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Ng CS, Qin J. Switch/Sucrose Nonfermentable-Deficient Tumors-Morphology, Immunophenotype, Genetics, Epigenetics, Nosology, and Therapy. J Transl Med 2025; 105:102185. [PMID: 39542101 DOI: 10.1016/j.labinv.2024.102185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 11/03/2024] [Accepted: 11/07/2024] [Indexed: 11/17/2024] Open
Abstract
About 20% of human cancers harbor mutations of genes encoding switch/sucrose nonfermentable (SWI/SNF) complex subunits. Deficiency of subunits of the complex is present in 10% of non-small-cell lung cancers (NSCLC; SMARCA4/SMARCA2 deficient), 100% thoracic SMARCA4/A2-deficient undifferentiated tumors (TSADUDT; SMARCA4/A2 deficient), malignant rhabdoid tumor, and atypical/teratoid tumor (SMARCB1-deficient), >90% of small cell carcinoma of the ovary, hypercalcemic type (SMARCA4/SMARCA2 deficient), frequently in undifferentiated/dedifferentiated endometrial carcinoma (SMARCA4, SMARCA2, SMARCB1, and ARID1A/B deficient), 100% SMARCA4 deficient undifferentiated uterine sarcoma (SMARCA4 deficient); and in various other tumors from multifarious anatomical sites. Silencing of SWI/SNF gene expression may be genomically or epigenetically driven, causing loss of tumor suppression function or facilitating other oncogenic events. The SWI/SNF-deficient tumors share the phenotype of poor or no differentiation, often with a variable component of rhabdoid tumor cells. They present at advanced stages with poor prognosis. Rhabdoid tumor cell phenotype is a useful feature to prompt investigation for this group of tumors. In the thoracic space, the overlap in morphology, immunophenotype, genetics, and epigenetics of SMARCA4/A2-deficient NSCLC and TSADUDT appears more significant. This raises a possible nosologic relationship between TSADUDT and SMARCA4/A2-deficient NSCLC. Increased understanding of the genetics, epigenetics, and mechanisms of oncogenesis in these poor prognostic tumors, which are often resistant to conventional treatment, opens a new horizon of therapy for the tumors.
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Affiliation(s)
- Chi Sing Ng
- Department of Pathology, Caritas Medical Center, Kowloon, Hong Kong.
| | - Jilong Qin
- Department of Pathology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Gjeorgjievski SG, Gandhi JS, Bahrami A. Non-myxoid solid variant of extraskeletal myxoid chondrosarcoma: An underrecognized subtype. Hum Pathol 2025; 155:105719. [PMID: 39828007 DOI: 10.1016/j.humpath.2025.105719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 01/10/2025] [Accepted: 01/14/2025] [Indexed: 01/22/2025]
Abstract
INTRODUCTION Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma defined by NR4A3 gene rearrangements, typically featuring uniform cells with eosinophilic cytoplasm and mild atypia, arranged in cords or clusters within a chondromyxoid stroma. A cellular variant, characterized by increased cellular density and a solid growth pattern, has been recognized. METHODS We encountered three cases of round cell sarcomas, diagnosed as EMC based on NR4A3 or NR4A2 rearrangements. To identify additional pure solid EMC cases, we performed a retrospective review of our institutional files spanning 22 years, focusing on cases labeled as "myxoid chondrosarcoma" with "cellular" features. Histologic slides and clinical data were reviewed. RESULTS In addition to the three study cases, 43 cases of EMC with cellular features were identified, none of which exhibited the exclusive round-to-spindle cell morphology seen in the study cases. The three unique cases involved two females and one male (ages 42-62) with tumors in the proximal extremities and trunk. The tumors (3.5-10 cm) were well-circumscribed and densely cellular. One tumor exhibited a biphasic pattern with distinct round and spindle cell areas, whereas the other two were composed purely of round/epithelioid cells. High-grade nuclear atypia and brisk mitotic activity (9-13 per 10 HPFs) were observed, with necrosis identified in one case. Next-generation sequencing revealed TCF12::NR4A3, EWSR1::NR4A3, and EWSR1::NR4A2 fusions. Two patients developed metastases (lymph nodes and lungs), whereas one remained disease-free at last follow-up. CONCLUSION We describe a round cell subtype of EMC, distinct from the traditional cellular variant, characterized by a sheet-like proliferation of large, uniform round-to-epithelioid cells and the absence of chondromyxoid stroma. This potentially underrecognized subtype requires molecular testing for accurate diagnosis. Moreover, the presence of NR4A2 fusions, although rare, suggests that the absence of NR4A3 rearrangements does not entirely exclude EMC.
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Affiliation(s)
| | - Jatin S Gandhi
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Armita Bahrami
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
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Adeniran AJ, Shuch B, Humphrey PA. Sarcomatoid and Rhabdoid Renal Cell Carcinoma: Clinical, Pathologic, and Molecular Genetic Features. Am J Surg Pathol 2024; 48:e65-e88. [PMID: 38736105 DOI: 10.1097/pas.0000000000002233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2024]
Abstract
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.
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Affiliation(s)
| | - Brian Shuch
- Department of Urology, University of California Los Angeles, Los Angeles, CA
| | - Peter A Humphrey
- Department of Pathology, Yale University School of Medicine, New Haven, CT
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Sánchez-Guixé M, Muiños F, Pinheiro-Santin M, González-Huici V, Rodriguez-Hernandez CJ, Avgustinova A, Lavarino C, González-Pérez A, Mora J, López-Bigas N. Origins of Second Malignancies in Children and Mutational Footprint of Chemotherapy in Normal Tissues. Cancer Discov 2024; 14:953-964. [PMID: 38501975 PMCID: PMC11145171 DOI: 10.1158/2159-8290.cd-23-1186] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 12/20/2023] [Accepted: 02/15/2024] [Indexed: 03/20/2024]
Abstract
Pediatric cancers are rare diseases, and children without known germline predisposing conditions who develop a second malignancy during developmental ages are extremely rare. We present four such clinical cases and, through whole-genome and error-correcting ultra-deep duplex sequencing of tumor and normal samples, we explored the origin of the second malignancy in four children, uncovering different routes of development. The exposure to cytotoxic therapies was linked to the emergence of a secondary acute myeloid leukemia. A common somatic mutation acquired early during embryonic development was the driver of two solid malignancies in another child. In two cases, the two tumors developed from completely independent clones diverging during embryogenesis. Importantly, we demonstrate that platinum-based therapies contributed at least one order of magnitude more mutations per day of exposure than aging to normal tissues in these children. SIGNIFICANCE Using whole-genome and error-correcting ultra-deep duplex sequencing, we uncover different origins for second neoplasms in four children. We also uncover the presence of platinum-related mutations across 10 normal tissues of exposed individuals, highlighting the impact that the use of cytotoxic therapies may have on cancer survivors. See related commentary by Pacyna and Nangalia, p. 900. This article is featured in Selected Articles from This Issue, p. 897.
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Affiliation(s)
- Mònica Sánchez-Guixé
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Ferran Muiños
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Morena Pinheiro-Santin
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Víctor González-Huici
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | | | - Alexandra Avgustinova
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Institut de Recerca Sant Joan de Déu, Barcelona, Spain
| | - Cinzia Lavarino
- Pediatric Cancer Center Barcelona (PCCB), Hospital Sant Joan de Déu, Barcelona, Spain
| | - Abel González-Pérez
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
- Universitat Pompeu Fabra, Barcelona, Spain
| | - Jaume Mora
- Pediatric Cancer Center Barcelona (PCCB), Hospital Sant Joan de Déu, Barcelona, Spain
| | - Núria López-Bigas
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
- Universitat Pompeu Fabra, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
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Xie S, Fang Y, Yang Y, Liu L, Bai J, Lin S, Zhang B, Fang Y. Extracranial malignant rhabdoid tumors in children: high mortality even with the help of an aggressive clinical approach. Eur J Pediatr 2024; 183:557-567. [PMID: 38019286 DOI: 10.1007/s00431-023-05345-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 10/27/2023] [Accepted: 11/18/2023] [Indexed: 11/30/2023]
Abstract
This paper aims to explore the epidemiology, clinical characteristics, and prognosis of extracranial malignant rhabdoid tumors (eMRTs) in children. A systematic review and meta-analysis of studies published in PUBMED, MEDLINE, Web of Science, Embase, Cochrane, and China National Knowledge Infrastructure (CNKI) was conducted. The search was limited to studies published between Jan 1, 1990 to Dec 31, 2022, with the last search done on Jan 31, 2023. We identified 496 papers through the literature search, and 12 retrospective cohort studies with 398 patients were included. The pooled age at diagnosis for malignant rhabdoid tumor of the kidney (MRTK) was 10.009 months (95%CI (7.542-12.476)), while extracranial malignant rhabdoid tumor (EERT) was 25.917 months (95%CI (17.304-34.530)). Among the 398 patients with eMRTs, chemotherapy treatment rate (86.8% (95%CI (74.4-96.0%))) was more frequently than radiotherapy treatment (45.4% (95%CI (38.1-52.6%))). The rate of metastasis in all patients was 41.4% (95%CI (33.9-48.9%)), in which the lung metastasis was occupied 70.4% (95%CI (58.0-81.6%)). SMARCB1/INI1 mutation was up to 93.2% (95%CI (81.3-99.8%)). The rate of total surgical resection was 50.4% (95%CI (35.2-65.6%)), while pooled proportion of death in all patients was 68.7% (95%CI (56.9-79.5%)). Conclusion: EMRTs are highly malignant tumors associated with high mortality rates. The loss of SMARCB1/INI1 gene and the protein expression is observed in the vast majority of eMRTs patients. Patients that suffered MRTK are younger than patients with extrarenal EERT and are more prone to lung metastasis, but there is no significant difference in overall survival, possibly due to the higher rate of R0 resection of primary tumors in MRTK. Trial registration: The study was registered on PROSPERO with registration number CRD42023400985. What is Known: • Malignant rhabdoid tumor (MRT) is a rare and highly malignant tumor that may originate from embryonic stem cells. The incidence of MRT is exceptionally low, estimated at 0.00006%. • Malignant rhabdoid tumor of the kidney (MRTK) and extrarenal extra-cranial malignant rhabdoid tumor (EERT) tend to manifest between 11 to 18 months of age, with a 5-year survival rate of approximately 17%-36%. What is New: • There is no comprehensive meta-analysis or large-scale case series that reported to systematically introduce the eMRTs clinic outcome and prog-nosis based on largely pooled data. • This study performed a meta-analysis through an extensive literature search and clinical data analysis in order to mainly explore the clinical characteris-tics and prognosis of eMRTs, improving the understanding of eMRTs in children..
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Affiliation(s)
- Siqi Xie
- Department of Pediatric Surgery, Fujian Children's Hospital (Fujian Branch of Shanghai Children's Medical Center), College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350000, Fujian, China
| | - Yuanyuan Fang
- Department of Pediatric Surgery, Fujian Children's Hospital (Fujian Branch of Shanghai Children's Medical Center), College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350000, Fujian, China
| | - Yingying Yang
- Department of Pediatric Surgery, Fujian Children's Hospital (Fujian Branch of Shanghai Children's Medical Center), College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350000, Fujian, China
| | - Lan Liu
- Department of Pediatric Surgery, Fujian Children's Hospital (Fujian Branch of Shanghai Children's Medical Center), College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350000, Fujian, China
| | - Jianxi Bai
- Department of Pediatric Surgery, Fujian Children's Hospital (Fujian Branch of Shanghai Children's Medical Center), College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350000, Fujian, China
| | - Sheng Lin
- Department of Pediatric Surgery, Fujian Children's Hospital (Fujian Branch of Shanghai Children's Medical Center), College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350000, Fujian, China
| | - Bing Zhang
- Department of Pediatric Surgery, Fujian Children's Hospital (Fujian Branch of Shanghai Children's Medical Center), College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350000, Fujian, China
| | - Yifan Fang
- Department of Pediatric Surgery, Fujian Children's Hospital (Fujian Branch of Shanghai Children's Medical Center), College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350000, Fujian, China.
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Merlini A, Rabino M, Brusco S, Pavese V, Masci D, Sangiolo D, Bironzo P, Scagliotti GV, Novello S, D'Ambrosio L. Epigenetic determinants in soft tissue sarcomas: molecular mechanisms and therapeutic targets. Expert Opin Ther Targets 2024; 28:17-28. [PMID: 38234142 DOI: 10.1080/14728222.2024.2306344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 01/12/2024] [Indexed: 01/19/2024]
Abstract
INTRODUCTION Soft tissue sarcomas are a group of rare, mesenchymal tumors characterized by dismal prognosis in advanced/metastatic stages. Knowledge of their molecular determinants is still rather limited. However, in recent years, epigenetic regulation - the modification of gene expression/function without DNA sequence variation - has emerged as a key player both in sarcomagenesis and sarcoma progression. AREAS COVERED Herein, we describe and review the main epigenetic mechanisms involved in chromatin remodeling and their role as disease drivers in different soft tissue sarcoma histotypes, focusing on epithelioid sarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumors. Focusing on chromatin-remodeling complexes, we provide an in-depth on the role of BAF complex alterations in these soft tissue sarcoma histotypes. In parallel, we highlight current state-of-the-art and future perspectives in the development of rational, innovative treatments leveraging on epigenetic dysregulation in soft tissue sarcomas. EXPERT OPINION Therapeutic options for metastatic/advanced sarcomas are to date very limited and largely represented by cytotoxic agents, with only modest results. In the continuous attempt to find novel targets and innovative, effective drugs, epigenetic mechanisms represent an emerging and promising field of research, especially for malignant peripheral nerve sheath tumors, epithelioid and synovial sarcoma.
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Affiliation(s)
| | - Martina Rabino
- Department of Oncology, University of Turin, Orbassano (TO), Italy
| | - Silvia Brusco
- Department of Oncology, University of Turin, Orbassano (TO), Italy
- Division of Molecular Pathology, The Institute of Cancer Research Royal Cancer Hospital, London, UK
| | - Valeria Pavese
- Department of Oncology, University of Turin, Orbassano (TO), Italy
| | - Debora Masci
- Department of Oncology, University of Turin, Orbassano (TO), Italy
| | - Dario Sangiolo
- Department of Oncology, University of Turin, Orbassano (TO), Italy
| | - Paolo Bironzo
- Department of Oncology, University of Turin, Orbassano (TO), Italy
- Medical Oncology, S. Luigi Gonzaga University Hospital, Orbassano (TO), Italy
| | - Giorgio Vittorio Scagliotti
- Department of Oncology, University of Turin, Orbassano (TO), Italy
- Medical Oncology, S. Luigi Gonzaga University Hospital, Orbassano (TO), Italy
| | - Silvia Novello
- Department of Oncology, University of Turin, Orbassano (TO), Italy
- Medical Oncology, S. Luigi Gonzaga University Hospital, Orbassano (TO), Italy
| | - Lorenzo D'Ambrosio
- Department of Oncology, University of Turin, Orbassano (TO), Italy
- Medical Oncology, S. Luigi Gonzaga University Hospital, Orbassano (TO), Italy
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Ueno-Yokohata H, Okita H, Nakasato K, Kiyokawa N. Hypermethylation of RASSF1A gene in pediatric rhabdoid tumor of the kidney and clear cell sarcoma of the kidney. Pediatr Blood Cancer 2023; 70:e30058. [PMID: 36250993 DOI: 10.1002/pbc.30058] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 09/06/2022] [Accepted: 09/25/2022] [Indexed: 01/09/2023]
Abstract
BACKGROUND Among pediatric renal tumors, rhabdoid tumor of the kidney (RTK) and clear cell sarcoma of the kidney (CCSK) are rare and associated with an unfavorable prognosis, while congenital mesoblastic nephroma (CMN) is associated with a good prognosis. Methylation of the Ras association domain-containing protein 1 isoform A (RASSF1A) promoter has been reported to correlate with a poor prognosis in patients with Wilms tumors, while its methylation status is unclear in other types of pediatric renal tumors. METHOD DNA methylation of the RASSF1A promoter in several pediatric renal tumors was analyzed with pyrosequencing. In order to clarify the correlation between expression of RASSF1A and DNA methylation of its promoter, the RTK cell line was treated with 5-Aza-2'-deoxycytidine (5-Aza-dC). RASSF1A was overexpressed in the RTK cell line to evaluate its functional effects. RESULTS Quantitative methylation analysis demonstrated hypermethylation in the RASSF1A promoter region in RTK and CCSK, but not CMN. The 5-Aza-dC treatment induced demethylation of the RASSF1A promoter as well as increased RASSF1A mRNA expression. The transduction of RASSF1A has an effect on the suppression of viability and proliferation of RTK cells. CONCLUSION DNA methylation-mediated deficiency of RASSF1A might be involved in the development and aggressiveness of some pediatric renal tumors and correlated with a poor prognosis.
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Affiliation(s)
- Hitomi Ueno-Yokohata
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan
| | - Hajime Okita
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.,Division of Diagnostic Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Keiko Nakasato
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan
| | - Nobutaka Kiyokawa
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan
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Yolk sac tumor of postpubertal-type does not exhibit immunohistochemical loss of SMARCB1/INI1 and SMARCA4/BRG1…but choriocarcinoma? Pathol Res Pract 2023; 241:154269. [PMID: 36502737 DOI: 10.1016/j.prp.2022.154269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/05/2022] [Accepted: 12/05/2022] [Indexed: 12/12/2022]
Abstract
The recently described SWI/SNF complex-deficient sinonasal carcinoma (SMARCB1 & SMARCA4) may exhibit a yolk sac-like morphology. Tumors with similar features (yolk sac-like histology combined with the immunohistochemical loss of SMARCB1/INI1 and/or SMARCA4/BRG1) have also been described in other sites, such as the female genital tract. In this study, we immunohistochemically assessed SMARCB1/INI1 and SMARCA4/BRG1 expression to evaluate if these proteins could be involved in the pathogenesis of testicular yolk sac tumors of postpubertal type (YSTpt). Specifically, we analyzed a retrospective case series comprising pure YSTpt and mixed germ cell tumors of the testis (GCTT) with YSTpt components. In the present study, no testicular YSTpt showed loss of SMARCB1/INI1 (0/24, 0%) or SMARCA4/BRG1 (0/24, 0%). However, testicular choriocarcinoma (CHC) and isolated syncytiotrophoblast cells (iSTCs) demonstrated abnormal staining patterns for SMARCA4/BRG1 [CHC: 4/4 (100%); iSTCs: 12/12 (100%), respectively], including focal or diffuse loss of expression in a subset of cases. The results of our study suggest that functional loss of SMARCA4/BRG1 represents a recurrent event that may be relevant for the pathogenesis of a subset of testicular CHC.
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Gupta S, Noona SW, Pambuccian SE, Robinson B, Martin LW, Williams E, Stelow EB, Raghavan SS. Malignant undifferentiated and rhabdoid tumors of the gastroesophageal junction and esophagus with SMARCA4 loss: a case series. Hum Pathol 2022; 134:56-65. [PMID: 36549598 DOI: 10.1016/j.humpath.2022.12.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022]
Abstract
Undifferentiated SMARCA4-deficient carcinoma of the esophagus and gastroesophageal junction is a rare, highly aggressive, and diagnostically challenging malignancy. Here we present a case series of high-grade undifferentiated malignant neoplasms of the esophagus and gastroesophageal junction that share SMARCA4 loss by immunohistochemistry and demonstrate a rhabdoid phenotype. Five cases are presented, including 4 men and 1 woman with an age range of 48-79 years. Interestingly, only one case showed intestinal metaplasia (Barrett's esophagus) and no cases demonstrated glandular dysplasia or glandular differentiation. In all, the lesional cells were immunoreactive with antibodies to keratins (3/5), CD34 (2/4), and CD138 (4/5). SMARCA4 expression was diffusely lost in all cases, whereas SMARCB1 expression was intact. OncoScan™ assay demonstrated loss of SMARCA4 in all cases analyzed. Additional OncoScan™ findings included abnormalities of CDKN2A in 2 of 3 cases, abnormalities of TP53 in 2 of 3 cases, and abnormalities of PTPRD in 2 of 3 cases, among other abnormalities.
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Affiliation(s)
- Srishti Gupta
- Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA
| | - Sean W Noona
- Department of Surgery, University of Virginia, Charlottesville, VA 22908, USA
| | | | - Brian Robinson
- Department of Pathology, Emory University, Atlanta, GA 30322, USA
| | - Linda W Martin
- Department of Surgery, University of Virginia, Charlottesville, VA 22908, USA
| | - Eli Williams
- Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA
| | - Edward B Stelow
- Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA
| | - Shyam S Raghavan
- Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
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Differential expression profiling of onco and tumor-suppressor genes from major-signaling pathways in Wilms' tumor. Pediatr Surg Int 2022; 38:1601-1617. [PMID: 36107237 DOI: 10.1007/s00383-022-05202-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/22/2022] [Indexed: 10/14/2022]
Abstract
PURPOSE Wilms' tumor is the most-frequent malignant-kidney tumor in children under 3-4 years of age and is caused by genetic alterations of oncogenes (OG) and tumor-suppressor genes (TG). Wilms' tumor has been linked to many OG-&-TG. However, only WT1 has a proven role in the development of this embryonic-tumor. METHODS The study investigates the level of mRNA expression of 16 OGs and 20 TGs involved in key-signaling pathways, including chromatin modification; RAS; APC; Cell Cycle/Apoptosis; Transcriptional Regulation; PI3K; NOTCH-&-HH; PI3K & RAS of 24-fresh Wilms'-tumor cases by capture-and-reporter probe Code-Sets chemistry, as CNVs in these pathway genes have been reported. RESULTS Upon extensively investigating, MEN1, MLL2, MLL3, PBRM1, PRDM1, SMARCB1, SETD2, WT1, PTPN11, KRAS, HRAS, NF1, APC, RB1, FUBP1, BCOR, U2AF1, PIK3CA, PTEN, EBXW7, SMO, ALK, CBL, EP300-and-GATA1 were found to be significantly up-regulated in 58.34, 62.5, 79.17, 91.67, 58, 66.66,54, 58.34, 66.67, 75, 62.5, 62.5, 58, 79.17, 79.17, 75, 70.84, 50, 50, 75, 66.66, 62.50, 61.66, 58.34-and-62.50% of cases respectively, whereas BRAF, NF2, CDH1, BCL2, FGFR3, ERBB2, MET, RET, EGFR-and-GATA2 were significantly down regulated in 58, 87.50, 79.16, 54.16, 79.17, 91.66, 66.66, 58.33, 91.66-and-62.50% of cases, respectively. Interestingly, the WT1 gene was five-fold down regulated in 41.66% of cases only. CONCLUSION Hence, extensive profiling of OGs and TGs association of major-signaling pathways in Wilms' tumor cases may aid in disease diagnosis. PBRM1 (up-regulated in 91.67% of cases), ERBB2 and EGFR (down-regulated in 91.66 and 91.66% of cases, respectively) could be marker genes. However, validation of all relevant results in a larger number of samples is required.
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Mondragón-Soto MG, Del Valle L, González-Soto JA, De Leo-Vargas RA. Metastatic primary brain rhabdomyosarcoma in a pediatric patient: illustrative case. JOURNAL OF NEUROSURGERY: CASE LESSONS 2022; 4:CASE22189. [PMID: 36046269 PMCID: PMC9329863 DOI: 10.3171/case22189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 05/19/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND
Primary intracranial rhabdomyosarcoma is an extraordinarily rare malignant tumor, with even fewer presenting with distant metastasis. To date, only five cases, including the one presented here, have been reported to present metastatic activity.
OBSERVATIONS
A 12-year-old boy presented with a few days of headache, nausea, vomiting, but no neurological deficit. Brain computed tomography and magnetic resonance imaging demonstrated hydrocephalus and a cystic lesion with left parieto-occipital extension. After resection, pathology reported primary rhabdomyosarcoma, with positive desmin and myogenin on immunohistochemistry. The patient presented with pulmonary metastasis. The patient had an overall survival of 21 months after diagnosis with optimal treatment.
LESSONS
Rhabdomyosarcoma is a malignant neoplasm arising from undifferentiated skeletal muscle cells, with morphological, immunohistochemical, ultrastructural, or molecular genetic evidence of primary skeletal muscle differentiation. It presents with a rapidly worsening clinical course and the final outcome is poor. Treatment is widely based on protocols that have been proven to be effective in extracranial versions of these tumors, although repeatedly ineffective. Primary brain rhabdomyosarcoma poses a diagnostic challenge because of its infrequent presentation, grade of undifferentiation and tumor heterogeneity. Immunohistochemical and genetic testing have proven to be useful tools for diagnosis.
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Affiliation(s)
| | - Luis Del Valle
- Molecular Histopathology & Microscopy Core, Stanley S. Scott Cancer Center Louisiana State University Health, New Orleans, Louisiana
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12
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Hannon Barroeta P, Magnano S, O'Sullivan MJ, Zisterer DM. Evaluation of targeting autophagy for the treatment of malignant rhabdoid tumours. Cancer Treat Res Commun 2022; 32:100584. [PMID: 35679755 DOI: 10.1016/j.ctarc.2022.100584] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/31/2022] [Accepted: 06/01/2022] [Indexed: 06/15/2023]
Abstract
Malignant rhabdoid tumour (MRT) is a rare and aggressive paediatric tumour that typically arises in the kidneys or central nervous system (CNS). The malignancy often affects patients under the age of three and is associated with an extremely poor survival rate, with most deaths occurring within the first year of presentation. Thus, there is an unmet and urgent medical need for novel therapeutic strategies for this malignancy. One of the major issues when treating MRT patients is the emergence of chemoresistance. Autophagy has become an area of focus in the study of chemoresistance due to its reported dual role as both a pro-survival and pro-death mechanism. The role of autophagy in the chemotherapeutic response of MRT remains largely unknown. A greater understanding of the role of autophagy may lead to the development of therapeutic strategies to enhance chemotherapeutic effect and improve the clinical outcome of MRT patients. This study evaluated the cellular response to cisplatin, a representative chemotherapeutic agent used in the treatment of MRT, and the role of autophagy in mediating cisplatin resistance. Our results demonstrated that cisplatin induced apoptosis and autophagy concomitantly in a panel of MRT cell lines. Furthermore, inhibition of caspase-induced apoptosis with Z-VAD-FMK also inhibited autophagy levels demonstrating a complex interplay between these two pathways. In addition, blocking autophagy at the early stages of the autophagic process using the pharmacological inhibitor SAR405 or through the genetic knockdown of critical autophagic protein ATG5 by siRNA did not sensitise cells to cisplatin-induced apoptosis. Collectively, these results suggest that induction of autophagy does not appear to elicit a pro-survival effect in the chemotherapeutic response of MRT cells.
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Affiliation(s)
- Patricia Hannon Barroeta
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
| | - Stefania Magnano
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Maureen J O'Sullivan
- The National Children's Research Centre, Children's Health Ireland at Crumlin, Dublin 12, Ireland
| | - Daniela M Zisterer
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
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13
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Calandrini C, Drost J. Normal and tumor-derived organoids as a drug screening platform for tumor-specific drug vulnerabilities. STAR Protoc 2022; 3:101079. [PMID: 35036959 PMCID: PMC8752949 DOI: 10.1016/j.xpro.2021.101079] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Patient-derived tumor organoids can be predictive of patient's treatment responses, and normal tissue-derived organoids allow for drug toxicity testing. Combining both types of organoids therefore enables screening for tumor-specific drug vulnerabilities. Here, we provide a detailed protocol for organoid drug screening using, as proof-of-principle, patient-derived malignant rhabdoid tumor organoids. The protocol can be adapted for drug testing on any tumor and/or normal tissue-derived organoid culture. For complete details on the use and execution of this protocol, please refer to Calandrini et al. (2021).
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Affiliation(s)
- Camilla Calandrini
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands
- Oncode Institute, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands
| | - Jarno Drost
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands
- Oncode Institute, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands
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14
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Role of Cyclin D1 and BCOR Immunohistochemistry in Differentiating Clear Cell Sarcoma of Kidney From its Mimics. J Pediatr Hematol Oncol 2021; 43:294-300. [PMID: 34673711 DOI: 10.1097/mph.0000000000002262] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 06/21/2021] [Indexed: 01/14/2023]
Abstract
BACKGROUND AND AIM Clear cell sarcoma of kidney (CCSK) is the second most common pediatric renal malignancy, constituting ∼3% of renal tumors. Due to its morphologic diversity, the diagnosis of CCSK is often challenging. Recent studies have identified internal tandem duplication of BCL6 corepressor (BCOR) gene in CCSKs which coupled with cyclin D1 immunoreactivity, is helpful in differentiating it from its mimics, particularly blastema-rich Wilms tumor (WT), malignant rhabdoid tumor (MRT), and congenital mesoblastic nephroma (CMN). We aimed to evaluate the utility of cyclin D1 and BCOR immunohistochemistry in differentiating CCSK from its morphologic mimics. MATERIALS AND METHODS Our cohort comprised of 38 pediatric renal tumors which included CCSK (n=18), WT (n=10), MRT (n=5), and CMN (n=5) cases. A detailed clinicopathologic analysis was performed, and tissue microarray were constructed for CCSK and WT, while MRT and CMN tumors were individually stained. RESULTS The age ranged from 2 months to 16 years with male:female ratio of 3:1. Strong, diffuse nuclear immunoreactivity for cyclin D1 and BCOR was noted in 61% (n=11/18) and 83% (n=15/18) of CCSK, respectively, while it was significantly less in WT (n=3/10 for cyclin D1) (n=2/10 for BCOR). None of the MRT and CMN examples demonstrated any immunoreactivity. Interestingly, only the blastemal component of WTs showed distinct, rare nuclear immunoreactivity for cyclin D1 or BCOR and the combination of these was never positive in a given case. CONCLUSION Our results provide evidence that concurrent immunopositivity with cyclin D1 and BCOR is helpful in distinguishing CCSK from its morphologic mimics.
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15
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Abstract
Transcription factors (TFs) are essential mediators of epigenetic regulation and modifiers of penetrance. Studies from the past decades have revealed a sub-class of TF that is capable of remodeling closed chromatin states through targeting nucleosomal motifs. This pioneer factor (PF) class of chromatin remodeler is ATP independent in its roles in epigenetic initiation, with nucleosome-motif recognition and association with repressive chromatin regions. Increasing evidence suggests that the fundamental properties of PFs can be coopted in human cancers. We explore the role of PFs in the larger context of tissue-specific epigenetic regulation. Moreover, we highlight an emerging class of chimeric PF derived from translocation partners in human disease and PFs associated with rare tumors. In the age of site-directed genome editing and targeted protein degradation, increasing our understanding of PFs will provide access to next-generation therapy for human disease driven from altered transcriptional circuitry.
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16
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Tse RTH, Zhao H, Wong CYP, Chiu PKF, Teoh JYC, Ng CF. Current status of organoid culture in urological malignancy. Int J Urol 2021; 29:102-113. [PMID: 34643976 DOI: 10.1111/iju.14727] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 09/21/2021] [Indexed: 12/28/2022]
Abstract
Urological cancers are common malignancies worldwide. Several conventional models, for example, two-dimensional cell culture and animal models have been used for decades to study tumor genetics. Nonetheless, these methods have limitations in reflecting the real tumor microenvironment in vivo, thereby hindering the development of anti-cancer therapeutic agents. Recently, three-dimensional culture models have gained attention because they can overcome the drawbacks of traditional methods. Above all, three-dimensional organoid models are able to mimic the tumor microenvironment in human bodies more closely as they are able to demonstrate the interactions between cells and extracellular matrix. This type of model has therefore extended our understanding of urological cancers. Tumor cells in organoid models can also be co-cultured with other cellular components, such as peripheral blood lymphocytes, and allow further understanding of the effect of tumor microenvironments on tumor growth. Furthermore, organoid models allow a prolonged culturing period, therefore, tumor evolution, progression and maintenance can also be assessed. Organoid models can be derived from each specific patient, and this facilitates investigation of individual cancer-specific mutations and their subtypes. As a result, the development of personalized medication targeting the signaling pathways or biomolecules of interest will be possible. In the present review, we summarize the development and applications of three-dimensional organoid cultures in urological cancers, mainly focusing on prostate, urinary bladder and kidney cancers, and assess the future prospects of this model.
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Affiliation(s)
- Ryan Tsz-Hei Tse
- S.H. Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
| | - Hongda Zhao
- S.H. Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
| | - Christine Yim-Ping Wong
- S.H. Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
| | - Peter Ka-Fung Chiu
- S.H. Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
| | - Jeremy Yuen-Chun Teoh
- S.H. Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
| | - Chi-Fai Ng
- S.H. Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
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17
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Histologic and genomic features of breast cancers with alterations affecting the SWI/SNF (SMARC) genes. Mod Pathol 2021; 34:1850-1859. [PMID: 34079072 PMCID: PMC8448940 DOI: 10.1038/s41379-021-00837-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/04/2021] [Accepted: 05/05/2021] [Indexed: 02/04/2023]
Abstract
The SWI/SNF family of proteins is a multisubunit ATPase complex frequently altered in human cancer. Inactivating mutations in SWI/SNF-related matrix-associated actin-dependent regulator of chromatin (SMARCs) underpin a subset of tumors such as the malignant rhabdoid tumor and small cell carcinoma of the ovary, hypercalcemic type. Here, we investigated the genotypic and phenotypic characteristics of breast cancers harboring somatic genetic alterations affecting genes of the SMARC family. We analyzed a series of 6026 primary and metastatic breast cancers subjected to targeted-capture sequencing. SMARC core subunit (SMARCA4, SMARCB1, and SMARCA2) alterations were identified in <1% of all breast cancers, consisting of 27 primary and 30 recurrent/metastatic tumors. The majority of SMARC alterations were monoallelic mutations (47/57, 82%) and thus categorized into two groups: Class 1 alterations consisting of potentially pathogenic mutations and rearrangements and Class 2 alterations consisting of missense mutations and small in-frame deletions of unknown significance. Biallelic events in a SMARC gene were present in a minority of cases (10/57, 18%). Histologic patterns in the form of rhabdoid, composite rhabdoid, sarcomatoid or anaplastic features were observed in a subset of Class 1 primary and metastatic tumors (7/57, 12%). SMARC protein was preserved in nearly all tumors analyzed with immunohistochemistry (26/30, 87%). Four Class 1 tumors demonstrated altered SMARC protein expression in the form of loss (1/30, 3%) or mosaic pattern (3/30, 10%). Complete loss of SMARCA2 (BRM) was observed in a sole tumor with composite rhabdoid morphology, and biallelic hits in the SMARCA2 gene. The genomic landscape of both primary Class 1 and 2 breast cancers did not reveal any characteristic findings. In summary, SMARC alterations likely contribute to the biology of a rare subset of breast cancers in the form of biallelic or pathogenic alterations in SMARC, as evidenced by SMARC-deficient phenotype or altered expression of SMARC protein.
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18
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Wang YW, Song HL, Chiang CY, Song HF, Chang HY, Chu CA, Tuan YL, Tsai KH, Ou YC, Chow NH, Tsai YS. The significance of SMARCB1 in the pathogenesis of renal cell carcinoma with rhabdoid features. Transl Oncol 2021; 14:101175. [PMID: 34243015 PMCID: PMC8273225 DOI: 10.1016/j.tranon.2021.101175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 06/23/2021] [Accepted: 07/04/2021] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Renal cell carcinoma with rhabdoid features (RCC-RF) is an aggressive histologic variant in the adults and is usually unresponsive to standard chemotherapy. METHODS Expression of SMARCB1/INI1 was examined in primary RCC-RF (n = 5). Stable INI1 with/without prostaglandin E2 receptor 1 (EP1) knockdown cell lines were created in the ACHN and 786-O RCC cell lines and measured for epidermal growth factor receptor (EGFR)-related signaling pathways. Chemosensitivity to targeted drugs in vitro was tested after knocking down of INI1 in both cell lines. The outcome of co-targeting of INI1 and EP1 in RCC was examined using a tumorigenicity assay. RESULTS Expression of INI1 was markedly reduced at both transcriptional and translational levels in primary RCC-RF. Immunohistochemical expression of INI1 protein was lost in the nuclei of rhabdoid cells compared with conventional RCC (n = 8). Using two cell lines with different genetic background, we showed that knocking down of INI1 activates the EGFR signaling with up-regulated AKT and ERK pathways and sensitizes cancer cells to Erlotinib treatment in vitro. However, cell-line dependent effects were also demonstrated with reference to impact of INI1 or EP1 on cell growth, migration and response to Gefitinib or Everolimus treatment in vitro. CONCLUSION Inactivation of INI1 may play a role in the pathogenesis of RCC-RF. Erlotinib is recommended in the management of patients with INI1-related RCC.
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Affiliation(s)
- Yi-Wen Wang
- Departments of Pathology, College of Medicine, National Cheng Kung University, Tainan, TAIWAN
| | - Hsiang-Lin Song
- Department of Pathology, National Cheng Kung University Hospital, Tainan, TAIWAN
| | - Cheng-Yao Chiang
- Departments of Pathology, College of Medicine, National Cheng Kung University, Tainan, TAIWAN
| | - Hong-Fang Song
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, TAIWAN
| | - Hong-Yi Chang
- Department of Biotechnology and Food Technology, College of Engineering, Southern Taiwan University of Science and Technology, Tainan, TAIWAN
| | - Chien-An Chu
- Departments of Pathology, College of Medicine, National Cheng Kung University, Tainan, TAIWAN
| | - Yih-Lin Tuan
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, TAIWAN
| | - Kun-Hao Tsai
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, TAIWAN
| | - Yin-Chien Ou
- Departments of Urology, College of Medicine, National Cheng Kung University, Tainan, TAIWAN
| | - Nan-Haw Chow
- Departments of Pathology, College of Medicine, National Cheng Kung University, Tainan, TAIWAN; Department of Pathology, National Cheng Kung University Hospital, Tainan, TAIWAN; Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, TAIWAN.
| | - Yuh-Shyan Tsai
- Departments of Urology, College of Medicine, National Cheng Kung University, Tainan, TAIWAN.
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19
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Ichikawa D, Yamashita K, Okuno Y, Muramatsu H, Murakami N, Suzuki K, Kojima D, Kataoka S, Hamada M, Taniguchi R, Nishikawa E, Kawashima N, Narita A, Nishio N, Hama A, Kasai K, Mizuno S, Shimoyama Y, Nakaguro M, Okita H, Kojima S, Nakazawa A, Takahashi Y. Integrated diagnosis based on transcriptome analysis in suspected pediatric sarcomas. NPJ Genom Med 2021; 6:49. [PMID: 34131151 PMCID: PMC8206218 DOI: 10.1038/s41525-021-00210-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 04/09/2021] [Indexed: 12/24/2022] Open
Abstract
Pediatric solid tumors are a heterogeneous group of neoplasms with over 100 subtypes. Clinical and histopathological diagnosis remains challenging due to the overlapping morphological and immunohistochemical findings and the presence of atypical cases. To evaluate the potential utility of including RNA-sequencing (RNA-seq) in the diagnostic process, we performed RNA-seq in 47 patients with suspected pediatric sarcomas. Histopathologists specialized in pediatric cancer re-evaluated pathological specimens to reach a consensus diagnosis; 42 patients were diagnosed with known subtypes of solid tumors whereas 5 patients were diagnosed with undifferentiated sarcoma. RNA-seq analysis confirmed and refined consensus diagnoses and further identified diagnostic genetic variants in four of the five patients with undifferentiated sarcoma. Genetic lesions were detected in 23 patients, including the novel SMARCA4-THOP1 fusion gene and 22 conventional or recently reported genetic events. Unsupervised clustering analysis of the RNA-seq data identified a distinct cluster defined by the overexpression of rhabdomyosarcoma-associated genes including MYOG and CHRNG. These findings suggest that RNA-seq-based genetic analysis may aid in the diagnosis of suspected pediatric sarcomas, which would be useful for the development of stratified treatment strategies.
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Affiliation(s)
- Daisuke Ichikawa
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kyoko Yamashita
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yusuke Okuno
- Medical Genomics Center, Nagoya University Hospital, Nagoya, Japan
| | - Hideki Muramatsu
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Norihiro Murakami
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kyogo Suzuki
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Daiei Kojima
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shinsuke Kataoka
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Motoharu Hamada
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Rieko Taniguchi
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Eri Nishikawa
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Nozomu Kawashima
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Atsushi Narita
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Nobuhiro Nishio
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Department of Advanced Medicine, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
| | - Asahito Hama
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kenji Kasai
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Seiji Mizuno
- Department of Pediatrics, Central Hospital, Aichi Developmental Disability Center, Kasugai, Japan
| | - Yoshie Shimoyama
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Masato Nakaguro
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Hajime Okita
- Department of Pathology, National Center for Child Health and Development, Tokyo, Japan.,Division of Diagnostic Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Seiji Kojima
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Atsuko Nakazawa
- Department of Pathology, National Center for Child Health and Development, Tokyo, Japan.,Department of Clinical Research, Saitama Children's Medical Center, Saitama, Japan
| | - Yoshiyuki Takahashi
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
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20
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Infantile Extracranial Rhabdoid Tumor of the Scalp. Case Rep Med 2021; 2021:6682960. [PMID: 34054966 PMCID: PMC8131137 DOI: 10.1155/2021/6682960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Accepted: 05/05/2021] [Indexed: 11/30/2022] Open
Abstract
Extracranial rhabdoid tumor is a rare tumor that can originate in multiple organs, and it is most commonly seen in the kidneys. This tumor has a grave prognosis. We report to the best of our knowledge the first case of infantile scalp extracranial rhabdoid tumor in a 6-month-old male baby who presented with a right parietal scalp mass since the age of 1 month. This mass was initially diagnosed as scalp hemangioma based on clinical and imaging findings. However, this mass was growing fast which necessitated excision. Pathologic examination after excision showed a malignant tumor composed of sheets of rhabdoid cells. Immunohistochemically, this tumor tested positive for vimentin, CD 99, glypican-3, synaptopysin, WT-1, CK, and EMA. INI-1 immunostain was lost in the tumor cells. Subsequently, this tumor was pathologically diagnosed as extracranial scalp rhabdoid tumor. After tumor excision, the patient was referred to pediatric oncology to receive chemotherapy. Experience with scalp extracranial rhabdoid tumors is limited. However, this tumor in other organs carries a grave prognosis. Although scalp extracranial rhabdoid tumor is an extremely rare tumor, it should be kept in mind in the differential diagnosis of infantile scalp masses given the need of combined surgical and chemotherapeutic treatment.
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21
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Abstract
The SMARCB1/INI1 gene was first discovered in the mid-1990s, and since then it has been revealed that loss of function mutations in this gene result in aggressive rhabdoid tumors. Recently, the term "rhabdoid tumor" has become synonymous with decreased SMARCB1/INI1 expression. When genetic aberrations in the SMARCB1/INI1 gene occur, the result can cause complete loss of expression, decreased expression, and mosaic expression. Although SMARCB1/INI1-deficient tumors are predominantly sarcomas, this is a diverse group of tumors with mixed phenotypes, which can often make the diagnosis challenging. Prognosis for these aggressive tumors is often poor. Moreover, refractory and relapsing progressive disease is common. As a result, accurate and timely diagnosis is imperative. Despite the SMARCB1/INI1 gene itself and its implications in tumorigenesis being discovered over two decades ago, there is a paucity of rhabdoid tumor cases reported in the literature that detail SMARCB1/INI1 expression. Much work remains if we hope to provide additional therapeutic strategies for patients with aggressive SMARCB1/INI1-deficient tumors.
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Affiliation(s)
- Nathaniel A Parker
- University of Kansas School of Medicine, 1010 N Kansas St, Wichita, KS, 67214, USA
| | - Ammar Al-Obaidi
- University of Kansas School of Medicine, 1010 N Kansas St, Wichita, KS, 67214, USA
| | - Jeremy M Deutsch
- Cancer Center of Kansas, 818 N. Emporia #403, Wichita, KS, 67214, USA
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22
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Singh M, Singh H, Hambro B, Kaur J, Rao R. Integrase Interactor 1 (INI-1) Deficient Renal Cell Carcinoma. Cureus 2021; 13:e13082. [PMID: 33680622 PMCID: PMC7932046 DOI: 10.7759/cureus.13082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Members of the SWItch/sucrose nonfermentable (SWI-SNF) family, including SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), SWI/SNF related, matrix‐associated, actin‐dependent regulator of chromatin, subfamily B member 1 (SMARCB1)/integrase interactor 1 (INI-1) are known tumor suppressor genes. Interactions between SMARCB1/INI-1 and key protein components in various cellular pathways are related to tumor progression and proliferation.SMARCB1/INI-1 protein was undetectable in rhabdoid tumor cells, whereas non-tumorous cells express the SMARCB1/INI-1 genes. Germline and sporadic mutations of several genes encoding for proteins in this complex are known to cause a spectrum of cancers, usually with sarcomatoid features which include a very aggressive renal medullary carcinoma. We report a case of a 29-year-old male who presented with SMARCA4 deficient renal tumor with a very aggressive clinical behavior which ultimately led to his death.
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Affiliation(s)
| | | | | | - Jasleen Kaur
- Internal Medicine, St Agnes Medical Center, Fresno, USA
| | - Ravi Rao
- Hematology and Oncology, St Agnes Medical Center, Fresno, USA
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23
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Howitt BE, Folpe AL. Update on SWI/SNF-related gynecologic mesenchymal neoplasms: SMARCA4-deficient uterine sarcoma and SMARCB1-deficient vulvar neoplasms. Genes Chromosomes Cancer 2020; 60:190-209. [PMID: 33252159 DOI: 10.1002/gcc.22922] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/23/2020] [Accepted: 11/24/2020] [Indexed: 01/22/2023] Open
Abstract
Our knowledge regarding the role of genes encoding the chromatin remodeling switch/sucrose non-fermenting (SWI/SNF) complex in the initiation and progression of gynecologic malignancies continues to evolve. This review focuses on gynecologic tumors in which the sole or primary genetic alteration is in SMARCA4 or SMARCB1, two members of the SWI/SNF chromatin remodeling complex. In this review, we present a brief overview of the classical example of such tumors, ovarian small cell carcinoma of hypercalcemic type, and then a detailed review and update of SMARCB1-deficient and SMARCA4-deficient tumors of the uterus and vulva.
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Affiliation(s)
- Brooke E Howitt
- Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
| | - Andrew L Folpe
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
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24
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Kasturi N, Gera P, Panicker G, Jossy A, Rangarajan V, Hanuman SB. Primary Intraocular Malignant Rhabdoid Tumor Mimicking Retinoblastoma in a Child. Ocul Oncol Pathol 2020; 6:438-441. [PMID: 33447594 PMCID: PMC7772879 DOI: 10.1159/000510206] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 07/09/2020] [Indexed: 11/19/2022] Open
Abstract
Primary rhabdoid tumors are highly malignant, rare tumors occurring in the renal, extrarenal soft tissue or central nervous system. They have non-specific radiological features and present with several histological components that create a problem in differential diagnosis with other embryonal tumors. We report a rare case of malignant rhabdoid tumor of the retina that presented with clinical features like those of retinoblastoma.
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Affiliation(s)
- Nirupama Kasturi
- Department of Ophthalmology, Jawaharlal Postgraduate Medical Education and Research, Puducherry, India
| | - Pratik Gera
- Department of Ophthalmology, Jawaharlal Postgraduate Medical Education and Research, Puducherry, India
| | - Gayatri Panicker
- Department of Ophthalmology, Jawaharlal Postgraduate Medical Education and Research, Puducherry, India
| | - Ajax Jossy
- Department of Ophthalmology, Jawaharlal Postgraduate Medical Education and Research, Puducherry, India
| | - Vidhyalakshmi Rangarajan
- Department of Pathology, Jawaharlal Postgraduate Medical Education and Research, Puducherry, India
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25
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Desmoplastic Small Round Cell Tumor of the Kidney: Report of a Case, Literature Review, and Comprehensive Discussion of the Distinctive Morphologic, Immunohistochemical, and Molecular Features in the Differential Diagnosis of Small Round Cell Tumors Affecting the Kidney. Adv Anat Pathol 2020; 27:408-421. [PMID: 32804706 DOI: 10.1097/pap.0000000000000279] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Desmoplastic small round cell tumor (DSRCT) is a rare, highly aggressive neoplasm typically presenting with widespread involvement of the abdominopelvic peritoneum of adolescent males, usually without organ-based primary. Although it is believed to originate from the serous (mainly peritoneal) membranes, intracranial, sinonasal, intraosseous, and other soft tissue sites are also documented. A chromosomal translocation t(11:22)(p13;q12) signature that fuses EWSR1 and WT1 genes results in the production of a chimeric protein with transcriptional regulatory activity that drives oncogenesis. Integration of clinical, morphologic, immunohistochemical, and genetic data is necessary to arrive at the correct diagnosis, especially when the tumor arises in an atypical site. A 15-year-old male presented with hematuria and was found to have a large renal tumor associated with adrenal, liver, lung, and bone metastases. Histopathologic and immunophenotypic features were distinctive for DSRCT. This diagnosis was confirmed by means of fluorescence in situ hybridization and cytogenetic analysis, which documented the pathognomonic t(11;22) translocation, and by reverse transcription polymerase chain reaction on snap-frozen tissue, which revealed the EWSR1/WT1-specific chimeric transcript. Despite high-dose chemotherapy and radiation therapy targeted to a single T11 vertebral metastasis, the disease progressed, and the patient died 4 years after the diagnosis. A search of electronic databases for DSRCT yielded 16 cases of well-documented renal primaries out of around 1570 cases from all sites gathered from the global literature. Desmoplastic small round blue cell tumor and other primary renal tumors considered in the differential diagnosis with DSRCT are discussed.
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Abstract
Molecular characterization has led to advances in the understanding of pediatric renal tumors, including the association of pediatric cystic nephromas with DICER1 tumor syndrome, the metanephric family of tumors with somatic BRAF mutations, the characterization of ETV6-NTRK3-negative congenital mesoblastic nephromas, the expanded spectrum of gene fusions in translocation renal cell carcinoma, the relationship of clear cell sarcoma of the kidney with other BCOR-altered tumors, and the pathways affected by SMARCB1 alterations in rhabdoid tumors of the kidney. These advances have implications for diagnosis, classification, and treatment of pediatric renal tumors.
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27
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Ross J, Li G, Yang XJ. Application and Pitfalls of Immunohistochemistry in Diagnosis of Challenging Genitourinary Cases. Arch Pathol Lab Med 2020; 144:290-304. [PMID: 32101059 DOI: 10.5858/arpa.2019-0550-ra] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Immunohistochemistry (IHC) has become increasingly important in the evaluation of pathologic conditions in the genitourinary (GU) organs. In addition to careful evaluation of hematoxylin-eosin sections and generation of a differential diagnosis, choosing the optimal panel of IHC markers becomes even more important when the biopsy material is very limited. The following summary of our experience supplemented with relevant literature review exemplifies how to use IHC to facilitate pathologic diagnosis in the GU system. OBJECTIVE.— To describe our experience with the most common immunohistochemical markers used in GU pathology. DATA SOURCES.— Institutional experience and literature search comprise our data sources. CONCLUSIONS.— Application of IHC provides enormous benefits to the interpretation of GU pathologic conditions, including benign and malignant lesions. However, both insufficient and excessive types of use of IHC, as well as incorrect interpretations in common and rare GU conditions, could present pitfalls in diagnosis.
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Affiliation(s)
- Jenny Ross
- From the Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Guangyuan Li
- From the Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Ximing J Yang
- From the Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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28
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Malgulwar PB, Kakkar A, Sharma MC, Ghosh R, Pathak P, Sarkar C, Suri V, Singh M, Kale SS, Faruq M. Loss of SMARCB1/INI1 Immunoexpression in Chordoid Meningiomas. Neurol India 2020; 67:1492-1497. [PMID: 31857543 DOI: 10.4103/0028-3886.273647] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Background Chordoid meningiomas have an aggressive clinical course characterized by frequent recurrences. Recent whole-genome sequencing studies demonstrated Chr22 loss in chordoid meningiomas not accounted for by NF2 mutations. SMARCB1/INI1 is a candidate gene on Chr22, which has not been analyzed extensively in meningiomas. AKT1 mutation has been recently identified to be a driver of meningiomagenesis. Materials and Methods Cases of chordoid meningioma were retrieved along with meningiomas of other subtypes for comparison. INI1 immunohistochemistry was performed. SMARCB1 and AKT1 were analyzed by sequencing. Results Sixteen chordoid meningiomas were identified (1.1% of all meningiomas). Six cases (37.5%) showed loss of INI1 immunoexpression. All other meningioma subtypes (n = 16) retained INI1 immunoexpression. AKT1 E17K mutation was identified in one case (16.7%). Notably, SMARCB1 mutations were not identified in any of the chordoid meningiomas analyzed, including those showing INI1 loss immunohistochemically. Conclusion This is the first study to demonstrate loss of SMARCB1/INI1 immunoexpression in chordoid meningiomas, adding to the tumors with INI1 loss. However, in absence of INI1 mutation, mechanisms for INI1 loss require further evaluation. Identification of AKT1 mutation opens up new avenues for targeted therapy in patients with such aggressive tumors.
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Affiliation(s)
- Prit B Malgulwar
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Aanchal Kakkar
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Mehar C Sharma
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Ranajoy Ghosh
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Pankaj Pathak
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Chitra Sarkar
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Vaishali Suri
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Manmohan Singh
- Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India
| | - Shashank S Kale
- Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India
| | - Mohammed Faruq
- Genomics and Molecular Medicine, Institute of Genomics and Integrative Biology-Council of Scientific and Industrial Research, New Delhi, India
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29
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Mallereau CH, Ganau M, Todeschi J, Cebula H, Santin MDN, Virbel G, Pop R, Lhermitte B, Proust F, Chibbaro S. Primary Brain Rhabdomyosarcoma Causing Extracranial Metastases: Case Report with Narrative Review of Atypical Presentations and Their Diagnostic Challenges. World Neurosurg 2020; 138:363-368. [PMID: 32229305 DOI: 10.1016/j.wneu.2020.03.110] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 03/17/2020] [Accepted: 03/18/2020] [Indexed: 01/21/2023]
Abstract
BACKGROUND Rhabdomyosarcoma is a rare malignant tumor originating from striated muscle cells. It accounts for only 3% of all soft tissue sarcomas in adults, and its metastases can also reach the central nervous system. Only sporadic cases of primary brain rhabdomyosarcoma (PBRMS) have been reported so far. CASE DESCRIPTION We discuss the atypical presentation and diagnostic challenge of PBRMS in a 65-year-old man. He presented with a 3-day history of progressive right hemiparesis caused by an unspecific left frontoparietal heterogeneously enhancing lesion. Total body computed tomography and positron emission tomography scans performed at baseline did not reveal other secondarisms. The patient underwent radical excision of the lesion, which allowed to establish the diagnosis, with immunohistochemical staining positive for desmin and myogenin. Stereotactic radiotherapy guaranteed local disease control; nonetheless, the patient also required adjuvant chemotherapy when he developed large right lung metastases 6 months postoperatively. CONCLUSIONS PBRMS can be hardly distinguished from other malignant brain tumors during preoperative radiologic workup; only histology can raise the suspicion of primary or metastatic rhabdomyosarcoma, depending on the presence of other distant lesions. Our review of the literature demonstrates that prognosis is poor: 44% of patients die within 1 year from diagnosis. Overall, survival seems to correlate with radical resection, tolerance of stereotactic or if necessary full neuraxis radiotherapy, and adjuvant chemotherapy. Given the high relapse rate, close monitoring and restaging are imperative.
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Affiliation(s)
| | - Mario Ganau
- Neurosurgery Department, Strasbourg University Hospital, Strasbourg, France
| | - Julien Todeschi
- Neurosurgery Department, Strasbourg University Hospital, Strasbourg, France
| | - Hélène Cebula
- Neurosurgery Department, Strasbourg University Hospital, Strasbourg, France
| | | | - Guillaume Virbel
- Radiotherapy Department, ICANS University Hospital, Strasbourg, France
| | - Raoul Pop
- Interventional Neuroradiology Unit, Strasbourg University Hospital, Strasbourg, France
| | - Benoit Lhermitte
- Neuro-histopathology Unit, Strasbourg University Hospital, Strasbourg, France
| | - Francois Proust
- Neurosurgery Department, Strasbourg University Hospital, Strasbourg, France
| | - Salvatore Chibbaro
- Neurosurgery Department, Strasbourg University Hospital, Strasbourg, France
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30
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Calandrini C, Schutgens F, Oka R, Margaritis T, Candelli T, Mathijsen L, Ammerlaan C, van Ineveld RL, Derakhshan S, de Haan S, Dolman E, Lijnzaad P, Custers L, Begthel H, Kerstens HHD, Visser LL, Rookmaaker M, Verhaar M, Tytgat GAM, Kemmeren P, de Krijger RR, Al-Saadi R, Pritchard-Jones K, Kool M, Rios AC, van den Heuvel-Eibrink MM, Molenaar JJ, van Boxtel R, Holstege FCP, Clevers H, Drost J. An organoid biobank for childhood kidney cancers that captures disease and tissue heterogeneity. Nat Commun 2020; 11:1310. [PMID: 32161258 PMCID: PMC7066173 DOI: 10.1038/s41467-020-15155-6] [Citation(s) in RCA: 190] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 02/21/2020] [Indexed: 01/02/2023] Open
Abstract
Kidney tumours are among the most common solid tumours in children, comprising distinct subtypes differing in many aspects, including cell-of-origin, genetics, and pathology. Pre-clinical cell models capturing the disease heterogeneity are currently lacking. Here, we describe the first paediatric cancer organoid biobank. It contains tumour and matching normal kidney organoids from over 50 children with different subtypes of kidney cancer, including Wilms tumours, malignant rhabdoid tumours, renal cell carcinomas, and congenital mesoblastic nephromas. Paediatric kidney tumour organoids retain key properties of native tumours, useful for revealing patient-specific drug sensitivities. Using single cell RNA-sequencing and high resolution 3D imaging, we further demonstrate that organoid cultures derived from Wilms tumours consist of multiple different cell types, including epithelial, stromal and blastemal-like cells. Our organoid biobank captures the heterogeneity of paediatric kidney tumours, providing a representative collection of well-characterised models for basic cancer research, drug-screening and personalised medicine. Pre-clinical cell culture models capturing the heterogeneity of childhood kidney tumours are limited. Here, the authors establish and characterise an organoid biobank of tumour and matched normal organoid cultures from over 50 children with different subtypes of kidney cancer.
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Affiliation(s)
- Camilla Calandrini
- Oncode Institute, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Frans Schutgens
- Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.,University Medical Center, Department of Nephrology and Hypertension, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| | - Rurika Oka
- Oncode Institute, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Thanasis Margaritis
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Tito Candelli
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Luka Mathijsen
- Oncode Institute, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Carola Ammerlaan
- Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.,University Medical Center, Department of Nephrology and Hypertension, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| | - Ravian L van Ineveld
- Oncode Institute, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Sepide Derakhshan
- Oncode Institute, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Sanne de Haan
- Oncode Institute, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Emmy Dolman
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Philip Lijnzaad
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Lars Custers
- Oncode Institute, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Harry Begthel
- Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands
| | - Hindrik H D Kerstens
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Lindy L Visser
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Maarten Rookmaaker
- University Medical Center, Department of Nephrology and Hypertension, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| | - Marianne Verhaar
- University Medical Center, Department of Nephrology and Hypertension, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| | - Godelieve A M Tytgat
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Patrick Kemmeren
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Ronald R de Krijger
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands.,University Medical Center, Department of Pathology, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| | - Reem Al-Saadi
- University College London, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK
| | - Kathy Pritchard-Jones
- University College London, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK
| | - Marcel Kool
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands.,Hopp Children's Cancer Center (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Research Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Anne C Rios
- Oncode Institute, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | | | - Jan J Molenaar
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Ruben van Boxtel
- Oncode Institute, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Frank C P Holstege
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Hans Clevers
- Oncode Institute, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands.,Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands
| | - Jarno Drost
- Oncode Institute, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands.
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31
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Fuller MY. Pediatric Renal Tumors: Diagnostic Updates. KIDNEY CANCER 2020. [DOI: 10.1007/978-3-030-28333-9_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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32
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Ciarimboli G, Theil G, Bialek J, Edemir B. Contribution and Expression of Organic Cation Transporters and Aquaporin Water Channels in Renal Cancer. Rev Physiol Biochem Pharmacol 2020; 181:81-104. [PMID: 32772272 DOI: 10.1007/112_2020_34] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The body homeostasis is maintained mainly by the function of the kidneys, which regulate salt and water balance and excretion of metabolism waste products and xenobiotics. This important renal function is determined by the action of many transport systems, which are specifically expressed in the different parts of the nephron, the functional unit of the kidneys. These transport systems are involved, for example, in the reabsorption of sodium, glucose, and other important solutes and peptides from the primary urine. They are also important in the reabsorption of water and thereby production of a concentrated urine. However, several studies have shown the importance of transport systems for different tumor entities. Transport systems, for example, contributed to the proliferation and migration of cancer cells and thereby on tumor progression. They could also serve as drug transporters that could enable drug resistance by outward transport of, for example, chemotherapeutic agents and other drugs. Although many renal transporters have been characterized in detail with respect to the significance for proper kidney function, their role in renal cancer progression is less known. Here, we describe the types of renal cancer and review the studies that analyzed the role of organic cation transporters of the SLC22-family and of the aquaporin water channel family in kidney tumors.
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Affiliation(s)
- Giuliano Ciarimboli
- Medicine Clinic D, Experimental Nephrology, University Hospital of Münster, Münster, Germany
| | - Gerit Theil
- Clinic of Urology, University Hospital, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Joanna Bialek
- Clinic of Urology, University Hospital, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Bayram Edemir
- Department of Medicine, Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
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33
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Immunohistochemical Expression of Wilms’ Tumor 1 Protein in Human Tissues: From Ontogenesis to Neoplastic Tissues. APPLIED SCIENCES-BASEL 2019. [DOI: 10.3390/app10010040] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The human Wilms’ tumor gene (WT1) was originally isolated in a Wilms’ tumor of the kidney as a tumor suppressor gene. Numerous isoforms of WT1, by combination of alternative translational start sites, alternative RNA splicing and RNA editing, have been well documented. During human ontogenesis, according to the antibodies used, anti-C or N-terminus WT1 protein, nuclear expression can be frequently obtained in numerous tissues, including metanephric and mesonephric glomeruli, and mesothelial and sub-mesothelial cells, while cytoplasmic staining is usually found in developing smooth and skeletal cells, myocardium, glial cells, neuroblasts, adrenal cortical cells and the endothelial cells of blood vessels. WT1 has been originally described as a tumor suppressor gene in renal Wilms’ tumor, but more recent studies emphasized its potential oncogenic role in several neoplasia with a variable immunostaining pattern that can be exclusively nuclear, cytoplasmic or both, according to the antibodies used (anti-C or N-terminus WT1 protein). With the present review we focus on the immunohistochemical expression of WT1 in some tumors, emphasizing its potential diagnostic role and usefulness in differential diagnosis. In addition, we analyze the WT1 protein expression profile in human embryonal/fetal tissues in order to suggest a possible role in the development of organs and tissues and to establish whether expression in some tumors replicates that observed during the development of tissues from which these tumors arise.
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Thway K, Folpe AL. Update on selected advances in the immunohistochemical and molecular genetic analysis of soft tissue tumors. Virchows Arch 2019; 476:3-15. [PMID: 31701221 DOI: 10.1007/s00428-019-02678-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 09/05/2019] [Accepted: 09/22/2019] [Indexed: 12/12/2022]
Abstract
Although traditional morphological evaluation remains the cornerstone for the diagnosis of soft tissue tumors, ancillary diagnostic modalities such as immunohistochemistry and molecular genetic analysis are of ever-increasing importance in this field. New insights into the molecular pathogenesis of soft tissue tumors, often obtained from high-throughput sequencing technologies, has enabled significant progress in the characterization and biologic stratification of mesenchymal neoplasms, expanding the spectrum of immunohistochemical tests (often aimed towards recently discovered genetic events) and molecular genetic assays (most often fluorescence in situ hybridization and reverse transcription-polymerase chain reaction). This review discusses selected novel molecular and immunohistochemical assays with diagnostic applicability in mesenchymal neoplasms, with emphasis on diagnosis, refinement of tumor classification, and treatment stratification.
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Affiliation(s)
- Khin Thway
- Sarcoma Unit, Royal Marsden Hospital, 203 Fulham Road, London, SW3 6JJ, UK
| | - Andrew L Folpe
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
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35
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Tsuzuki S, Kataoka TR, Ito H, Ueshima C, Asai S, Yokoo H, Haga H. A case of renal cell carcinoma unclassified with medullary phenotype without detectable gene deletion. Pathol Int 2019; 69:710-714. [DOI: 10.1111/pin.12858] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 08/27/2019] [Indexed: 01/16/2023]
Affiliation(s)
- Sadatoshi Tsuzuki
- Department of Diagnostic PathologyKyoto University Hospital Kyoto Japan
| | | | - Hiroaki Ito
- Department of Diagnostic PathologyKyoto University Hospital Kyoto Japan
| | - Chiyuki Ueshima
- Department of Diagnostic PathologyKyoto University Hospital Kyoto Japan
| | - Satsuki Asai
- Department of Diagnostic PathologyKyoto University Hospital Kyoto Japan
| | - Hideaki Yokoo
- Department of Human PathologyGunma University Graduate School of Medicine Gunma Japan
| | - Hironori Haga
- Department of Diagnostic PathologyKyoto University Hospital Kyoto Japan
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36
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Vokuhl C. [Rare childhood kidney tumors]. DER PATHOLOGE 2019; 40:600-608. [PMID: 31338565 DOI: 10.1007/s00292-019-0638-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Pediatric kidney tumors are rare and account for about 6% of all childhood malignancies. By far the most common tumors are nephroblastomas. This review presents rare childhood renal tumors. Mesoblastic nephroma, as tumors of the low risk group, as well as the clear-cell sarcomas of the kidney and malignant rhabdoid tumors, as tumors of the high-risk group, and the so-called anaplastic sarcomas of the kidney will be discussed.Due to the significantly divergent therapy, a correct diagnosis is important. Due to the often overlapping morphology, pathologic diagnosis is often difficult. In addition to the typical morphologic features, the specific immunohistochemical aspects as well as the known molecular changes will be presented.
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Affiliation(s)
- C Vokuhl
- Kindertumorregister der GPOH, Sektion Kinderpathologie, Institut für Pathologie, Universitätsklinikum SH, Campus Kiel, Arnold-Heller-Str. 10, Haus 4, 24105, Kiel, Deutschland.
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37
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Okumura Y, Adachi Y, Shirahase T, Nagashima Y, Tanaka Y, Taki Y, Watanabe J, Uegaki M, Sakatani T, Ikehara S. Malignant rhabdoid tumour in an adult kidney: A case report. Mol Clin Oncol 2019; 11:55-58. [PMID: 31289678 PMCID: PMC6535637 DOI: 10.3892/mco.2019.1848] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 03/20/2019] [Indexed: 12/19/2022] Open
Abstract
Malignant rhabdoid tumours (MRTs) in the kidney are rare paediatric tumours that are extremely rare in adults. We herein report the case of an adult patient with a renal MRT. A 79-year-old Japanese woman was found to have a tumour sized 63×48 mm in the left kidney, in addition to multiple metastatic bone and lymph node lesions. The needle biopsy specimen obtained from the patient's kidney revealed tumour cells with rhabdoid characteristics: The cells appeared large, round or polygonal, with eccentrically located nuclei and prominent nucleoli. Immunohistochemically, the tumour cells were positive for vimentin, epithelial membrane antigen, CAM 5.2, and p53, and negative for INI1, cytokeratin (CK)7, CK20, α-methylacyl-CoA racemase, S100, CD45, renal cell carcinoma marker, anaplastic lymphoma kinase, α-smooth muscle actin, desmin, MyoD, myogenin, human melanoma black 45 and melan A. Therefore, the tumour was diagnosed as an MRT located in the kidney. Although the patient was treated with axitinib, a tyrosine kinase inhibitor, the renal tumour and its metastatic lesions continued to progress, and the number of metastatic lesions increased. The patient succumbed to the disease 5 months after the first hospital visit. The disease progression was rapid, with a poor prognosis, consistently with previous reports that of MRTs in the adult kidney.
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Affiliation(s)
- Yoshinaga Okumura
- Department of Urology, Toyooka Hospital, Toyooka, Hyogo 668-8501, Japan
| | - Yasushi Adachi
- Department of Diagnostic Pathology, Toyooka Hospital, Toyooka, Hyogo 668-8501, Japan
| | | | - Yoji Nagashima
- Department of Surgical Pathology, Tokyo Women's Medical University, Tokyo 162-8666, Japan
| | - Yukichi Tanaka
- Clinical Research Institute and Department of Pathology, Kanagawa Children's Medical Center, Yokohama, Kanagawa 232-8555, Japan
| | - Yoji Taki
- Department of Urology, Toyooka Hospital, Toyooka, Hyogo 668-8501, Japan
| | - Jun Watanabe
- Department of Urology, Toyooka Hospital, Toyooka, Hyogo 668-8501, Japan
| | - Masayuki Uegaki
- Department of Urology, Toyooka Hospital, Toyooka, Hyogo 668-8501, Japan
| | - Toru Sakatani
- Department of Urology, Toyooka Hospital, Toyooka, Hyogo 668-8501, Japan
| | - Susumu Ikehara
- Professor Emeritus, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
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Impact of rhabdoid differentiation on postoperative outcome for patients with N0M0 renal cell carcinoma. Urol Oncol 2019; 37:711-720. [PMID: 31174957 DOI: 10.1016/j.urolonc.2019.05.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 05/01/2019] [Accepted: 05/17/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND AND OBJECTIVE We assessed the aggressiveness of localized renal cell carcinoma (N0M0 RCC) with rhabdoid differentiation (RD) after partial or radical nephrectomy. METHODS A total of 604 patients with N0M0 RCC who had undergone partial or radical nephrectomy at a single institution were included in this study. Clinicopathological and outcome data on recurrence-free survival (RFS), cancer-specific survival (CSS), and time to recurrence (TTR) were analyzed using Kaplan-Meier methods, log-rank test, univariate and multivariable Cox proportional hazard models, and concordance index. We also evaluated the RFS and CSS in a propensity score-matched cohort to reduce inherent differences. Among the 604 patients, RD was identified in RCC specimens from 24 patients. RESULTS At the median postoperative follow-up period of 53 months, 58 patients (12 with RD) showed recurrence and 26 patients (7 with RD) had died from RCC. Multivariate analyses showed that RD was an independent risk factor of RFS (hazard ratio 2.81; P = 0.0266) and CSS (hazard ratio 5.18; P = 0.00182). By RD adding to standard risk factors, the concordance indices for RFS and CSS increased 0.77 to 0.79, and 0.76 to 0.79, respectively. Subgroup analysis showed that the presence of RD in RCC specimens was more important for predicting poor RFS and CSS in the early pathological tumor category (≤pT2) subgroup compared to in the advanced tumor category (≥pT3) subgroup. Patients with RD showed a significantly shorter TTR than patients with RCC without RD (7.5 vs. 18 months: P = 0.0150). The propensity score-matched cohort included 24 patients with RD and 24 without RD, of which patients RD showed significantly shorter RFS than those without RD (P = 0.0026). CONCLUSIONS In summary, the aggressiveness of N0M0 RCC with RD increased the risk of postoperative recurrence, particularly in the early pathological stage. The short TTR also demonstrated the aggressiveness of RCC with RD.
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Papke DJ, Jo VY. Practical Application of Cytology and Core Biopsy in the Diagnosis of Mesenchymal Tumors. Surg Pathol Clin 2019; 12:227-248. [PMID: 30709446 DOI: 10.1016/j.path.2018.11.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Soft tissue neoplasms are increasingly being sampled by core needle biopsy and fine-needle aspiration (FNA), and these small biopsy specimens pose unique diagnostic challenges. Many advances in ancillary testing enable detection of characteristic immunophenotypes and molecular alterations, allowing accurate classification of soft tissue tumors in these small biopsy samples. This review outlines pattern-based diagnostic approaches to core biopsies and FNAs of soft tissue neoplasms, including formulation of practical differential diagnoses and relevant application of ancillary tests.
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Affiliation(s)
- David J Papke
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - Vickie Y Jo
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
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Uddin N, Minhas K, Abdul-Ghafar J, Ahmed A, Ahmad Z. Expression of cyclin D1 in clear cell sarcoma of kidney. Is it useful in differentiating it from its histological mimics? Diagn Pathol 2019; 14:13. [PMID: 30736802 PMCID: PMC6368701 DOI: 10.1186/s13000-019-0790-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 02/01/2019] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Clear cell sarcoma of the kidney (CCSK) is a rare malignant pediatric renal neoplasm with a heterogeneous histological appearance which often results in misdiagnosis. There are no specific immunohistochemical markers which can help in differentiating CCSK from other pediatric renal neoplasms. Recently Cyclin D1 has been investigated as a possible marker in this regard. In this study, we aim to determine the usefulness of Cyclin D1 in differentiating between CCSK and other pediatric renal neoplasms and to compare our results with those of recently published studies. METHODS A total of 48 cases of CCSK, Wilms tumor (WT), renal rhabdoid tumor, mesoblastic nephroma, renal Ewing sarcoma and neuroblastoma were included in the study. All cases were stained with cyclin D1. Extent of Cyclin D1 staining was graded according to percentage of positive tumor cells as diffuse (> 70%), focal (5 to 70%), and negative (< 5%). Intensity of Cyclin D1 staining was graded as strong or 3+, moderate or 2+ and weak or 1 + . RESULTS Most or all cases of CCSK, neuroblastoma and renal Ewing sarcoma demonstrated diffuse and strong positivity for Cyclin D1. Most cases of Wilms tumor (epithelial component) also demonstrated diffuse and often strong positivity for Cyclin D1. In most cases of WT, blastemal component was negative. CONCLUSIONS Cyclin D1 is a sensitive but not specific immunohistochemical marker for CCSK and many other pediatric renal malignant neoplasms as well as for neuroblastoma. Hence, careful examination of histological features is important in reaching an accurate diagnosis in CCSKs. However, Cyclin D1 is very helpful in distinguishing between blastema-rich WT and CCSK.
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Affiliation(s)
- Nasir Uddin
- Department of Pathology and Laboratory Medicine, Aga Khan University Hospital, Karachi, Pakistan
| | - Khurram Minhas
- Department of Pathology and Laboratory Medicine, Aga Khan University Hospital, Karachi, Pakistan
| | - Jamshid Abdul-Ghafar
- Department of Pathology and Laboratory Medicine, French Medical Institute for Mothers and Children (FMIC), Kabul, Afghanistan
| | - Arsalan Ahmed
- Department of Pathology and Laboratory Medicine, Aga Khan University Hospital, Karachi, Pakistan
| | - Zubair Ahmad
- Department of Pathology and Laboratory Medicine, Aga Khan University Hospital, Karachi, Pakistan
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Singh JA, Ohe C, Smith SC. High grade infiltrative adenocarcinomas of renal cell origin: New insights into classification, morphology, and molecular pathogenesis. Pathol Int 2018; 68:265-277. [PMID: 29665139 DOI: 10.1111/pin.12667] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Accepted: 03/02/2018] [Indexed: 12/11/2022]
Abstract
Collecting duct carcinoma was described over 30 years ago as a renal tumor, based in the medullary collecting system, with tubulopapillary morphology, prominent infiltrative growth, and stromal desmoplasia. While diagnostic workup has always emphasized exclusion of upper tract urothelial carcinoma and metastatic adenocarcinoma to the kidney, the molecular era of renal cell carcinoma classification has enabled recognition of and provided tools for diagnosis of new entities in this morphologic differential. In this review, we consider these developments, with emphasis on renal medullary carcinoma, closely related renal cell carcinoma, unclassified with medullary phenotype, and fumarate hydratase-deficient renal cell carcinoma. Integration of ancillary studies with suggestive patterns of morphology is emphasized for practical implementation in contemporary diagnosis, and several emerging tumor types in the morphologic differential are presented.
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Affiliation(s)
- Jaime A Singh
- Department of Pathology, VCU School of Medicine, Richmond, VA, USA
| | - Chisato Ohe
- Department of Pathology and Laboratory Medicine, Kansai Medical University, Osaka, Japan
| | - Steven Christopher Smith
- Department of Pathology, VCU School of Medicine, Richmond, VA, USA.,Division of Urology, Department of Surgery, VCU School of Medicine, Richmond, VA, USA
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42
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McBride MJ, Kadoch C. Disruption of mammalian SWI/SNF and polycomb complexes in human sarcomas: mechanisms and therapeutic opportunities. J Pathol 2018; 244:638-649. [PMID: 29359803 DOI: 10.1002/path.5042] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 01/11/2018] [Accepted: 01/12/2018] [Indexed: 01/01/2023]
Abstract
Soft-tissue sarcomas are increasingly characterized and subclassified by genetic abnormalities that represent underlying drivers of their pathology. Hallmark tumor suppressor gene mutations and pathognomonic gene fusions collectively account for approximately one-third of all sarcomas. These genetic abnormalities most often result in global transcriptional misregulation via disruption of protein regulatory complexes which govern chromatin architecture. Specifically, alterations to mammalian SWI/SNF (mSWI/SNF or BAF) ATP-dependent chromatin remodeling complexes and polycomb repressive complexes cause disease-specific changes in chromatin architecture and gene expression across a number of sarcoma subtypes. Understanding the functions of chromatin regulatory complexes and the mechanisms underpinning their roles in oncogenesis will be required for the design and development of new therapeutic strategies in sarcomas. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Matthew J McBride
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Chemical Biology Program, Harvard University, Cambridge, MA, USA
| | - Cigall Kadoch
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, USA
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43
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Lorzadeh A, Bilenky M, Hammond C, Knapp DJHF, Li L, Miller PH, Carles A, Heravi-Moussavi A, Gakkhar S, Moksa M, Eaves CJ, Hirst M. Nucleosome Density ChIP-Seq Identifies Distinct Chromatin Modification Signatures Associated with MNase Accessibility. Cell Rep 2017; 17:2112-2124. [PMID: 27851972 DOI: 10.1016/j.celrep.2016.10.055] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 07/05/2016] [Accepted: 09/12/2016] [Indexed: 12/22/2022] Open
Abstract
Nucleosome position, density, and post-translational modification are widely accepted components of mechanisms regulating DNA transcription but still incompletely understood. We present a modified native ChIP-seq method combined with an analytical framework that allows MNase accessibility to be integrated with histone modification profiles. Application of this methodology to the primitive (CD34+) subset of normal human cord blood cells enabled genomic regions enriched in one versus two nucleosomes marked by histone 3 lysine 4 trimethylation (H3K4me3) and/or histone 3 lysine 27 trimethylation (H3K27me3) to be associated with their transcriptional and DNA methylation states. From this analysis, we defined four classes of promoter-specific profiles and demonstrated that a majority of bivalent marked promoters are heterogeneously marked at a single-cell level in this primitive cell type. Interestingly, extension of this approach to human embryonic stem cells revealed an altered relationship between chromatin modification state and nucleosome content at promoters, suggesting developmental stage-specific organization of histone methylation states.
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Affiliation(s)
- Alireza Lorzadeh
- Department of Microbiology and Immunology, Michael Smith Laboratories Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Misha Bilenky
- Canada's Michael Smith Genome Science Center, BC Cancer Agency Vancouver, BC V5Z 4S6, Canada
| | - Colin Hammond
- Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - David J H F Knapp
- Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Luolan Li
- Department of Microbiology and Immunology, Michael Smith Laboratories Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Paul H Miller
- Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Annaick Carles
- Department of Microbiology and Immunology, Michael Smith Laboratories Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Alireza Heravi-Moussavi
- Canada's Michael Smith Genome Science Center, BC Cancer Agency Vancouver, BC V5Z 4S6, Canada
| | - Sitanshu Gakkhar
- Canada's Michael Smith Genome Science Center, BC Cancer Agency Vancouver, BC V5Z 4S6, Canada
| | - Michelle Moksa
- Department of Microbiology and Immunology, Michael Smith Laboratories Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Connie J Eaves
- Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada
| | - Martin Hirst
- Department of Microbiology and Immunology, Michael Smith Laboratories Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Canada's Michael Smith Genome Science Center, BC Cancer Agency Vancouver, BC V5Z 4S6, Canada.
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Sirohi D, Smith SC, Ohe C, Colombo P, Divatia M, Dragoescu E, Rao P, Hirsch MS, Chen YB, Mehra R, Amin MB. Renal cell carcinoma, unclassified with medullary phenotype: poorly differentiated adenocarcinomas overlapping with renal medullary carcinoma. Hum Pathol 2017; 67:134-145. [DOI: 10.1016/j.humpath.2017.07.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 06/22/2017] [Accepted: 07/05/2017] [Indexed: 10/19/2022]
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Chung CT, Liu YL, Cheng CJ, Hsieh KLC, Tsai ML, Wong TT. Extrarenal rhabdoid tumor presented with an immobile arm in a one-year-old boy. Brain Dev 2017; 39:717-721. [PMID: 28434767 DOI: 10.1016/j.braindev.2017.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2016] [Revised: 03/30/2017] [Accepted: 04/03/2017] [Indexed: 10/19/2022]
Abstract
Infants with an immobile arm may be easily overlooked in primary care settings. Differential diagnoses include injuries, infections, neuropathies, ischemia and rarely, neoplasms. We report the case of a one-year-old boy with weakness in his left arm after minor trauma with a diagnosis of brachial plexus palsy initially. After rehabilitation for 2months, his weakness progressed to unsteady gait and quadriparesis. MRI revealed a huge solid tumor in the left supraclavicular fossa, which also involved the left brachial plexus, upper thoracic cavity, and left paravertebral space with invasion into the spinal canal. Microscopically, the medium-large polygonal tumor cells had an eccentric eosinophilic cytoplasm and immunostaining showed a loss of nuclear INI1 expression. Array comparative genomic hybridization of the tumor tissue confirmed a segmental deletion at chromosome region 22q11.23 involving the SMARCB1 gene. The final diagnosis was cervical paravertebral malignant rhabdoid tumor with intraspinal epidural and intradural invasion, a rare case of extrarenal extracranial rhabdoid tumor (ERRT). The intraspinal part of the tumor was resected followed by interval-compressed chemotherapy with vincristine-doxorubicin-cyclophosphamide alternating with ifosfamide-etoposide (VDC/IE). The tumor showed very good partial response to four cycles of chemotherapy with gradual recovery of neurological symptoms. ERRT is a very rare and aggressive tumor that mainly occurs in infants and children and may manifest with vague neurological symptoms when it involves the spinal cord and/or peripheral nerves. A neoplasm such as ERRT originating from or involving the brachial plexus should be considered in the differential diagnosis of an immobile arm in infancy.
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Affiliation(s)
- Chi-Ting Chung
- School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Medical Education, Taipei Medical University Hospital, Taipei, Taiwan
| | - Yen-Lin Liu
- School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Pediatrics, Taipei Medical University Hospital, Taipei, Taiwan; Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
| | - Chien-Jui Cheng
- Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan; Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Kevin Li-Chun Hsieh
- Department of Medical Imaging, Taipei Medical University Hospital, Taipei, Taiwan; Research Center of Translational Imaging, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Min-Lan Tsai
- School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Pediatrics, Taipei Medical University Hospital, Taipei, Taiwan.
| | - Tai-Tong Wong
- Division of Pediatric Neurosurgery, Department of Neurosurgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
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46
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Cha YJ, Hong CK, Kim DS, Lee SK, Park HJ, Kim SH. Poorly differentiated chordoma with loss of SMARCB1/INI1 expression in pediatric patients: A report of two cases and review of the literature. Neuropathology 2017; 38:47-53. [DOI: 10.1111/neup.12407] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 07/12/2017] [Accepted: 07/12/2017] [Indexed: 11/29/2022]
Affiliation(s)
- Yoon Jin Cha
- Department of Pathology; Gangnam Severance Hospital, Yonsei University College of Medicine; Seoul South Korea
| | - Chang-Ki Hong
- Department of Neurosurgery; Gangnam Severance Hospital, Yonsei University College of Medicine; Seoul South Korea
| | - Dong-Seok Kim
- Department of Pediatric Neurosurgery; Severance Children's Hospital, Yonsei University College of Medicine; Seoul South Korea
| | - Seung-Koo Lee
- Department of Radiology; Severance Hospital, Yonsei University College of Medicine; Seoul South Korea
| | - Hyeon Jin Park
- Center for Pediatric Cancer; National Cancer Center; Goyang South Korea
| | - Se Hoon Kim
- Department of Pathology; Severance Hospital, Yonsei University College of Medicine; Seoul South Korea
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47
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Mitrofanova AM, Roshchin VY, Kislyakov AN, Abramov DS, Rogozhin DV, Konovalov DM. [Extrarenal rhabdoid tumor: A review of literature and a report of cases with atypical morphology]. Arkh Patol 2017. [PMID: 28631714 DOI: 10.17116/patol201779334-41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Extrarenal extracranial rhabdoid tumor (EERT) is a rare malignant pediatric tumor characterized by extremely aggressive behavior, rapid metastatic spread, low survival rates, and no targeted therapy. The morphological diagnosis of classical cases of EERT is not difficult and it is based on its characteristic histologic pattern and immunohistochemical findings in a relatively short time, which allows one to immediately initiate therapy. The paper describes two cases of ERRT in the complete absence of classical rhabdoid morphology, as revealed by light microscopy when the material was primarily assessed. The final diagnostic search could establish a diagnosis of EERT in both cases on the basis of immunohistochemical findings.
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Affiliation(s)
- A M Mitrofanova
- Dmitry Rogachev Federal Research Clinical Center of Pediatric Hematology, Oncology, and Immunology, Moscow, Russia
| | - V Yu Roshchin
- Dmitry Rogachev Federal Research Clinical Center of Pediatric Hematology, Oncology, and Immunology, Moscow, Russia
| | - A N Kislyakov
- Dmitry Rogachev Federal Research Clinical Center of Pediatric Hematology, Oncology, and Immunology, Moscow, Russia
| | - D S Abramov
- Dmitry Rogachev Federal Research Clinical Center of Pediatric Hematology, Oncology, and Immunology, Moscow, Russia
| | | | - D M Konovalov
- Dmitry Rogachev Federal Research Clinical Center of Pediatric Hematology, Oncology, and Immunology, Moscow, Russia; Department of Pathological Anatomy, Russian Medical Academy of Postgraduate Education, Moscow, Russia
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Caltabiano R, Magro G, Polizzi A, Praticò AD, Ortensi A, D'Orazi V, Panunzi A, Milone P, Maiolino L, Nicita F, Capone GL, Sestini R, Paganini I, Muglia M, Cavallaro S, Lanzafame S, Papi L, Ruggieri M. A mosaic pattern of INI1/SMARCB1 protein expression distinguishes Schwannomatosis and NF2-associated peripheral schwannomas from solitary peripheral schwannomas and NF2-associated vestibular schwannomas. Childs Nerv Syst 2017; 33:933-940. [PMID: 28365909 DOI: 10.1007/s00381-017-3340-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 01/05/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND The INI1/SMARCB1 gene protein product has been implicated in the direct pathogenesis of schwannomas from patients with one form of schwannomatosis [SWNTS1; MIM # 162091] showing a mosaic pattern of loss of protein expression by immunohistochemistry [93% in familial vs. 55% in sporadic cases]. AIM OF STUDY To verify whether such INI1/SMARCB1 mosaic pattern could be extended to all schwannomas arising in the sporadic and familial schwannomatoses [i.e. to SMARCB1-related (SWNTS1) or LZTR1-related (SWNTS2) schwannomatosis or to SMARCB1/LZTR1-negative schwannomatosis] and whether it could be involved in classical NF2 or solitary peripheral schwannomas METHODS: We blindly analysed schwannoma samples obtained from a total of 22 patients including (a) 2 patients (2 males; aged 38 and 55 years) affected by non-familial SMARCB1-associated schwannomatosis (SWTNS1); (b) 1 patient (1 female; aged 33 years) affected by familial schwannomatosis (SWTNS1/ SMARCB1 germ line mutations); (c) 5 patients (3 males, 2 females; aged 33 to 35 years) affected by non-familial (sporadic) LZTR1-associated schwannomatosis (SWNTS2); (d) 3 patients (3 males; aged 35 to 47 years) affected by familial schwannomatosis (SWTNS2/ LZTR1 germ line mutations); (e) 2 patients (1 male, 1 female; aged 63 and 49 years, respectively) affected by non-familial schwannomatosis (SWTNS, negative for SMARCB1, LZTR1 and NF2 gene mutations); (f) 4 patients (3 males, 1 females; aged 15 to 24 years) affected by classical NF2 (NF2: harbouring NF2 germ line mutations; and (g) 5 patients (3 males, 2 females; aged 33 to 68 years) who had solitary schwannomas. [follow-up = 15-30 years; negative for constitutional/somatic mutation analysis for the SMARCB1, LZTR1 and NF2 genes] were (blindly) analyzed. The INI1/SMARCB1 immunostaining pattern was regarded as (1) diffuse positive nuclear staining [= retained expression] or (2) mosaic pattern [mixed positive/negative nuclei = loss of expression in a subset of tumour cells]. RESULTS All solitary peripheral schwannomas and NF2-associated vestibular schwannomas showed diffuse nuclear INI1/SMARCB1 staining in 97-100% of neoplastic cells; schwannomas obtained from all cases of non-familial and familial schwannomatosis and NF2-associated non-vestibular schwannomas showed a mosaic pattern ranging from 10 to 70% of INI1/SMARCB1-positive expression. We did not record a complete lack of nuclear staining. CONCLUSIONS The present data suggests that (a) mosaic loss of immunohistochemical INI1/SMARCB1 expression, despite the interlesional variability, is a reliable marker of schwannomatosis regardless of the involved gene and it might help in the differential diagnosis of schwannomatosis vs. solitary schwannomas and (b) INI1/SMARCB1 expression is not useful in the differential with mosaic NF2, since NF2-associated peripheral schwannomas show the same immunohistochemical pattern.
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Affiliation(s)
- Rosario Caltabiano
- Department of Medical and Surgical Sciences and Advanced Technologies "G. F. Ingrassia", Section of Anatomic Pathology, University of Catania, Catania, Italy
| | - Gaetano Magro
- Department of Medical and Surgical Sciences and Advanced Technologies "G. F. Ingrassia", Section of Anatomic Pathology, University of Catania, Catania, Italy
| | - Agata Polizzi
- National Centre for Rare Diseases, Istituto Superiore di Sanità, Rome, Italy
- Institute of Neurological Sciences, National Research Council, Catania, Italy
| | - Andrea Domenico Praticò
- Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, AOU "Policlinico-Vittorio Emanuele", Via S. Sofia, 78, 95124, Catania, Italy
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Andrea Ortensi
- Unit of General Microsurgery and Hand Surgery, University of Rome "La Sapienza" and Hospital "Fabia Mater", Rome, Italy
| | - Valerio D'Orazi
- Unit of General Microsurgery and Hand Surgery, University of Rome "La Sapienza" and Hospital "Fabia Mater", Rome, Italy
| | - Andrea Panunzi
- Unit of General Microsurgery and Hand Surgery, University of Rome "La Sapienza" and Hospital "Fabia Mater", Rome, Italy
| | - Pietro Milone
- Department of Medical and Surgical Sciences and Advanced Technologies "G. Ingrassia", Section of Radiology, University of Catania, Catania, Italy
| | - Luigi Maiolino
- Department of Medical and Surgical Sciences and Advanced Technologies "G. Ingrassia", Section of Otolaryngology, University of Catania, Catania, Italy
| | - Francesco Nicita
- Department of Paediatrics and Child Neuropsychiatry, Section of Paediatric Neurology, Sapienza University of Rome, Rome, Italy
| | - Gabriele Lorenzo Capone
- Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", Section of Medical Genetics, University of Florence, Florence, Italy
| | - Roberta Sestini
- Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", Section of Medical Genetics, University of Florence, Florence, Italy
| | - Irene Paganini
- Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", Section of Medical Genetics, University of Florence, Florence, Italy
| | - Mariella Muglia
- 11 Unit of Molecular Genetics, Institute of Neurological Sciences, National Research Council, Cosenza, Italy
| | - Sebastiano Cavallaro
- 11 Unit of Molecular Genetics, Institute of Neurological Sciences, National Research Council, Cosenza, Italy
| | - Salvatore Lanzafame
- Department of Medical and Surgical Sciences and Advanced Technologies "G. F. Ingrassia", Section of Anatomic Pathology, University of Catania, Catania, Italy
| | - Laura Papi
- Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", Section of Medical Genetics, University of Florence, Florence, Italy
| | - Martino Ruggieri
- Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, AOU "Policlinico-Vittorio Emanuele", Via S. Sofia, 78, 95124, Catania, Italy.
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Guilmette J, Laverdière C, Soulières D, Patey N, Soucy G, Trudel D, Bouron-Dal Soglio D. Malignant Rhabdoid Tumor of Soft Tissue. Pediatr Dev Pathol 2017; 20:262-266. [PMID: 28429647 DOI: 10.1177/1093526617706814] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Introduction Malignant rhabdoid tumor (MRT) is defined as a high-grade sarcoma derived from an uncertain cell of origin. Its diagnosis is associated with poor prognosis and patient's life expectancy is greatly reduced. Material and method Here, we describe a unique case of 9-month-old boy who presented with a large MRT arising from the soft tissue of the neck. Following intensive multimodal treatment, the patient benefited from a 25 years' remission until the discovery of multiple liver metastases. Conclusion MRT of soft tissue needs to be distinguished from other soft tissue neoplasms, as MRT is highly aggressive and is usually associated with a poor outcome. In addition, this is the longest remission time reported in a patient with soft tissue MRT and this might be related to the use of early intensive multimodal treatments.
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Affiliation(s)
- Julie Guilmette
- 1 Department of Anatomo-Pathology, University of Montreal Heath Care Center, Montreal, Quebec, Canada
| | - Caroline Laverdière
- 2 Hematology-Oncology Division, Department of Pediatrics, Ste-Justine Hospital, Montreal, Quebec, Canada
| | - Denis Soulières
- 3 Department of Hematoly-Oncology, Notre-Dame Hospital, Montreal, Quebec, Canada
| | - Natasha Patey
- 4 Department of Pathology, Ste-Justine Hospital, Montreal, Quebec, Canada
| | - Geneviève Soucy
- 1 Department of Anatomo-Pathology, University of Montreal Heath Care Center, Montreal, Quebec, Canada
| | - Dominique Trudel
- 1 Department of Anatomo-Pathology, University of Montreal Heath Care Center, Montreal, Quebec, Canada
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The Expression of Cyclin D1, VEGF, EZH2, and H3K27me3 in Atypical Teratoid/Rhabdoid Tumors of the CNS: A Possible Role in Targeted Therapy. Appl Immunohistochem Mol Morphol 2017; 24:729-737. [PMID: 26469332 DOI: 10.1097/pai.0000000000000247] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Atypical teratoid/rhabdoid tumor (AT/RT) is an uncommon malignancy with a dismal outcome, which responds poorly to multimodality therapies. Animal studies have revealed Cyclin D1 as a possible therapeutic target. The addition of vascular endothelial growth factor (VEGF) inhibitors to chemotherapeutic regimens has shown promising results in pediatric central nervous system tumors. Enhancer of Zeste homolog 2 (EZH2) overexpression has been implicated in various cancers, including medulloblastomas. H3K27me3 is a new marker for pediatric high-grade gliomas. However, their role in AT/RT has not been evaluated sufficiently. We retrieved cases of AT/RT, and reviewed their clinical data and histopathologic features. Immunohistochemistry for Cyclin D1, VEGF, EZH2, and H3K27me3 was performed. Follow-up was noted when available. Fourteen cases of AT/RT were identified (mean age, 3.4 y; range, 10 mo to 8 y). Cyclin D1 immunopositivity was noted in all cases [labeling index (LI): 5% to 98%; mean, 41.3%]. VEGF positivity was seen in 83.3% of the cases. All cases showed EZH2 overexpression (mean LI, 74.3%; range, 32% to 96%). Reduction of H3K27me3 expression was noted in 63% of the cases, with no correlation with EZH2 LI. Two patients died of postoperative complications. Of the rest, follow-up was available for 7 (range, 7 to 120 wk): 1 achieved clinical remission, whereas 6 developed progressive disease, including 3 deaths. Varying degrees of immunoreactivity to Cyclin D1, VEGF, and EZH2 were noted in the majority of the AT/RTs, and detection of these markers may be of value in the development of novel therapeutic agents and in determining which patients can benefit from them. AT/RTs show reduction in H3K27me3 expression, independent of EZH2 expression, indicating that their interaction requires further evaluation.
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