Ovarian tumors with functioning manifestations

Various categories of ovarian tumors, particularly those of gonadal stromal origin, are capable of producing a variety of hormones that occasionally induce interesting clinical manifestations. The endocrine manifestations associated with gonadal stromal tumors are often due to hormone production by the tumor cells. Sometimes the tumor cells produce only one hormone, while more frequently the hormonal manifestations result from a summation of various hormones including transformation of a variety of prehormones produced by different components of the tumor including its supportive or reactive stroma. The mechanisms involved in the production and transformation of various hormones and prehormones are complex and not thoroughly established at this time. This review will focus on gonadal stromal tumors and discuss evidence available for linkage of the clinical manifestations to hormones produced by the various neoplasms.     

Inhibin expression in ovarian-type stroma in mucinous cystic neoplasms of the pancreas.

Mucinous cystic neoplasms (MCNs) of the pancreas are typically found in middle-aged to elderly women and contain ovarian-type stroma in the cyst wall. Whether the resemblance of this stroma to ovarian stroma is only morphologic or has more functional similarity is still unclear. Estrogen receptors (ER) and progesterone receptors (PR) have been shown to be expressed in a wide variety of tissues and tumors, including the ovarian-type stroma of MCN. Inhibin, on the other hand, has been shown to have a more restricted expression, limited to ovarian sex cord-stromal components and placental cells, and has recently been shown to be expressed in pancreatic MCNs. However, it is still unclear whether this expression is limited to MCNs of the pancreas and whether it has any diagnostic role. Seven cases of MCN (4 mucinous cystadenoma, 2 borderline MCN, and 1 mucinous cystadenocarcinoma with microinvasion), 6 cases of intraductal papillary mucinous tumor, 1 of mucinous cystic tumor of uncertain classification, 2 of mucinous noncystic adenocarcinoma, 4 of serous cystadenoma, and 4 solid pseudopapillary neoplasms were selected for this study. Five cases with normal pancreatic tissue were included as controls. Immunohistochemical stains for alpha-inhibin, ER, and PR were performed on a representative section from each case on formalin-fixed, paraffin-embedded tissue sections using a standard indirect immunoperoxidase method. All cases of MCN were in female patients with an average age of 55.3 years, showing ovarian-type stroma and clusters of alpha-inhibin-positive luteinized theca-like cells. In all these cases, moderate to strong PR positivity was also noted in the ovarian-type stroma, including many of the alpha-inhibin-positive luteinized theca-like cells. ER was expressed in 2 cases. The epithelial cells of MCNs were all negative for ER, PR, and alpha-inhibin staining. Of the other tumors, 4 solid pseudopapillary neoplasms showed positivity for only PR in the tumor cells. The remaining tumors were negative for all markers. In conclusion, the finding of alpha-inhibin positivity in MCN with ovarian-type stroma further supports its similarity to true ovarian stromal tissue and may suggest a role of complex hormonal interaction in the pathogenesis. In addition, its limited expression in MCNs of the pancreas may be diagnostically useful in difficult cases.     

Luteoma of pregnancy: ultrastructural features.

The ultrastructural configuration of the cells in one case of pregnancy luteoma was studied by conventional electron microscopy. The fine structure of these cells conforms closely to that of steroid hormone producing cells in other human organs, such as the adrenal cortex, testicular interstitium, and corpus luteum, particularly in terms of the presence of abundant smooth endoplasmic reticulum, dispersed Golgi apparatus, and tubular cristae in the mitochondria. Similarities were noted between the pregnancy luteoma cells and, as described by other authors, the luteinized granulosa and theca cells of the human corpus luteum and the cells of spontaneous mouse luteoma. There was a more pronounced resemblance to the granulosa cells of the corpus lutemum than to the luteinized theca cells or the mouse luteoma cells but with considerable overlap among all of them. Distinctive features, not previously described, were noted in the pregnancy luteoma cells in the form of deep cytoplasmic invaginations of the cell membrane closed by tight junctions, and peculiar pleated sinuous membranous arrays within the cytoplasm. The significance of these structures is not known. In addition mesenchymal cells of ambiguous differentiation were noted in the stroma of the tumor, suggesting that the stimulus to luteinized cell proliferation may transcend the specific ovarian mesenchymal cells and may also be exerted on the supporting stroma. On the basis of previous reports concerning the biochemical and biosynthetic patterns of sex steroid hormone production by these tumors, it is concluded that although the latter recapitulate the endocrine functions of the normal ovarian stroma rather than those of the corpus luteum, the cytoarchitecture of these tumors covers a much broader spectrum of differentiation, which may come to resemble closely although not exclusively that of luteinized granulosa cells.     

Value of inhibin in the identification of granulosa cell tumors of the ovary

Inhibins are peptide hormones that participate in the regulation of the pituitary-gonadal feedback system and are selectively expressed by cells of sex cord—stromal derivation. To determine the efficacy of this marker for distinguishing granulosa cell tumors, 134 primary and metastatic lesions of the ovary were evaluated for expression of the alpha-subunit of inhibin in routinely processed formalin-fixed, paraffin-embedded tissue. A variety of sex cord—stromal tumors (SCST), including 35 adult and juvenile granulosa cell tumors, 14 fibroma-thecomas, and 18 other sex cord—stromal proliferations, were studied. In addition, 33 surface epithelial neoplasms, 12 germ cell tumors, 11 metastases, and 11 miscellaneous ovarian neoplastic proliferations were evaluated. Among the non-granulosa cell neoplasms, special emphasis was placed on primary neoplasms and metastases that histologically simulated granulosa cell tumors. Thirty-three of 35 (94%) granulosa cell tumors were immunoreactive compared with 2 of 12 (17%) primary ovarian endometrioid tumors, one of nine (11%) primary ovarian transitional cell (Brenner) proliferations, and 3 of 17 (18%) other primary and metastatic poorly differentiated (undifferentiated) carcinomas. In 31 of the 35 granulosa cell tumors, inhibin staining was of moderate to strong intensity or was present in at least half of the constituent cells, whereas only 2 of 33 primary surface epithelial neoplasms fulfilled the same criteria, showing weak staining of 70% to 80% of the cells. In contrast, 10 of 14 (71%) ovarian fibroma-thecomas and 17 of 18 (94%) other sex cord—stromal proliferations were positive for inhibin. Nonneoplastic luteinized stromal cells stained for inhibin in 29 of 85 cases in which they could be evaluated. The results of this study show that although it is not completely specific and cannot reliably distinguish granulosa cell tumors from fibroma-thecomas or other ovarian sex cord—stromal proliferations, inhibin can be used to help distinguish sex cord—stromal neoplasms from most primary and metastatic non-SCST. Caution should be exercised in the interpretation of inhibin-positive cells, because a wide variety of primary and metastatic ovarian tumors may contain significant numbers of positively staining luteinized cells.     

Immunoreactive beta-endorphin in ovarian sex cord-stromal tumors

The possible production of the opioid polypeptide beta-endorphin (beta-EP) was investigated in paraffin-embedded tissue from 17 ovarian tumors with the use of a specific anti-beta-EP antibody and the avidin-biotin-peroxidase staining technique. Only sex cord-stromal tumors (ten cases) showed positive staining. Strong beta-EP immunoreactivity was present in Leydig's cells of Sertoli-Leydig cell tumors; weaker sporadic staining was present in cells of granulosa cell tumors, and faint staining was present in occasional, luteinized theca cells of fibrothecomata. These findings suggest that cells with the sex cord-stromal phenotype that are capable of steroid production can also produce beta-EP. The latter may be a component of the "functional" status associated with some ovarian sex cord-stromal tumors and may serve as a helpful marker in distinguishing this type of tumors from germ cell or epithelial neoplasms.     

Immunohistochemical analysis of steroidogenic enzymes in ovarian‐type stroma of pancreatic mucinous cystic neoplasms: Comparative study of subepithelial stromal cells in intraductal papillary mucinous neoplasms of the pancreas

Mucinous cystic neoplasms (MCNs) are generally defined as cyst‐forming epithelial neoplasms that arise in the pancreas and harbor characteristic ovarian‐type stroma beneath the epithelium. In this study, we compared the immunoreactivity of steroid‐related factors in these subepithelial stromal cells in MCNs to those in intraductal papillary mucinous neoplasms (IPMNs) to further characterize this unique MCN ovarian‐type stroma through evaluation of sex steroid biosynthesis. Twenty MCNs and twenty IPMNs were examined. Immunoreactivity of steroid hormone receptors, including estrogen receptor (ERα and ERβ), progesterone receptor (PR, PR‐A, and PR‐B), and androgen receptor (AR), was more frequently detected in MCN ovarian‐type stromal cells than in IPMN stromal cells (P < 0.01). The H‐scores (mean ± SD) of steroidogenic factor (SF)‐1 were also significantly higher in MCNs (112.3 ± 33.1) than in IPMNs (0.9 ± 1.2) (P < 0.01). The steroidogenic enzymes cytochrome P450 cholesterol side‐chain cleavage enzyme (P450scc), cytochrome P450 17 alpha‐hydroxylase (P450c17) and 3β‐hydroxysteroid dehydrogenase (3β‐HSD) showed immunoreactivity in 9/20 (45.0 %), 15/20 (75.0 %) and 13/20 (65.0 %), respectively, of ovarian‐type stroma from MCN cases. These results demonstrate that the ovarian‐type stroma of MCNs can express steroidogenic enzymes. Thus, the ovarian‐type stroma of MCNs can produce sex steroids that may also act on these cells.     

Ovarian enzymatically active stromal cells can be a promoter of ovarian surface epithelial tumor

Surface epithelial tumors (SETs) are the most common neoplasms of the ovary. They are traditionally thought derived from the ovarian surface or, as a recent hypothesis suggests, from various sources outside of ovary. Enzymatically active stromal cells (EASCs) are scattered in stroma of ovary, and characterized by their steroid-producing ability. With my observation of the increased EASCs near the epithelial cells of SETs, I hypothesize the epithelial cells of SETs can cause the increase of EASCs by converse adjacent stromal cells to EASCs; and EASCs, as a positive feedback, can prompt the proliferation of their neighbouring epithelial cells of SETs by secreting steroid hormone.     

Anti-Müllerian hormone is a specific marker of sertoli- and granulosa-cell origin in gonadal tumors

Sex cord stromal tumors are gonadal neoplasms containing Sertoli, granulosa, Leydig, or thecal cells, which originate from cells derived from either the sex cords (Sertoli and granulosa cell tumors) or the specific mesenchymal stroma (Leydig and thecal cell tumors) of the embryonic gonad. Only granulosa and Sertoli cells produce anti-Müllerian hormone (AMH). Our purpose was to investigate whether AMH can be used as a specific marker of human granulosa or Sertoli cell origin in gonadal tumors, to distinguish them from other primary or metastatic neoplasms, using immunohistochemistry. We studied 7 juvenile and 6 adult-type granulosa cell tumors of ovarian localization and 3 extraovarian metastases, 20 other ovarian tumors, 6 testicular Sertoli cell tumors, 2 gonadoblastomas, and 13 extragonadal tumors. Granulosa cell tumors, both juvenile- and adult-type of either ovarian or metastatic localization, showed an heterogeneous pattern of AMH immunoreactivity: Areas containing intensely or weakly AMH-positive cells were intermingled with AMH-negative areas. Although in most cases AMH-positive areas represented a minor proportion of tumor cells, we found a positive reaction in all the cases examined. In testes, although normal prepubertal Sertoli cells were intensely positive, testicular Sertoli cell tumors showed large areas of negative reaction, with few positive cells scattered throughout the tumor. AMH was also reactive in most of the cells of sex-cord origin in gonadoblastomas. No AMH immunoreaction was observed in other gonadal and extragonadal tumors. We conclude that AMH expression is conserved in only a small proportion of tumor cells of granulosa or Sertoli cell origin; however, a positive reaction in a few cells helps to distinguish between granulosa or Sertoli cell tumors or gonadoblastomas and other gonadal tumors of different origin.     

Functional ovarian tumors of stromal and sex cord origin.

Most functional ovarian tumors are of specific stromal or sex cord origin, capable of differentiating in either a female direction or, less commonly, a male direction. Tumors of stromal origin such as thecoma, stromal luteoma, and Leydig cell tumors are for all practical purposes benign, and evolve from mature ovarian stroma, recapitulating common non-neoplastic transformations such as stromal changes associated with follicle development and nodular stromal hyperplasia. Sex cord tumors of granulosa or Sertoli cell types are generally of a low order of malignancy, tending to late recurrence, occasional peritoneal seeding, and only rarely to distant metastasis. Nonfunctional tumors of the ovary may trigger hormone production from adjacent reactive stroma. Massive edema of the ovary due to partial torsion may simulate neoplasm and may produce hormonal syndromes by an unknown mechanism.     

Immunohistochemical staining for calretinin is useful in the diagnosis of ovarian sex cord–stromal tumours

AIMS: Ovarian sex cord-stromal tumours are a heterogeneous group of neoplasms which may be confused morphologically with a wide variety of tumours. Calretinin positivity has previously been demonstrated in a small number of ovarian sex cord-stromal tumours. The aim of this study was to investigate calretinin staining in a series of these tumours and their histological mimics in order to determine the value of calretinin staining in a diagnostic setting. METHODS AND RESULTS: Seventy-two neoplasms, including 37 ovarian sex cord-stromal tumours and 35 miscellaneous neoplasms which may enter into the differential diagnosis, were stained with a commercially available polyclonal antibody against calretinin. All sex cord-stromal tumours exhibited positivity except for a single fibrothecoma. In this group of tumours staining was generally diffuse and strong. Small numbers of the miscellaneous group of neoplasms exhibited positivity but this tended to be focal and weak, although this was not always the case. There was consistent strong positive staining of granulosa cells in follicular cysts and corpora lutea. There was also positive staining of luteinized stromal cells in two cases of ovarian stromal hyperplasia and hyperthecosis. CONCLUSIONS: Calretinin is a sensitive immunohistochemical marker of ovarian sex cord-stromal tumours and may be useful in a diagnostic setting. However, the value is somewhat limited since occasional neoplasms which enter into the morphological differential diagnosis may be positive. Be that as it may, calretinin positivity may be of value in the diagnosis of an ovarian sex cord-stromal tumour and its differentiation from other neoplasms. In this regard, calretinin should always be used as part of a larger panel.     

Pancreatic, hepatic, splenic, and mesenteric mucinous cystic neoplasms (MCN) are lumped together as extra ovarian MCN

Mucinous cystic neoplasms (MCN) of the pancreas are mucin-producing cystic tumors with an ovarian-like stroma (OLS). In the present study MCN were obtained from 27 patients. These MCN were derived from 22 pancreas, three livers, spleen, and mesentery. MCN in various organs have common clinicopathological profiles, being unilocular or multilocular cystic tumors, with a fibrous capsule and lined by mucin-secreting epithelium associated with an underlying subepithelial OLS. The OLS showed strong positivity for alpha-smooth muscle actin (alpha-SMA) and vimentin and weak, focal positivity for desmin. Both estrogen receptors and progesterone receptors were expressed in the nuclei of OLS cells. In addition, 20 ovarian MCN and 13 normal ovaries were studied with particular attention to the stroma. The stroma of ovarian MCN was strongly immunopositive for alpha-SMA and vimentin and focally positive for desmin, whereas normal ovarian stroma was immunonegative for both alpha-SMA and desmin. The OLS of MCN mentioned here was similar to the septa of ovarian MCN but not to ovarian stroma. In conclusion, MCN in various organs should be lumped together as 'extra ovarian' MCN. The OLS was identified on the basis of myofibroblastic proliferation both in response to neoplastic development and dependent on hormones.     

具有内分泌功能的卵巢肿瘤

目的探讨具有内分泌功能的卵巢肿瘤的临床病理特征.方法对本院临床表现有内分泌功能并经手术治疗的24例卵巢肿瘤进行临床内分泌表现、组织学类型分析,并行免疫组织化学EnVision二步法染色,抗体为AE1/AE3、上皮膜抗原(EMA)、α-抑制素、Calretini、平滑肌肌动蛋白(SMA).结果 (1)临床内分泌的表现主要为性激素异常, 在幼女或绝经后妇女均有较明显的症状和体征,而在生育年龄妇女则表现的较为隐匿和复杂.(2)肿瘤的组织学类型主要为卵巢性索-间质肿瘤卵巢型13例(颗粒细胞瘤8例,泡膜纤维瘤2例,硬化性间质瘤3例),睾丸型7例(支持细胞瘤1例,支持- Leydig细胞瘤5例,Leydig细胞瘤1例),非特异性类固醇细胞瘤2例;这类肿瘤11例直径<5 cm,4例较大或巨大,最大直径达18 cm;切面多为灰粉黄色,实性或囊实性.另外2例为原发上皮性肿瘤,直径分别为12 cm和14 cm.(3)免疫组织化学染色显示卵巢性索-间质肿瘤α-抑制素全部(22/22)和Calretini绝大多数(18/22)呈阳性表达,组织形态分化好的区域表达强于分化差的区域;2例上皮性肿瘤的间质黄素化细胞也呈阳性表达.SMA在5例泡膜纤维瘤和硬化性间质瘤均呈强阳性表达,部分(3/8)颗粒细胞瘤呈弱阳性表达.部分(6/22)性索-间质肿瘤AE1/AE3阳性表达,但EMA均为阴性.结论具有内分泌功能的卵巢肿瘤多数临床表现为性激素的异常,临床表现与肿瘤的组织学类型不完全一致.其组织学类型主要为性索-间质肿瘤.非性索-间质性卵巢肿瘤也可表现为性激素异常.免疫组织化学染色可协助诊断,并用于与上皮性肿瘤鉴别.     

胰腺黏液性囊性肿瘤临床病理分析

目的；探讨胰腺黏液性囊性肿瘤（MCN）的临床病理学特点。方法：6例MCN均行B超或CT检查。除1例外，均作了手术切除治疗。对6例（MCN）作常规HE及免疫组织化学染色观察。结果：6例MCN中，女性4例，男性2例，平均年龄47岁，均位于胰腺体尾部。黏液性囊腺瘤（MCA）3例，囊壁内衬高柱状黏液上皮，上皮周围可见卵巢样间质组织；黏液性囊腺癌（MCC）3例，黏液上皮 有不典型增生，均有囊壁或胰腺组织的浸润，1例上皮周围可见卵巢样间质。CEA和CK 7在上皮中均阳性，c-erbB－2均阴性，间质SMA均阳性。结论：胰腺MCN是好发于中年女性的少见肿瘤，绝大多数发生于胰腺体尾部。MCA内衬高柱状上皮，上皮外来卵巢样间质包绕；MCC上皮细胞有不典型增生， 浸润性生长。MCN手术切除率高。     

Histological classification of ovarian cancer

The histology of ovarian tumors exhibits a wide variety of histological features. The histological classification of ovarian tumors by the World Health Organization (WHO) is based on histogenetic principles, and this classification categorizes ovarian tumors with regard to their derivation from coelomic surface epithelial cells, germ cells, and mesenchyme (the stroma and the sex cord). Epithelial ovarian tumors, which are the majority of malignant ovarian tumors, are further grouped into histological types as follows: serous, mucinous, endometrioid, clear cell, transitional cell tumors (Brenner tumors), carcinosarcoma, mixed epithelial tumor, undifferentiated carcinoma, and others. Clear cell and endometrioid carcinomas are highly associated with endometriosis. In stage distribution, serous carcinoma is found predominantly is stage III or IV. In contrast, clear cell and endometrioid carcinomas tend to remain confined to the ovary. Clear cell and endometrioid carcinomas may be unique histological types compared with serous carcinomas with respect to stage distribution and association with endometriosis.     

Mitotically active cellular luteinized thecoma of the ovary and luteinized thecomatosis associated with sclerosing peritonitis: Case studies,comparison, and review of the literature

In this study, we distinguish two clinical and pathological entities that are similarly named: luteinized thecoma and luteinized thecoma associated with sclerosing peritonitis. Ovarian luteinized thecoma lacks definitive criteria for malignancy. Based on our case study of a mitotically active neoplasm without nuclear atypia in which the patient was living and well 19 years after operation and comparison with prior studies of luteinized thecoma and the closely related entity of cellular fibroma, we propose presumptive criteria for malignancy for this rare neoplasm. Increased mitotic activity in luteinized thecoma without significant nuclear atypia is not an indication of malignant behavior, and such cases should therefore be referred to as mitotically active cellular luteinized thecoma. We also contrast neoplasms in the luteinized thecoma category with the entity originally reported as luteinized thecoma associated with sclerosing peritonitis. In the latter, the ovarian stromal proliferations are typically bilateral, can have an exceedingly high mitotic rate as was seen in our illustrative case, often incorporate non-neoplastic ovarian structures at their periphery, and are responsive to medical therapy. In our patient with sclerosing peritonitis, both the ovarian masses and peritoneal sclerosis underwent complete regression following treatment with gonadotropin-releasing hormone agonist and high doses of steroids, and an ovarian biopsy taken 2 months after therapy showed a histologically normal ovary. The patient subsequently became pregnant and delivered a normal infant. This is, to our knowledge, the first case of successful medically conservative treatment of a young patient with this entity that led to complete relief of symptoms and allowed preservation of fertility. Because recent observations support the non-neoplastic nature of the ovarian stromal proliferations, we advocate use of the previously proposed term luteinized thecomatosis associated with sclerosing peritonitis for this entity.     

Determination of steroid hormone-dependency of tumours utilizing tissue sections. Survey of histochemical techniques and their application in surgical pathology

The growth of neoplasms originating from steroid hormone target tissues may be hormone-dependent. It has been clearly demonstrated that the oestrogen and/or progestagen receptor status predicts the response to endocrine treatment and the prognosis of breast cancer. However steroid receptor determination in tumour cytosols has several limitations, which can partly be resolved by (immuno) histochemical detection of steroid hormone-responsive tumour cells. A variety of histochemical techniques including autoradiography of tritiated steroids, immunohistochemistry with antibodies to steroid hormones, histochemistry with fluorescent ligands of low molecular weight and fluorochrome- or enzyme-labelled macromolecular probes are discussed. It is concluded that there is as yet no substantial evidence that these methods visualize steroid receptors or detect steroid hormone-responsiveness of tumour cells. On the other hand, immunohistochemical demonstration of oestrogen receptors with monospecific antibodies seems validated and indications have been obtained that this information is clinically relevant. Recent developments suggest that immunocytochemistry of receptors and specific hormone-induced proteins, flow cytometric analysis and probably hybridocytochemistry in the future will help to improve management of steroid hormone-dependent tumours.     

Hormone-producing tumors of the ovary

The ovary is an endocrine organ that gives rise to a wide variety of neoplastic and tumorlike nonneoplastic conditions, some of which are associated with endocrine activity. The hormones produced may be steroidal or nonsteroidal. The ovary is unique among endocrine organs in reacting to the presence of nonendocrine tumors within it by abnormal or inappropriate production of sex steroidal hormones. A classification of hormone-producing ovarian lesions is proposed based on the World Health Organization’s histologicai typing of ovarian tumors.     

Calcifications in ovary and endometrium and their neoplasms.

In this study, we investigated the role of hormones in the pathogenesis of calcifications in ovary and in endometrium and their neoplasms of the gynecologic tract and assessed the anatomic location and incidence of these calcifications. The study consists of three parts designed to investigate the pathogenesis, the location, and the incidence of calcifications in ovary and endometrium and their neoplasms. In the first part, 79 female guinea pigs were divided into 10 groups, and different hormones, given weekly for 12 months, were administered to the guinea pigs by group. A control group of 7 guinea pigs received sterile water. Calcifications developed in 5 of 7 guinea pigs treated with prolactin, 10 of 20 treated with human chorionic gonadotropin, 5 of 11 treated with estradiol, 3 of 7 treated with estrone, 1 of 6 treated with growth hormone, and 1 of 10 treated with testosterone; in 20 of the guinea pigs, the calcifications developed in the stroma of the endometrium, and in 5 guinea pigs, they developed in the ovary. The second part of the study consisted of an evaluation of the specific location of calcifications in 43 consecutive human surgical ovaries and endometria. Calcifications were seen only in the stroma in 100% of the ovarian serous adenofibroma specimens; in ovarian serous borderline neoplasms, the stroma contained 70 to 100% of the calcifications, and the epithelium had 0 to 30% of the calcifications. In ovarian serous carcinoma specimens, the calcifications were seen in the stroma in 50 to 60% of the cases, in the epithelium in 40% of the cases, and in areas of necrosis in 10% of the cases. The third part of the study was directed to determine the frequency of calcifications in ovarian lesions. We found that all cases of endosalpingiosis and ovarian low-grade serous carcinoma had calcifications, whereas 80% of the cases of serous borderline tumor had calcifications, and only 50% of the cases of ovarian high-grade serous carcinoma contained calcifications. The results of this study indicate that the majority of the calcifications in the ovary and the endometrium and their neoplasms are present in the stroma. This is most probably secondary to metabolic changes, which could be related to hormones and not caused by degenerative changes in epithelial cells.     

Surface epithelium of the developing ovary. Possible correlation with ovarian neoplasia.

The surface epithelium of the fetal ovary undergoes diffuse proliferation during the fourth and fifth months of gestation, after which it reverts to a single layer separated from the developing cortex by a tunica albuginea. The proliferation is associated with marked nuclear irregularity and pleomorphism similar to that seen in surface epithelial neoplasms. The epithelial changes occur during the same time period that interstitial cells with ultrastructural and histochemical properties of steroid-secreting tissue appear in the ovarian stroma. The possible role of steroid hormones in stimulating surface epithelial proliferation is discussed.