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.     

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。     

Tumor development in the Beckwith-Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1.

Dysregulation of imprinted genes on human chromosome 11p15 has been implicated in Beckwith-Wiedemann syndrome (BWS), an overgrowth syndrome associated with congenital malformations and tumor predisposition. The molecular basis of BWS is complex and heterogeneous. The syndrome is associated with alterations in two distinct imprinting domains on 11p15: a telomeric domain containing the H19 and IGF2 genes and a centromeric domain including the KCNQ1OT1 and CDKNIC genes. It has been postulated that disorders of imprinting in the telomeric domain are associated with overgrowth and cancer predisposition, whereas those in the centromeric domain involve malformations but not tumor development. In this study of 125 BWS cases, we confirm the association of tumors with constitutional defects in the 11p15 telomeric domain; six of 21 BWS cases with uniparental disomy (UPD) of 11p15 developed tumors and one of three of the rare BWS subtype with hypermethylation of the H19 gene developed tumors. Most importantly, we find that five of 32 individuals with BWS and imprinting defects in the centromeric domain developed embryonal tumors. Furthermore, the type of tumors observed in BWS cases with telomeric defects are different from those seen in BWS cases with defects limited to the centromeric domain. Whereas Wilms' tumor was the most frequent tumor seen in BWS cases with UPD for 11p15 or H19 hypermethylation, none of the embryonal tumors with imprinting defects at KCNQ1OT1 was a Wilms' tumor. This suggests that distinct tumor predisposition profiles result from dysregulation of the telomeric domain versus the centromeric domain and that these imprinting defects activate distinct genetic pathways for embryonal tumorigenesis.     

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。     

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.     

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.     

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.     

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.     

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.     

Die Rolle der Neuropathologie bei familiären Tumorerkrankungen

Inherited cancer syndromes often involve the central and peripheral nervous system. For the surgical neuropathologist the possibilty in individual patients of a familial tumour syndrome needs to be considered in the case of special tumours such as malignant peripheral nerve sheath tumour (MPNST), medulloblastoma with extensive nodularity (MBEN) or even atypical teratoid/rhabdoid tumour (AT/RT) of the brain. Furthermore, tumour location and patient age may point to a familial tumour syndrome as in the case of neurofibromatosis type 2 (NF2) with typical bilateral vestibular schwannoma in young age. This short review discusses some of the diagnostic aspects in this field relating to neurofibromatosis type 1 and 2 (NF1, NF2), as well as the two rare tumors MBEN in Gorlin-Goltz syndrome and AT/RT in particular.     

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.     

SWI/SNF deficient central nervous system neoplasms

The SWItch/Sucrose Non-Fermentable (SWI/SNF) complexes are ubiquitous ATP dependent chromatin remodeling complexes that provide epigenetic regulation of gene expressions across the genome. Different combination of SWI/SNF subunits allow tissue specific regulation of critical cellular processes. The identification of SMARCB1 inactivation in pediatric malignant rhabdoid tumors provided the first example that the SWI/SNF complex may act as a tumor suppressor. It is now estimated at least 20% of all human tumors contain mutations in the subunits of the SWI/SNF complex. This review summarizes the central nervous system tumors with alterations in the SWI/SNF complex genes. Atypical teratoid/rabdoid tumor (AT/RT) is a highly aggressive embryonal tumor genetically characterized by bi-allelic inactivation of SMARCB1, and immunohistochemically shows complete absence of nuclear expression of its protein product INI1. A small subset of AT/RT show retained INI1 expression but defects in another SWI/SNF complex gene SMARCA4. Embryonal tumors with medulloblastoma, pineoblastoma, or primitive neuroectodermal morphology but loss of INI1 expression are now classified as AT/RT. Cribriform neuroepithelial tumor (CRINET) is an intra or para-ventricular tumor that has similar SMARCB1 alterations as AT/RT but generally has a benign clinical course. Besides AT/RT and CRINET, compete loss of nuclear INI1 expression has also been reported in poorly differentiated chordoma and intracranial myxoid sarcoma within the central nervous system. Families with non-truncating SMARCB1 mutations are prone to develop schwannomatosis and a range of developmental syndromes. The schwannomas in these patients usually demonstrate a mosaic INI1 staining pattern suggestive of partial residual protein function. Finally, clear cell meningioma is a WHO grade II variant meningioma characterized by bi-allelic inactivation of the SMARCE1 gene and immunohistochemically show loss of its protein product BAF57 expression in tumor cell nuclei.     

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.     

Calcifying nested stromal-epithelial tumor (CNSET) of the liver in Beckwith-Wiedemann syndrome

Calcifying nested stromal-epithelial tumor (CNSET) is a rare neoplasm. In the 31 reported cases, CNSET is predominantly found in young girls and women. Beckwith-Wiedemann syndrome (BWS) (OMIM #130650) is an overgrowth syndrome with an increased risk to develop cancer. Associations have been seen between BWS and embryonal tumors, especially Wilms tumor, hepatoblastoma, and adrenocortical carcinoma. Here we report on a female patient with BWS who presented with CNSET. Two other cases with the same association have been reported, with our case representing the third such reported in the literature. Although we recognize a potential reporting bias we speculate that CNSET may represent an unrecognized addition to the spectrum of BWS tumorigenesis.     

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.     

Hereditary SWI/SNF complex deficiency syndromes

The SWItch Sucrose non-fermentable (SWI/SNF) complex is a highly conserved multi-subunit complex of proteins encoded by numerous genes mapped to different chromosomal regions. The complex regulates the process of chromatin remodelling and hence plays a central role in the epigenetic regulation of gene expression, cell proliferation and differentiation. During the last three decades, the SWI/SNF complex has been increasingly recognized as a central molecular event driving the initiation and/or progression of several benign and malignant neoplasms of different anatomic origin and having diverse histomorphological appearance. Atypical teratoid/rhabdoid tumors (AT/RT) and renal/extrarenal malignant rhabdoid tumors of childhood, epithelioid sarcoma and small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) represent the most commonly recognized SWI/SNF-driven neoplasms. Approximately one-third of pediatric malignant rhabdoid tumors are linked to germline SWI/SNF alterations (SMARCB1/INI1, rarely SMARCA4) resulting in occasional familial clustering of these highly aggressive malignancies (so-called rhabdoid tumor predisposition syndrome, RTPS, types 1 and 2, respectively). However, more recently, inherited SWI/SNF-deficiency has been linked to several benign syndromic tumors including a subset of familial schwannomatosis (linked to SMARCB1) and multiple meningiomas (linked to SMARCE1) as well as others. Beyond neoplasms, several congenital developmental functional disorders such as Coffin-Siris syndrome and intellectual disability are now known to be SWI/SNF-related. The latter are essentially not associated with SWI/SNF-driven neoplasms, although at least anecdotal cases have documented concurrence of both neoplastic and developmental disorders. This review summarizes the most important SWI/SNF-driven diseases with a main focus on neoplasms.     

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.     

Mutation of the INI1 gene in composite rhabdoid tumor of the endometrium

Composite rhabdoid tumors are typically adult tumors that contain a component of rhabdoid cells, which are characteristic of the aggressive childhood malignant rhabdoid tumor. Pediatric rhabdoid tumors are characterized by the inactivation of the hSNF5/INI1/SMARCB1 gene, with subsequent loss of expression of the protein. In contrast, only a single composite rhabdoid tumor has demonstrated involvement of the INI1 gene. In our study, INI1 protein expression was studied in 2 uterine carcinosarcomas with rhabdoid components (composite rhabdoid tumors). The rhabdoid component of 1 tumor showed lack of immunoreactivity for the INI1 protein and strong positivity for cyclin D1, whereas the adenocarcinomatous component of the tumor and both components of the second tumor were immunoreactive for the INI1 protein and negative for cyclin D1. Loss of one INI1 allele and a mutation in exon 7 of the remaining allele were detected in the first tumor, consistent with the immunohistochemistry results. Our results demonstrate that deletions and mutations of the INI1 gene can occur also in rare composite rhabdoid tumors of adulthood. Further studies are necessary, however, to determine the prognostic significance of this finding.     

Atypical teratoid/rhabdoid tumor of the central nervous system associated with congenital cataract

Atypical teratoid /rhabdoid tumor (AT/RT) of the central nervous system is a rare but highly aggressive neoplasm that usually affects young children and infants and follows a rapidly fatal course. We report a case of AT/RT in a 3-month-old male infant who also had coincidental unilateral congenital cataract even though there was no associated congenital infectious disease.