Article

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

ABSTRACT

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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