Normal Ovarian Development and Biology

Human Ovarian Development

As early as 3 weeks gestation, large primordial germ cells appear intermixed with other cells in the endoderm of the yolk sac wall of the primitive hindgut. These germ-cell precursors migrate and are contained in the mesenchyme of the urogenital ridge by 8 weeks.²

At 4 weeks gestational age, a thickening of the coelomic epithelium on the ventromedial surface of the urogenital ridge occurs. This bulging of the genital ridge is produced by the rapid proliferation of the coelomic epithelium medial, but parallel to the mesonephric ridge. Prior to the 5th week, this indifferent gonad consists of a surface epithelium (derived from the coelomic epithelium) surrounding the internal blastema. The blastema is a primordial mesenchymal cellular mass, destined to become the ovarian medulla. After 5 weeks, projections of the surface epithelium extend into the blastema to form primary sex cords. In the absence of the Y chromosome, definitive ovarian characteristics do not appear until the 12th through the 16th week.²

At 20 weeks, the first evidence of follicles is seen, consisting of germ cells surrounded by flattened cells derived from the cortical sex cords. The flattened cells, granulosa cells are of surface/coelomic epithelial origin and theca cells of mesenchymal origin.²

Regression of the primary sex cords produces the rete ovarii, found in the hilus of the ovary.²

Approximately 90% of human ovarian carcinomas arise from the ovarian surface epithelium, a single layer of flat-to-cuboidal epithelial cells.³ The ovarian surface epithelium is derived from the coelomic epithelium.³

The coelomic epithelium also gives rise to the Mullerian (paramesonephric) ducts, which will, in turn, differentiate into the epithelia of the oviduct, endometrium, and endocervix.²

Human Ovarian Structure

Each ovary is connected, by its anterior straight margin, to the broad ligament; by its lower extremity, to the uterus by the ligament of the ovary.² Due to the fact that that vast majority of ovarian carcinomas are derived from the surface epithelium, it is important to discuss the morphology and structure of this cellular layer. The surface epithelium is characterized by keratin types 7,8,18, and 19, the same keratin complement as other simple epithelia.³

Figure 1, Human Ovary, *CK19 staining

Intracellular contact is maintained by desmosomes, incomplete tight junctions, integrins, and cadherins.³ Cadherins are calcium-dependent adhesion molecules mediating selective cell-cell adhesion and gene expression through catenins. In humans, the ovarian surface epithelium is connected through N-cadherin, which is found in mesodermally-derived tissues. In contrast, E-cadherin is the principal intercellular adhesion molecule of most epithelia, outside of the ovarian surface epithelium. Mouse and porcine ovarian surface epithelia contain E-cadherin. E-cadherin also forms the junctions of human oviductal, endometrial, and endocervical epithelia. In contrast, E-cadherin is found where human ovarian surface epithelium assumes a columnar shape, approaching a metaplastic phenotype. Coexpression of E-cadherin and N-cadherin in human ovarian surface epithelium may signify a progression towards neoplasia.³ CA-125 is expressed by oviductal, endometrial, and endocervical epithelia, the Mullerian duct-derived epithelia. In tissue culture, CA-125 is expressed by normal human ovarian surface epithelium.⁴ Hence, in ovarian surface epithelia-derived carcinomas often express CA-125.³ Like traditional epithelia, the ovarian surface epithelium secretes a basement membrane. However, the ovarian surface epithelium is only loosely attached to its basement membrane.³ The ovarian surface epithelium is able to differentiate in response to ovulatory rupture. After rupture, the ovarian surface epithelium assumes a stromal phenotype. Acquiring epithelial characteristics of Mullerian duct-derived epithelia is a step in the progression of the ovarian surface epithelium towards neoplasia.³

Ovarian Cancer

Malignancies of the ovarian surface epithelium represent 90% of all malignant ovarian neoplasms. Other tumors derive from the granulosa cells, and, even more rarely, from the stroma or germ cells.³

The 5-year survival for so-called epithelial ovarian cancer is 30-40%, largely due to the fact that most ovarian carcinomas are diagnosed at an advanced stage. In addition, ovarian cancers are, or may become, refractory to therapy.

Several environmental factors have been implicated in the etiology of ovarian cancer, including diet, talc, industrial pollutants, smoking, asbestos, and infectious agents.³

The first hypothesis as to why the surface epithelium might be predisposed to malignant transformation was put forward by Fathalla in 1971.⁵ This pathologist speculated that the process was somehow related to the rupture of the surface epithelium that happens when ovulation occurs. He based this theory on several lines of evidence, which mainly focused on epidemiological studies that associated nulliparity, ie, frequent ovulations, with an increased risk of ovarian cancer. He also cited data that purported a high frequency of peritoneal carcinomatosis believed to be of ovarian origin in chickens forced to incessantly ovulate by the elimination of seasonal anovulatory rest.^6,7 The idea was that there must be something about the repetitious requirement for the surface epithelial cells to divide and repair the ovulatory wound that contributed to transformation. Now, of course, it is known that the process of DNA replication itself is mutagenic.⁸ Before considering in more detail, theories about why ovulation may drive ovarian oncogenesis and how the inhibition of ovulation is preventative, it is helpful to recall what is known about normal surface epithelium and its transformed counterpart. This is especially true with regard to information about how the growth of the surface epithelium is regulated, since repetitious growth of these cells figures so highly in how it is believed ovarian cancer arises.

The ovarian surface epithelial cells are modified peritoneal mesothelial cells and are contiguous with those cells that line the peritoneal cavity. It is of interest that these cells, even in their normal surface context, are often more differentiated than the peritoneal mesothelium. This may well be due to their proximity to the hormone and growth factor-producing components of the ovary for which they have receptors and is clearly evident when they become entrapped in the ovarian cortex and form inclusion cysts.^9,10

Figure 2. Human Ovary with Inclusion Cyst

An estimated 5%-10% of epithelial ovarian cancer is inherited.¹¹ Analysis of these patients reveals factors that are now considered principles of cancer genetics. These factors include:

• Early age of onset, 15-20 years earlier than the sporadic counterpart. The median age of diagnosis of familial ovarian cancer is 47 years of age, whereas the median age of diagnosis of sporadic ovarian cancer is 59 years.
• Bilaterality in paired organs.
• Hallmark sites for tumors in specific cancer syndromes.
• Presence of precursor physical or microscopic biologic markers.
• Classic Mendelian inheritance patterns; the most prevalant is autosomal dominant.¹²

There are 3 autosomal dominant ovarian cancer syndromes.

• Family history of ovarian cancer as the only site of disease - incurs an approximate 3.6-fold increase in risk.
• Lynch Syndrome II or Heredity Nonpolyposis Colon Cancer - ovarian cancer concomitant with a high incidence of colon and endometrial cancer, associated with mutations in DNA mismatch-repair genes
• Heredity breast/ovarian cancer - approximate 10% to 50% increase in ovarian cancer or breast cancer risk among women with a family history of breast or ovarian cancer, respectively. Linked to mutations in the BRCA1 and BRCA2 tumor suppressor genes, associated with DNA damage response.

In the transformation to neoplasia, the ovarian surface epithelium takes on characteristics of Mullerian duct-derived epithelia (oviduct, endometrium, and uterine cervix). This abberant differentiation forms the basis for ovarian cancer classification. Serous, mucinous, endometrioid, clear cell, and transitional cell neoplasms arise from the surface epithelium. Serous adenocarcinomas comprise 80% of all epithelial ovarian cancers, and their histology is reminiscent of the fallopian-tube. [Figure 3] Endometrioid carcinomas [Figure 4] and mucinous carcinomas [Figure 5] have histological features similar to endometrial and endocervical tissues, respectively.

Figure 3. Serous Adenocarcinoma. A tall, columnar, ciliated epithelial cell lining and aclear serous fluid filling the cystic space are characteristic of these most common ovarian surface epithelial malignancies.13	Figure 4. Endometrioid carcinoma. Approximately 40% of endometrioid carcinomas involve both ovaries. Endometrioid carcinomas are distinguished from serous and mucinous tumors by the presence of tubular glands resembling endometrium.13	Figure 5. Mucinous cystadenocarcinoma. Nonciliated, mucin-secreting, columnar epithelium lines mucinous cystadenocarcinomas.13

Germ cell tumors [Figure 6] are the second most common type of malignant ovarian tumors and include the teratomas, dysgerminomas, endodermal sinus tumors, and choriocarcinomas. Sex-cord and stromal-derived tumors are the most rare ovarian tumors and consist of fibromas, granulosa-theca cell tumors [Figure 7], and Sertoli-Leydig cell tumors.¹³

Figure 6. Germ cell tumor. Teratomas are the predominant germ cell tumor and occur primarily in children and young adults. The vast majority of these tumors are benign.13	Figure 7. Granulosa tumor. Granulosa tumors have several histologic patterns. Cuboidal to polygonal cells may grow in anastamosing cords, sheets, or strands. In some cases, Call-Exner bodies, gland-like structures filled with acidophillic material, may be present.13

The rarest of all malignant ovarian tumors are clear-cell carcinomas [Figure 8].¹³ Occasionally these aggressive tumors occur concomitantly with endometriosis or endometrioid carcinoma of the ovary.

Figure 8. Clear-cell tumor. Characterized by large epithelial cells with abundant cytoplasm, clear-cell tumors are extremely rare. Either solid or cystic, these tumors are thought to be of mullerian-duct origin.13