Immunohistochemical Expression of Embryonic Stem Cell Markers in Malignant Rhabdoid Tumors

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Pediatric and Developmental Pathology (Impact Factor: 0.87). 03/2011; 14(5):353-9. DOI: 10.2350/10-09-0902-OA.1
Source: PubMed


Malignant rhabdoid tumor is a highly aggressive pediatric neoplasm molecularly characterized by inactivating mutations of the SMARCB1 gene, a potent tumor suppressor and member of the SWI/SNF chromatin remodeling complex. It has been suggested that oncogenesis in SMARCB1-deficient cancers, such as malignant rhabdoid tumors, is driven not by the loss of SWI/SNF function but by an aberrant functioning of the BRG1-containing SWI/SNF complex. Since Brg1 is required for self-renewal and pluripotency of mouse embryonic stem cells, we hypothesized that the human malignant rhabdoid tumors may express pluripotency genes such as SALL4 , LIN28 , OCT3 and OCT4 (OCT3/4) , NANOG , and TCL1 . To test this hypothesis, we studied the immunohistochemical expression of SALL4, LIN28, OCT3/4, NANOG, and TCL1 in 11 malignant rhabdoid tumors of the central nervous system (atypical teratoid/rhabdoid tumors) and 5 malignant rhabdoid tumors of the kidney. Of the 16 malignant rhabdoid tumors, 14 (88%) tumors showed robust SALL4 and/or LIN28 expression. No tumor showed any significant OCT3/4, NANOG, or TCL1 expression. Our results suggest that malignant rhabdoid tumors may arise from and/or share features with embryonic stem cells or germ cells.

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    • "Notably, although we observed cytoplasmic LIN28 expression uniformly (100 %) in C19MC amplified CNS-PNETs, our analyses also revealed cytoplasmic as well as nuclear LIN28 staining in a subset of MBs, ATRTs, EPNs and HGGs but not CPCs. Similar to prior reports of cytoplasmic LIN28 staining in 20–60 % of pediatric and adult gliomas [15] and 64 % of ATRTs [3], we observed strong LIN28 cytoplasmic staining in up to 20–25 % of ATRTs and HGGs analyzed (Supplemental Tables 1, 3), which contrasts with a report of cytoplasmic LIN28 immunostaining exclusively in ETANTRs [11]. The reason underlying these discrepant observations is unclear and may be related to the limitations of tissue microarray analyses to comprehensively capture tumor heterogeneity. "
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    ABSTRACT: Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity. Electronic supplementary material The online version of this article (doi:10.1007/s00401-014-1291-1) contains supplementary material, which is available to authorized users.
    Full-text · Article · May 2014 · Acta Neuropathologica
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    • "SALL4 is important for the stem cell renewal and forms a regulatory circuit with OCT4, NANOG, and SOX2 to maintain embryonic stem cell pluripotency [13]. In addition to germ cell tumors, SALL4 has been shown to be expressed in somatic malignancy including lung [14], breast [9], leukemia [15] malignant rhabdoid tumor [16], and Wilm's tumor [17]. SALL4 appears to involve the proliferation and the self-renewal of cancer cells [10, 14]. "
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    ABSTRACT: Malignant mixed Mullerian tumor (MMMT) is an uncommon aggressive neoplasm composed of both malignant epithelial and mesenchymal components. In this study, immunohistochemical stains of germ cell markers, including SALL4, OCT3/4, glypican-3, and alpha-fetal protein (AFP), and CDX2 were performed in a series of MMMTs. SALL4 nuclear immunoreactivity was detected in 6 out of 19 cases (33%). The staining extent ranged from focal to extensive. The staining intensity was usually intermediate to strong (the score ranged from 1.5 to 3, and average score was 2.3 ± 0.5 in the positive cases). In addition, glypican-3 cytoplasmic reactivity was detected in 14 out of 16 cases (88%) with a mean score of 1.8 ± 0.7 (score ranging from 1 to 3). In contrast, OCT3/4 was only positive in 1 out of 19 cases and AFP in 2 out of 18 cases (11%). In summary, SALL4 and glypican-3 were frequently expressed in a subset of MMMTs. Their roles in the pathogenesis and biology of MMMT are yet to be determined. MMMT should be included in the differential diagnosis when a tumor is positive for SALL4 and/or glypican-3.
    Full-text · Article · Jul 2012 · Pathology Research International
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    ABSTRACT: Ushiku T, Shinozaki-Ushiku A, Maeda D, Morita S & Fukayama M (2012) Histopathology Distinct expression pattern of claudin-6, a primitive phenotypic tight junction molecule, in germ cell tumours and visceral carcinomas Aims: This study aimed to clarify claudin-6 expression patterns in cancers. Methods and results: We surveyed claudin-6 expression by immunohistochemistry using tissue microarray in 860 tumours, including germ cell tumours and major carcinomas. Claudin-6 was expressed consistently in germ cell tumours (28 of 28, 100%), whereas only 64 (8%) of 832 non-germ cell tumours demonstrated claudin-6 expression. Further immunohistochemical study in full tissue sections demonstrated diffuse claudin-6 staining in all seminomas (n = 14), embryonal carcinomas (n = 10), yolk sac tumours (n = 12) and mononuclear trophoblastic cells of choriocarcinomas (n = 3), and focal staining in immature epithelial components of immature teratomas (n = 6). Additionally, because alpha-fetoprotein (AFP)-producing gastric adenocarcinomas and pulmonary high-grade fetal adenocarcinomas were among the claudin-6 expressing non-germ cell tumours in the microarray studies, we predicted that claudin-6 may be a biomarker for them and studied additional tumours in full sections, which showed claudin-6 expression in AFP-producing gastric adenocarcinomas (18 of 20, 90%) and pulmonary high-grade fetal adenocarcinomas (four of five, 80%). Only one of 11 hepatoblastomas demonstrated focal claudin-6 staining. Conclusions: This study demonstrated that claudin-6 is a novel diagnostic marker for primitive germ cell tumours and is also expressed frequently in some cancers with a primitive phenotype.
    No preview · Article · Apr 2012 · Histopathology
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