Ovarian Neoplasms

Introduction

Ovarian neoplasms, or tumours, encompass a wide range of conditions: benign, malignant and indeterminate lesions, known as borderline. Pathologically, these are distinct, as shown in Fig. 12.1 . They pose challenges for both early detection and correct diagnosis.

Ovarian cancer is the second most common gynaecological malignancy in high-income countries (endometrial cancer being the most common). There are many histological subtypes of ovarian cancer; epithelial ovarian cancer (EOC) represents 90% of cases. In the United Kingdom, there are approximately 7400 cases diagnosed each year, and approximately 4300 women die from the disease annually. The continuing challenge with ovarian cancer is that 70% of women present at an advanced stage of disease (Stage III or IV). Consequently, the overall 5-year survival remains around 40% despite many advances in treatment. EOC is the leading cause of death from gynaecological cancer in the United Kingdom. The most common and most lethal subtype of EOC is high-grade serous carcinoma (HGSC).

Risk Factors

Ovarian cancer is predominantly a disease of older, postmenopausal women with the majority (>80%) of cases being diagnosed in women over 50 years. The lifetime risk of developing ovarian cancer is 1 in 54 and there are a number of risk factors identified associated with its development. A woman's reproductive history appears to contribute to her lifetime risk – women who have had pregnancies have a lower risk than those with no pregnancies. Early menarche, late menopause and obesity also seem to contribute to a greater risk of ovarian cancer. Family history plays a very important role in the development of ovarian cancer – direct genetic risk is discussed on page 141.

Conversely, the use of the oral contraceptive pill, tubal ligation, breastfeeding and suppression of ovulation appear to offer protection against ovarian cancer. These factors support the theory that a higher number of ovulations correlate with the risk of developing ovarian cancer. However, our knowledge of how EOC develops has advanced significantly and it is now considered that some of these cancers arise not from the ovary itself but from the fallopian tube.

Natural History

There are 3 broad categories of ovarian tumour based on their cell of origin: epithelial, sex cord/stromal and germ cell. These are divided into different histological subtypes, as shown in Fig. 12.2 .

EOCs were believed to only arise from the surface epithelium of the ovary and include the subtypes of serous (high and low grade), endometrioid, clear cell and mucinous. However, recently it has been discovered that the majority of ovarian and peritoneal HGSC tumours may originate not from the ovary but from the fimbria of the fallopian tube via the development of a serous tubal intraepithelial carcinoma (STIC) lesion. The STIC lesion forms and sheds onto the ovary surface and progresses to form HGSC ( Fig. 12.3 ). This method of development is particularly relevant for women who carry a BRCA gene mutation and has led to the development of risk reduction strategies in which BRCA mutation carriers are offered prophylactic bilateral salpingo-ophorectomy (BSO). The theory that some of these cancers arise other than from the ovary itself is also supported by the fact that ovarian-like tumours can arise in the peritoneum of women who have previously had both ovaries and fallopian tubes removed. Cancer in this case is called ‘primary peritoneal cancer’.

Endometriosis is associated with the development of clear cell and endometrioid carcinomas. Borderline tumours, which have malignant potential, can evolve, as evidenced by cases of serous borderline tumours being the precursor to a proportion of low-grade serous carcinomas.

Genetics

The development of cancer (oncogenesis) results from mutations in one or more of the vast array of genes that regulate cell growth and programmed cell death. When cancer occurs as part of a hereditary cancer syndrome, the initial cancer-causing mutation is inherited through the germline and, therefore, is present in every cell of the body. Up to 10% to 15% of cases of ovarian cancer are believed to be familial. The majority of these are BRCA1 and BRCA2 mutations, and Lynch syndrome.

BRCA genes function as tumour suppressor genes by helping to repair DNA breaks which could otherwise lead to cancer and the uncontrolled growth associated with tumours. However, when these genes are mutated ( BRCA positive), it results in an inability to repair DNA in damaged cells and, therefore, stop cancer cells from proliferating.

Women with BRCA mutation positive ovarian cancer have better outcomes than women with non-hereditary ovarian cancer. Reasons for this include that they develop serous histology and have high response rates to first and second lines of platinum-based chemotherapy. Newer therapies, including poly (ADP-ribose) poly­merase (PARP) inhibitors, take advantage of the fact that BRCA mutation carriers cannot repair deoxyribonucleic acid  (DNA) effectively, as PARP inhibitors block an enzyme that makes it harder for cancer cells to repair, leading to cell death. Focused family history taking and referral to genetic clinics can lead to identification of carriers and testing of their family members. These genes are inherited in an autosomal-dominant manner. Although there is still no effective screening method for ovarian cancer, prophylactic surgery will reduce the risk of developing cancer in these higher-risk women.

Lynch syndrome, also known as ‘hereditary non-polyposis colorectal cancer’ (HNPCC), predisposes to the development of several cancers – most notably, colorectal ovarian and endometrial cancer. This is a mismatch repair mutation involving a number of genes, such as MLH1 , MSH2 , MSH6 , PMS2 and EPCAM . The lifetime risk for the development of BRCA and Lynch syndrome–associated cancer in presented in Table 12.1 .

Pathology

Table 12.2 summarizes the pathological classification of ovarian tumours.

Epithelial Tumours

Serous Tumours

Serous tumours are the most common ovarian neoplasm, accounting for almost 70% of ovarian cancers. Serous cystadenocarcinomas involve both ovaries in over 50% of cases and may have both cystic and solid components. They also account for 20% of all benign ovarian tumours (serous cystadenomas), occurring primarily in women of reproductive age. Serous cystadenomas are usually unilateral, unilocular cysts, filled with serous (straw-coloured) fluid, and are of variable size ( Fig. 12.4 ).

Mucinous Tumours

These comprise 20% of all ovarian tumours and less than 5% are malignant. Benign tumours are usually unilateral. Mucinous tumours are usually multiloculated and contain mucinous fluid of variable viscosity. They are generally the largest in size of the common epithelial tumours. Uncommonly, pseudomyxoma peritonei may also be present, which is characterised by a gelatinous tumour within the peritoneal cavity. These pose histological challenges in determining the primary origin, which may be ovarian or a primary mucinous tumour of the appendix.

Endometrioid Tumours

Endometrioid tumours are usually malignant and closely mimic endometrial cancer in histological appearance. In around 30% of cases, there is a co-existent second primary tumour of the endometrium.

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