I. NORMAL GROSS AND MICROSCOPIC ANATOMY. The ovaries rest on either side of the uterus and are anchored by the broad ligament. Age and reproductive status greatly impact size and weight, which range from 3 to 5 cm and 5 to 8 g, respectively. The outer surface of the ovary is white-tan and smooth during early reproductive years but becomes more bosselated with age due to repeated rupture of ovarian follicles. The cut surface is vaguely organized into three ill-defined zones: an outer cortex, underlying medulla, and inner hilum. The cortex and medulla contain cystic follicles, yellow or orange corpora lutea, and gritty, white corpora albicantia.
Histologic sections of the ovary show a simple cuboidal surface epithelial layer derived from mesothelium. Within the ovarian cortex and medulla, follicular structures composed of an inner layer of granulosa cells and an outer layer of theca cells (e-Fig. 31.1*. and e-Fig. 31.2), in varying phases of development, are surrounded by a stroma comprised closely packed S-shaped spindled cells and collagen (e-Fig. 31.3). Centrally hemorrhagic corpora lutea composed of granulosa cells with abundant eosinophilic cytoplasm and smaller theca cells (e-Fig. 31.4 and e-Fig. 31.5), as well as white acellular corpora albicantia (e-Fig. 31.6), may also be seen. The hilus, where the ovary connects to the broad ligament, is composed of abundant blood vessels, nerves, and interspersed eosinophilic hilar cells that are histologically similar to the Leydig cells of the testis (e-Fig. 31.7). Rete ovarii, the developmental analogue of the rete testis that are composed of slit-like spaces lined by nonciliated cuboidal epithelium, are also present in the hilum (e-Fig. 31.8).
II. GROSS EXAMINATION AND TISSUE SAMPLING. The most common ovarian specimens encountered in surgical pathology are from oophorectomy (with or without hysterectomy) or cystectomy procedures. The weight and gross measurements of all three dimensions are recorded. The capsule is inspected for areas of rupture, adhesions, tumor involvement, or other abnormalities. In most cases, the ovary is then bivalved along the long axis and any lesions on the cut surface are noted. Solid, cystic, or papillary lesions are thoroughly sampled (one section per cm). If no lesions are identified, one section for every 2 cm is adequate. If cysts are present, the color and consistency of the cyst fluid are noted, and any areas of nodularity or papillary excrescences are sampled. Prophylactic oophorectomy specimens, performed for a personal history of cancer or family history of a hereditary cancer syndrome, are cut perpendicular to the long axis and entirely submitted.
The surgical management of malignant primary ovarian tumors typically includes a staging procedure, and so an ovary excised for a primary malignancy will usually be accompanied by multiple abdominal-peritoneal biopsies, an omentectomy specimen, and regional lymph nodes. The small peritoneal biopsies are submitted entirely. The omentum sample must be serially sectioned. If grossly visible tumor is present, it should be measured and only one section needs to be submitted; when no tumor is identified, from 5 to 10 sections are submitted. All identified lymph nodes are submitted from the lymph node dissections.
III. DIAGNOSTIC FEATURES OF COMMON BENIGN DESEASES OF THE OVARY
A. Inflammatory Diseases
1. Infection of the ovary is almost always accompanied by infection of the fallopian tube (e-Fig. 31.9), systemic infection, or the development of a
tubo-ovarian abscess (e-Fig. 31.10). The most common cause of oophoritis is ascending pelvic inflammatory disease (PID), which typically causes intense pelvic pain and is usually polymicrobial. The ovary contains sheets of neutrophils and often shows paraovarian adhesions or adhesions to an inflamed fallopian tube. Severe PID may require hospitalization and treatment, while mild PID may resolve on its own. The subsequent fibrosis and scarring from PID is a leading cause of infertility (e-Fig. 31.11).
2. Autoimmune oophoritis typically presents with oligomenorrhea and infertility and is often associated with other autoimmune disorders. The ovaries are normal in size but filled with a lymphoplasmacytic infiltrate in developing follicles and corpora lutea. Premature ovarian failure and premature menopause is the final sequelae of the disease.
3. Noninfectious granulomas may also be seen within the ovary as an incidental finding. These may form secondary to systemic diseases such as sarcoidosis, or represent a foreign body response following a pelvic or abdominal surgery.
B. Cysts
1. Follicular cysts are commonly found in prepubescent and reproductive-aged women. Normal follicles measure only up to 1 cm in greatest dimension, while follicular cysts measure 2.5 to 10 cm in diameter and contain serosanguineous fluid. Most cysts are asymptomatic, but women may present with an abdominal mass or rupture. Follicular cysts are typically unilateral with a thin, smooth lining comprised an inner layer of granulosa cells and an outer layer of theca cells similar to normal follicles. Multiple follicular cysts may be associated with polycystic ovarian syndrome (PCOS) and McCune-Albright syndrome.
2. Corpus luteum cysts are also common in women of reproductive age. Like follicular cysts, they may present as a mass or with rupture. On gross examination, corpus luteum cysts are >3 cm, filled with thick hemorrhagic fluid, and rimmed by a yellow lining. Microscopically, the cyst has an undulating wall of luteinized granulosa cells (that have abundant, eosinophilic cytoplasm) with interspersed peripheral theca cells with an overall architecture similar to that of a normal corpus luteum.
3. Polycystic ovarian syndrome is an incompletely understood disease characterized by anovulation, infertility, hirsutism, and obesity. It is estimated that up to 10% of American women are affected by this syndrome, which typically presents between the ages of 20 and 30. In general, the ovaries are enlarged with a thickened, collagenized cortical surface; multiple, uniform follicles all in a similar phase of development (typically antral); and an absence of corpora lutea (indicting infrequent ovulation) (e-Fig. 31.12).
4. Surface epithelial inclusion cysts, thought to be formed by repeated invaginations of ovarian epithelium secondary to surface rupture with ovulation, are common. By convention, inclusion cysts measure <1 cm in diameter. The cysts are lined by a single layer of bland flat, cuboidal, or ciliated columnar cells (e-Fig. 31.13). Psammoma bodies may be seen. It is hypothesized that benign, borderline, and low-grade serous epithelial neoplasms arise from these inclusions.
5. Paraovarian or paratubal cysts are found in the hilar region of the ovary and arise from mesonephric (Wolffian) or paramesonephric (Müllerian) duct remnants. Mesonephric cysts are lined by simple or stratified epithelium and have prominent muscular walls (e-Fig. 31.14). Paramesonephric cysts are lined by columnar epithelium with a mixture of ciliated and nonciliated cells similar to epithelial inclusion cysts (e-Fig. 31.13).
6. Endometriosis, characterized by endometrial glands and stroma outside the uterus, is frequently seen within the ovary. Symptomatic patients typically present during the reproductive years with menstrual-associated pain and
infertility. Grossly, the ovary shows a thickened cortex, surface adhesions, and a cyst filled with thick brown fluid resembling chocolate syrup, the so-called chocolate cyst. Histologically, endometrial epithelium or glands and stroma with associated hemosiderin-laden macrophages and fibrosis are diagnostic (e-Fig. 31.15). Endometriotic cysts frequently contain areas with atypical cytologic features associated with acute inflammation, but areas of epithelial tufting, more complex architectural changes, or increased mitotic activity should raise suspicion for malignancy arising in endometriosis.
C. Hyperplastic changes
1. Stromal hyperplasia, defined as a proliferation of non-luteinized ovarian stroma in the cortex and medulla, and hyperthecosis, luteinized stromal cells in a background of stromal hyperplasia (e-Fig. 31.16), are changes most commonly seen in the sixth to seventh decades of life and in women with PCOS. The ovaries are enlarged bilaterally. While most women are asymptomatic, some present with estrogenic symptoms (endometrial hyperplasia) or androgenic symptoms (acne) due to hormone production by the luteinized cells.
2. Hilus (Leydig) cell hyperplasia is most common in postmenopausal women who also have stromal hyperplasia and hyperthecosis. The hilus cell proliferation rarely causes symptoms on its own. Microscopically, eosinophilic cells with hyperchromatic nuclei are arranged in nests or clusters found most often in the hilar region of the ovary. Elongated, eosinophilic intracytoplasmic inclusions, called Reinke’s crystals, may be seen (e-Fig. 31.17).
D. Pregnancy changes
1. Solitary luteinized follicle cysts are benign, unilocular, unilateral cysts that may grow up to 25 cm in diameter. They have the same lining of inner granulosa cells and outer theca cells as normal follicles.
2. Hyperreactio luteinalis is characterized by symmetric, bilateral enlargement of the ovaries with multiple luteinized cysts. The condition is associated with high levels of human chorionic gonadotropin, which also occurs with multiple pregnancies, ovulation induction protocols, and gestational trophoblastic disease. The cysts usually resolve in the months after completion of pregnancy. Microscopically, the follicular cysts are lined by luteinized granulosa and theca cells with stromal edema.
3. Pregnancy luteoma is seen in the second half of pregnancy and is most common in multiparous African American women. The lesion consists of hyperplastic proliferations of luteinized cells, likely stromal and theca cells. Most pregnancy luteomas are incidental findings, but 25% of patients will have symptoms of virilization. Grossly, the nodules are multiple (50%), bilateral (33%), yellow-brown, hemorrhagic, and soft. Microscopically, they are well-circumscribed collections of large eosinophilic cells that may have many mitotic figures (e-Fig. 31.18). The nodules regress after pregnancy.
E. Ovarian torsion is frequently accompanied by torsion of the fallopian tube as well. Torsion is caused by twisting of the adnexa on its fibrovascular pedicle impeding blood flow into and out of the adnexal structures, ultimately resulting in infarction. The ovary is often enlarged and hemorrhagic or dusky. Microscopically, there is extensive interstitial hemorrhage, edema, and necrosis of normal tissue. Frequently there is an associated ovarian mass or neoplasm. Pregnant women and women with adnexal masses are at increased risk, but torsion can occur in children, infants, and occasionally in utero. Patients typically present with acute abdominal pain, nausea, and vomiting, and may have a palpable adnexal mass.
IV. OVARIAN NEOPLASMS. Table 31.1 presents a simplified version of the World Health Organization (WHO) histologic classification of tumors of the ovary.
TABLE 31.1 Modified WHO Histologic Classification of Tumors of the Ovary
Surface epithelial-stromal tumors
Serous tumors
Malignant
Adenocarcinoma
Borderline tumor
Benign
Cystadenoma, adenofibroma, cystadenofibroma
Mucinous tumors
Malignant
Adenocarcinoma
Borderline tumor
Benign
Cystadenoma, adenofibroma, cystadenofibroma
Mucinous cystic tumor with pseudomyxoma peritonei
Endometrioid tumors including variants with squamous differentiation
Malignant
Adenocarcinoma
Malignant mixed Müllerian tumor (carcinosarcoma)
Endometrioid stromal sarcoma (low grade)
Undifferentiated ovarian sarcoma
Borderline tumor
Benign
Cystadenoma, adenofibroma, cystadenofibroma
Clear cell tumors
Malignant
Adenocarcinofibroma
Borderline tumor
Benign
Cystadenoma, adenofibroma, cystadenofibroma
Transitional cell tumors
Malignant
Transitional cell carcinoma (non-Brenner type)
Malignant Brenner tumor
Borderline
Benign
Brenner tumor
Squamous cell tumors
Squamous cell carcinoma
Mixed epithelial tumors (specify components)
Malignant
Borderline
Benign
Undifferentiated and unclassified tumors
Undifferentiated carcinoma
Adenocarcinoma, not otherwise specified
Sex cord-stromal tumors
Granulosa-stromal cell tumors
Granulosa cell tumor group
Adult granulosa cell tumor
Juvenile granulosa cell tumor
Thecoma-fibroma group
Thecoma, not otherwise specified
Typical
Luteinized
Fibroma
Cellular fibroma
Fibrosarcoma
Stromal tumor with minor sex cord elements
Sclerosing stromal tumor
Signet-ring stromal tumor
Unclassified (fibrothecoma)
Sertoli-stromal cell tumors
Sertoli-Leydig cell tumor group
Well differentiated
Of intermediate differentiation
Variant with heterologous elements (specify type)
Poorly differentiated (sarcomatoid)
Variant with heterologous elements (specify type)
Retriform
Variant with heterologous elements (specify type)
Sertoli cell tumor
Stromal-Leydig cell tumor
Sex cord-stromal tumors of mixed or unclassified cell types
Sex cord tumor with annular tubules
Gynandroblastoma (specify components)
Sex cord-stromal tumor, unclassified
Steroid cell tumors
Stromal luteoma
Leydig cell tumor group
Hilus cell tumor
Leydig cell tumor, non-hilar type
Leydig cell tumors, not otherwise specified
Steroid cell tumor, not otherwise specified
Well differentiated
Malignant
Germ cell tumors
Primitive germ cell tumors
Dysgerminoma
Yolk sac tumor
Embryonal carcinoma
Polyembryoma
Nongestational choriocarcinoma
Mixed germ cell tumor (specify components)
Biphasic or triphasic teratoma
Immature teratoma
Mature teratoma
Solid
Cystic
Fetiform teratoma (homunculus)
Monodermal teratoma and somatic-type tumors associated with dermoid cysts
Thyroid tumor group
Struma ovarii
Benign
Malignant (specify type)
Carcinoid group
Neuroectodermal tumor group
Carcinoma group
Melanocytic group
Malignant melanoma
Melanocytic nevus
Sarcoma group (specify type)
Sebaceous tumor group
Pituitary-type tumor group
Retinal anlage tumor group
Others
Germ cell sex cord-stromal tumors
Gonadoblastoma
Variant with malignant germ cell tumor
Mixed germ cell-sex cord-stromal tumor
Variant with malignant germ cell tumor
Tumors of the rete ovarii
Adenocarcinoma
Adenoma
Cystadenoma
Cystadenofibroma
Miscellaneous tumors
Small cell carcinoma, hypercalcemic type
Small cell carcinoma, pulmonary type
Large cell neuroendocrine carcinoma
Hepatoid carcinoma
Primary ovarian mesothelioma
Wilms tumor
Gestational choriocarcinoma
Hydatidiform mole
Adenoid cystic carcinoma
Basal cell tumor
Ovarian Wolffian tumor
Paraganglioma
Myxoma
Soft tissue tumors not specific to the ovary
Others
Tumor-like conditions
Luteoma of pregnancy
Stromal hyperthecosis
Stromal hyperplasia
Fibromatosis
Massive ovarian edema
Others
Lymphoid and hematopoietic tumors
Malignant lymphoma (specify type)
Leukemia (specify type)
Plasmacytoma
Secondary tumors
From: Tavassoli FA, Devilee P, eds. World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of the Breast and Female Genital Organs. Lyon: IARC Press; 2003. Used with permission.
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The Ovary
The Ovary
Meredith E. Pittman
John D. Pfeifer
Phyllis C. Huettner
