Serous papillary adenocarcinoma possibly related to the presence of primitive oocyte-like cells in the adult ovarian surface epithelium: a case report
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The presence of oocytes in the ovarian surface epithelium has already been confirmed in the fetal ovaries. We report the presence of SSEA-4, SOX-2, VASA and ZP2-positive primitive oocyte-like cells in the adult ovarian surface epithelium of a patient with serous papillary adenocarcinoma.
Ovarian tissue was surgically retrieved from a 67-year old patient. Histological analysis revealed serous papillary adenocarcinoma. A proportion of ovarian cortex sections was deparaffinized and immunohistochemically stained for the expression of markers of pluripotency SSEA-4 and SOX-2 and oocyte-specific markers VASA and ZP2. The analysis confirmed the presence of round, SSEA-4, SOX-2, VASA and ZP2-positive primitive oocyte-like cells in the ovarian surface epithelium. These cells were possibly related to the necrotic malignant tissue.
Primitive oocyte-like cells present in the adult ovarian surface epithelium persisting probably from the fetal period of life or developed from putative stem cells are a pathological condition which is not observed in healthy adult ovaries, and might be related to serous papillary adenocarcinoma manifestation in the adult ovarian surface epithelium. This observation needs attention to be further investigated.
Keywordshuman oocytes ovarian surface epithelium serous adenocarcinoma
Stage Specific Embryonic Antigen-4
In fetal ovaries, the number of germ cells reaches a peak of ~6 to 7 million during the fifth month post-fertilization , after which germ cell reduction occurs during prenatal development, resulting in the presence of only 1 million of female germ cells before birth. Two mechanisms have been proposed to restrict the pool of female gametes during prenatal life: 1) germ cell degeneration inside the developing ovary and, 2) germ cell extension into the ovarian surface epithelium and exfoliation from the ovarian surface into the coelomic cavity [1, 2, 3, 4, 5, 6, 7]. Therefore, primitive oocytes can be found in the ovarian surface epithelium and on the surface of fetal ovaries, as revealed by the transmission and scanning electron microscopy. Germ cells may reach the site of ovarian surface epithelium by still retained amoeboid movements in early developmental stages, or are passively pushed there by the morphogenetic rearrangement of somatic cells in later stages of ovarian development. This phenomenon is observed in human fetal ovaries, might persist until the puberty, but is not present in adult ovaries. It has already been proposed that these residual primitive oocytes in the adult ovarian surface epithelium may give rise to abnormal cell growth, such as teratomas [1, 2], but not much experimental evidence has been available.
Recent findings have confirmed the presence of putative stem cells in the adult human ovarian surface epithelium [8, 9, 10]; they can also be found in the ovaries of older women [9, 11]. Putative stem cells are small round cells with diameters of 2 to 4 μm that express some markers of pluripotent stem cells and can develop in vitro into primitive oocyte-like cells. Putative stem cells found in adult ovarian surface epithelium resemble very small embryonic-like stem cells (VSELs) found in other adult tissues and organs [12, 13, 14]. It is proposed that VSELs originate in the epiblast and persist in adult tissues and organs from the embryonic period of life .
Serous adenocarcinoma is a type of epithelial ovarian cancer, which is the most common among ovarian cancers. Ovarian cancers account for 6 percent of all cancers among women according to the American Cancer Society. The five-year survival rate in women with advanced ovarian cancer is 15 to 20 percent, but if the disease is found at an early stage, survival approaches 90 percent . Women with a personal/family history of ovarian or other cancers are at the highest risk of having ovarian serous carcinoma, especially if their mother or sister had ovarian cancer. Other risk factors include: increased age, use of high-dose estrogens without progesterone for a long period, uninterrupted ovulation due to infertility, no pregnancies, no use of birth control, and defects in the BRCA1 or BRCA2 genes. Unfortunately, in most women ovarian serous carcinoma is not diagnosed until the disease is advanced, and has spread into the abdomen or beyond due to non-clear physical symptoms. Therefore, early diagnosis is very important. Here we report the presence of primitive oocyte-like cells in the adult human ovarian surface epithelium as related to epithelial ovarian cancer. These cells resembled primitive oocytes in the ovarian surface epithelium of fetal ovaries, and might have been involved in the manifestation of serous papillary adenocarcinoma in this patient. They expressed the analyzed markers of pluripotency SSEA-4 and SOX-2 and oocyte-specific markers VASA and ZP2 (glycoprotein of zona pellucida), therefore, the germline character of these cells is quite possible. The primitive oocyte-like cells in the ovarian surface epithelium of this patient might have persisted from the fetal period of life or developed from the putative stem cells in the ovarian surface epithelium. They might present a pathological state leading to the manifestation of ovarian serous papillary adenocarcinoma. It has been confirmed that teratoma and other germ cell tumors can be formed from oocytes/parthenogenetic embryos [17, 18]. Similar primitive oocyte-like cells as reported here have already been described in the adult ovarian surface epithelium in a mouse model; ovarian surface epithelium of adult mouse ovaries seems to possess rare premeiotic germ cells that can generate oocytes following transplantation into a young host environment , but to our knowledge there has been no evidence in humans until now.
Primitive oocyte-like cells present in the adult ovarian surface epithelium of the postmenopausal patient that probably persisted from the fetal period of life or had developed from putative stem cells in the ovarian surface epithelium are a pathological condition and might be related to serous papillary adenocarcinoma manifestation in this patient. This observation needs attention to be further investigated.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
We acknowledge Prof. Peter Dovc, Biotechnical Faculty, University of Ljubljana, who kindly provided us the anti-goat secondary antibodies to analyze oocyte-specific markers VASA and ZP2 by immunohistochemistry and Ms. Mojca Pirc, B.A., for revision of the English language. We also greatly acknowledge the Slovenian Research Agency (ARRS, grant J3-0415/Irma Virant-Klun) and German Federal Ministry of Education and Research (BMBF, grant 01GN1001/Thomas Skutella) for the financial support.
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