Normal Ovarian Histology: A Pathology Resident's Guide
The ovary consists of three main anatomical compartments that you must recognize on every slide: the outer cortex containing follicles at various developmental stages, the inner medulla with vascular and stromal elements, and the surface epithelium 1, 2.
Surface Epithelium
The ovarian surface is lined by a single layer of cuboidal to flattened mesothelial-type cells (surface epithelium), which is continuous with the peritoneum and distinct from the underlying cortical stroma 2. This surface epithelium is the traditional (though now disputed) origin theory for epithelial ovarian cancers 3. You'll frequently encounter surface epithelial invaginations forming inclusion cysts, which are benign structures lined by similar cuboidal epithelium and should be distinguished from endosalpingiosis 1.
Cortex: The Follicular Compartment
The cortex contains the defining feature of ovarian histology: follicles at all stages of development embedded in a dense cellular stroma 1, 2.
Primordial Follicles
- Primordial follicles consist of an oocyte surrounded by a single layer of flattened granulosa cells 2
- Distribution is highly variable—you may see them concentrated in the superficial cortex or scattered throughout, even extending into the medulla, particularly in cases with multiple follicular cysts 1
- The number and distribution of primordial follicles varies significantly not only between patients but even between the two ovaries in the same patient 1
Developing Follicles
- Primary follicles show an oocyte surrounded by a single layer of cuboidal granulosa cells 2
- Secondary (preantral) follicles display multiple layers of granulosa cells with early theca cell layer formation around the basement membrane 2
- Tertiary (antral/Graafian) follicles are characterized by a fluid-filled antrum, a multilayered granulosa cell population, and a well-developed theca interna and externa 2
Corpus Luteum and Corpus Albicans
- The corpus luteum consists of large luteinized granulosa cells with abundant eosinophilic cytoplasm arranged in folds, surrounded by luteinized theca cells 2
- The corpus albicans represents the hyalinized scar tissue remnant of a regressed corpus luteum 2
Medulla: Vascular and Stromal Core
The medulla contains loose connective tissue stroma with abundant blood vessels, lymphatics, and nerves 4, 2.
Hilar (Leydig) Cells
- Hilar cells (Leydig-like cells) may be present near the ovarian hilum, appearing as clusters of polygonal cells with eosinophilic cytoplasm and round nuclei 4, 2
- These cells can produce androgens and are a normal finding, not to be confused with pathology 2
Ovarian Stroma: Sex Cord-Stromal Derivatives
The ovarian stroma is not inert connective tissue but contains specialized cells derived from embryonic gonadal sex cords 4. You must recognize these normal cellular components:
- Granulosa cells: surround developing oocytes in follicles 4
- Theca cells: form layers around developing follicles (theca interna and externa) 4
- Sertoli cells and Leydig cells: sex cord derivatives that may be present in small numbers 4
These stromal elements are the origin of sex cord-stromal tumors (granulosa cell tumors, thecomas, Sertoli-Leydig cell tumors) 5, 4.
Critical Variations and Pitfalls
Normal Histologic Variation
Significant variation exists in the amount and distribution of primordial follicles, follicular cysts, and endosalpingiosis within a single ovary and between both ovaries in the same patient 1. Don't overcall pathology based on asymmetry or focal findings.
Follicular Cysts
- Follicular cysts are common normal findings, defined as follicles >2.5-3 cm 1, 2
- Multiple follicular cysts correlate with increased primordial follicles in the medulla 1
Endosalpingiosis vs. Inclusion Cysts
Endosalpingiosis consists of glands lined by tubal-type epithelium (ciliated and secretory cells) and is closely associated with low-grade serous neoplasia, whereas simple inclusion cysts are lined by flattened to cuboidal mesothelial-type cells without cilia and have no known disease association 1. This distinction matters for risk stratification.
Age-Related Changes
In premenopausal patients, expect active follicular development with primordial follicles readily identifiable 1. The ovarian cortex becomes progressively more fibrotic and follicle-depleted with advancing age 2.
Practical Sampling Considerations
When examining ovarian specimens, meticulous macroscopic examination must precede histological analysis, with multiple well-directed samples (one section per centimeter along the greatest diameter) from all ovarian lesions 5. For normal-appearing ovaries removed during staging procedures, adequate sampling of both cortex and medulla is essential to exclude occult pathology 5.