Rhabdoid Cells Research Articles

Absence of SMARCB1 in rhabdoid tumor cells increases sensitivity to translation inhibition and alters translation efficiency of specific mRNAs.

Rhabdoid tumors, characterized and driven by the loss of the mSWI/SNF (mammalian SWItch/Sucrose Non-Fermentable) subunit SMARCB1, are very aggressive childhood cancers that can arise in the brain, the kidney, or soft tissues. Cell lines derived from these tumors are specifically sensitivity to the translation inhibitor homoharringtonin (HHT). Having recently demonstrated mSWI/SNF roles in translation, we assessed SMARCB1 potential roles in translation in rhabdoid tumor cells. We first revealed by cell viability assays that rhabdoid tumor cells' sensitivity to HHT were dependent on the absence of SMARCB1. Polysome profiling and immunoprecipitation experiments demonstrated the interaction of SMARCB1 with translation machinery. Global translation assays and ribosome profiling experiments further revealed that SMARCB1 re-expression increased global translation and altered translation efficiency of specific mRNAs. Most regulated mRNAs presented an increased translation efficiency and were involved in differentiation. In comparison with the entire transcriptome, these mRNAs presented a longer coding sequence and were enriched in GC. Finally, we demonstrated that SMARCB1 re-expression increased cytoplasmic localization of these mRNAs and that gene encoding these transcripts were bound by SMARCA4 and SMARCC1. In conclusion, this study reveals that the loss of SMARCB1 in rhabdoid tumors has specific consequences on mRNAs translation with potential to unveil new dependencies.

Prognosis prediction via histological evaluation of cellular heterogeneity in glioblastoma

Glioblastomas (GBMs) are the most aggressive types of central nervous system tumors. Although certain genomic alterations have been identified as prognostic biomarkers of GBMs, the histomorphological features that predict their prognosis remain elusive. In this study, following an integrative diagnosis of 227 GBMs based on the 2021 World Health Organization classification system, the cases were histologically fractionated by cellular variations and abundance to evaluate the relationship between cellular heterogeneity and prognosis in combination with O-6-methylguanine-DNA methyltransferase gene promoter methylation (mMGMTp) status. GBMs comprised four major cell types: astrocytic, pleomorphic, gemistocytic, and rhabdoid cells. t-distributed stochastic neighbor embedding analysis using the histological abundance of heterogeneous cell types identified two distinct groups with significantly different prognoses. In individual cell component analysis, the abundance of gemistocytes showed a significantly favorable prognosis but confounding to mMGMTp status. Conversely, the abundance of epithelioid cells was correlated with the unfavorable prognosis. Linear model analysis showed the favorable prognostic utility of quantifying gemistocytic and epithelioid cells, independent of mMGMTp. The evaluation of GBM cell histomorphological heterogeneity is more effective for prognosis prediction in combination with mMGMTp analysis, indicating that histomorphological analysis is a practical and useful prognostication tool in an integrative diagnosis of GBMs.

Anaplastic transformation of papillary thyroid carcinoma in the cervical lymph nodes showing a variety of rhabdoid, epithelioid and spindle cell phenotype

Abstract Introduction/Objective Anaplastic thyroid carcinoma (ATC) is a rare undifferentiated tumor of thyroid follicular cells with a dismal prognosis. Most ATCs derive from pre-existing, well-differentiated thyroid carcinomas, most commonly papillary thyroid carcinoma (PTC). In nearly all instances, ATC arises within the thyroid gland. Completely divergent morphologies of this tumor between the bilateral cervical nodes as well as the almost exclusive presence of ATC in the metastatic and nodal locations are very unusual and are reported here. Methods/Case Report A 67-year-old man presented with a rapidly enlarging left cervical mass, hoarseness, dry cough, and drooping left eye. MRI demonstrated bilateral enlarged cervical lymph nodes spanning levels II to V, and nodules in thyroid lobes. Subsequent total thyroidectomy with bilateral radical neck dissection was performed. Histologically, the left lateral cervical masses revealed undifferentiated tumor cells with rhabdoid, epithelioid and spindle cells features. Conversely, the tumor within the thyroid lobes and the right cervical lymph nodes exhibited PTC with tall cell features. All undifferentiated tumor components stained positive with AE1-3, CK7, PAX8, and negative with thyroglobulin, EMA, CD34, S100, Melan-A, Sox 10, desmin, myogenin, and P40. INI-1 staining is retained. Only the spindle cell component stained positive with TTF1. Based on the morphology and immunoprofile, a diagnosis of anaplastic thyroid carcinoma was rendred. Results (if a Case Study enter NA) NA Conclusion Diagnosing anaplastic thyroid carcinoma outside the thyroid lesion can be challenging. In our case, only extensive sampling of the surgical specimen identified a small focus of well-differentiated PTC, staining positive for thyroglobulin, in the left cervical anaplastic carcinoma component, identifying its origin. This case adds to the scarce literature documenting unilateral anaplastic transformation in the left cervical metastatic lymph nodes, while the right cervical lymph nodes contained pure well differentiated PTC. This represents a significant potential pitfall in presurgical fine needle aspiration (FNA) evaluation of patients with ATC.

Metastatic prostate adenocarcinoma to the brain – a clinicopathologic analysis of 21 cases

BackgroundBrain metastasis from prostate adenocarcinoma (PCa) is rare, often leading to death within a year. Its infrequent occurrence and atypical histopathologic features contribute to lower consideration in the differential diagnosis of tumor brain metastasis. This study aims to assess the clinical characteristics and distinctive histopathologic features of metastatic PCa in the brain for timely and enhanced diagnostic accuracy.DesignA retrospective search spanning 20 years (2003–2022) was conducted on our archives and identified 21 cases diagnosed as “metastatic prostate adenocarcinoma (mPCa)” in brain biopsies and resections. All existing slides were thoroughly reviewed to evaluate the histopathology of the mPCa.ResultThe mean age at presentation for brain metastasis was 70 years. Of 21 cases, 5 were dural-based lesions, 16 were true intraparenchymal metastases, including 2 sellar/suprasellar masses, 3 frontal, 3 temporal, 3 occipital, 1 cerebellum, and 4 involving multiple brain lobes. The average interval between initial diagnosis and brain metastasis was 90.75 months. Notably, brain metastasis was the initial presentation for one patient, while another patient, initially diagnosed with prognostic grade group (GG) 2 PCa in 1/12 cores, presented with isolated brain metastasis two years later. Architecturally, tumor cells were arranged in sheets or nests in most cases; however, four cases showed histologic cribriform patterns, and five displayed papillary architecture. Cytohistology varied from uniform monomorphic to highly pleomorphic cells with prominent nucleoli (8/19) and high mitotic activity. Interestingly, 1 case showed small round blue cell morphology, another had focal areas of rhabdoid and spindle cell differentiation, and 6 had cytoplasmic clearing. Almost half of the cases (47%) showed necrosis.ConclusionmPCa to the brain can present with variable histomorphology. Therefore, consideration of mPCa in the differential diagnosis of metastatic brain lesions, even with non-suggestive imaging, is imperative in male patients with or without a history of primary disease. Accurate and prompt diagnosis is crucial, given the recent advancements in treatment that have improved survival rates.

NTRK fusion cervical sarcoma with rhabdoid cells and misleading molecular testing.

NTRK fusion cervical sarcoma with rhabdoid cells and misleading molecular testing.

Features of Vascular Endothelial Growth Factor А (Vegf-А) Expression in Atypical Teratoid-Rhabdoid Tumor of the Central Nervous System in Children

Atypical teratoid rhabdoid tumors (AT/RT) are highly malignant neoplasms composed of poorly differentiated germline cells and a variable number of rhabdoid cells that can differentiate into different cell types. A key diagnostic factor for AT/RT is the absence of nuclear expression of the INI1 protein (SMARCB1 gene product) when tested with an anti-INI1 antibody in an immunohistochemical study. Currently, there is no standard treatment for AT/RT, but treatment approaches have become more aggressive and multimodal. In one study, AT/RT was found to be positive for VEGF. The purpose of our study was to examine the expression of VEGF-A in AT/RT in the central nervous system of children. We analyzed biopsy samples from 6 male patients aged 3 months to 8 years (average age 4.5 years). The level of VEGF-A expression was measured by counting the number of brown pixels in the cytoplasm of tumor cells using the PhotoM program in 1 mm2 of tumor tissue. Immunohistochemistry (IHC) revealed varying levels of cytoplasmic staining with an antibody to VEGF-A in 5 out of 6 patients, with the youngest patient (No. 6) showing staining only in endothelial cells. In conclusion, children with AT/RT exhibit different patterns of VEGF-A expression, potentially dependent on the molecular subgroup. Identifying this marker in these highly aggressive tumors could aid in developing new treatment protocols and determining which patients would benefit most from treatment.

ATRT-08. ATYPICAL TERATOID RHABDOID TUMOR IN AN ADULT PATIENT WITH DOWN SYNDROME

Abstract BACKGROUND Atypical teratoid/rhabdoid tumor (ATRT) is a malignant, highly aggressive embryonal tumor of the central nervous system. Long-term survival remains dismal despite aggressive multimodal therapy, including a maximal safe surgical resection and intensive systemic chemotherapy +/- radiation therapy. While these tumors typically present in infancy or early childhood, there are scattered case reports of adult-onset ATRT. Making prognostic conclusions or therapeutic decisions for this older patient population remains challenging due to the paucity of these reports. CASE REPORT A 25-year-old female with Down syndrome presented with nausea, vomiting, dysphagia, and facial droop and was found to have an avidly enhancing, left cerebellopontine angle mass. There was initial clinical suspicion for leukemic chloroma given the patient’s Down syndrome status and known association with higher rates of hematologic malignancy concurrent with a dramatic scarcity of solid tumors in the Down syndrome population. However, histology demonstrated sheets of high-grade rhabdoid cells with loss of INI1 expression, pathognomonic for ATRT. Further sequencing defined a frameshift mutation in SMARCB1 (p.C298), and methylation profiling matched with high confidence to the MYC subclass of ATRT. The patient was treated with subtotal surgical resection and focal proton radiation, followed by chemotherapy on a modified regimen based on the Children’s Oncology Group protocol, ACNS0333. Systemic methotrexate and all consolidative high-dose chemotherapy with stem cell rescue were omitted due to concern for heightened risk of treatment-related toxicity. The patient remains alive and clinically asymptomatic 19 months from diagnosis. CONCLUSION This report represents the first known case of ATRT in an adult patient with Down syndrome, offering unique mechanistic insight into the tumorigenesis of ATRT. Adult ATRT is a rare entity without standardized treatment or established prognostic understanding. Further studies are needed to define an appropriate risk-adapted therapeutic approach for this patient population.

ALK-Rearranged Renal Cell Carcinoma: A Multi-Institutional Study of 9 Cases With Expanding the Morphologic and Molecular Genetic Spectrum

ALK-rearranged renal cell carcinoma (ALK-RCC) is rare, molecularly defined RCC subtype in the recently published fifth edition of World Health Organization classification of tumors. In this study, we described 9 ALK-RCCs from a clinicopathologic, immunohistochemical, and molecular genetic aspect, supporting and extending upon the observations by previous studies regarding this rare subgroup of RCC. There were 6 male and 3 female patients with ages ranging from 14 to 59 years (mean, 34.4 years). None of the patients had sickle cell trait. The diagnosis was based on radical or partial nephrectomy specimen for 8 patients and on biopsy specimen for 1. Tumor size ranged from 2.5 to 7.2 cm (mean, 2.8 cm). Follow-up was available for 6 of 9 patients (6-36 months); 5 had no tumor recurrence or metastasis and 1 developed lung metastasis at 24 months. The patient was subsequently treated with resection of the metastatic tumor followed by crizotinib-targeted therapy, and he was alive without tumor 12 months later. Histologically, the tumors showed a mixed growth of multiple patterns, including papillary, solid, tubular, tubulocystic, cribriform, and corded, often set in a mucinous background. The neoplastic cells had predominantly eosinophilic cytoplasm. Focally, clear cytoplasm with polarized nuclei and subnuclear vacuoles (n = 1), and pale foamy cytoplasm (n = 1) were observed on the tumor cells. The biopsied tumor showed solid growth of elongated tubules merging with bland spindle cells. Other common and uncommon features included psammomatous microcalcifications (n = 5), rhabdoid cells (n = 4), prominent intracytoplasmic vacuoles (n = 4), prominent chronic inflammatory infiltrate (n = 3), signet ring cell morphology (n = 2), and pleomorphic cells (n = 2). By immunohistochemistry, all 9 tumors were diffusely positive for ALK(5A4) and 4 of 8 tested cases showed reactivity for TFE3 protein. By fluorescence in situ hybridization analysis, ALK rearrangement was identified in all the 9 tumors; none of the tested tumors harbored TFE3 rearrangement (0/4) or gains of chromosomes 7 and 17 (0/3). ALK fusion partners were identified by RNA-sequencing in all 8 cases analyzed, including EML4 (n = 2), STRN (n = 1), TPM3 (n = 1), KIF5B (n = 1), HOOK1 (n = 1), SLIT1 (n = 1), and TPM1(3′ UTR) (n = 1). Our study further expands the morphologic and molecular genetic spectrum of ALK-RCC.

Sarcomatoid and Rhabdoid Renal Cell Carcinoma: Clinical, Pathologic, and Molecular Genetic Features.

Renal cell carcinoma (RCC) with sarcomatoid and rhabdoid morphologies has an aggressive biological behavior and a typically poor prognosis. The current 2022 WHO classification of renal tumors does not include them as distinct histologic entities but rather as transformational changes that may arise in a background of various distinct histologic types of RCC. The sarcomatoid component shows malignant spindle cells that may grow as intersecting fascicles, which is reminiscent of pleomorphic undifferentiated sarcoma. The rhabdoid cells are epithelioid cells with eccentrically located vesicular nuclei with prominent nucleoli and large intracytoplasmic eosinophilic inclusions. Studies have shown that RCCs with sarcomatoid and rhabdoid differentiation have distinctive molecular features. Sarcomatoid RCC harbors shared genomic alterations in carcinomatous and rhabdoid components, but also enrichment of specific genomic alterations in the sarcomatoid element, suggesting molecular pathways for development of sarcomatoid growth from a common clonal ancestor. Rhabdoid differentiation also arises through clonal evolution although less is known of specific genomic alterations in rhabdoid cells. Historically, treatment has lacked efficacy, although recently immunotherapy with PD-1/PD-L1/CTLA-4 inhibitors has produced significant clinical responses. Reporting of sarcomatoid and rhabdoid features in renal cell carcinoma is required by the College of American Pathologists and the International Collaboration on Cancer Reporting. This manuscript reviews the clinical, pathologic, and molecular features of sarcomatoid RCC and rhabdoid RCC with emphasis on the morphologic features of these tumors, significance of diagnostic recognition, the molecular mechanisms of tumorigenesis and differentiation along sarcomatoid and rhabdoid lines, and advances in treatment, particularly immunotherapy.

Cytomorphology of metastatic colonic MXD4::NUTM1-rearranged sarcoma.

This report describes the cytologic features of a recently described MXD4::NUTM1-rearranged colonic sarcoma metastatic to the midclavicular soft tissue. Thirteen years ago, a 65-year-old woman presented with a cecal mass and subsequent liver mass. The cecal mass was diagnosed as malignant undifferentiated spindled and epithelioid neoplasm based on morphology and lack of tumor immunoreactivity with a panel of epithelial, smooth muscle, skeletal, melanoma, hematologic, and GIST markers. The liver mass showed morphologic and immunophenotypic similarity to the epithelioid component of the patient's cecal mass, albeit devoid of the spindled component. Fine needle aspiration of the midclavicular soft tissue mass showed singly scattered to clustered epithelioid to rhabdoid tumor cells with centrally to eccentrically located nuclei, prominent nucleoli, and moderate eosinophilic cytoplasm. Immunohistochemical stains performed on the concurrent biopsy showed the tumor cells were positive for NUT and negative for all other additional markers with retained normal expression of SMARCA2 and SMARCA4. Next-generation sequencing showed the presence of MXD4::NUTM1 gene fusion. Due to the identical cytomorphologic findings with the epithelioid component of the patient's prior cecal and liver masses, the tumor was deemed as consistent with a NUTM1-rearranged sarcoma. To our knowledge, this case represents the first reported cytologic features of a NUTM1-rearranged sarcoma on fine needle aspiration. Familiarity with the cytologic features, inclusion of this entity in the differential diagnosis of tumors with epithelioid and/or rhabdoid morphology, and performance of ancillary tests (immunohistochemistry and molecular) will be helpful in arriving at the right diagnosis.

Super-Enhancer Dysregulation in Rhabdoid Tumor Cells Is Regulated by the SWI/SNF ATPase BRG1.

Mutations in the SWI/SNF chromatin remodeling complex occur in ~20% of cancers. In rhabdoid tumors defined by loss of the SWI/SNF subunit SMARCB1, dysregulation of enhancer-mediated gene expression is pivotal in driving oncogenesis. Enhancer dysregulation in this setting is tied to retention of the SWI/SNF ATPase BRG1-which becomes essential in the absence of SMARCB1-but precisely how BRG1 contributes to this process remains unknown. To characterize how BRG1 participates in chromatin remodeling and gene expression in SMARCB1-deficient cells, we performed a genome-wide characterization of the impact of BRG1 depletion in multiple rhabdoid tumor cell lines. We find that although BRG1-regulated open chromatin sites are distinct at the locus level, the biological characteristics of the loci are very similar, converging on a set of thematically related genes and pointing to the involvement of the AP-1 transcription factor. The open chromatin sites regulated by BRG1 colocalize with histone-marked enhancers and intriguingly include almost all super-enhancers, revealing that BRG1 plays a critical role in maintaining super-enhancer function in this setting. These studies can explain the essentiality of BRG1 to rhabdoid tumor cell identity and survival and implicate the involvement of AP-1 as a critical downstream effector of rhabdoid tumor cell transcriptional programs.

A Case of Myxoid Pleomorphic Liposarcoma with Rhabdoid Cells: A Diagnostic Pitfall.

Myxoid pleomorphic liposarcoma (MPLS) is an extremely rare tumor listed in the fifth edition of the WHO classification (2020). Histologically, it mainly comprises a mixture of myxoid and pleomorphic liposarcoma-like components. Genetically, it lacks FUS/EWSR1::DDIT3 fusion and MDM2 amplification. Herein, we describe an example of MPLS with rhabdoid cells in a 10-year-old girl who presented with a growing mass in the right inguinal region. The specimen from the wide excision measured 68 mm × 55 mm × 43 mm, and a circumscribed and lobulated mass was observed in the subcutaneous tissue. Histologically, oval-to-short, spindle-shaped, proliferating tumor cells with moderate nuclear atypia and mesh-like capillaries against a myxoid background were noted. Adipocytes were observed focally, while rhabdoid cells were observed multifocally. Immunohistochemically, the tumor showed inconsistent reactivity for desmin but was negative for MYOD1, myogenin, MDM2, and CDK4. Fluorescence in situ hybridization revealed no DDIT3 rearrangement. Despite adjuvant chemotherapy, the tumor metastasized to the thoracic cavity 24 months after excision. The metastatic lesions contained abundant lipoblasts rather than rhabdoid cells, and we concluded this tumor was a MPLS. The presence of rhabdoid cells could be a diagnostic pitfall, and recognizing such a variation in histology would help improve diagnostic accuracy.

Enhanced Antipediatric Sarcoma Effect of Everolimus with Secukinumab by Targeting IL17A.

In this study, we explored the therapeutic potential of everolimus, an mTOR inhibitor, in a patient-derived xenograft (PDX) of rhabdomyosarcoma, the most prevalent malignant pediatric sarcoma. In addition, rhabdoid tumor cell line A-204 and Ewings sarcoma cell line A-673 were cultured to assess the in vitro effect of everolimus. Furthermore, the cell-derived xenograft (CDX) of A-673 was established and treated with everolimus in vivo. IHC and Western blotting were performed to detect the expressions of pertinent proteins. Results showed that everolimus intervention had limited inhibitory effect on PDX tumor growth compared with cyclophosphamide. Nevertheless, everolimus treatment significantly influenced the phosphorylation levels of S6 kinase beta 1 (S6K1) and eIF4E-binding protein 1 (p-4E-BP1), resulting in the inhibition of angiogenesis in vitro and in vivo. Interestingly, everolimus led to an upregulation in the level of IL17A in sarcoma cells. Notably, when secukinumab, a mAb of IL17A, was combined with everolimus, it synergistically enhanced the inhibitory effect of everolimus on sarcoma cell proliferation in vitro and on the growth of PDX or CDX xenograft tumors in vivo. Importantly, this combination therapy did not affect the mTOR signaling. These results indicate that everolimus exerts an antipediatric sarcoma effect by inhibiting mTOR signal. However, everolimus induces sarcoma cells to produce IL17A, which promotes tumor cell survival and counteracts its antipediatric sarcoma effect. The combination of secukinumab effectively eliminates the effects of IL17A, thereby improving the therapeutic efficacy of everolimus in the context of pediatric sarcomas.

SMARCB1 Gene Therapy Using a Novel Tumor-Targeted Nanomedicine Enhances Anti-Cancer Efficacy in a Mouse Model of Atypical Teratoid Rhabdoid Tumors.

Atypical teratoid rhabdoid tumor (ATRT) is a deadly, fast-growing form of pediatric brain cancer with poor prognosis. Most ATRTs are associated with inactivation of SMARCB1, a subunit of the chromatin remodeling complex, which is involved in developmental processes. The recent identification of SMARCB1 as a tumor suppressor gene suggests that restoration of SMARCB1 could be an effective therapeutic approach. We tested SMARCB1 gene therapy in SMARCB1-deficient rhabdoid tumor cells using a novel tumor-targeted nanomedicine (termed scL-SMARCB1) to deliver wild-type SMARCB1. Our nanomedicine is a systemically administered immuno-lipid nanoparticle that can actively cross the blood-brain barrier via transferrin receptor-mediated transcytosis and selectively target tumor cells via transferrin receptor-mediated endocytosis. We studied the antitumor activity of the scL-SMARCB1 nanocomplex either as a single agent or in combination with traditional treatment modalities in preclinical models of SMARCB1-deficient ATRT. Restoration of SMARCB1 expression by the scL-SMARCB1 nanocomplex blocked proliferation, and induced senescence and apoptosis in ATRT cells. Systemic administration of the scL-SMARCB1 nanocomplex demonstrated antitumor efficacy as monotherapy in mice bearing ATRT xenografts, where the expression of exogenous SMARCB1 modulates MYC-target genes. scL-SMARCB1 demonstrated even greater antitumor efficacy when combined with either cisplatin-based chemotherapy or radiation therapy, resulting in significantly improved survival of ATRT-bearing mice. Collectively, our data suggest that restoring SMARCB1 function via the scL-SMARCB1 nanocomplex may lead to therapeutic benefits in ATRT patients when combined with traditional chemoradiation therapies.

SMARCA4 / BRG1 -deficient Uterine Neoplasm With Hybrid Adenosarcoma and Carcinoma Features: Expanding the Molecular-morphologic Spectrum of SMARCA4 -driven Gynecologic Malignancies.

SMARCA4 gene encodes BRG1 , a member of the SWItch/sucrose non-fermentable protein family involved in epigenetic transcriptional regulation of important cellular processes. In the uterine corpus, SMARCA4 / BRG1 deficiency is associated with a novel class of undifferentiated uterine sarcomas, characterized by younger age onset, rhabdoid histology, focal phyllodiform architecture, high-risk pathologic findings, and dismal prognosis. Herein, we report a case of a 34-year-old Asian woman with a SMARCA4 / BRG1 -deficient uterine tumor fulfilling the clinicopathologic features of an undifferentiated uterine sarcoma. However, the tumor exhibited several unique features that have not been previously emphasized, including (1) conspicuous phyllodiform architecture recapitulating conventional adenosarcoma, (2) rhabdoid tumor cells forming cords and keratin-positive cohesive epithelial islands, and (3) cooccurrence with a spatially distinct and discrete endometrial complex atypical hyperplasia from the rest of the proliferation. By immunohistochemistry, the tumor cells were diffusely positive for synaptophysin, whereas BRG1 was lost. Pertinent molecular findings included frameshift mutations in the SMARCA4 gene, mutations in histone modification and chromatin remodeling genes, including KMT2C , ARID1B , KAT6A , and NCOR1 , and mutations in Wnt signaling involving APC and CTNNB1 . Copy number gain in MDM2 and CDK4 were also identified. The tumor mutation burden was intermediate (6.8/MB) and it was microsatellite stable. On balance, our case exhibited morphologic and molecular features that overlap with (1) an undifferentiated uterine sarcoma, (2) an adenosarcoma with sarcomatous overgrowth, and (3) a mixed adenosarcoma and undifferentiated endometrial carcinoma. These hybrid features further expand the molecular-morphologic spectrum of SMARCA4 / BRG1 -deficient uterine neoplasms.

CSF cytology of common primary CNS neoplasms categorized by CNS WHO 2021.

The detection of neoplastic cells in cerebral spinal fluid (CSF) is pivotal for the management of patients with central nervous system (CNS) tumours. This article delves into the CSF cytological characteristics of common CNS neoplasms, aligning with the 2021 World Health Organization (WHO) classification of CNS tumours. A retrospective review of CSF specimens positive for primary CNS neoplasms was performed at three tertiary medical centres. Only cases that had histopathologic confirmation and/or molecular workup were included. Common primary CNS neoplasms seen in CSF cytology specimens include medulloblastoma, (non-WNT/non-SHH as well as SHH-activated and TP53 mutant), pineoblastoma, atypical teratoid/rhabdoid tumour (AT/RT), IDH-wildtype glioblastoma, and primary diffuse large B-cell lymphoma of the CNS. Ependymomas and germinomas can also have CSF involvement but are less common. Although the typical histologic architecture of these tumours may not be preserved in the CSF, unique cytomorphologic features such as nuclear moulding, nuclear pleomorphism, rhabdoid cells, prominent nucleoli and rosette formation can still be appreciated. Adopting the updated terminology and correlating cytologic observations with molecular findings will streamline the diagnostic process, reducing the complexities and ambiguities pathologists often encounter when analysing CSF specimens for potential primary CNS neoplasms.

Abstract C096: Targeting the p53 pathway to treat pediatric Malignant Rhabdoid and Atypical Teratoid Rhabdoid Tumors

Abstract Background: Pediatric rhabdoid tumors, namely Malignant Rhabdoid Tumors (MRTs) and Atypical Teratoid Rhabdoid Tumors (ATRTs) in the central nervous system (CNS), are aggressive pediatric malignancies characterized by the loss of functional INI1 protein due to SMARCB1 gene mutations. Current treatment options for these tumors are limited and ineffective, necessitating the exploration of novel therapeutic strategies. Rhabdoid cells retain an intact p53 pathway, a critical tumor suppressor pathway involved in regulating cell cycle and apoptosis. Previous studies have shown that the MDM2 inhibitor, Idasanutlin, effectively eliminates flanked rhabdoid tumors, suggesting that targeting the p53 pathway holds promise for developing effective therapies against MRTs and ATRTs. Methods: In this study, we employed a combination approach using the MDM2 inhibitor, Idasanutlin, and the XPO1 inhibitor, Selinexor, to activate the p53 pathway. The impact of this combination treatment on tumor cell viability, proliferation, and apoptosis was assessed both in vitro and in vivo using MRT and ATRT models. Additionally, CRISPR screening and proteomic studies were conducted to identify specific dependencies in refractory models and investigate their influence on treatment response. Results: Treatment with the combination of Idasanutlin and Selinexor activated the p53 signaling pathway, leading to increased levels of MDM2 and p21 proteins, two direct targets of p53, and resulting in apoptosis in MRT and ATRT models. In vitro experiments demonstrated a significant reduction in cell viability and proliferation upon treatment. In vivo studies using MRT and ATRT xenograft models showed a remarkable decrease in tumor growth following the combination treatment. However, variable responses were observed among different models, indicating the presence of dependency patterns influencing treatment sensitivity. Proteomic studies and genetic manipulation provided further insights into the potential dependencies Conclusions: Our findings highlight the potential of the combination of Idasanutlin and Selinexor to activate the p53 pathway and induce apoptosis in MRT and ATRT models. Although the treatment strategy effectively activated p53, we identified dependencies that may contribute to incomplete treatment sensitivity. Further investigation into these dependency patterns is necessary to optimize the therapeutic approach. Overall, targeting the p53 pathway using combination therapies shows promise for the development of effective treatments for pediatric MRTs and ATRTs, warranting further preclinical and clinical investigations. Citation Format: Alaa Refaat, Hyekyung Cho, Jennifer Stripay, Charles Roberts, Christopher Tinkle, Anang Shelat, Martine Roussel. Targeting the p53 pathway to treat pediatric Malignant Rhabdoid and Atypical Teratoid Rhabdoid Tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C096.

SMARCB1/INI1-deficient epithelioid and myxoid neoplasms in paratesticular region: Expanding the clinicopathologic and molecular spectrum

SMARCB1/INI1-deficient soft tissue tumors with epithelioid and myxoid features are diverse and mainly include soft tissue myoepithelial tumor, extraskeletal myxoid chondrosarcoma, and the recently described myoepithelioma-like tumor of the vulvar region and myxoepithelioid tumor with chordoid features. Because of their overlapping features, the accurate diagnosis and classification of these tumors are often challenging. Herein, we report two unique cases of SMARCB1/INI1-deficient soft tissue neoplasm with epithelioid and myxoid features occurring in male paratesticular region. The first case was a 52-year-old man presented with an intermittent painful left paratesticular mass for 1 year. The second case was a 41-year-old man presented with a painless paratesticular mass on the right side for 3 months. Both patients underwent an orchiectomy. After 6 and 26 months of follow-up, both were alive with no evidence of recurrence or metastasis. In both cases, the tumor was relatively well-demarcated and showed monomorphic round to epithelioid cells arranged in a nested, trabecular, reticular, and corded pattern, setting in a myxohyalinized and vascularized matrix. The tumor cells showed relatively uniform round nuclei with vesicular chromatin and variably prominent nucleoli. No rhabdoid cells were identified. Mitoses numbered 3 and 2 per 10 high-power fields. Tumor necrosis or lymphovascular invasion was absent. Immunohistochemically, both tumors expressed epithelial membrane antigen (focal), calponin (focal), and CD99. SMARCB1/INI1 expression was deficient in both cases. In addition, case 1 diffusely expressed pan-cytokeratin, and case 2 diffusely expressed CD34 and synaptophysin. Molecular genetically, case 1 showed SMARCB1 homozygous deletion as detected by fluorescence in-situ hybridization (FISH), and case 2 demonstrated SMARCB1 copy number deletions by next-generation sequencing and SMARCB1 monoallelic deletion by FISH. Both cases lacked EWSR1 rearrangements by FISH. The overall clinicopathologic profiles of the two cases made it difficult to classify them as one of the established categories of SMARCB1/INI1-deficient mesenchymal tumors. Our study further expands the clinicopathologic and molecular spectrum of SMARCB1/INI1-deficient epithelioid and myxoid neoplasms and highlights the challenges to diagnose these tumors.

Atypical Teratoid Rhabdoid Tumor: 28-years institutional experience

Abstract Introduction/Objective Atypical teratoid/rhabdoid tumor (ATRT) is a malignant central nervous system tumor affecting young children, characterized by biallelic mutations of SMARCB1 (hSNF5/INI1), consisting of a varying mixture of rhabdoid cells, small round blue cell (SRBC) and epithelial/mesenchymal components. Combination of surgical resection, chemoradiotherapy and autologous stem cell transplantation (SCT) has led to significant improvement in survival. Methods/Case Report Cases of ATRT in the past 28 years have been re-examined, including H&E stains, immunohistochemistry, available molecular studies and clinical charts. Results (if a Case Study enter NA) A total of 23 cases of ATRT were recruited to include 20 pediatric (age 3-36 months, median 13.5 months) and 3 adult cases (27, 38 and 46 years). 73.9% were male. Two pediatric cases presented in patients with Pierre-Robin sequence and Phelan-McDermid syndrome and one adult had history of Choriocarcinoma. 72.7% of cases initially presented in the posterior fossa, with 3 cases presenting in temporal lobe, 1 in frontal lobe, 1 in 3rd ventricle and 1 in pituitary gland. Mean size at presentation was 4.7 cm (range 2-10 cm). Median survival was 12.5 weeks with 8 patients surviving 5-13 years. 10/22 cases developed recurrences and/or spinal drop metastasis. Median time to first recurrence/ drop metastasis was 3.5 months (range 0-66 months). Cases showed varying proportions of rhabdoid, SRBC, epithelioid and mesenchymal components. By immunohistochemistry, INI1 was lost in 19/19 cases. Keratins, GFAP and Synaptophysin were positive in 13/17, 14/20 and 17/21 cases, respectively. Interestingly, GAB-1 and YAP1 were positive in 5/6 and 4/4 cases, respectively. Five cases had SMARCB1 mutation on NGS, one had NF2 truncation and another showed variation of unknown significance involving mainly NOTCH1 gene. 21/22 patients underwent surgical resection, of which 17 additionally received a combination of chemoradiotherapy and SCT and 1/22 underwent palliation. Conclusion Our data highlights the spectrum of presentation and survival of cases of ATRT and the importance of INI1 immunohistochemistry in the diagnosis, especially for the occasional cases co-expressing GAB1 and YAP, a potential diagnostic pitfall with medulloblastoma.

A Rare Case of Embryonal Rhabdomyosarcoma of Pineal Gland in An Adult Male

Abstract Introduction/Objective Rhabdomyosarcoma (RMS), mesenchymal derived tumor, is predominantly diagnosed in the pediatric population but may present at any age. Less than 1% of all adult solid malignant cancers are sarcomas, and rhabdomyosarcoma comprises <0.001% of adult sarcomas. Primary intracranial RMS is rare and has been reported in the cerebrum, cerebellum, brainstem, and the meninges. The occurrence of a primary intracranial RMS arising from the pineal gland is exceedingly rare. Methods/Case Report An adult male presented to the ED with complaint of several months of headaches, progressive confusion, forgetfulness and most recently difficulty in finding words. CT scan showed a large mass arising from the pineal gland causing obstructive hydrocephalus. Subsequently, the patient underwent excisional biopsy. The histopathology examination revealed small round basophilic cells and large polygonal cells with large eccentric nuclei and prominent nucleoli, abundant eosinophilic cytoplasm containing globular paranuclear eosinophilic inclusions, characteristic of rhabdoid cells. Immunohistochemical (IHC) showed tumor cells are positive for Desmin, MyoD1, CK8/18, INI1 (hSNF5; SMARCB1) with retained nuclear expression and faint positivity for Synaptophysin and focally positivity for Neurofilament. The tumor cells showed negative staining for Pankeratin, SOX10, Oct4, SALL4, INSM1, LCA AND CD30, which excluded the possibility of Germ cell tumor and Pineoblastoma. The case was finalized as primary malignant neoplasm, consistent with Embryonal Rhabdomyosarcoma of pineal gland. Results (if a Case Study enter NA) NA Conclusion This case highlights the rare occurrence of rhabdomyosarcoma originating from the pineal gland in an adult male. Morphologic and immunohistochemical findings were consistent with embryonal rhabdomyosarcoma. Since primary rhabdomyosarcoma of the pineal gland is rare, this case contributes to the limited body of literature on such cases. It underscores the importance of considering unusual entities in intracranial tumors. The distinct morphology and the use of IHC aids in diagnosing this rare entity.