The pathology of ovarian cysts and tumours - technical article.

Key Points

• Many ovarian cysts are not malignant.
• Ovarian tumours may be benign, borderline or malignant.
• Most ovarian tumours are non-functioning and tend to present late, i.e. at high stage.
• Some ovarian tumours (thecoma, granulosa cell tumour) secrete oestrogens or androgens, and present relatively early with endometrial abnormalities or virilization.

Non-neoplastic Ovarian Cysts

Non-neoplastic cysts of the ovary can be divided into three broad categories:

• functional
• inclusion
• endometriotic.

Endometriosis is discussed in detail here: endometriosis, and will not be considered further at this point. Inclusion cysts are generally found within the superficial ovarian cortex, and probably arise as a result of inclusion of surface epithelium at the time of ovulation. The majority of these are of serous type, i.e. they are lined by epithelium that resembles that lining the fallopian tube. Functional cysts are related to the cyclical development and atresia of ovarian follicles. Among functional cysts, follicular cysts are the most common type, and small cystic follicles are found in virtually all premenopausal ovaries. Luteal cysts, or cystic corpora lutea, are less common. Finally, follicular cysts may become luteinized during pregnancy to form luteinized follicular cysts.

Polycystic Ovary Syndrome (PCOS) 

It is important to appreciate that a diagnosis of PCOS cannot be made on morphological grounds alone, and both clinical and endocrine data are also required. However, the identification of patients with this syndrome is important in view of its association with endometrial hyperplasia and carcinoma. This complication is preventable by treatment of the underlying endocrine disorder.

Ovarian Tumours

Ovarian tumours are relatively common, with the majority (approximately 80%) being benign and occurring in women of reproductive age. Malignant tumours occur in older women, most commonly aged 40–65 years, although certain uncommon tumour types do occur at a younger age. Many ovarian tumours – particularly of epithelial type – are bilateral: it is not clear whether these represent synchronous primary tumours or the spread of a single original tumour from one ovary to the other. Most ovarian tumours are non-functional and, in view of their relatively hidden anatomical location, tend to present late, usually as abdominal swelling due to the presence of a mass or associated ascites.

Predisposing factors include nulliparity and gonadal dysgenesis. Recently, it has become clear that ovarian carcinoma runs in some families in association with inherited abnormalities of, for example, the BRCA1 gene. Patients with a strong family history of breast and/or ovarian cancer can now be screened for specific molecular abnormalities.

Primary ovarian tumours arise from three distinct cell types, and are classified according to the scheme presented in Table 1 (below). However, it must be remembered that, whenever a malignant ovarian tumour is encountered, the possibility that it is a metastasis should be considered, particularly if it is of an unusual histological type and is bilateral.

Epithelial Ovarian Tumours

Macroscopically, ovarian tumours may be smooth-walled cystic lesions or contain a mixture of solid and cystic areas. Papillary tumours are also relatively frequent and tend to be of serous type (see below). It is thought that epithelial ovarian tumours arise from the coelomic epithelium that lines the surface of the ovary and that has the capacity to differentiate along a variety of paths that reflect the pluripotentiality of the Müllerian ducts.Thus, the major types of ovarian carcinoma show patterns reminiscent of tubal epithelium (serous tumours), endocervical epithelium (mucinous tumours), and endometrium (endometrioid and clear cell tumours). Other less common tumour types are also found, such as the Brenner tumour; this has a transitional morphology similar to that of the epithelium lining the urinary tract.

Each category of epithelial tumour is divided into three subcategories, based on a combination of cytological and architectural features (Table 2).

This distinction is of fundamental importance, as the clinical behaviour of the tumour depends almost entirely on the presence of stromal invasion. Benign tumours effectively have no malignant potential. Invasive tumours are by definition malignant. Borderline tumours are not clearly malignant but, in a small proportion of patients, may be associated with malignant features at a later date. Clinical follow-up is therefore required. The distinction between benign and borderline tumours is made microscopically. Although invasive carcinomas are often identifiable macroscopically, formal diagnosis requires histological examination. It is important to appreciate that the defining features of invasive carcinomas are stromal invasion and metastasis. Invasive tumours are staged according to the extent of spread as shown in Table 3.

Serous tumours are the most common type, are usually cystic, and may appear papillary. A characteristic microscopic feature is the presence of psammoma bodies, which may be present in benign, borderline or malignant tumours, particularly if papillary. Mucinous tumours are more often unilateral than serous tumours. One important complication of benign (and particularly borderline) mucinous tumours is pseudomyxoma peritonei, which occurs as a result of mucin secretion by the tumour. This mucin can spread throughout the peritoneal cavity where it may be associated with intestinal obstruction and other anatomical complications. It is now recognized that the vast majority of tumours associated with pseudomyxoma peritonei are of appendiceal origin, with secondary spread to involve the ovaries. Endometrioid and clear cell tumours are associated with ovarian endometriosis. These tumour types are important as endometrioid tumours have a relatively good prognosis, whereas clear cell tumours tend to behave aggressively.

Germ Cell Tumours of the Ovary

Around 95% of these are mature cystic teratomas (‘dermoid cysts’). The characteristic of these tumours is that mature elements derived from all three embryonic germ layers are present. The most common elements are ectodermal (skin, hair, teeth, etc.), but endodermal (intestinal, respiratory epithelium) and mesodermal (fat, muscle) elements are also present. Rarely, malignant transformation has been described in these tumours. Immature teratomas are related to mature teratomas, but contain immature neuroectodermal elements and behave in a malignant fashion. The importance of these is that they constitute 85% of ovarian teratomas in children.

All other types of germ cell tumour can occur in the ovary, but are uncommon. Dysgerminoma – which is the ovarian counterpart of testicular seminoma – occurs in young women and is an important diagnosis to make as the tumour is radiosensitive. Yolk sac tumours and embryonal carcinomas are rare, and highly malignant.

Ovarian Sex Cord/Stromal Tumours

These tumours differentiate along female (granulosa and theca cell tumours) or male (Sertoli/Leydig cell tumours) lines. Granulosa cell tumours are fairly common, especially in post-menopausal women; these lesions behave in a low-grade malignant fashion and may secrete oestrogens. As a result of their oestrogen secretion, the tumours are associated with endometrial hyperplasia and endometrial carcinoma (see p. 408). Ovarian fibromas and thecomas are also fairly common, but are usually benign. They too may secrete oestrogens (particularly thecomas) and may be associated with endometrial neoplasia.

Sertoli/Leydig cell tumours are uncommon and reflect the pluripotential nature of ovarian stromal cells.They may be non-functioning, but may also secrete androgens leading to virilization. Occasionally, they may secrete oestrogens.

Metastases to the Ovary

Some non-primary ovarian tumours reflect transcoelomic spread from pelvic tumours, for example from a colorectal carcinoma. Others are haematogenous or lymphatic metastases from distant sites, for example other parts of the gastrointestinal and female genital tracts. It is important to consider this possibility when assessing patients with ovarian tumours, as the identification of the primary site affects both staging and clinical management. One specific example of ovarian metastasis is the Krukenberg tumour, which is usually bilateral and associated with diffuse ovarian enlargement and the presence of signet ring tumour cells. These tumours are characteristically of gastric origin.