Recurrent atypical teratoid/rhabdoid tumors (AT/RT) reveal discrete features of progression on histology, epigenetics, copy number profiling, and transcriptomics.

Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors manifesting in infancy. They split into four molecular types. The major three (AT/RT-SHH, AT/RT-TYR, and AT/RT-MYC) all carry mutations in SMARCB1, the fourth quantitatively smaller type is characterized by SMARCA4 mutations (AT/RT-SMARCA4). Molecular characteristics of disease recurrence or metastatic spread, which go along with a particularly dismal outcome, are currently unclear. Here, we investigated tumor tissue from 26 patients affected by AT/RT to identify signatures of recurrences in comparison with matched primary tumor samples. Microscopically, AT/RT recurrences demonstrated a loss of architecture and significantly enhanced mitotic activity as compared to their related primary tumors. Based on DNA methylation profiling, primary tumor and related recurrence were grossly similar, but three out of 26 tumors belonged to a different molecular type or subtype after second surgery compared to related primary lesions. Copy number variations (CNVs) differed in six cases, showing novel gains on chromosome 1q or losses of chromosome 10 in recurrences as the most frequent alterations. To consolidate these observations, our cohort was combined with a data set of unmatched primary and recurrent AT/RT, which demonstrated chromosome 1q gain and 10 loss in 18% (n = 7) and 11% (n = 4) of the recurrences (n = 38) as compared to 7% (n = 3) and 0% (n = 0) in the primary tumors (n = 44), respectively. Similar to the observations made by DNA methylation profiling, RNA sequencing of our cohort revealed AT/RT primary tumors and matched recurrences clustering closely together. However, a number of genes showed significantly altered expression in AT/RT-SHH recurrences. Many of them are known tumor driving growth factors, involved in embryonal development and tumorigenesis, or are cell-cycle-associated. Overall, our work identifies subtle molecular changes that occur in the course of the disease and that may help define novel therapeutic targets for AT/RT recurrences.

Histopathologic and Molecular Features of Central Nervous System Embryonal Tumors for Integrated Diagnosis Reporting.

Embryonal tumors of the pediatric central nervous system are challenging clinically and diagnostically. These tumors are aggressive, and patients often have poor outcomes even with intense therapy. Proper tumor classification is essential to patient care, and this process has undergone significant changes with the World Health Organization recommending histopathologic and molecular features be integrated in diagnostic reporting. This has especially impacted the workup of embryonal tumors because molecular testing has resulted in the identification of clinically relevant tumor subgroups and new entities. This review summarizes recent developments and provides a framework to workup embryonal tumors in diagnostic practice.

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.

Review of molecular classification and treatment implications of pediatric brain tumors.

PURPOSE OF REVIEW: Brain tumors are the most common solid tumors and leading cause of cancer-related death in children. The advent of large-scale genomics has resulted in a plethora of profiling studies that have mapped the genetic and epigenetic landscapes of pediatric brain tumors, ringing in a new era of precision diagnostics and targeted therapies. In this review, we highlight the most recent findings, focusing on studies published after 2015, and discuss how new evidence is changing the care of children with brain tumors. RECENT FINDINGS: Genome-wide and epigenome-wide profiling data have revealed distinct tumor entities within, virtually, all pediatric brain tumor groups including medulloblastoma; ependymoma; high-grade and low-grade gliomas; atypical teratoid/rhabdoid tumors; and other embryonal tumors, previously called CNS primitive neuroectodermal tumors. Whenever integrated with clinical information, many molecular alterations emerge as powerful prognostic markers and should thus be used to stratify patients and tailor therapies. SUMMARY: Optimal integration of this newly emerging knowledge in a timely and meaningful way into clinical care is a remarkable task and a matter of active debate. The historical morphology-based classification of tumors is being replaced by a genetic-based classification, and the first generation of molecularly informed clinical trials is underway.

Reclassification of rhabdoid tumor and pediatric undifferentiated/unclassified sarcoma with complete loss of SMARCB1/INI1 protein expression: three subtypes of rhabdoid tumor according to their histological features.

Rhabdoid tumor is characterized by rhabdoid cells and shows complete loss of SMARCB1/INI1 protein expression. In existing classifications, the diagnostic synonyms vary depending on the anatomic site: rhabdoid tumors in the central nervous system or extra-central nervous system are, respectively, classified as atypical teratoid/rhabdoid tumor or malignant rhabdoid tumor. In this study, we analyzed the histological, immunohistochemical, microRNA, and clinicopathological statuses of tumors initially diagnosed as malignant rhabdoid tumor (n=33), atypical teratoid/rhabdoid tumor (n=11), and pediatric undifferentiated/unclassified sarcoma (n=8) with complete loss of SMARCB1/INI1 expression, and considered the possibility of their histological reclassification. Our analysis indicated that the tumors could be histologically reclassified into three groups: conventional-type tumors resembling malignant rhabdoid tumor, atypical teratoid/rhabdoid-type tumors resembling atypical teratoid/rhabdoid tumor, and small cell-type tumors resembling malignant lymphoma. The reclassified conventional type was composed of 27 malignant rhabdoid tumors and 9 atypical teratoid/rhabdoid tumors (36 cases). The atypical teratoid/rhabdoid type consisted of six malignant rhabdoid tumors, two atypical teratoid/rhabdoid tumors, and two undifferentiated/unclassified sarcomas (10 cases). The six cases of small cell type were made up of six undifferentiated/unclassified sarcomas. All of the available tumor specimens were positive for vimentin and epithelial marker (EMA, CAM5.2, or AE1/AE3). MicroRNA profiles were not significantly different between the conventional- and small cell-type tumors (Pearson's correlation coefficient: 0.888300 or 0.891388). There was no significant difference in overall survival between atypical teratoid/rhabdoid tumor and malignant rhabdoid tumor (P=0.16). In addition, there were no significant differences in survival between any of the reclassified combinations. In conclusion, we could classify eight tumors initially diagnosed as undifferentiated/unclassified sarcomas into two cases of atypical teratoid/rhabdoid type and six cases of small cell type. We suggest that reclassification of malignant rhabdoid tumors into three groups according to their histologic features rather than the traditional classification by sites of origin would be favorable for their histopathological diagnosis.

Practical molecular pathology and histopathology of embryonal tumors.

There have been significant improvements in understanding of embryonal tumors of the central nervous system (CNS) in recent years. These advances are most likely to influence the diagnostic algorithms and methodology currently proposed by the World Health Organization (WHO) classification scheme. Molecular evidence suggests that the tumors presumed to be specific entities within the CNS/primitive neuroectodermal tumors spectrum are likely to be reclassified. All these developments compel reassessing current status and expectations from the upcoming WHO classification efforts. This review provides a synopsis of current developments and a practical algorithm for the work-up of these tumors in practice.

[Vancouver classification of renal tumors: Recommendations of the 2012 consensus conference of the International Society of Urological Pathology (ISUP)]. / Vancouver-Klassifikation von Nierentumoren : Empfehlungen der Konsenskonferenz der Internationalen Gesellschaft für Uropathologie (ISUP) 2012.

The 2012 consensus conference of the International Society of Urological Pathology (ISUP) has formulated recommendations on classification, prognostic factors and staging as well as immunohistochemistry and molecular pathology of renal tumors. Agreement was reached on the recognition of five new tumor entities: tubulocystic renal cell carcinoma (RCC), acquired cystic kidney disease-associated RCC, clear cell (tubulo) papillary RCC, microphthalmia transcription factor family RCC, in particular t(6;11) RCC and hereditary leiomyomatosis-associated RCC. In addition three rare forms of carcinoma were considered as emerging or provisional entities: thyroid-like follicular RCC, succinate dehydrogenase B deficiency-associated RCC and anaplastic lymphoma kinase (ALK) translocation RCC. In the new ISUP Vancouver classification, modifications to the existing 2004 World Health Organization (WHO) specifications are also suggested. Tumor morphology, a differentiation between sarcomatoid and rhabdoid and tumor necrosis were emphasized as being significant prognostic parameters for RCC. The consensus ISUP grading system assigns clear cell and papillary RCCs to grades 1-3 due to nucleolar prominence and grade 4 is reserved for cases with extreme nuclear pleomorphism, sarcomatoid and/or rhabdoid differentiation. Furthermore, consensus guidelines were established for the preparation of samples. For example, agreement was also reached that renal sinus invasion is diagnosed when the tumor is in direct contact with the fatty tissue or loose connective tissue of the sinus (intrarenal peripelvic fat) or when endothelialized cavities within the renal sinus are invaded by the tumor, independent of the size. The importance of biomarkers for the diagnostics or prognosis of renal tumors was also emphasized and marker profiles were formulated for use in specific differential diagnostics.

Rhabdoid tumor predisposition syndrome.

Rhabdoid tumors (RT), or malignant rhabdoid tumors, are among the most aggressive and lethal forms of human cancer. They can arise in any location in the body but are most commonly observed in the brain, where they are called atypical teratoid/rhabdoid tumors (AT/RT), and in the kidneys, where they are called rhabdoid tumors of the kidney. The vast majority of rhabdoid tumors present with a loss of function in the SMARCB1 gene, also known as INI1, BAF47, and hSNF5, a core member of the SWI/SNF chromatin-remodeling complex. Recently, mutations in a 2nd locus of the SWI/SNF complex, the SMARCA4 gene, also known as BRG1, were found in rhabdoid tumors with retention of SMARCB1 expression. Familial cases may occur in a condition known as rhabdoid tumor predisposition syndrome (RTPS). In RTPS, germline inactivation of 1 allele of a gene occurs. When the mutation occurs in the SMARCB1 gene, the syndrome is called RTPS1, and when the mutation occurs in the SMARCA4 gene it is called RTPS2. Children presenting with RTPS tend to develop tumors at a younger age, but the impact that germline mutation has on survival remains unclear. Adults who carry the mutation tend to develop multiple schwannomas. The diagnosis of RTPS should be considered in patients with RT, especially if they have multiple primary tumors, and/or in individuals with a family history of RT. Because germline mutations result in an increased risk of carriers developing RT, genetic counseling for families with this condition is recommended.

Rhabdoid tumor: the Irish experience 1986-2013.

Nomenclature for the three recognized forms of rhabdoid tumor reflect their anatomic localization and include malignant rhabdoid tumor of the kidney (MRTK), extrarenal extracranial rhabdoid tumor (EERT), and atypical teratoid rhabdoid tumor (ATRT) involving the central nervous system. A strikingly simple karyotype belies the fact that rhabdoid tumors are among the most lethal human cancers, and now early strides are beginning to elucidate their molecular pathogenesis. Rhabdoid tumors are largely confined to the pediatric population, where they occur preferentially during infancy. Given the rarity of this tumor, international consensus on best treatment has only recently been achieved in conjunction with the establishment of the European Rhabdoid Tumor Registry. Between 1986 and 2013, 25 pediatric patients were diagnosed with rhabdoid tumor in the Republic of Ireland. Of these patients, 13 presented with ATRT, eight had MRTK, and four had EERT. The mean age at diagnosis was 38.8 months, with an equal sex incidence. Because of the lack of a standardized treatment strategy for rhabdoid tumors, these patients have been treated largely according to anatomic site, based on sarcoma, renal, or brain tumor protocols contemporary to their diagnoses. Of the patients, 84% received chemotherapy, 80% underwent surgery, and 44% had radiation therapy. The outcome overall was poor, independent of anatomic location. The overall survival rate was 24%, and mean time to death was just under 9 months.

High expression of BMP pathway genes distinguishes a subset of atypical teratoid/rhabdoid tumors associated with shorter survival.

Molecular profiling of tumors has proven to be a valuable tool for identification of prognostic and diagnostic subgroups in medulloblastomas, glioblastomas, and other cancers. However, the molecular landscape of atypical teratoid/rhabdoid tumors (AT/RTs) remains largely unexplored. To address this issue, we used microarrays to measure the gene expression profiles of 18 AT/RTs and performed unsupervised hierarchical clustering to determine molecularly similar subgroups. Four major subgroups (clusters) were identified. These did not conform to sex, tumor location, or presence of monosomy 22. Clusters showed distinct gene signatures and differences in enriched biological processes, including elevated expression of some genes associated with choroid plexus lineage in cluster 4. In addition, survival differed significantly by cluster, with shortest survival (mean, 4.7 months) in both clusters 3 and 4, compared with clusters 1 and 2 (mean, 28.1 months). Analysis showed that multiple bone morphogenetic protein (BMP) pathway genes were upregulated in the short survival clusters, with BMP4 showing the most significant upregulation (270-fold). Thus, high expression of BMP pathway genes was negatively associated with survival in this dataset. Our study indicates that molecular subgroups exist in AT/RTs and that molecular profiling of these comparatively rare tumors may be of diagnostic, prognostic, and therapeutic value.

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.

Clinical and molecular features in patients with atypical teratoid rhabdoid tumor or malignant rhabdoid tumor.

The SMARCB1 gene status in 50 patients with atypical teratoid rhabdoid tumor and/or malignant rhabdoid tumor recruited to a German registry was prospectively analyzed with FISH and PCR. Altogether we found 40 SMARCB1 mutations in 28 patients. Two patients were positive for SMARCB1 staining at immunochemistry. Germline mutations were identified in 10 of 41 patients with CNS disease, including three large heterozygous deletions, six truncating mutations and one donor splice site mutation. No missense mutation was identified. Analysis of first degree relatives did not detect any carriers. Mutations were distributed over the SMARCB1-gene without particular clustering. No germline mutation was found in nine patients without CNS disease. Patients with germline mutation had a lower median age at diagnosis in comparison to those without detectable germline mutation (5.5 vs. 13 months, P = 0.001), a higher rate of primary multicentric CNS disease (5/10 vs. 5/36) and synchronous or metachronous mixed CNS and extracranial disease (4/10 vs. 1/36). Two year overall survival was 0% in patients with germline mutation and 48% in those without detectable germline mutation (P < 0.001). Patients with germline mutation of SMARCB1 manifest at an early age and have a very high risk for progression which has to be considered with respect to the outcome of further treatment studies.

Update on diagnostic practice: tumors of the nervous system.

CONTEXT: Changes in the practice of diagnosing brain tumors are formally reflected in the evolution of the World Health Organization classification. Beyond this classification, the practice of diagnostic pathology is also changing with the availability of new tests and the introduction of new treatment options. OBJECTIVE: Glioblastomas, oligodendrogliomas, glioneuronal tumors, and primitive pediatric tumors are discussed in an exemplary way to illustrate these changes. DATA SOURCES: Review of relevant publications through Medline database searches. CONCLUSIONS: The example of glioblastomas shows how new predictive markers may help identify subgroups of tumors that respond to certain therapy regimens. The development of new treatment strategies also leads to different questions in the assessment of brain tumors, as seen in the example of pseudoprogression or the changes in tumor growth pattern in patients taking bevacizumab. Oligodendrogliomas illustrate how the identification of 1p/19q loss as a cytogenetic aberration aids our understanding of these tumors and changes diagnostic practice but also introduces new challenges in classification. Glioneuronal tumors are an evolving group of lesions. Besides a growing list of usually low-grade entities with well-defined morphologic features, these also include more poorly defined cases in which a component of infiltrating glioma is often associated with focal neuronal elements. The latter is biologically interesting but of uncertain clinical significance. Oligodendrogliomas and glioneuronal tumors both illustrate the importance of effective communication between the pathologist and the treating oncologist in the discussion of these patients. Finally, the discussion of primitive pediatric tumors stresses the clinical importance of the distinction between different entities, like atypical teratoid rhabdoid tumor, "central" (supratentorial) primitive neuroectodermal tumor, "peripheral" primitive neuroectodermal tumor, and medulloblastoma. In medulloblastomas, the recognition of different variants is emerging as a prognostic factor that may in the future also predict therapy responsiveness.

Small cell undifferentiated variant of hepatoblastoma: adverse clinical and molecular features similar to rhabdoid tumors.

BACKGROUND: Small cell undifferentiated (SCU) histology in patients with stage I hepatoblastoma (HB) predicts an increased risk of relapse. We sought to determine the significance of SCU histology in patients with unresectable HB. PROCEDURE: Patients enrolled on the pediatric Intergroup (INT0098) trial for HB and patients from the personal consultation files of two of the authors (MF, LG) were reviewed for cases with SCU histology. These patients were compared with SCU HB patients identified by literature review. RESULTS: Eleven patients were studied. All patients with reported AFP results exhibited normal or minimally increased serum AFP levels. None of the patients survived: 10 died of disease progression, and 1 died from treatment complications. Immunostaining revealed that tumors from six of six patients tested were INI1 negative. Cytogenetic and molecular abnormalities in one patient (and two patients from the literature review) were similar to those described in rhabdoid tumors. Comparison with patients from the literature review revealed similar results except that 4 of 29 patients survived without evidence of disease. CONCLUSIONS: SCU histology in HB patients is associated with an adverse outcome. These tumors appear to be biologically different from non-SCU HB. Evaluation of patient characteristics and outcomes for children with SCU HB and/or those with low AFP levels should be determined from large cooperative group studies. In the meantime, we suggest patients with unresectable HB containing SCU elements have careful cytogenetic, molecular, and immunohistochemical evaluation to ascertain rhabdoid features and receive treatment that differs from that provided for other HB patients.

Molecular genetics of pediatric central nervous system tumors.

Recent advances in molecular biology have enhanced our understanding of the pathogenesis of brain tumors, particularly in children. The use of molecular diagnostic tools is quickly becoming a standard component in the diagnosis and classification of brain tumors in children, in addition to providing insight leading to treatment stratification and improved outcome prediction. All new protocols involving treatments for brain tumors in children include studies of biomarkers and biologic correlates as a means to identify new targets for therapeutics and possible intervention strategies.

P-Akt expression distinguishes two types of malignant rhabdoid tumors.

Highly aggressive pediatric malignant rhabdoid tumors (MRT) arise in the kidney and central nervous system (CNS) with no curative treatment available. Multiple studies have shown that inactivation of the SNF5 tumor suppressor gene occurs in virtually all MRTs. However, few studies have addressed whether additional genetic events may contribute to MRT development. In this report, we demonstrate that phosphorylated Akt (P-Akt) is expressed in a subpopulation of cells in at least 10% of primary rhabdoid tumors as well as at high levels in three MRT cell lines. Similar to other high P-Akt expressing tumor cell lines, MRTs have decreased sensitivity to p21 induced growth arrest. Therefore, P-Akt expression may distinguish between two types of MRTs. Because drugs directed against the PI3-K/Akt have shown promise in clinical trials for other tumor types, they may prove useful for treatment of patients with P-Akt positive MRTs. P-Akt expression also provides a potential mechanistic link between these pediatric tumors and adult malignancies.

["Proximal type" epithelioid sarcoma of the vulva: differential diagnosis with other extrarenal rhabdoid tumors]. / Sarcoma epitelioide di tipo prossimale della vulva: diagnosi differenziale con altri tumori rabdoidi extrarenali.

Proximal type epithelioid sarcoma is a rare neoplasia in which morphological findings are characterized by nodular proliferation of epithelioid cells with focal rhabdoid features. It shares some histological features with other neoplasias and this gives an account of several differential diagnosis with other extrarenal rhabdoid tumors. Immunohistochemical and ultrastructural analysis are important in defining this entity: vimentin, cytokeratin, EMA and often CD34 expression of tumoral cells, moreover ultrastructurally evidence of large paranuclear whorls of intermediate filaments, are requested for diagnosis. A correct diagnostic framing is necessary because of the aggressive clinical behaviour of this tumor, that has a tendency to early spreading. We describe a case of vulvar proximal type epithelioid sarcoma in a 34 years old woman.

Newly defined central nervous system neoplasms.

In recent years, numerous new entities or variants of recognized central nervous system tumors have been described in the literature, and the morphologic spectrum of these neoplasms is delineated incompletely. The accurate diagnosis and classification of these lesions is important to ensure that patients receive adequate therapy and prognostic information. The clinicopathologic features and differential diagnosis of 4 new entities, including the chordoid glioma of the third ventricle, cerebellar liponeurocytoma, atypical teratoid/rhabdoid tumor, and papillary glioneuronal tumor, are discussed in this review.

Pancreatic endocrine tumour with cytoplasmic keratin whorls. Is the term "rhabdoid" appropriate?

A 50 year old woman presented with acute abdominal pain accompanied by nausea and vomiting and was found to have a mass in the head of the pancreas by imaging. The clinical impression was of a pancreatic carcinoma and a Whipple's procedure was performed. Microscopic examination of the tumour showed it to be a low grade neuroendocrine carcinoma arranged in a tubuloacinar or tubulopapillary pattern, and composed of cells harbouring very prominent intracytoplasmic inclusions. These inclusions varied in appearance from being pale pink and hyaline in quality to more eosinophilic and globular causing displacement of the nucleus. Ultrastructural examination showed typical paranuclear aggregates of intermediate filaments. Inclusions of this type have been described previously as "signet ring like" and "rhabdoid". It was felt that the inclusions more closely resemble the fibrous bodies that are seen in pituitary adenomas. In addition, it is suggested that both signet ring and rhabdoid are not appropriate because they do not reflect histogenesis and are not necessarily reflective of tumour biology. It is suggested that the term "cytokeratin aggresomes" should be used to describe this distinctive phenotype.