predictive biomarkers. The neuropathologist uniquely stands at the crossroads between pathology and molecular genetics, often overseeing the creation, development, implementation, delivery, and reporting of the newest bioassays. This review serves to highlight the key microscopic and genetic features of the most common pediatric brain tumors. For example, INI-1 immunohistochemistry has assisted in identifying several previously unrecognized cases of rhabdoid cell-poor atypical teratoid rhabdoid tumor (ATRT). The latest discovery involving the tandem duplication and fusion BRAF-KIAA1549 on chromosome 7q34 in pilocytic astrocytoma has drawn attention to the MAPK-ERK pathway and its potential chemotherapeutic manipulation. The newly identified IDH1 mutation, which appears characteristic of "secondary astrocytomas," has yet to be studied in the pediatric population, but some researchers have extolled concomitant BRAF-KIAA1549/IDH1 analysis in the neuropathologic workup of many astrocytomas. Through these and other advances, our understanding of pediatric brain tumors will continue to expand exponentially, and as such will set the stage for truly effectual future treatments.     

A case of an atypical teratoid/rhabdoid tumor with distinctive histology in the pineal region in an adult patient

A 31-year-old man suffered from headaches and presented at a hospital after the symptom worsened. Obstructive hydrocephalus and a pineal tumor were identified, and he was transferred to our hospital for further investigation and treatment. Cranial computed tomography revealed a hypodense mass lesion on the right of the pineal region, and calcifications and enlargement of the lateral and third cerebral ventricles were also evident. Blood tests were negative for all tumor markers. Laparoscopic biopsy and third-ventricle fenestration were performed that day as an emergency surgery to treat the obstructive hydrocephalus. Postoperative cranial magnetic resonance imaging revealed a solid tumor that was hypointense on T1-weighted imaging, hyperintense on T2-weighted imaging, and heterogeneously enhanced by Gd. Subsequently, the tumor increased in size, and craniotomy and tumorectomy were performed. Histologically, the tumor proliferated as round or short spindle-shaped cells in a myxoid matrix, forming arrays that surrounded the blood vessels. As a few cells with eosinophilic cytoplasm were also present and immunostaining for INI-1 was negative, the patient was diagnosed with atypical teratoid/rhabdoid tumor (AT/RT). AT/RT of the pineal region in adults is rare, and herein, we report the morphological characteristics of this case and reviewed the relevant literature.     

Pigmented Intracerebral Neuroepithelial Cyst: Report of a Case

A 35-year-old man with seizure disorder was found to have a parietal lobe neuroepithelial cyst. The lining of the cyst was made up of ependymal cells containing neuromelanin, which was confirmed ultrastructurally. This appears to be the first report of a pigmented neuroepithelial cyst in the brain parenchyma.     

Congenital tumors of the central nervous system: an institutional review of 64 cases with emphasis on tumors with unique histologic and molecular characteristics

Congenital brain tumors are rare accounting for 0.5%–1.9% of all pediatric brain tumors. While different criteria have been used to classify a tumor as congenital, those diagnosed prior to 6 months of age are considered to be “probably” congenital in origin. We performed an institutional review of all central nervous system (CNS) tumors (surgical and autopsy specimens from 1990 to 2019) in patients less than 6 months old. Sixty‐four unique cases were identified, and these accounted for 2.0% of all CNS tumor specimens at our institution. The most common tumor types were high‐grade gliomas, low‐grade gliomas and medulloblastomas. Atypical teratoid rhabdoid tumors, choroid plexus tumors and germ cell tumors also accounted for a significant portion of the cohort. Seven tumors were diagnosed prenatally. The most common clinical presentation at diagnosis was increased head circumference. At the conclusion of the study, over half of the patients were alive including all patients with WHO grade I and II tumors. Ninety‐two percent of cases were classifiable using the 2016 WHO system, and when available, molecular findings supported the histologic diagnoses. However, several gliomas had unusual histologic features and did not correspond to a well‐defined entity. Molecular testing was essential for accurate classification of a subset of these tumors, and several high‐grade gliomas exhibited fusions considered unique to infantile gliomas, including those involving the MET, ALK and NTRK genes. To our knowledge, this cohort represents the largest single‐institution study of congenital CNS tumors and highlights many ways in which congenital CNS tumors are distinct from CNS tumors of older pediatric patients and adults.