Primordial germ cells as a potential shared cell of origin for mucinous cystic neoplasms of the pancreas and mucinous ovarian tumors.

Mucinous ovarian tumors (MOTs) morphologically and epidemiologically resemble mucinous cystic neoplasms (MCNs) of the pancreas, sharing a similar stroma and both occurring disproportionately among young females. Additionally, MOTs and MCNs share similar clinical characteristics and immunohistochemical phenotypes. Exome sequencing has revealed frequent recurrent mutations in KRAS and RNF43 in both MOTs and MCNs. The cell of origin for these tumors remains unclear, but MOTs sometimes arise in the context of mature cystic teratomas and other primordial germ cell (PGC) tumors. We undertook the present study to investigate whether non-teratoma-associated MOTs and MCNs share a common cell of origin. Comparisons of the gene expression profiles of MOTs [including both the mucinous borderline ovarian tumors (MBOTs) and invasive mucinous ovarian carcinomas (MOCs)], high-grade serous ovarian carcinomas, ovarian surface epithelium, Fallopian tube epithelium, normal pancreatic tissue, pancreatic duct adenocarcinomas, MCNs, and single-cell RNA-sequencing of PGCs revealed that both MOTs and MCNs are more closely related to PGCs than to either eutopic epithelial tumors or normal epithelia. We hypothesize that MCNs may arise from PGCs that stopped in the dorsal pancreas during their descent to the gonads during early human embryogenesis, while MOTs arise from PGCs in the ovary. Together, these data suggest a common pathway for the development of MCNs and MOTs, and suggest that these tumors may be more properly classified as germ cell tumor variants. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Dietary fat intake and risk of epithelial ovarian cancer by tumour histology.

BACKGROUND: Studies of fat intake and epithelial ovarian cancer (EOC) risk have reported inconsistent findings, hence we hypothesised that associations may vary by histologic subtype. METHODS: We evaluated fat intake in a New England case-control study including 1872 cases and 1978 population-based controls (1992-2008). Epithelial ovarian cancer risk factors and diet were assessed using a food frequency questionnaire at enrolment. Logistic regression was used to estimate associations between fat intake and EOC risk and polytomous logistic regression was used to test whether associations varied by histologic subtype. RESULTS: We observed a decreased risk of EOC when comparing the highest vs lowest quartiles of intake of omega-3 (odds ratio (OR)=0.79, 95% confidence interval (CI) 0.66-0.96, P-trend=0.01) and omega-6 (OR=0.77, 95% CI 0.64-0.94, P-trend=0.02) and an increased risk with high consumption of trans fat (OR=1.30, 95% CI 1.08-1.57, P-trend=0.002). There was no significant heterogeneity by tumour histologic subtype; however, we observed a strong decreased risk for endometrioid invasive tumours with high intake of omega-3 (quartile (Q) 4 vs Q1, OR=0.58, 95% CI 0.41-0.82, P-trend=0.003). CONCLUSIONS: These findings suggest that higher intake of omega-3 may be protective for EOC overall and endometrioid tumours in particular, whereas greater consumption of trans fat may increase risk of EOC overall.

Low-grade serous carcinoma: new concepts and emerging therapies.

For the past several years, all women with epithelial ovarian cancer have been treated identically, whether in a clinical trial or off protocol. Over the past decade, we have come to appreciate the magnitude of the heterogeneity of ovarian cancer. The development of the binary grading system for serous carcinoma was a major advance leading to separate clinical trials for patients with this subtype originating from the Gynecologic Oncology Group's Rare Tumor Committee. The mitogen-activated protein kinase (MAPK) pathway appears to play a prominent role in the pathogenesis of this subtype. Approximately 20-40% of low-grade serous carcinomas have a KRAS mutation, while BRAF mutations are rare - about 5%. Primary treatment of low-grade serous carcinoma includes surgery+platinum-based chemotherapy (either adjuvant or neoadjuvant). Clinical behavior is characterized by young age at diagnosis, relative chemoresistance, and prolonged overall survival. Current options for treatment of relapsed disease include secondary cytoreduction in selected patients, salvage chemotherapy, or hormonal therapy. A recently completed trial of a MEK inhibitor for women with recurrent disease demonstrated promising activity. Future directions will include further investigations of the molecular biology and biomarker-driven clinical trials with targeted agent monotherapy and combinations.

Clinical characteristics of ovarian teratoma: age-focused retrospective analysis of 580 cases.

OBJECTIVE: The objective of the study was to evaluate the clinical characteristics of ovarian teratoma by age. STUDY DESIGN: This was a retrospective study. Five hundred eighty medical records were reviewed from patients who underwent operative removal of ovarian teratomas at Samsung Medical Center between January 1996 and February 2010. RESULTS: The proportion of asymptomatic patients increased significantly after 20 years of age (P = .0006). Ovarian torsion was noted in 26 patients (4.9%), without an age-specific difference (P = .5019; range, 0.0-8.2%). Tumor size was different according to age group (P < .0001), with larger tumor size in younger patients (<20 years old) relative to older patients. Immature teratoma revealed a higher incidence of symptomatic tumors on the first visit and significantly larger tumor size (P = .0004) compared with mature teratoma. CONCLUSION: Patients with ovarian teratoma have different clinical manifestations by age. It could help us understand clinical characteristics of the disease.

BAX-mediated cell death affects early germ cell loss and incidence of testicular teratomas in Dnd1(Ter/Ter) mice.

A homozygous nonsense mutation (Ter) in murine Dnd1 (Dnd1(Ter/Ter)) results in a significant early loss of primordial germ cells (PGCs) prior to colonization of the gonad in both sexes and all genetic backgrounds tested. The same mutation also leads to testicular teratomas only on the 129Sv/J background. Male mutants on other genetic backgrounds ultimately lose all PGCs with no incidence of teratoma formation. It is not clear how these PGCs are lost or what factors directly control the strain-specific phenotype variation. To determine the mechanism underlying early PGC loss we crossed Dnd1(Ter/Ter) embryos to a Bax-null background and found that germ cells were partially rescued. Surprisingly, on a mixed genetic background, rescued male germ cells also generated fully developed teratomas at a high rate. Double-mutant females on a mixed background did not develop teratomas, but were fertile and produced viable off-spring. However, when Dnd1(Ter/Ter) XX germ cells developed in a testicular environment they gave rise to the same neoplastic clusters as mutant XY germ cells in a testis. We conclude that BAX-mediated apoptosis plays a role in early germ cell loss and protects from testicular teratoma formation on a mixed genetic background.

Fetiform Teratoma in the Ovary of a 7-Year-Old Girl: A Case Report.

BACKGROUND: Fetiform teratoma, a highly differentiated mature cystic teratoma resembling a fetus, is rare and typically found in the ovaries of women of reproductive age. In this report we describe, to our knowledge, the youngest case of ovarian fetiform teratoma. CASE: A 7-year-old girl presented with acute abdominal pain. Radiological examinations revealed a 5.2-cm ovarian complex cystic mass with fetal-like components in favor of fetus in fetu and teratoma. After surgical removal, the mass resembled a fetus consisting of a head, two eye slits, two small upper limb projections, and hair. Pathology indicated mature cystic teratoma supporting the diagnosis of fetiform teratoma. SUMMARY AND CONCLUSION: Although not commonly found in children, fetiform teratoma must be considered in the diagnosis of a child who presents with an adnexal mass resembling a fetus.

[Fetal ovarian cyst. A report of a case]. / Quiste de ovario fetal. Presentación de un caso.

Fetal ovarian cyst is uncommon; it represents the second place of fetal abdominal tumors, after urinary tract tumors. The cause of fetal ovarian cysts still remains unclear, although it is likely to be promoted by hormones. Its prognosis is usually good. Differential diagnosis should rule out urinary tract malformations. A case of a female newborn with giant fetal ovarian cyst, diagnosed on week 37 of the pregnancy period, treated with exploratory laparotomy and cyst exeresis, with serum cystadenoma histopathology diagnosis is presented.

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.

Immature endodermal teratoma of the ovary: embryologic correlations and immunohistochemistry.

Two grade 2 ovarian immature, predominantly endodermal teratomas are reported. The teratomas were in stage I and occurred in two girls, 9 and 10 years of age, who were treated with triple chemotherapy. These neoplasms differed from the usual immature ovarian teratoma as they contained no neuroectodermal components and had high alpha-fetoprotein and low human chorionic gonadotropin levels as their serum markers despite the absence of other concomitant germ cell tumors. The epithelia of the teratomas demonstrated exclusively the embryologic development of endoderm, ranging from early endoderm to tissues similar to esophagus, liver, and intestinal structures. All epithelial derivatives were positive for alpha-fetoprotein and alpha 1-antitrypsin. Liver and esophagus expressed fibrinogen, while intestine and esophagus were positive not only for carcinoembryonic antigen and chromogranins but also for thyroglobulin, thus reflecting yet another type of endodermal differentiation into thyroid. Focal human chorionic gonadotropin positivity associated with primitive intestinal and esophageal epithelia may reflect the early embryologic relationships between endoderm and trophoblast. These cases demonstrate that simultaneous alpha-fetoprotein and human chorionic gonadotropin secretion may occur in immature teratoma. The mesenchymal component also showed a wide range of differentiation, from primitive mesoblastic cells to differentiated cells, such as hemopoietic foci, smooth muscle, bone, and cartilage. Both the primitive endoderm and the mesenchyme co-expressed vimentin and keratin, reflecting their intimate developmental relationships and possibly supporting the hypothesis of mesenchyme originating from endoderm, as suggested by previous embryologic studies. Since endodermal and mesenchymal areas similar to those described here are found in association with yolk sac tumors and embryonal carcinoma, it is possible that the present cases may represent an endodermal differentiation accomplished by either of these developmentally related germ cell tumors.

The deduction of tumor histogenesis, with special reference to teratomas and ovarian tumors.

The secure deduction of tumor histogenesis in vivo is notoriously difficult, owing to the retrospective form of the inquiry, which implies that no histogenetic theory makes certain-enough predictions. Deduction of a tumor's parent tissue currently relies on 1) its location relative to that of small early tumors, 2) correlation of its relative availability with tumor frequency, 3) its resemblance to the tumor tissue in various respects, and 4) its microscopic continuity with the tumor through transitional forms. Each of these criteria has pitfalls, owing to possible failure of the relevant factor to persist or to subsequent mimicry of it by other processes. This makes reliance on only one or two criteria undesirable. The application of these criteria to teratomas shows that there are no convincing data provided by the fourth. A dysgerminoma containing multiple small teratoid foci, which was studied in detail, is described, and the origin of the second tissue from the first is argued. The apparently somatic origin of some of the mesenchyma and the role of the mesenchyma in promoting teratoma development and segregation are discussed.

Renal handling of carboplatin.

The mechanism for renal handling of carboplatin was studied in 17 ovarian cancer patients treated with a combination of carboplatin and cyclophosphamide. Carboplatin and [51Cr]-ethylenediaminetetraacetic acid (EDTA) renal clearances were measured simultaneously during short intervals of from 45 to 120 min. A total of 131 clearance intervals were analyzed during 35 chemotherapy courses. The carboplatin/[51Cr]-EDTA clearance ratio (R) served as an indicator of the net tubular reabsorption (R less than 1) or secretion (R greater than 1). The R value was calculated for each sampling interval. No significant difference was found between interpatient and intertreatment variation. The intertreatment variation as tested against the variation in the short intervals by an F-test was highly significant. We calculated the average R value for each treatment and consequently based our results on a total of 35 observations. The mean R value was 0.77 (t-test for R = 1; P less than 0.001). We conclude that the renal elimination of carboplatin takes place by glomerular filtration followed by tubular reabsorption.

Spectrum of germ cell tumors: from head to toe.

Germ cell tumors (GCTs) occur most frequently in the gonads and are relatively rare in other sites, such as the pineal gland, neurohypophysis, mediastinum, and retroperitoneum. GCTs are thought to originate from primordial germ cells, which migrate to the primitive gonadal glands in the urogenital ridge. Extragonadal GCTs might also originate from these cells when the cells are sequestered during their migration. Pathologic subtypes of GCTs vary, and the prevalence of mixed tumors is high. These factors produce a diversity of radiologic findings and make prospective radiologic diagnosis difficult in many cases. However, similar radiologic findings have been observed in pathologically equivalent tumors in varying sites. Seminomas appear as uniformly solid, lobulated masses with fibrovascular septa that enhance intensely. Nonseminomatous GCTs appear as heterogeneous masses with areas of necrosis, hemorrhage, or cystic degeneration. Fat and calcifications are hallmarks of teratomas, most of which are benign. In immature teratomas, scattered fat and calcification within larger solid components are occasionally seen. These imaging characteristics reflect the pathologic features of each tumor, and histologically similar GCTs at varying sites have similar radiologic features. Knowledge of the pathologic appearances of GCTs and their corresponding radiologic appearances will allow radiologists to diagnose these tumors correctly.

Classification of tumors of the ovary: developmental and ultrastructural considerations.

The classification of ovarian tumors presents a difficult problem because of the great variety of tumor types that can occur. The complex structure of the normal ovary and the diversity of cell types present at different stages of development contribute to this difficulty. Developmental and ultrastructural studies have helped to clarify the problem by indicating specific cell types that correspond directly with the major tumor categories. Tumors may thus be grouped as being of epithelial, germ cell or sex cord stromal origin. The ultrastructural features of tumors in the different categories indicate common characteristics shared with corresponding cell types in the developing ovary. The findings clearly support a histogenetic approach in the classification of ovarian tumors.

Embryology of the gonad with reference to special tumors of the ovary and testis.

The ovaries and testes have very similar development patterns until about the fourth month of embryonic life. A review of the similar development (until the fourth month) provides an explanation for the origin of tumors commonly associated with ovarian tissue appearing in the testis and vice versa. Embryonic surface epithelium gives rise to mesothelial tissue from which the common epithelial tumors arise in the ovary. Since these cells disappear from the testis when the tunica albuginea develops, this offers an explanation for the lack of common epithelial tumors in the testis. The embryonic gonadal tissue or sex cord epithelium and the primitive germ cells give rise to similar tumors in both the ovary and the testis. The extraembryonal tumors arise from the extraembryonal cells and trophoblastic cells, which give rise to the endodermal sinus tumors and choriocarcinomas, respectively. Since there is such a similarity in the development of the ovary and testis with the potential for residual cells to remain, an explanation is offered for the development of similar tumors in the ovary and the testis.

Tumors originating in supernumerary ovaries. A report of two cases.

The supernumerary ovary is a rare gynecologic anomaly; 13 cases have been reported on since 1890. Three were associated with tumors arising in the ectopic ovarian tissue. We encountered two cases of benign neoplasms discovered to have originated in supernumerary ovaries.

[Clear cell carcinoma of the female genital tract]. / Les carcinomes à cellules claires du tractus génital féminin

Even though the existence of clear cell carcinomata is universally acknowledged at all levels of the female genital tract, the nomenclature and the pathogenesis are still controversial. Following the observation of several examples of these tumours, we have been tempted to define and state the origin of these tumours. In the light of urogenital embryogenesis we think that it is discretion that has led to purely descriptive terms to describe these carcinomata. A critical study of the hypotheses as to the pathogenesis that have been suggested about these tumours in the literature allows the summary of numerous arguments in favour of a müllerian origin or viewed in a broader aspect, coelomic origin for these tumours.

[Cystadenomas with ovarian stroma in liver and pancreas: indications of embryonic migration of the gonadal epithelium]. / Cystadenomen met ovarieel stroma in lever en pancreas: aanwijzingen voor embryonale migratie van gonadaal epitheel.

OBJECTIVE: To provide an embryological explanation for the presence of ovarian stroma in cystadenomas of the liver and pancreas. DESIGN: Investigation of patients and embryos. METHOD: From 1997 to 2001 in the Academic Medical Centre, Amsterdam, the Netherlands, nine women were treated for a cystadenoma with ovarian stroma, six of which were situated in the liver and three in the tail of pancreas. In one patient with a cystadenoma in the liver, malignant changes had taken place. In embryos at 5-8 weeks development, the regional differences in the morphology of the epithelium of the peritoneal cavity and the position of the gonads in relation to the embryonic liver, pancreas and spleen were examined. RESULTS: In the foetal period before the gonads begin to descend, they are situated directly dorsal to the liver, tail of pancreas and spleen, but are separated from these by the peritoneal cavity. The cells that cover the urogenital folds distinguish themselves from those elsewhere in the peritoneal cavity as they are bulging in shape as opposed to flattened. This activated morphology suggests that on physical contact with a neighbouring organ the cells covering the gonads may become detached and lodge in that organ. CONCLUSION: It is likely that cystadenomas of the liver and pancreas have their origin in the cells that cover the embryonic gonads. The anomalous morphology of these covering cells in fact suggests that they are relatively easily mobilized. They are probably comparable with inoculation metastasis in the coelomic cavity. Taking the chance of malignant transformation of a cystadenoma into account, the treatment of choice is radical resection of the abnormality.

[Parthenogenesis in mammals]. / Partenogenez mlekopitaiushchikh.

A review of studies dealing with spontaneous and induced parthenogenesis in mammals. The main methods of artificial egg activation, ways of their development and causes of mortality of the parthenogenetic mouse embryos are considered. The possibilities of using parthenogenesis for solving urgent problems of mammalian developmental biology are estimated and prospects of further studies in this field are outlined.

[The role of embryoid bodies in the development of germinogenous tumors of complex structure and of the teratoma]. / Rol' émbrioidnykh telets v razvitii germinogennykh opukholei slozhnogo stroeniia i teratomy.

250 germinal gonadal and extragonadal tumors were studied in children and adolescents under 16 years of age. Germinal tumours of complex structure were found in 42 patients and in 36 of them embryoid bodies of various types (full, not-full, amorphous) were distinguished. Certain features were revealed indicating the development of the immature teratoma by means of maturation of preexisting embryoid bodies. The arguments in favour of complex germinal tumour development due to the loss of maturation and differentiation capacity of one or several structural elements of the embryoid bodies are presented. The observation of mature, immature embryonal tissues and proliferating elements of the embryoid bodies in the composition of one and the same tumour may be explained by different biological potency of individual clones of atypical and primordial germinal cells which are the source of the development of these tumours.

[Yolk sac tumor by fetectomy in the rat: histopathological characteristics and histogenesis (author's transl)].

Experimentally induced yolk sac tumors in rats were investigated with special regard to morphological and histochemical characteristics. Pregnant rats whose fetuses were removed on the 12th day of gestation, developed tumors which were derived from fetal membranes left outside the uterus. Out of 119 operated rats which had been mated with syngenic males, 95 rats beared tumors, which were histologically yolk sac tumors (46 cases), adenocarcinomas (29 cases), choriocarcinomas (5 cases) and teratomas (69 cases). An early lesion of yolk sac tumor was observed as early as 3 weeks after the surgical procedure, and the sera from these tumor-bearing rats were positive for alpha-fetoprotein (AFP). Morphological features of both the induced tumors and the cultured tumor cell masses revealed a thick stroma consisting of a PAS-positive basement membrane-like material, which closely resembled Reichert's membrane of the parietal yolk sac in the normal placenta. The intracellular localization of AFP in cultured cells was investigated by immuno-electron microscopic method, and the reaction product for AFP was seen in the endoplasmic reticulum and Golgi complex. Histogenesis of the tumor is also discussed.