CSF cytology of atypical teratoid/rhabdoid tumor of the brain in a two-year-old girl: a case report

Atypical teratoma/rhabdoid tumor (AT/RT) of the central nervous system is a highly malignant neoplasm in infants and early childhood. Approximately one third of patients develop intracranial dissemination with involvement of cerebral spinal fluid (CSF). The clinical, radiological, and pathological features have been described, but cytology of the tumor cells in CSF has not. Multiple CSF samples were examined in a case of AT/RT in a 2-yr-old girl. The most consistent cytologic features of AT/RT are the large size of the tumor cells, eccentricity of the nuclei, and prominent nucleoli. The differential diagnosis includes medulloblastoma/primitive neuroectodermal tumor (PNET) of the brain. Because AT/RT often contains PNET-like regions, the differential diagnosis mainly relies on the presence or absence of large rhabdoid tumor cells. Cytological examination of CSF from a patient with AT/RT is important in the early diagnosis, disease progression analysis, and therapy modulation.     

A role for fluorescence in situ hybridization detection of chromosome 22q dosage in distinguishing atypical teratoid/rhabdoid tumors from medulloblastoma/central primitive neuroectodermal tumors

It has been postulated that infants with medulloblastomas/central primitive neuroectodermal tumors (MB/PNET) may fare worse than older patients because some of them harbor unrecognized atypical teratoid/rhabdoid tumors (AT/RT), rare intracranial neoplasms that are typically unresponsive to therapy and rapidly fatal. Although small primitive cells are common to both entities, chromosome 22q11.2 deletions are common only in AT/RTs. Using fluorescence in situ hybridization (FISH) on archival, paraffin-embedded biopsy tissue with commercially available probes to 22q11.2, the region associated with RTs, we studied 8 cases of AT/RT, 12 cases of MB/PNET, and 4 cases of primitive central nervous system (CNS) neoplasms, which were difficult to classify. 22q Deletions were identified in 6 of 8 (75%) conventional AT/RTs and 0 of 12 (0%) children with classic MB/PNET. Of the 4 originally "difficult to classify" cases, 3 had deletions of 22q. In light of the FISH results, review of the morphology and immunophenotype resulted in 3 tumors being reclassified as AT/RTs and 1 as a large cell MB. These 4 cases highlight the potential diagnostic use of FISH for selected cases of primitive CNS malignancies in children and substantiate the notion that misdiagnosed AT/RTs may, in part account for the worse prognosis associated with "MB/PNET" in children younger than 2 years of age.     

中枢神经系统非典型畸胎瘤样/横纹肌样瘤临床病理特点

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)的临床病理特征、组织发生及预后。方法应用光镜、特殊染色及免疫组化染色观察1例2岁儿童大脑AT／RT的病理组织学特点，结合国内外文献进行讨论。结果肿瘤含有横纹肌样细胞、原始神经外胚层、上皮及间叶多向分化成分。肿瘤中网状纤维丰．富。免疫组化染色Vim、EMA、CKpan、GFAP、Syn及CgA均呈阳性表达，PLAP、CD117、SMA及：NF?呈阴性反应。结论AT／RT为发生在儿童中枢神经系统罕见的高度恶性肿瘤，多数患者1年内死亡。肿瘤极易误诊为髓母细胞瘤、原始神经外胚叶肿瘤(PNET)、脉络丛乳头状癌及生殖细胞肿瘤。免疫组化染色对确诊AT／RT十分重要。本瘤的组织发生仍不清楚。     

Atypical teratoid/rhabdoid tumor: cytology and differential diagnosis in adults

Atypical teratoid/rhabdoid tumors (AT/RTs) are malignant intracranial neoplasms that usually occur in the posterior fossa of children. They are characterized by cells with paranuclear rhabdoid inclusions, a mesenchymal and epithelial immunohistochemical profile, and 22q deletions with inactivation of the INI1/hSNF5 gene. Although they usually occur in young children, AT/RTs are being recognized in adults with increasing frequency. We report the cytologic features of an AT/RT from the cerebellum of a 45-year-old man and discuss the differential diagnosis in adults.     

Atypical teratoid/rhabdoid tumor: analysis of cytomorphologic features in CSF, focused on the differential diagnosis from mimickers

Atypical teratoid and rhabdoid tumor (AT/RT) is a rare tumor with fatal clinical consequences, usually affecting young children. A significant portion of patients present with dissemination to cerebrobspinal fluid (CSF). However, a limited number of studies are available regarding the cytomorphologic findings of AT/RT in CSF. We collected eight cases of CSF cytology of AT/RT and describe the cytomorphologic features of AT/RT in CSF. Typical rhabdoid cells are found in most cases and they are characterized by eccentric nuclei, abundant cytoplasm, and clustering of the tumor cells. The presence of these cells in CSF indicates disseminated diseases and aggressive therapeutic consideration for patient management is required.     

Cytologic features of papillary tumor of the pineal region: A case report showing tigroid background

Papillary tumor of the pineal region (PTPR) is a rare neuroepithelial tumor of the pineal region of adults. We herein describe on a 34‐year‐old female the cytologic features of a PTPR studied using Diff‐Quik stain. The patient presented hydrocephalia secondary to a pineal tumor. During surgery an intraoperative pathologic consultation was requested. Smears were hypercellular with numerous papillary tissue fragments and single cells. Papillary fragments had an evident inner vascular core. Neoplastic cells displayed moderate pleomorphism, plasmocytoid morphology, and cytoplasmic fragility. The background had a foamy, lace‐like, tigroid appearance. Pathologic analysis revealed morphologic and immunohistochemical features of PTPR. When evaluating smears of a pineal tumor in an adult, the presence of true papillary structures and numerous single cells should raise the possibility of PTPR. This is particularly useful during intraoperative pathologic evaluation since, on frozen sections, the epithelial morphology of the tumor may be misleading. The papillary morphology which gives name to this neoplams is best appreciated on squash smears. An interesting feature seen in the present case was a prominent tigroid background. This is a characteristic cytologic feature observed in Romanowsky‐type stained smears of germinoma and related tumors. It can be seen in other clear cell, glycogen‐rich tumors. PTPR shares with these neoplasms its clear cell morphology and PAS positive cytoplasmic granules. As seen from the present case, germinoma is not the only tumor of the pineal region that may show a tigroid background. Cytologic features of PTPR differ from those of germinoma allowing their distinction during intraoperative consultations. Diagn. Cytopathol. 2016;44:1098–1101. © 2016 Wiley Periodicals, Inc.     

中枢神经系统非典型畸胎样/横纹肌样瘤临床病理及免疫表型特征

目的 探讨中枢神经系统非典型畸胎样／横纹肌样瘤的临床病理特征、诊断及鉴别诊断。方法 对2例非典型畸胎样／横纹肌样瘤应用光镜行HE、网状纤维染色及免疫组织化学染色观察,并结合文献复习。结果 非典型畸胎样／横纹肌样瘤具有特征性的横纹肌样细胞,伴有不同程度的原始神经外胚叶、上皮和间质分化。肿瘤组织富于网状纤维,免疫组织化学标记示波形蛋白、CD99、上皮细胞膜抗原、细胞角蛋白、胶质纤维酸性蛋白、S-100蛋白、神经微丝蛋白、结蛋白、平滑肌肌动蛋白阳性,突触素、肌调节蛋白、胎盘碱性磷酸酶和HMB45阴性。结论 非典型畸胎样／横纹肌样瘤是中枢神经系统一种罕见的高度恶性肿瘤,好发于儿童,偶见于成人,呈异源性组织学和免疫组织化学表型。其诊断需与脑内其他多形性肿瘤鉴别。     

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.     

Claudin 6 Is a Positive Marker for Atypical Teratoid/Rhabdoid Tumors

Atypical teratoid/rhabdoid tumors (AT/RTs) are highly aggressive pediatric brain tumors characterized by the presence of rhabdoid cells and negative immunostaining for INI1 (BAF47). Histogenesis is unknown and diagnosis can be challenging because of their extreme morphological and immunophenotypic heterogeneity. Currently no signature markers other than INI1 loss have been identified. To search for possible candidate proteins of interest in AT/RTs, Affymetrix GeneChip® microarrays were utilized to investigate nine AT/RTs vs. 124 other tumor samples. The most distinctive gene identified was claudin 6 ( CLDN6 ), a key component of tight junctions. CLDN6 showed moderate or higher mRNA expression in eight of nine AT/RTs, with little to no expression in 114 of 115 other tumors. Average expression was 38-fold higher in AT/RTs vs. other samples. Immunohistochemical (IHC) staining of 33 tumor specimens found positive membrane staining in seven of seven AT/RTs, and was negative in 26 of 27 other brain tumor samples. Notably, none of the 16 medulloblastomas/primitive neuroectodermal tumors showed IHC staining for CLDN6. IHC staining results closely matched the level of mRNA expression detected by microarray. CLDN6 may be a useful positive marker to help further identify AT/RTs for diagnostic and treatment purposes.     

Immunocytochemical demonstration of glial fibrillary acidic protein in imprint smears of human brain tumors

Papanicolaou-destained imprint smears from 24 brain tumors were investigated by means of avidin-biotin-peroxidase complex method (ABC) with the use of monoclonal antibodies against glial fibrillary acidic protein (GFAP). Positive staining reaction to GFAP antibody has been demonstrated in cells from the following tumors: astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, mixed glioma, and ependymoma. The reaction for GFAP was negative for the following tumors: medulloblastoma, neurilemmoma, melanoma, hemangioblastoma, and metastatic tumors. In astrocytoma, the cell bodies and processes were positive with delicate fibrillary patterns; in anaplastic astrocytoma, cytoplasm and the processes were intensively stained. In glioblastoma multiforme, the staining patterns were also mixed, and the short, thickened processes were characteristic. Use of both a smear preparation and the immunoperoxidase staining technique is of great value in diagnosis of tumors of the central nervous system.     

Ependymoblastoma: Dear,Damned, Distracting Diagnosis,Farewell!

Ependymoblastoma is a diagnostic label that has been applied to a variety of rare central nervous system (CNS) tumors over the last eight decades. Consequently, there is uncertainty about whether such an entity exists and what its characteristic features might be. The current study, based on 14 cases from our institutional archives and identified by the search terms “ependymoblastoma,”“ependymoblastomatous,”“ependymoblastic” or “PNET with ependymal differentiation,” aimed to test the hypothesis that the ependymoblastoma is a distinct and recognizable entity. Ependymoblastic rosettes are a key diagnostic feature and were present in 11/14 (79%) tumors, eight (73%) of which were embryonal tumors with abundant areas of neuropil‐like differentiation. Three other cases showed rare ependymoblastic rosettes in the histopathological setting of a typical primitive neuroectodermal tumor (PNET), medulloblastoma (MB) or atypical teratoid/rhabdoid tumor (AT/RT). The remaining cases were all embryonal tumors with structures that mimicked ependymoblastic rosettes. Our results indicate that ependymoblastic rosettes are most frequently encountered in embryonal tumors with abundant neuropil and less frequently in other CNS embryonal neoplasms, including PNET, MB and AT/RT. We believe that ependymoblastoma as a diagnosis is neither precise nor specific and that it is time once and for all to retire this diagnosis from the lexicon of neuropathology.     

胰岛素样生长因子-1在不同类型脑肿瘤患儿血清中水平的研究

目的：探讨血清胰岛素样生长因子-1(insulin-like growth factor 1,IGF-1)表达水平与儿童不同类型脑肿瘤的关系。方法：采用化学发光法检测86例儿童脑肿瘤患儿及20例正常对照者的IGF-1水平并进行比较,其中胶质瘤53例(星形细胞瘤22例,室管膜瘤18例,髓母细胞瘤13例),颅咽管瘤22例,生殖细胞瘤11例。结果：胶质瘤组患儿血清中的IGF-1水平显著高于颅咽管瘤组、生殖细胞瘤组患儿和对照组,差异有统计学意义(P<0.05);同时高级别胶质瘤组患儿的IGF-1表达水平也同样高于低级别胶质瘤组患儿,差异有统计学意义(P<0.05)。结论：血清中IGF-1在不同类型的脑肿瘤中存在显著差异,能为临床早期诊断提供一定的参考依据。     

Chromosome 22q dosage in composite extrarenal rhabdoid tumors: clonal evolution or a phenotypic mimic?

Composite extrarenal rhabdoid tumors (CERTs) represent a diverse group of neoplasms with rhabdoid shape in combination with one of several distinctive tumor types. Like the classic renal and extrarenal malignant rhabdoid tumor (MRT), as well as the atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system, CERTs typically show aggressive clinical behavior. Deletions and mutations of the INII gene on 22q11.2 have been identified in most classic MRTs and AT/RTs; however, it is not known whether the rhabdoid components in CERTs have similar genetic abnormalities. Using fluorescence in situ hybridization (FISH) on archival, paraffin-embedded tissue with a commercially available probe in close proximity to the INII locus (bcr), as well as other chromosome 22 probes, we studied 4 cases of MRT, 13 of AT/RT, and 16 of CERT (3 melanoma, 4 meningioma, 7 carcinoma, 1 rhabdomyosarcoma, and 1 neuroblastoma). Deletion of the 22q11.2 locus was demonstrated in 10 (77%) of 13 AT/RTs and 3 (75%) of 4 MRT, including 1 congenital MRT. Of the 16 CERTs, only 2 (a rhabdoid meningioma and a carcinoma with rhabdoid features; 13%) harbored a deletion at this locus. This difference was statistically significant (P <.001). We conclude that deletion of 22q11.2, typical of most classic MRTs and AT/RTs, is infrequently seen in CERTs. This suggests that the rhabdoid component of CERTs does not evolve by way of the genetic alteration characteristic of MRTs or AT/RTs, but represents instead a distinct phenotype shared by a number of tumors as they undergo anaplastic progression.     

The new WHO classification of tumors of the nervous system 2000. Pathology and genetics

New developments in neuro-oncology have prompted an update of the World Health Organization (WHO) classification of tumors of the nervous system. Major changes include the addition of new entities and the refinement of criteria for the diagnosis and grading of various neoplasms, in particular the meningiomas. As novel clinico-pathological entities, the chordoid glioma of the third ventricle, the atypical teratoid/rhabdoid tumor (AT/RT), the solitary fibrous tumor, and the perineurioma have been listed. The former lipomatous medulloblastoma of the cerebellum, previously incorporated in the family of embryonal tumors, is now classified as cerebellar liponeurocytoma. The term mixed pineocytoma/pineoblastoma has been replaced by pineal parenchymal tumor of intermediate differentiation. Furthermore, the large cell medulloblastoma and the tanycytic ependymoma were established as novel tumor variants. A separate chapter on the peripheral neuroblastic tumors has now been included in the classification. Substantial revisions were introduced in the meningioma chapter. For both atypical meningioma WHO grade II and anaplastic meningioma WHO grade III, histopathological criteria are now precisely defined. An important new addition to the WHO 2000 classification of nervous system tumors is the inclusion of molecular pathology findings. With this combination of pathology and genetics it has set the stage for a new format of the WHO tumor classification series.     

Double immunolabeling of central nervous system atypical teratoid/rhabdoid tumors.

The central nervous system atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant tumor with a heterogeneous immunohistochemical profile and with some morphologic similarity to central nervous system primitive neuroectodermal tumors (PNET). Although several studies have investigated double immunolabeling in PNET, we are aware of no studies of double labeling of ATRT. A total of 10 ATRT from surgical and consultation materials at the Children's Hospital of Philadelphia were selected and stained for a variety of antigens using indirect immunofluorescence to detect single and double labeling. Most tumor cells showed only single labeling; rare cells showed double labeling as follows: 70% of tumors coexpressed (VIM) and glial fibrillary acidic protein (GFAP), 30% smooth muscle actin and GFAP, 20% epithelial membrane antigen (EMA) and VIM, 20% EMA/GFAP, and 20% EMA/SMA. These results are discussed in view of current debates over the histogenesis of CNS PNET and ATRT, and in reference to the classification of rhabdoid tumors as an entity or phenotype.     

Central Nervous System Primitive Neuroectodermal Tumors: A Clinicopathologic and Genetic Study of 33 Cases

Central nervous system (CNS) primitive neuroectodermal tumors (PNETs) include supratentorial, brain stem, and spinal cord tumors with medulloblastoma‐like histopathology. The prognostic impact of various pathologic and genetic features has not been thoroughly investigated. After re‐diagnosis of three infantile cases as atypical teratoid/rhabdoid tumor (AT/RT), 33 remaining CNS PNETs were retrieved for clinicopathologic and fluorescence in situ hybridization studies. Anaplastic and/or large cell features were seen in 18 of 33 (55%) examples and survival was decreased in these patients (P = 0.036). MYCN or MYCC gene amplifications were noted in about half, with a trend towards decreased survival (P = 0.112). Polysomies of chromosomes 2 and 8 were each individually associated with decreased survival in children, with an even stronger association when combined (P = 0.013). Neither EWS gene rearrangements, nor AT/RT‐like 22q deletions were encountered. We conclude that in CNS PNET: (i) routine application of INI1 immunohistochemistry helps rule out AT/RT, particularly in infants; (ii) MYC gene amplifications (especially MYCN) are common; (iii) involvement of CNS parenchyma by Ewing sarcoma/peripheral PNET is rare enough that EWS gene testing is not necessary unless significant dural involvement is present; and (iv) both anaplastic/large cell features and polysomies of 2 and 8 are associated with more aggressive clinical behavior.     

Intraoperative diagnosis of tanycytic ependymoma: pitfalls and differential diagnosis

Smear preparations have become increasingly popular in the intraoperative assessment of central nervous system pathology. The cytological features of a histologically proven tanycytic ependymoma are presented with the pitfalls and differential diagnosis. The smear preparation showed a glial neoplasm composed of cells with long, bipolar glial processes and oval to spindle-shaped nuclei resembling those seen in pilocytic astrocytoma smears. The smear characteristics of an ependymoma usually show remarkably uniform round-to-oval nuclei, fluffy glial processes, and a perivascular nuclear-free zone (pseudorosetting). None of these features were present in our case. The accompanying frozen section showed a fascicular spindle-cell tumor that resembled a schwanomma, a commonly reported misinterpretation of the histology of tanycytic ependymomas on frozen sections. Careful attention to the radiological findings, the surgeon's impression, and the intraoperative smear preparation details should allow one to include this uncommon entity in the differential diagnosis of spinal neoplasms.     

Chromosome 22q deletions in atypical teratoid/rhabdoid tumors in adults

Atypical teratoid/rhabdoid tumors (AT/RTs) are rare, malignant brain tumors that usually occur in the posterior fossa. Both AT/RT and the analogous tumor outside the brain, malignant rhabdoid tumor, share a polyphenotypic immunoprofile and frequent 22q deletions with inactivation of the IN11/hSNF5 gene. Reports, so far, indicate that AT/RTs occur almost exclusively in children, most of whom are 5-years-old or less. The rarity of the tumor and the polyphenotypic immunoprofile, characterized by antigen expression that is often patchy, make diagnosis in adults difficult and controversial. We describe three AT/RTs in adults in which the diagnoses were supported by detection of 22q11.2 deletions, INI1 mutation and/or loss of INI1 protein expression. Two patients were female, ages 20 and 31 and one was male, age 45.Two tumors occurred in the sella or sellar region and one in the cerebellum. In all cases, fluorescence in situ hybridization with probes to the BCR (22q11.2) and NF2 (22q12) regions of chromosome 22 revealed single copy deletions of BCR with normal dosages of NF2 and, in all cases, immunohistochemistry demonstrated loss of INI1 protein expression. In one case, a single base pair deletion was detected in the INI1/hSNF5 gene. These molecular findings confirm the occurrence of AT/RTs in adults. Although rare, AT/RT should be considered in the differential diagnosis of poorly differentiated intracranial tumors in adults.