Immunohistochemical expression of CRX in extracranial malignant small round cell tumors.

Department of Pathology, Children's Hospital Boston, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
The American journal of surgical pathology (Impact Factor: 4.59). 08/2012; 36(8):1165-9. DOI: 10.1097/PAS.0b013e3182601d84
Source: PubMed

ABSTRACT Tumor-specific immunohistochemical markers are valuable in the differential diagnosis of malignant small round cell tumors (MSRCTs). The cone-rod homeobox-containing gene (CRX) is a transcription factor that is preferentially expressed in retinal photoreceptor cells. It has been shown that the CRX antibody is a good immunohistochemical marker to differentiate retinoblastoma from other intracranial MSRCTs. Outside of the central nervous system, however, the usefulness of CRX immunohistochemistry in establishing a diagnosis of metastatic retinoblastoma is uncertain, as the expression of CRX in primitive neuroectodermal tumor/Ewing sarcoma (PNET/ES), neuroblastoma, and other MSRCTs is unknown. Archival specimens from resections, core biopsies, and bone marrow biopsies of 41 neuroblastomas, 24 PNET/ES, 19 embryonal rhabdomyosarcomas, 17 alveolar rhabdomyosarcomas, 17 Wilms tumors, 14 desmoplastic small round cell tumors, 20 medulloblastomas, 9 pineal tumors, 17 melanocytic tumors (compound and Spitz nevi), and 8 retinoblastomas were immunostained for CRX. All retinoblastomas had strong diffuse nuclear immunoreactivity for CRX; 8 of the 20 medulloblastomas showed strong nuclear immunoreactivity either in occasional clusters of tumor cells or in rare single scattered tumor cells; 3 of the 9 pineal tumors showed strong nuclear immunoreactivity in approximately 40% to 50% of the tumor cells. Neuroblastomas, PNET/ES, embryonal rhabdomyosarcomas, alveolar rhabdomyosarcomas, Wilms tumors, desmoplastic small round cell tumors, and melanocytic tumors were all negative. Scant nonspecific cytoplasmic staining was observed in some tumors, mostly PNET/ES. These findings suggest that CRX is a useful marker to discriminate metastatic retinoblastoma from other, more common, MSRCTs of childhood.

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    ABSTRACT: PURPOSE: To define the maturational sequence of 3 infantile intraocular medulloepitheliomas. DESIGN: Retrospective clinicohistopathologic and immunohistochemical study. METHODS: Immunoreactivity of paraffin sections for CRX (cone-rod homebox transcription factor) and NeuN (biomarker for neuronal differentiation) were investigated together with other biomarkers, including S100, glial fibrillary acidic protein, epithelial membrane antigen, and various cytokeratins. RESULTS: Three infants (aged 1, 6, and 8 months) had iris neovascularization, 2 had anterior ciliary body tumors, and 1 a posterior tumor associated with a retinochoroidal coloboma. Each tumor displayed a premedullary monolayer of cuboidal epithelium that was S100(+), NeuN(-), and CRX- and that transitioned into a multilaminar medullary epithelium forming neurotubules with adluminal cells that were CRX+. NeuN first appeared in ablumenal neurotubular cells in 1 tumor and was also discovered among neuroblast-appearing cells in another. The third tumor associated with a coloboma was CRX- and NeuN(-). CONCLUSIONS: A simple premedullary epithelial monolayer appears to be the fundamental source for the tumor and its multilaminar medullary epithelium. CRX+ and NeuN(+) cells within the multilayered medullary layer approximate expression patterns similar to those found in retinal development and differentiation. Discovery of these biomarkers in the neoplastic ciliary epithelium in a small number of tumors indicates preliminarily that the most anterior layers of the optic cup have a retained retinal and neuroglial differentiation potentiality. The third case was CRX- and NeuN(-) and possibly arose from embryonic pigment epithelium at the edge of the retinochoroidal coloboma. These immunohistochemical findings offer histogenetic and potential diagnostic insights.
    American Journal of Ophthalmology 08/2014; 158(6). DOI:10.1016/j.ajo.2014.08.036 · 4.02 Impact Factor
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    ABSTRACT: microRNAs are small non-coding RNAs of ~22 nucleotides that function at post-transcriptional level as negative regulators of gene expression. Aberrant expression of microRNAs could promote uncontrolled proliferation, migration and invasion of human cancer cells. In this study, we analyzed the expression of microRNA-18b (miR-18b) in breast cancer cell lines and in a set of clinical specimens. Our results showed that miR-18b was upregulated in four out of five breast cancer cell lines and also in breast tumors. In order to identify potential gene targets, we carried out transcriptional profiling of MDA-MB-231 breast cancer cells that ectopically expressed miR-18b. Our results showed that 263 genes were significantly modulated in miR-18b-deficient cells (fold change >1.5; P≤0.05). We found that knock-down of miR-18b induced the upregulation of 55 olfactory receptor (OR) genes and nine genes (NLRP7, KLK3, OLFM3, POSTN, MAGED4B, KIR3DL3, CRX, SEMG1 and CEACAM5) with key roles in cell migration and metastasis. Consistently, we found that ectopic inhibition of miR-18b suppressed the migration of two breast cancer cell models in vitro. In conclusion, we have uncovered genes directly or indirectly modulated by miR-18b which may represent potential therapeutic targets in breast cancer. Our data also pointed out a role of miR-18b in migration of breast cancer cells.
    Oncology Reports 08/2013; 30(5). DOI:10.3892/or.2013.2691 · 2.19 Impact Factor
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    ABSTRACT: Background The tumor suppressor protein p16INK4a has been extensively studied in many tumors with very different results, ranging from its loss to its clear overexpression, which may be associated with degree of tumor differentiation and prognosis. However, its expression remains unclear in human retinoblastoma (RB), a common malignant tumor of retina in childhood. The aim of this study was to explore the expression pattern of p16INK4a in RB, and the correlation between p16INK4a expression and histopathological features of RB.Methods Sixty-five cases of RB were retrospectively analyzed. Paraffin-embedded blocks were retrieved from the archives of ocular pathology department at Zhongshan Ophthalmic Center of Sun Yat-sen University, China. Serial sections were cut and subjected to hematoxylin and eosin staining. Immunohistochemical staining was further done with antibodies p16INK4a, CRX and Ki67. The correlation of p16 INK4a expression with CRX and Ki67 and clinicopathological features of RB were analyzed.ResultsRB tumor histologically consists of various differentiation components including undifferentiated (UD) cells, Homer-Wright rosettes (HWR) or Flexner-Winterstein rosettes (FWR) and fleurettes characteristic of photoreceptor differentiation or Retinocytoma (RC). p16INK4a expression was negative in both fleurette region and the residual retinal tissue adjacent to the tumor, weakly to moderately positive in FWR, strongly positive in both HWR and UD region. However, CRX had the reverse expression patterns in comparison with p16INK4a. It was strongly positive in photoreceptor cells within the residual retina and fleurettes, but weakly to moderately positive in UD area. Together with Ki67 staining, high p16INK4a expression was associated with poor histological differentiation of RB tumors, which had higher risk features with the optic nerve invasion and uveal invasion.Conclusionsp16INK4a expression increased with the decreasing level of cell differentiation of RBs. RB tumors extensively expressing p16INK4a tended to have higher risk features with poor prognosis. This study suggested that p16INK4a would be a valuable molecular marker of RB to distinguish its histological phenotypes and to serve as a predictor of its prognosis.Virtual SlidesThe virtual slide(s) for this article can be found here:
    Diagnostic Pathology 12/2014; 9(1):180. DOI:10.1186/s13000-014-0180-1 · 2.41 Impact Factor