The role of reproductive hormones in epithelial ovarian carcinogenesis.

Epithelial ovarian cancer comprises ∼85% of all ovarian cancer cases. Despite acceptance regarding the influence of reproductive hormones on ovarian cancer risk and considerable advances in the understanding of epithelial ovarian carcinogenesis on a molecular level, complete understanding of the biologic processes underlying malignant transformation of ovarian surface epithelium is lacking. Various hypotheses have been proposed over the past several decades to explain the etiology of the disease. The role of reproductive hormones in epithelial ovarian carcinogenesis remains a key topic of research. Primary questions in the field of ovarian cancer biology center on its developmental cell of origin, the positive and negative effects of each class of hormones on ovarian cancer initiation and progression, and the role of the immune system in the ovarian cancer microenvironment. The development of the female reproductive tract is dictated by the hormonal milieu during embryogenesis. Intensive research efforts have revealed that ovarian cancer is a heterogenous disease that may develop from multiple extra-ovarian tissues, including both Müllerian (fallopian tubes, endometrium) and non-Müllerian structures (gastrointestinal tissue), contributing to its heterogeneity and distinct histologic subtypes. The mechanism underlying ovarian localization, however, remains unclear. Here, we discuss the role of reproductive hormones in influencing the immune system and tipping the balance against or in favor of developing ovarian cancer. We comment on animal models that are critical for experimentally validating existing hypotheses in key areas of endocrine research and useful for preclinical drug development. Finally, we address emerging therapeutic trends directed against ovarian cancer.

[Comparative clinical and morphological analysis of technogenic and cryptogenic papillary thyroid carcinoma in children and adolescents].

OBJECTIVE: To make a comparative retrospective clinical and morphological analysis of cases of post-Chernobyl (technogenic) and sporadic (cryptogenic) papillary thyroid carcinoma (PTC) in children and adolescents in the Republic of Belarus. MATERIAL AND METHODS: Nine hundred and thirty-six patients aged less than 19 years, operated on in 1990-2005, when cancer incidence in this age group was directly related to the consequences of the Chernobyl accident (technogenic carcinoma) were examined. A comparison group included their 140 peers who were born after March 1987 and treated in 2005-2010 for PTC (cryptogenic carcinoma). The Kruskal-Wallis test was used to compare quantitative variables; the Fisher, Pearson, and Fisher-Freeman-Halton tests were employed to compare categorical variables. All calculations were made using the R package version 2.15.0. The results were considered to be statistically significant at p<0.05. RESULTS: Comparison of cases of cryptogenic carcinoma and those of technogenic carcinomas diagnosed in 1990-1995 and 1996-2001 revealed substantial differences in the clinical and morphological patterns of the disease. In both mentioned periods, the patients with technogenic PTC were younger than those with cryptogenic PTC (p<0.0001 and p=0.0014, respectively). The proportion of male patients in the technogenic carcinoma group was much higher than that in the cryptogenic carcinoma one (p=0.0006 and p=0.0031). The patients with technogenic carcinoma were also more frequently observed to have infiltrative tumor growth (p=0.0003 and p=0.0169) and lung metastastic involvement (p=0.0001 and p=0.0008). What is more, the architectonics of technogenic versus cryptogenic carcinoma more often contained a solid component (p<0.0001 and p<0.0001), marked intratumoral fibrosis (p=0.0008 and p=0.0266), mononuclear infiltration (p<0.0001 and p<0.0001), and no baseline abnormality (p<0.0001 and p<0.0001). CONCLUSION: In spite of its age similarity, technogenic carcinoma proved to be more clinically aggressive than cryptogenic carcinoma: the extent of organ invasion and the infiltrative growth of carcinoma were more frequently observed.

Fluoxetine-induced regulation of heat shock protein 90 and 14-3-3ε in human embryonic carcinoma cells.

Fluoxetine, a serotonin-selective reuptake inhibitor, exerts antidepressant and antianxiety effects on major depressive and anxiety disorders. Previous studies suggest that treatment with fluoxetine influences the expression of various proteins that are involved in proliferation, differentiation, and apoptosis in the neuronal cells of the brain. However, many aspects of the molecular pathways that modulate antidepressant action are not well understood. Here, with the aim of identifying proteins involved in antidepressant action, we examined the protein expression profile of human embryonic carcinoma (NCCIT) cells in response to fluoxetine treatment using proteomic techniques such as two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). We found several upregulated and downregulated proteins in fluoxetine-treated NCCIT cells, and then biochemically confirmed the increased expression of heat shock protein 90 and 14-3-3ε, which play an essential role in many cellular mechanisms including cell cycle control and other signaling pathways. Our data suggest that the regulated expression of heat shock protein 90, 14-3-3ε, and other identified proteins may be associated with the therapeutic action of fluoxetine.

Fetal tumors of the choroid plexus: is differential diagnosis between papilloma and carcinoma possible?

Fetal choroid plexus tumors are uncommon. The prognosis is widely variable and depends on the histological findings: papilloma or carcinoma. We report a case of prenatal diagnosis of choroid plexus mass detected by ultrasound at 33 weeks of gestation. Prenatal (T1, T2, T2* and diffusion weighted sequences) magnetic resonance imaging (MRI) was used to rule out a hematoma. Follow-up examination by ultrasound and MRI revealed a significant increase in the volume of the mass, suggesting a diagnosis of malignant tumor. A healthy neonate was delivered by Cesarean section at 38 weeks of gestation. Full surgical excision of the tumor was performed at 20 days after delivery and histological analysis revealed a papilloma.

[Epithelial mesenchymal transition during development in fibrosis and in the progression of carcinoma]. / La transition épithéliomésenchymateuse au cours du développement dans la fibrose et dans la progression tumorale.

Epithelial mesenchymal transition (EMT) is a fundamental mechanism controlling multiple events during embryonic development. Mesenchymal cells appear transiently in some diploblasts, the most primitive species characterized by two epithelial layers. Since almost 800 million years, EMT has been conserved throughout evolution to control morphogenetic events, such as the formation of the three primary germ layers during gastrulation. Most interestingly, specific molecular pathways have been conserved in many different species to drive EMT. In the animal kingdom, a recurrent theme is that EMT controls the intercellular adhesion machinery and the dynamics of its associated cytoskeleton. EMT pathways are also tightly connected to determination and differentiation programs, and are reactivated in adult tissues following injury or exposure to toxic agents. EMT is now shown to operate during the early stages of carcinoma invasion leading to blood or lymph vessel intravasation of malignant cells. The converse mechanism - mesenchymal-epithelial transition (MET) - then operates at distant sites from the primary tumor to form macrometastases from isolated micrometastatic cells. The mesenchymal-like state of carcinoma confers stemness, protection from cell death, escape from immune response and, most importantly, resistance to conventional and targeted therapies. Our laboratory has designed an EMT high-throughput screen of small molecular weight compounds and biologics in order to establish new therapeutic approaches that interfere with the plasticity of carcinoma cells. New therapeutic interventions are envisioned to delay tumor recurrence.

FAVL elevation in human tumors disrupts Fanconi anemia pathway signaling and promotes genomic instability and tumor growth.

Fanconi anemia (FA) is a rare human genetic disease caused by mutations in any one of 13 known genes that encode proteins functioning in one common signaling pathway, the FA pathway, or in unknown genes. One characteristic of FA is an extremely high incidence of cancer, indicating the importance of the FA pathway in tumor suppression. However, the role of this pathway in the development and progression of human cancers in individuals who do not have FA has not been clearly determined. Here, we report that elevated expression of what we believe to be a novel splice variant of FA complementation group L (FANCL), which we identified and named FAVL, can impair the FA pathway in non-FA human tumor cells and act as a tumor promoting factor. FAVL expression was elevated in half of the human carcinoma cell lines and carcinoma tissue samples tested. Expression of FAVL resulted in decreased FANCL expression by sequestering FANCL to the cytoplasm and enhancing its degradation. Importantly, this impairment of the FA pathway by FAVL elevation provided human cancer cells with a growth advantage, caused chromosomal instability in vitro, and promoted tumor development in a xenograft mouse model. These data indicate that FAVL impairment of the FA pathway likely contributes to the development of non-FA human cancers and therefore add a challenging layer of complexity to the pathogenesis of human cancer. We further believe that these data will prove useful for developing additional tools for fighting human cancer.

Development of mammary tumors by conditional expression of GLI1.

A diverse set of cellular defects, presumably elicited by multiple genetic alterations, underlies cancer development. Aberrant Hedgehog (Hh) signaling has recently been implicated in the development and maintenance of breast cancer. However, evidence conclusively showing that activated Hh signaling can induce mammary tumors is lacking. We now show that transgenic expression of the Hh effector protein GLI1 under the regulation of the mouse mammary tumor virus promoter, expressed in the mouse mammary gland, is associated with the appearance of hyperplastic lesions, defective terminal end buds, and tumor development. The GLI1-induced tumors are histologically heterogeneous and involve the expansion of a population of epithelial cells expressing the progenitor cell markers keratin 6 and Bmi-1. Moreover, tumor cells express genes involved in proliferation, cell survival, and metastasis. GLI1-induced tumors do not fully regress following transgene deinduction, indicating that some tumors develop and are maintained autonomously, independent of sustained transgenic GLI1 expression. The data strongly support a role of Hh/GLI signaling in breast cancer development and suggest that inhibition of this signaling pathway represents a new therapeutic opportunity for limiting tumorigenesis and early tumorigenic progression.

Diagnosis of adrenocortical tumor in a neonate by detection of elevated blood 17-hydroxyprogesterone measured as a routine neonatal screening for congenital adrenal hyperplasia: a case report.

We report herein a case of prenatally detected neonatal adrenocortical tumor (ACT). The patient was an otherwise healthy newborn girl. No signs of Beckwith-Wiedemann syndrome were identified, and her family medical history did not suggest predisposition to cancer. Computed tomography and ultrasonography after birth revealed a round solid tumor 40 mm in diameter in the right suprarenal area. The precise diagnosis of ACT was unexpectedly obtained based on results from the Japanese neonatal mass screening program. Blood 17-hydroxyprogesterone is routinely measured as a part of this program for early detection of congenital adrenal hyperplasia in Japan. Abnormally elevated level of 17-hydroxyprogesterone was reported in the patient and, thus, led to the diagnosis of ACT. Surgical resection was safely performed with perioperative steroid replacement. Adrenocortical tumors are extremely rare in childhood, particularly in the neonatal period. Some of these tumors secrete abnormally high levels of cortisol, suppressing function of the contralateral adrenal gland and, thus, leading to life-threatening postoperative adrenal insufficiency. Scheduled steroid replacement enables safe perioperative management in such cases. Adrenocortical tumor should always be considered among the differential diagnoses for neonatal suprarenal mass because precise diagnosis will enable the physician to develop appropriate treatment strategies.

Reactivation of Snail genes in renal fibrosis and carcinomas: a process of reversed embryogenesis?

While the activity of Snail genes is required during embryonic development for the formation of different tissues and organs, they must be repressed in the adult in order to maintain epithelial integrity and homeostasis. Indeed, pathological activation of Snail in epithelial tumors induces malignancy and the recurrence of tumors. Here we show that in dedifferentiated areas of human renal carcinomas, Snail undergoes a process of reactivation. In addition to tumor progression, renal fibrosis is also linked to the activity of Snail genes and indeed, reactivation of Snail in the adult kidney is sufficient to induce fibrosis. Thus, Snail genes illustrate a paradigm whereby reactivation of crucial embryonic genes in adult tissues provokes the onset of devastating diseases.

Biliary carcinoma risk in patients with pancreaticobiliary maljunction and the degree of extrahepatic bile duct dilatation.

BACKGROUND/AIMS: Pancreaticobiliary maljunction (PBM) carries a high risk of biliary carcinoma. This study aimed to examine the biliary complications of patients with PBM in relation to the degree of extra-hepatic bile duct dilatation. METHODOLOGY: Ninety-eight cases of PBM could be divided into 5 groups according to the maximum diameter of the extrahepatic bile duct: < or = 10mm, 11-15mm, 16-20mm, 21-30mm, > or = 31mm. The clinicopathological findings of biliary carcinomas associated with PBM were compared with 232 cases of gallbladder carcinoma and 159 cases of bile duct carcinoma that were not associated with PBM. RESULTS: Gallbladder carcinoma occurred in 36 of 65 patients (55%) with PBM whose maximum diameter of the extrahepatic bile duct was < or = 30mm, but no gallbladder carcinoma occurred in patients with PBM whose diameter was > or = 31mm. Bile duct carcinoma occurred in 6 of 52 patients (12%) with PBM whose diameter was > or = 21mm, but no bile duct carcinoma occurred in patients with PBM whose diameter was < or = 20mm. The age at diagnosis of the patients with gallbladder or bile duct carcinoma associated with PBM was significantly younger than those without PBM (p<0.01). CONCLUSIONS: PBM with an extrahepatic bile duct diameter < or = 30mm is associated with a high risk of gallbladder carcinoma. PBM with an extrahepatic bile duct diameter > or = 21mm is associated with a high risk of bile duct carcinoma. Prophylactic cholecystectomy is recommended for patients with PBM without biliary dilatation.

Fetal origins of breast cancer.

Susceptibility to breast cancer might be pre-determined in utero. Alterations in the fetal hormonal environment, caused by either maternal diet or exposure to environmental factors with endocrine activities, can modify the epigenome, and these modifications are inherited in somatic daughter cells and maintained throughout life. These epigenetic modifications might lead to changes in mammary gland development, such as increased vulnerability of epithelial targets for malignant transformation. According to this hypothesis, on post-pubertal exposure to an initiating factor, such as a carcinogen, high levels of hormones and radiation, the mammary epithelial targets, perhaps stem cells, in terminal end buds/terminal ductal lobular units would be at an increased risk of malignant transformation. The increased susceptibility for cancer initiation might result from high levels of cell proliferation, reduced apoptosis and/or altered stromal regulation. Thus, maternal diet and environmental exposure might increase the risk of breast cancer by inducing permanent epigenetic changes in the fetus that alter the susceptibility to factors that can initiate breast cancer. Identifying the epigenetically altered target genes and their ligands might lead to strategies to prevent this disease in some women.

Cell-cell fusion as a means to establish pluripotency.

Embryonic stem cells (ESCs), embryonic germ cells (EGCs), and embryonic carcinoma cells (ECCs) are three types of pluripotent cells derived from mammalian embryos. The three cell types are capable not only of self-renewal, but also of having the potential to give rise to cells of all tissue types in the fetal and adult body. In several reports, ESCs, ECCs, and EGCs have been described to reprogram somatic cells in vitro. After reprogramming caused by fusion, somatic cells exhibit various features of pluripotent cells: expression of pluripotency markers (e.g., Oct4, nanog, and Rex-1), absence of tissue-specific gene expression, reactivation of inactive X chromosome of female somatic cells, demethylation, as well as histone modification. An activity in pluripotent stem cells appears to be capable of inducing the global changes inherent in the reprogramming of somatic cells. Investigations involving pluripotent stem cells will yield substantial insight into various fundamental biological processes, such as cellular differentiation and de-differentiation. Most importantly for the public, however, is that such studies might lead into cell-based therapies and as such have the potential to change regenerative medicine.

Papillomas and carcinomas of the choroid plexus: histological and immunohistochemical studies and comparison with normal fetal choroid plexus

CONTEXTO: Os tumores do plexo coróide são raros. Os resultados de dados imuno-histoquímicos são escassos e controversos, o mesmo valendo para o plexo coróide normal. MÉTODO: Treze casos de tumores do plexo coróide e cinco exemplares de plexo coróide fetal normal foram submetidos a estudo imuno-histoquímico, utilizando-se marcadores para antígenos epiteliais, neurais e estromais. RESULTADOS/CONCLUSAO: Os achados histológicos mais relevantes foram células claras em 3/5 papilomas (PP) e 7/8 carcinomas (CA) e em todos os 5 plexos fetais; células rabdóides, desmoplasia e proliferação vascular foram encontradas, respectivamente, em 3, 4 e 5 casos de 6 CA pouco diferenciados, mas não nos PP e CA bem diferenciados. A pancitoqueratina AE1/AE3 foi fortemente positiva em todos os 13 casos, mesmo no componente indiferenciado do CA pouco diferenciado, em que a reatividade foi focal em 3 casos e difusa em outros 3. A citoqueratina de baixo peso molecular (35bH11) não foi expressa em nenhum dos 8 CA, mas estava presente em todos os 5 PP. Em 4/6 CA pouco diferenciados houve reatividade para actina de músculo liso (1A4) em 10-30% das células. Este achado ocorreu também em um caso sem células rabdóides. Laminina não foi detectada em nenhum dos 6 CA pouco diferenciados, mas estava presente em 4 PP e em 2 CA bem diferenciados. Todos os 5 plexos fetais expressaram GFAP.

Papillomas and carcinomas of the choroid plexus: histological and immunohistochemical studies and comparison with normal fetal choroid plexus.

BACKGROUND: Choroid plexus tumors are rare. Results on immunohistochemical features are scanty and controversial even regarding normal plexus. METHOD: Thirteen cases of choroid plexus tumors and five samples of normal fetal choroid plexus were submitted to immunohistochemical study using a panel of epithelial, neuronal and stromal markers. RESULTS/CONCLUSIONS: Relevant histological findings were presence of clear cells in 3/5 papillomas (PP) and 7/8 carcinomas (CA) and all 5 fetal plexuses; rhabdoid cells, desmoplasia and vascular proliferation were found respectively in 3, 4 and 5 cases out of 6 poorly differentiated CA and were absent in PP and well differentiated CA. Pancytokeratin AE1/AE3 was strongly positive in all 13 cases, even in the undifferentiated component of poorly differentiated CA, where reactivity was focal in 3 and diffuse in 3 cases. Low molecular weight cytokeratin (35betaH11) was not expressed in any of the 8 CA, but was present in all 5 PP. In 4 of 6 poorly differentiated CA there was reactivity for smooth muscle actin (1A4) in 10 to 30% of the cells. This was true also for one case lacking rhabdoid cells. Laminin was undetectable in all 6 cases of poorly differentiated CA but was present in 4 PP and 2 well differentiated CA. All 5 fetal plexuses expressed GFAP.

Expression of inducible nitric oxide synthase in thyroid neoplasms: immunohistochemical and molecular analysis.

To understand the role of inducible nitric oxide synthase (iNOS) in thyroid tumorigenesis, immunohistochemical staining of 36 surgical specimens of thyroid neoplasm that consisted of seven follicular adenomas, 12 papillary carcinomas, seven follicular carcinomas, five medullary carcinomas, and five anaplastic carcinomas were analyzed. In addition, 20 specimens of normal thyroid were used as control samples. Reverse transcription-polymerase chain reaction and western blot analysis were also performed using a normal thyroid and a representative papillary carcinoma case. The intensity and proportion of the immunostained tumor cells were graded semiquantitatively. The grades of the intensity and the proportion were then summed to provide an immunohistochemical score. There was a variation in the staining intensity and proportion. The iNOS expression was low in normal follicular epithelia. Inducible nitric oxide synthase is present in the majority of thyroid tumor cells, including follicular adenomas, papillary carcinomas, follicular carcinomas, medullary carcinomas, and anaplastic carcinomas. Relatively low expression was shown in follicular neoplasms. Only a few inflammatory cells in the stroma were immunoreactive. These results suggest that iNOS may have a role in tumorigenesis, and iNOS in human thyroid carcinoma is mostly derived from tumor cells not from macrophages.

Overexpression of Stra13, a novel retinoic acid-inducible gene of the basic helix-loop-helix family, inhibits mesodermal and promotes neuronal differentiation of P19 cells.

We report the cDNA cloning of Stra13, a novel retinoic acid (RA)-inducible gene from P19 embryonal carcinoma cells that encodes a basic helix-loop-helix (bHLH) protein that shows the highest sequence similarities to the Drosophila Hairy and Enhancer of split and mouse Hes proteins. Stra13 does not bind to the known consensus motifs (E-box and N-box) for bHLH proteins, but can repress activated transcription (through an alpha-helix rich domain) in part by interaction with general factors of the basal transcription machinery. During mouse embryogenesis, Stra13 RNA is expressed in the neuroectoderm, and also in a number of mesodermal and endodermal derivatives. Remarkably, overexpression of Stra13 in P19 cells results in neuronal differentiation in monolayer culture, under conditions where wild-type P19 cells only undergo mesodermal/endodermal differentiation. This neuronal differentiation is accompanied by an altered expression of mesodermal and neuronal markers, indicating that Stra13 could be one of the earliest RA target genes whose expression is required for repression of mesodermal/endodermal differentiation and/or induction of neuronal differentiation when P19 cell aggregates are exposed to RA. Our results raise the possibility that Stra13 could be involved as a repressor in a number of decision events occurring during differentiation of various cell lineages.

Fucosyltransferase and alpha-L-fucosidase activities and fucose levels in normal and malignant endometrial tissue.

Previous immuno- and lectin-histochemical studies using mAbs and Ulex europaeus lectin I, which recognize various fucose-containing blood group antigens, have shown an increased expression of Lewis and H blood group antigens in endometrial carcinoma. We investigated the biochemical basis of aberrant fucose-containing antigen expression by comparing the activity of fucosyltransferases (FTase) and alpha-L-fucosidase in tissue biopsies from normal (n = 18) and malignant (n = 20) endometrium. Alteration of FTase activity in tumor tissue homogenates was evaluated by using a panel of FTase substrates including N-acetyllactosamine (type 2), lacto-N-biose I (type 1), and phenyl-beta-D-galactoside. Based on histological subtyping, the endometrioid group (n = 14) showed a significant (P < 0.05) increase in tumor FTase activity with all three substrates, while no significant increase was detected for the papillary serous group (n = 4). Matched pair analysis of normal and tumor tissue from a subgroup (n = 5) of the patients with increased tumor enzyme activity also showed higher FTase activity (P < 0.05) in the tumor tissue when the type 1 substrate was used. Regression analysis showed a correlation between the FTase activities acting on type 2 or type 1 substrates (r = 0.821 and r = 0.722, respectively) and the endogenous fucose levels in tumor homogenates. Spectrophotometric analysis of alpha-L-fucosidase activity using p-nitrophenyl-alpha-L-fucoside revealed a higher activity in tumor homogenates than in normal homogenates (P < 0.05) and, therefore, could not account for the enhanced expression of fucose-containing antigens. The current study suggests that aberrant expression of fucose-containing antigens, such as the H and the Lewis blood-group antigens, in endometrial carcinoma is consequential to the change in FTase rather than in alpha-L-fucosidase activity. In addition, the investigation suggests that different glycosylation mechanisms are operative in different subtypes of endometrial cancer.

Expression of neurofilament proteins during retinoic acid-induced differentiation of P19 embryonal carcinoma cells.

Retinoic acid (RA) induces P19 embryonal carcinoma cells to differentiate into neurons with the extension of neuritic processes. We used the P19 cell as a model system to elucidate the regulation of neurofilament (NF) expression. Four mammalian NF proteins, NF-66 (alpha-internexin), peripherin, NF-L and NF-M, and the neural-specific, growth-associated gene, GAP-43, were studied during the RA treatment of P19 cells in vitro. As controls, untreated P19 cells were maintained in parallel. Indirect immunofluorescent staining showed that in RA-treated, morphologically differentiated P19 cells NF-66 was expressed in neuron-like cells characterized by phase bright cell bodies and long neuritic processes. At various times P19 cells were harvested for protein analysis by immunoblotting with antibodies to individual NF proteins or for total RNA extraction and Northern blotting with cDNA probes for NF-66, -L, -M, peripherin and GAP-43. During induction, both NF-66 and NF-L were expressed but in distinct patterns. NF-66 mRNA and protein were detected after 6 days of induction. In contrast, NF-L mRNA, but not protein, was expressed in both induced and control cells. Neither NF-M nor peripherin were expressed during induction. During differentiation of P19 cells, NF-66 mRNA levels rose markedly by the 1st day, reached a plateau between the 3rd-5th days and declined by the 7th day. NF-66 protein accumulation lagged slightly, reaching maximum abundance about the 5th day. The kinetics of NF-66 expression were similar to that of GAP-43. However, the pattern of NF-L expression was distinct from that of NF-66. NF-L mRNA, and some protein, was expressed in both RA-treated and control cells within 6 h after plating, but was down-regulated to baseline level thereafter in both populations. Neither NF-M or peripherin expression was detected during the differentiation. In summary, NF-66 was up-regulated most robustly among the four NF proteins during differentiation in P19 cells and was the major NF protein correlated with neurite extension.

[Classification of ovarian tumors based on embryogenesis]. / Classification des tumeurs de l'ovaire basée sur l'embryogenèse.

This paper studies gonadal differentiation into the ovary from the earliest interaction between germ cells and somatic cells in the developing urogenital ridge up to the formation of primordial follicles. Granulosa cells appear to be derived from the breaking down of the cordlike arrangement of epithelial cells resulting from proliferation of surface coelomic mesothelium. Thecal cells arise from mesenchymal progenitors cells in the ovarian stroma. Based on the findings of embryology and biology, the authors then propose a classification of ovarian tumors by rearranging the WHO classification.