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.

Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors.

BACKGROUND: Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T cells. However, it is unclear which epitopes T cells might recognize on AT/RT cells. METHODS: Here, we report a comprehensive mass spectrometry (MS)-based analysis of naturally presented human leukocyte antigen (HLA) class I and class II ligands on 23 AT/RTs. MS data were validated by matching with a human proteome dataset and exclusion of peptides that are part of the human benignome. Cryptic peptide ligands were identified using Peptide-PRISM. RESULTS: Comparative HLA ligandome analysis of the HLA ligandome revealed 55 class I and 139 class II tumor-exclusive peptides. No peptide originated from the SMARCB1 region. In addition, 61 HLA class I tumor-exclusive peptide sequences derived from non-canonically translated proteins. Combination of peptides from natural and cryptic class I and class II origin gave optimal representation of tumor cell compartments. Substantial overlap existed with the cryptic immunopeptidome of glioblastomas, but no concordance was found with extracranial tumors. More than 80% of AT/RT exclusive peptides were able to successfully prime CD8+ T cells, whereas naturally occurring memory responses in AT/RT patients could only be detected for class II epitopes. Interestingly, >50% of AT/RT exclusive class II ligands were also recognized by T cells from glioblastoma patients but not from healthy donors. CONCLUSIONS: These findings highlight that AT/RTs, potentially paradigmatic for other pediatric tumors with a low mutational load, present a variety of highly immunogenic HLA class I and class II peptides from canonical as well as non-canonical protein sources. Inclusion of such cryptic peptides into therapeutic vaccines would enable an optimized mapping of the tumor cell surface, thereby reducing the likelihood of immune evasion.

Identification of prognostic immune-related genes in rhabdoid tumor of kidney based on TARGET database analysis.

BACKGROUND: Malignant rhabdoid tumor of the kidney (RTK) is a rare and highly aggressive pediatric malignancy. Immune system dysfunction is significantly correlated with tumor initiation and progression. METHODS: We integrated and analyzed the expression profiles of immune-related genes (IRGs) in 65 RTK patients based on the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. Prognostic related IRGs in RTK patients were analyzed using univariate and multivariate analysis, based on which a prognostic model with IRGs was constructed. Correlation analysis between the risk score of our model and tumor-infiltrating cell were also investigated. RESULTS: Twenty two IRGs were significantly associated with the clinical outcomes of RTK patients. Gene ontology (GO) analysis revealed that inflammatory pathways were most frequently implicated in RTK. A prognostic model was constructed using 7 IRGs (MMP9, SERPINA3, FAM19A5, CCR9, PLAUR, IL1R2, PRKCG), which were independent prognostic indices that could differentiate patients based on their survival outcomes. Furthermore, the risk scores from our prognostic model was positively associated with cancer-associated fibroblasts (CAFs). CONCLUSIONS: We screened seven IRGs of clinical significance to distinguish patients with different survival outcomes. This may enhance our understanding of the immune microenvironment of RTK, and could use to design individualized treatments for RTK patients. BACKGROUND: Malignant rhabdoid tumor of the kidney (RTK) is a rare and highly aggressive pediatric malignancy. Immune system dysfunction is significantly correlated with tumor initiation and progression. METHODS: We integrated and analyzed the expression profiles of immune-related genes (IRGs) in 65 RTK patients based on the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. Prognostic related IRGs in RTK patients were analyzed using univariate and multivariate analysis, based on which a prognostic model with IRGs was constructed. Correlation analysis between the risk score of our model and tumor-infiltrating cell were also investigated. RESULTS: Twenty two IRGs were significantly associated with the clinical outcomes of RTK patients. Gene ontology (GO) analysis revealed that inflammatory pathways were most frequently implicated in RTK. A prognostic model was constructed using 7 IRGs (MMP9, SERPINA3, FAM19A5, CCR9, PLAUR, IL1R2, PRKCG), which were independent prognostic indices that could differentiate patients based on their survival outcomes. Furthermore, the risk scores from our prognostic model was positively associated with cancer-associated fibroblasts (CAFs). CONCLUSIONS: We screened seven IRGs of clinical significance to distinguish patients with different survival outcomes. This may enhance our understanding of the immune microenvironment of RTK and could use to design individualized treatments for RTK patients.

Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma.

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.

Delta-24-RGD, an Oncolytic Adenovirus, Increases Survival and Promotes Proinflammatory Immune Landscape Remodeling in Models of AT/RT and CNS-PNET.

PURPOSE: Atypical teratoid/rhabdoid tumors (AT/RT) and central nervous system primitive neuroectodermal tumors (CNS-PNET) are pediatric brain tumors with poor survival and life-long negative side effects. Here, the aim was to characterize the efficacy and safety of the oncolytic adenovirus, Delta-24-RGD, which selectively replicates in and kills tumor cells. EXPERIMENTAL DESIGN: Delta-24-RGD determinants for infection and replication were evaluated in patient expression datasets. Viral replication and cytotoxicity were assessed in vitro in a battery of CNS-PNET and AT/RT cell lines. In vivo, efficacy was determined in different orthotopic mouse models, including early and established tumor models, a disseminated AT/RT lesion model, and immunocompetent humanized mouse models (hCD34+-NSG-SGM3). RESULTS: Delta-24-RGD infected and replicated efficiently in all the cell lines tested. In addition, the virus induced dose-dependent cytotoxicity [IC50 value below 1 plaque-forming unit (PFU)/cell] and the release of immunogenic markers. In vivo, a single intratumoral Delta-24-RGD injection (107 or 108 PFU) significantly increased survival and led to long-term survival in AT/RT and PNET models. Delta-24-RGD hindered the dissemination of AT/RTs and increased survival, leading to 70% of long-term survivors. Of relevance, viral administration to established tumor masses (30 days after engraftment) showed therapeutic benefit. In humanized immunocompetent models, Delta-24-RGD significantly extended the survival of mice bearing AT/RTs or PNETs (ranging from 11 to 27 days) and did not display any toxicity associated with inflammation. Immunophenotyping of Delta-24-RGD-treated tumors revealed increased CD8+ T-cell infiltration. CONCLUSIONS: Delta-24-RGD is a feasible therapeutic option for AT/RTs and CNS-PNETs. This work constitutes the basis for potential translation to the clinical setting.

A dynamic mutational landscape associated with an inter-regionally diverse immune response in malignant rhabdoid tumour.

Malignant rhabdoid tumour (MRT) is a childhood neoplasm of high malignancy characterised by biallelic mutation and/or loss of the epigenetic master regulator SMARCB1, accompanied by no or few other oncogenic drivers. In spite of their generally low mutational burden, an intratumoural T-cell response has been reported in a subset of MRTs, indicating that immune checkpoint inhibition may be considered a viable therapy option for some patients. We assess here the evolution over time and space of predicted neoantigens and indicators of immune checkpoint status in two MRT patients who progressed under treatment. Both patients showed an accumulation of novel clonal and subclonal mutations, including predicted neoantigens, in metastases compared to their inferred ancestral clones in the primary tumours. The first patient had peritoneal metastases from an MRT of the liver. Clonal deconvolution revealed polyclonal seeding from the primary tumour to a single metastatic site, followed by a local subclonal burst of mutations. The second patient had a renal MRT with multiple pulmonary metastases, each of which could be traced back to a single genetically unique founder cell, with formation of novel subclones in two metastases. Both patients showed a regionally heterogeneous landscape of predicted neoantigens and of tumour-infiltrating lymphocytes expressing CD8 and PD1. In both patients, some tumour regions fulfilled established criteria for PD-L1 positivity (> 1% of tumour cells), while others did not. This suggests that even in a tumour type like MRT, with a single driver mutation, there can be heterogeneity in neoantigen repertoire, immune response, and biomarkers for checkpoint blockade among sampled locations. This must be taken into account when assessing progressed MRT patients for checkpoint inhibition therapy. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors.

Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months1,2. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. 3,4), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT5,6, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.

Clonally Expanded T Cells Reveal Immunogenicity of Rhabdoid Tumors.

Rhabdoid tumors (RTs) are genomically simple pediatric cancers driven by the biallelic inactivation of SMARCB1, leading to SWI/SNF chromatin remodeler complex deficiency. Comprehensive evaluation of the immune infiltrates of human and mice RTs, including immunohistochemistry, bulk RNA sequencing and DNA methylation profiling studies showed a high rate of tumors infiltrated by T and myeloid cells. Single-cell RNA (scRNA) and T cell receptor sequencing highlighted the heterogeneity of these cells and revealed therapeutically targetable exhausted effector and clonally expanded tissue resident memory CD8+ T subpopulations, likely representing tumor-specific cells. Checkpoint blockade therapy in an experimental RT model induced the regression of established tumors and durable immune responses. Finally, we show that one mechanism mediating RTs immunogenicity involves SMARCB1-dependent re-expression of endogenous retroviruses and interferon-signaling activation.

Complete and Prolonged Response of Renal Cell Carcinoma With Rhabdoid Features to Checkpoint Inhibitor Therapy.

Checkpoint inhibitor immunotherapy has recently been proven to be an attractive treatment option for a wide variety of malignancies. Nivolumab, an anti-programmed cell death protein-1 antibody, has been proven effective and safe in treating metastatic renal cell carcinoma (RCC) with a clear cell component. We report the case of a patient with high-grade clear cell RCC with rhabdoid features who has achieved a durable complete response with nivolumab therapy after multiple surgical interventions and progression on pazopanib. Genomic evaluation in this case was characterized in part by a PBRM1 variant, similar to the only other described case of RCC with rhabdoid features obtaining a complete response to nivolumab. This case supports the potential utility of checkpoint inhibitors in aggressive, rare subtypes of RCC where there are limited options for therapy.

PD-1/PD-L1 and immune-related gene expression pattern in pediatric malignant brain tumors: clinical correlation with survival data in Korean population.

BACKGROUND: PD-L1 expression has been evaluated as a predictive biomarker for immunotherapy in numerous tumor types. However, very limited data are available in pediatric brain tumors. The aim of this study was to characterize PD-1 and PD-L1 expressions of four pediatric malignant brain tumors and gene expression profile. METHODS: This study included 89 pediatric patients receiving standard treatment at Seoul National University Children's Hospital and Seoul National University Bundang Hospital between 1990 and 2014: atypical teratoid/rhabdoid tumor (AT/RT) 20; ependymoma (EPN) 20; high grade glioma (HGG) 21; and medulloblastoma (MBL) 28. We performed immunohistochemistry assays for PD-1 and PD-L1. To characterize the gene expression, a custom immune-response focused gene panel was used. RESULTS: PD-1 expression was positive in 7 (35%) AT/RT, 7 (35%) EPN, 4 (19%) HGG, and 3 (11%) MBL patients. PD-L1 expression was positive in 8 (40%) AT/RT, 4 (20%) EPN, and 4 (19%) HGG; negative in all MBL patients. There was no statistically significant difference in the overall survival of PD-L1 positive patients. The gene expression analysis demonstrated differences in two clustering functional categories: cell-cell signaling and antigen presentation pathway. CONCLUSIONS: AT/RT, EPN, and HGG showed a relatively higher expression rate of PD-L1 (19-40%). This suggests these tumor types might be good candidates for PD-1 checkpoint blockade. We determined that gene expression may potentially serve as a molecular tool in predicting which patients will respond to immunotherapy. Further investigation is required to better understand the predictive and prognostic role of PD-L1 in pediatric brain tumors.

Immunotherapy in atypical teratoid-rhabdoid tumors: Data from a survey of the HGG-Immuno Group.

BACKGROUND AIMS: Atypical rhabdoid/teratoid tumors (AT/RT) are the most common brain tumors in infants and associated with a dismal prognosis. Although intensification of first-line therapy has resulted in improvement of overall survival, novel treatment strategies are needed. Because immunotherapy has resulted in remarkable results in several adult tumor entities, incorporation of immunotherapy into AT/RT treatment offers a novel alternative. METHODS: We retrospectively analyzed data from 7 AT/RT patients from five countries treated within the HGG-Immuno Consortium. Two patients were ≤1 year and 4 patients were ≤2 years of age at diagnosis. All received immunotherapy with autologous, tumor-lysate-loaded dendritic cells (DCs) on a compassionate use basis using a schedule of three to four weekly DC vaccinations with up to 2 × 10(7) DCs per vaccine, followed by three lysate boosts each 1 month apart. RESULTS: Monocyte collections (median age at apheresis 31.5, range 20-143 months) and vaccinations were uneventful without any severe adverse event related to the vaccine, demonstrating feasibility and safety in this very young age group. Two children received immunotherapy during their primary and the remaining five during second- or third-line therapy. Three of seven patients survived long term with a follow-up of 143, 138 and 46 months, with at least two of them harboring somatic mutations. One long-term survivor was vaccinated during primary treatment and the other two after first or second relapse/progression. Two analyzed patients showed positive CD8(+) T-cell responses after vaccination. DISCUSSION: Our data demonstrate that anti-tumor immunotherapy with autologous DCs is feasible and safe in young children with ATRTs and that this approach warrants further investigation in controlled clinical trials.

Histological and immunohistochemical characterization of AT/RT: a report of 15 cases from India.

Atypical teratoid rhabdoid tumor (AT/RT) is a highly malignant embryonal CNS tumor, generally unresponsive to any form of therapy, uniformly fatal within 1 year. We report 15 cases of AT/RT diagnosed at our center over a period of 5 years (2003-08). Tumors were located in different sites of the neuraxis, posterior fossa being the most common (n = 10) followed by cerebral lobes (n = 3). There was one each at the supra sellar and cervical spinal regions, respectively. Radiologically most of the tumors were heterodense and enhancing heterogeneously. The tumors exhibited diverse histological profile that included rhabdoid and PNET areas in all cases, mesenchymal and epithelial areas in 73.3% and 53.3% cases, respectively. Necrosis was evident in all cases and one showed calcification. Tumor cells displayed a polyphenotypic immunoprofile. All cases were consistently positive for vimentin and epithelial membrane antigen and were negative for desmin. Variable positivity was seen for other markers. The number of cases positive for these were: CK (53%), SMA (60%), synaptophysin (66%), NFP (33.3%) and GFAP (85%). CK staining was prominent in epithelial areas, while PNET cells labeled prominently with synaptophysin. There was lack of INI1 expression in all cases. Follow-up was available in 46.6% of cases which revealed a uniform poor prognosis.

Identification of CD133-positive radioresistant cells in atypical teratoid/rhabdoid tumor.

Atypical teratoid/rhabdoid tumor (AT/RT) is an extremely malignant neoplasm in the central nervous system (CNS) which occurs in infancy and childhood. Recent studies suggested that CD133 could be considered a marker for brain cancer stem-like cells (CSCs). However, the role of CD133 in AT/RT has never been investigated. Herein we report the isolation of CD133-positive cells (CD133(+)), found to have the potential to differentiate into three germ layer tissues, from tissues of nine AT/RT patients. The migration/invasion/malignancy and radioresistant capabilities of CD133(+) were significantly augmented when compared to CD133(-). The clinical data showed that the amount of CD133(+) in AT/RTs correlated positively with the degree of resistance to radiation therapy. Using cDNA microarray analysis, the genotoxic-response profiles of CD133(+) and CD133(-) irradiated with 10 Gy ionizing radiation (IR) were analyzed 0.5, 2, 6, 12 and 24 h post-IR. We then validated these microarray data and showed increased phosphorylation after IR of p-ATM, p-RAD17, and p-CHX2 as well as increased expression of BCL-2 protein in CD133(+) compared to CD133(-). Furthermore, we found that CD133(+) can effectively resist IR with cisplatin- and/or TRAIL-induced apoptosis. Immunohistochemical analysis confirmed the up-regulated expression of p-ATM and BCL-2 proteins in IR-treated CD133(+) xenotransgrafts in SCID mice but not in IR-treated CD133(-). Importantly, the effect of IR in CD133(+) transplanted mice can be significantly improved by a combination of BCL-2 siRNA with debromohymenialdisine, an inhibitor of checkpoint kinases. In sum, this is the first report indicating that CD133(+) AT/RT cells demonstrate the characteristics of CSCs. The IR-resistant and anti-apoptotic properties in CD133(+) may reflect the clinical refractory malignancy of AT/RTs and thus the activated p-ATM pathway and BCL-2 expression in CD133(+) could be possible targets to improve future treatment of deadly diseases like AT/RT.

Trastuzumab activates allogeneic or autologous antibody-dependent cellular cytotoxicity against malignant rhabdoid tumor cells and interleukin-2 augments the cytotoxicity.

PURPOSE: Malignant rhabdoid tumor (MRT) is an early childhood cancer with poor prognosis. Trastuzumab, a humanized monoclonal antibody against human epidermal growth factor receptor-2 (HER-2), has been shown to be effective against breast cancer and other cancers. We investigated the effect of trastuzumab on MRT cell lines. EXPERIMENTAL DESIGN: We examined expression of HER-2 on four MRT cell lines and two tumor tissues by indirect immunofluorescence, flow cytometry, and immunohistochemistry. The effect of trastuzumab against MRT cells was examined by cell growth assay. To observe the antibody-dependent cellular cytotoxicity of effector cells, we examined the cytotoxicity of trastuzumab in combination with allogeneic or autologous human peripheral blood mononuclear cells with and without IL-2 using the chromium release assay. RESULTS: All four MRT cell lines and both MRT tissues expressed HER-2 protein. Trastuzumab alone did not reduce the viability of the MRT cell lines. On the other hand, the cytotoxicity of trastuzumab against each of the MRT cell lines was significantly increased by the presence of allogeneic and autologous peripheral blood mononuclear cells (P < 0.01). There was a strong correlation coefficient (r = 0.825) between HER-2 expression and the cytotoxicity enhanced by trastuzumab. Moreover, trastuzumab in combination with peripheral blood mononuclear cells augmented by interleukin-2 (IL-2) was significantly more cytotoxic than trastuzumab alone or IL-2 alone (P < 0.01). CONCLUSIONS: Our results indicate that (1) trastuzumab can exert antitumor effects on MRT cells by using the antibody-dependent cellular cytotoxicity of effector cells and (2) IL-2 can enhance the cytotoxicity of trastuzumab against MRT cells.

Importance of re-examination for medulloblastoma and atypical teratoid/rhabdoid tumor.

Medulloblastoma may can be difficult to distinguish from atypical teratoid/rhabdoid tumor (AT/RT), since they resemble each other histologically. We re-examined whether AT/RT was included among cases who had been diagnosed as medulloblastoma. All of fifteen medulloblastomas (10 males and 5 females) diagnosed at the Kitasato University Hospital were collected and stained immunohistochemically. Two cases originally diagnosed as medulloblastoma were reclassified as AT/RT based on histological re-examination including immunohistochemical studies. While these two cases of AT/RT were found during infancy, only one medulloblastoma was found in infancy.Histologically, small rhabdoid cells and large, pale, bland cells were common but typical rhabdoid cells were not seen in the two AT/RTs. Gland-like structures were also seen. The tumor cells in AT/RT, but not those in medulloblastoma, were immunoreactive for vimentin, epithelial membrane antigen and smooth muscle actin. In conclusion, if a diagnosis of medulloblastoma is made histologically, it should be confirmed immunohistologically, since it is difficult to distinguish AT/RT from medulloblastoma. When appropriate treatment was specifically targeted at AT/RT it may improve the outcome.

Adult rhabdoid renal cell carcinoma.

BACKGROUND: Pediatric rhabdoid tumor of the kidney is regarded as a distinct neoplasm, whereas rhabdoid differentiation in adult renal cell carcinoma is usually found in association with conventional (clear cell) tumor, from which it is thought to evolve. OBJECTIVE: To further characterize the rhabdoid phenotype in adult renal cell carcinoma and to determine its origin by genetic analysis. DESIGN: We performed histologic, immunophenotypic, and genetic analyses on 5 cases of adult renal cell carcinoma with rhabdoid differentiation, 3 samples of adjacent conventional (clear cell) tumor, and 6 conventional (clear cell) control tumors. RESULTS: Rhabdoid tumors differed from conventional (clear cell) carcinoma as follows: (1) macroscopically, rhabdoid tumors were solid white uniform masses; (2) microscopically, they had large rhabdoid cells with abundant eosinophilic cytoplasm, reduced lipid content, and the absence of a branching vascular pattern; and (3) biologically, they had a high metastatic potential. Despite these differences, loss of chromosome 3p in both the rhabdoid and clear cell carcinoma samples from 1 patient suggested a clonal origin. An identical mutation of the VHL gene in both rhabdoid and clear cell tumor samples from 2 patients confirmed a clonal origin for the histologically distinct tumor types in those cases. CONCLUSION: Adult rhabdoid renal cell carcinoma can in some cases arise from conventional (clear cell) renal carcinoma and should be considered a clinically important form of renal cell carcinoma separate from, but analogous to, sarcomatoid change.

Lung carcinomas composed of rhabdoid cells.

Rhabdoid tumours form a distinctive morphological entity that is associated with aggressive biological behaviour. They have been described in several sites and tumour types. This paper presents three new cases of rhabdoid lung cancers. Lung cancers were analysed for the presence of cells with the rhabdoid phenotype: eccentric vesicular nuclei and abundant eosinophilic cytoplasm. Cells displaying this morphology were then subjected to immunohistochemistry and electron microscopy. The relevant clinical data on these cases were then accessed. Three cases conforming to the morphological, immunophenotypic and ultrastructural characteristics of rhabdoid cells were identified. Two of the cases were associated with foci of adenocarcinoma and the remaining case was a large cell neuroendocrine carcinoma. Two of the cases showed rapid clinical courses with the patients dying of disease within 6 months. Lung tumours with a rhabdoid phenotype are uncommon but are noteworthy because of their aggressive behaviour and, hence, poor prognosis.

Appraisal of the comparative utility of immunohistochemistry and electron microscopy in the diagnosis of childhood round cell tumors.

To provide an objective assessment of the comparative utility of fluorescence- and peroxidase-based immunohistochemistry and electron microscopy, an observer blinded study was conducted under realistic study conditions utilizing a large sampling of poorly differentiated pediatric round cell tumors. Working independently, using a single ancillary technique of particular expertise, each of three investigators attempted to render a specific diagnosis with regard to 50 diagnostically challenging tumors. The results were compared against the subsequent "file diagnosis" established by consensus with all relevant information made available. A grading scheme was applied wherein points were awarded based on the accuracy and confidence of diagnosis. A comparative efficiency rating, expressed as a percentage, was formulated by dividing the number of points awarded each technique by the total number of points theoretically available. Electron microscopy proved superior overall, with an efficiency rating of 89%. Immunoperoxidase and immunofluorescence studies yielded efficiency ratings of 71 and 61%, respectively. Used in combination, the techniques achieved an efficiency rating of 95%. Application of these ancillary techniques resulted in a revision of the provisional diagnosis in 11 of 50 cases, and left only two cases without a firm specific diagnosis.