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      Ovarian Cyst Fluid of Serous Ovarian Tumors Contains Large Quantities of the Brain Amino Acid N-acetylaspartate

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          Abstract

          Background

          In humans, N-acetyl L-aspartate (NAA) has not been detected in other tissues than the brain. The physiological function of NAA is yet undefined. Recently, it has been suggested that NAA may function as a molecular water pump, responsible for the removal of large amounts of water from the human brain. Ovarian tumors typically present as large cystic masses with considerable fluid accumulation.

          Methodology and Principal Findings

          Using Gas Chromatography-Mass Spectrometry, we demonstrated that NAA was present in a high micromolar concentration in oCF of epithelial ovarian tumors (EOTs) of serous histology, sometimes in the same range as found in the extracellular space of the human brain. In contrast, oCF of EOTs with a mucinous, endometrioid and clear cell histological subtype contained a low micromolar concentration of NAA. Serous EOTs have a cellular differentiation pattern which resembles the lining of the fallopian tube and differs from the other histological subtypes. The NAA concentration in two samples of fluid accumulation in the fallopian tube (hydrosalpinx) was in the same ranges as NAA found in oCF of serous EOTs. The NAA concentration in oCF of patients with serous EOTs was mostly 10 to 50 fold higher than their normal serum NAA concentration, whereas in patients with other EOT subtypes, serum and cyst fluid NAA concentration was comparable.

          Conclusions and Significance

          The high concentration of NAA in cyst fluid of serous EOTs and low serum concentrations of NAA in these patients, suggest a local production of NAA in serous EOTs. Our findings provide the first identification of NAA concentrations high enough to suggest local production outside the human brain. Our findings contribute to the ongoing research understanding the physiological function of NAA in the human body.

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          Most cited references19

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          The cell of origin of ovarian epithelial tumours.

          Although it is widely believed that ovarian epithelial tumours arise in the coelomic epithelium that covers the ovarian surface, it has been suggested that they could instead arise from tissues that are embryologically derived from the Müllerian ducts. This article revisits this debate by discussing recent epidemiological and molecular biological findings as well as evidence based on histopathological observations of surgical specimens from individuals with familial ovarian cancer predisposition. Morphological, embryological, and molecular biological characteristics of ovarian epithelial tumours that must be accounted for in formulating a theory about their cell of origin are reviewed, followed by comments about the ability of these two hypotheses to account for each of these characteristics. An argument is made that primary ovarian epithelial tumours, fallopian tube carcinomas, and primary peritoneal carcinomas are all Müllerian in nature and could therefore be regarded as a single disease entity. Although a substantial proportion of cancers currently regarded as of primary ovarian origin arise in the fimbriated end of the fallopian tube, this site cannot account for all of these tumours, some of which are most likely derived from components of the secondary Müllerian system.
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            Origins and molecular pathology of ovarian cancer.

            Jimmy Bell (2005)
            Epithelial ovarian cancer comprises the majority of malignant ovarian tumors in adult women. These neoplasms are classified into distinct morphologic categories based on the appearance of the epithelium into tumors of serous, mucinous, endometrioid, clear cell, transitional, squamous, mixed and undifferentiated type. Current data indicate that each of these histologic subtypes is associated with distinct morphologic and molecular genetic alterations: high-grade serous and possibly endometrioid carcinomas most probably arise from surface epithelial inclusion glands with TP53 mutations and dysfunction of BRCA1 and/or BRCA2; low-grade serous carcinomas probably arise in a stepwise fashion in an adenoma-borderline tumor-carcinoma sequence from typical to micropapillary borderline tumors to low-grade invasive serous carcinoma via activation of the RAS-RAF signaling pathway secondary to mutations in KRAS and BRAF; mucinous carcinomas arise via an adenoma-borderline tumor-carcinoma sequence with mutations in KRAS; low-grade endometrioid carcinomas arise from endometriosis via mutations in CTNNB1 (the gene encoding beta-catenin) and PTEN. Although the morphologic data strongly support an origin of clear cell carcinoma from endometriosis, there is limited data on the genetic alterations in these uncommon tumors. Thus it is likely that most low-grade, relatively indolent ovarian carcinomas of serous, mucinous and endometrioid type arise from pre-existing cystadenomas or endometriosis whereas most high-grade serous carcinomas arise without an easily identifiable precursor lesion.
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              Histologic subtypes of ovarian carcinoma: an overview.

              Reproducible subclassification of ovarian carcinomas is biologically and increasingly therapeutically important. The traditional morphologic approach that ignores genotype and immunophenotype is subjective and therefore suboptimal. This review covers the prevalence, morphology, immunophenotype and, in some cases, genotype of each major ovarian cancer subtype. Serous carcinomas, frequently WT1 positive, are morphologically diverse and mimic other tumors. Most transitional cell carcinomas are closely related to them. Mucinous carcinomas are uncommon and should only be diagnosed after extraovarian primaries are excluded; true ovarian mucinous carcinomas are usually low stage. Intestinal and mullerian mucinous (seromucinous) tumors are histogenetically and clinically distinct. Ovarian endometrioid carcinomas almost always resemble endometrioid carcinomas of endometrium, express estrogen receptors (ER) but not WT1, and are frequently low grade and low stage. Ovarian clear cell carcinomas, negative for ER and WT1 and lacking p53 overexpression, have a limited morphologic repertoire and are frequently low stage at presentation. Clinical biology, immunohistochemistry, and genotype can be used to enhance diagnostic objectivity.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2010
                22 April 2010
                : 5
                : 4
                : e10293
                Affiliations
                [1 ]Department of Obstetrics and Gynecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
                [2 ]Laboratory of Pediatrics and Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
                [3 ]Department of Gastroenterology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
                [4 ]Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
                [5 ]Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
                University of Southampton, United Kingdom
                Author notes

                Wrote the paper: EK. Study design and supervision: RAW LFAGM. NMR support and responsibility for first detection of NAA in cyst fluid samples: UE. Liver cyst study: JW. Pathological diagnoses: JB. GCMS measurements on NAA: HB.

                Article
                09-PONE-RA-14704R1
                10.1371/journal.pone.0010293
                2858663
                20421982
                a9088809-32b9-4b71-8566-0d159fe3d9b2
                Kolwijck et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 23 November 2009
                : 25 March 2010
                Page count
                Pages: 6
                Categories
                Research Article
                Biochemistry
                Women's Health
                Chemistry/Biochemistry

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