Pain

Abdominal swelling, bloating and pressure effects

Patients seldom note abdominal swelling until the tumour is very large. A benign mucinous cyst may occasionally fill the entire abdominal cavity. Bloating is a common symptom which can be associated with ovarian tumours but most often is not. Gastrointestinal or urinary symptoms may result from pressure effects. In extreme cases, oedema of the legs, varicose veins and haemorrhoids may result. Sometimes, uterine prolapse is the presenting complaint in a woman with an ovarian cyst.

An attempt to assess symptoms qualitatively and quantitatively in order to distinguish women who may have an ovarian cyst from those unlikely to have a cyst suggests that recent-onset, severe and persistent symptoms should warrant further investigation (Bankhead et al 2008).

Hormonal effects

Occasionally, the patient will complain of menstrual disturbances but this may be coincidence rather than due to the tumour. Rarely, ovarian tumours present with oestrogen effects such as precocious puberty, menorrhagia, glandular hyperplasia, breast enlargement and postmenopausal bleeding. Secretion of androgens may cause hirsutism and acne initially, progressing to frank virilism with deepening of the voice and clitoral hypertrophy. Very rarely indeed, thyrotoxicosis may occur. Some of these tumours are malignant, but are mentioned here because of their ability to produce hormones in some cases. The hormonal effects and histology are discussed later.

Pain

Abdominal swelling

Pressure effects

Hormonal effects

A full bladder should be considered in the differential diagnosis of any pelvic mass. In premenopausal women, a gravid uterus must always be considered. Fibroids can be impossible to distinguish from ovarian tumours. Rarely, a fimbrial cyst may grow sufficiently to cause anxiety.

Gynaecological history

Details of the presenting symptoms and a full gynaecological history should be obtained, with particular reference to the date of the last menstrual period, the regularity of the menstrual cycle, any previous pregnancies, contraception, medication and family history (particularly of ovarian or breast cancer).

General history and examination

Indigestion or dysphagia combined with profound weight loss might indicate a primary gastric cancer metastasizing to the pelvis. Similarly, a history of altered bowel habit or rectal bleeding should be sought as evidence of diverticulitis or large bowel carcinoma. Ovarian carcinoma may also present with these features.

If the patient has presented as an emergency, evidence of hypovolaemia should be sought. Hypotension is a relatively late sign of blood loss, as the blood pressure will be maintained for some time by peripheral and central venous vasoconstriction. When decompensation of this mechanism occurs, it often does so very rapidly. It is vital to recognize the early signs (i.e. tachycardia and cold peripheries). In these circumstances, it is not appropriate to delay surgery pending further investigations, and laparotomy is the correct course of action.

If a cyst is found, the chest should be examined for signs of a pleural effusion. Peripheral oedema can indicate both pressure symptoms and hypoproteinaemia. It is also important to rule out other sites of tumours that are known to metastasize to the ovary, such as the breasts; thus, a full clinical examination is indicated.

Abdominal examination

The abdomen should be inspected for signs of distension by fluid or by the tumour itself. Dilated veins may be seen on the lower abdomen. Gentle palpation will reveal areas of tenderness and peritonism. The best way of detecting a mass that arises from the pelvis is to palpate gently with the left hand, starting in the upper abdomen and working caudally. This is the reverse of the process taught to every medical student for feeling the liver edge. Use of the right hand alone is the most common reason for failing to detect pelvic–abdominal masses.

Shifting dullness is probably the easiest way of demonstrating ascites, but it remains a very insensitive technique. If present, examination of the chest is required to determine if a pleural effusion is also present. It is always worth listening for bowel sounds in any patient with an acute abdomen. Their complete absence in the presence of peritonism is an ominous sign.

Bimanual examination

This is an essential component of the assessment because, even in expert hands, ultrasound examination is not infallible. By palpating the mass between both the vaginal and abdominal hands, its mobility, texture and consistency, the presence of nodules in the pouch of Douglas and the degree of tenderness can be determined. While it is impossible to make a firm diagnosis with bimanual examination, a hard, irregular, fixed mass is likely to be invasive.

Investigations

As a minimum, urine should be tested for the presence of infection and pregnancy. Blood should be obtained for a full blood count, blood grouping and cross-match if the patient is haemodynamically unstable. If the clinical signs suggest the possibility of upper gastrointestinal pathology, liver function tests and serum amylase should be performed.

Serum tumour markers

CA125 is well established in the investigation of ovarian cysts. It is a tumour marker for peritoneal disease/irritation, and whilst not specific for ovarian cancer, a level above 30 u/ml is abnormal. Benign conditions that increase the level of CA125 are endometriosis and pelvic inflammatory disease. In an acute cyst accident, it may also be raised; however, levels above 250 u/ml are almost always associated with malignant disease. The level of CA125 is increased in 80% of ovarian cancers. Other tumour markers may be useful in certain circumstances. If the tumour has features suggestive of a teratoma (dermoid), alpha-fetoprotein and hCG help to determine its malignant potential. Carcinoembryonic antigen, C15.3 and C19.9 are indicated when there is a possibility of pathology other than primary ovarian. Occasionally, the ovary may contain a rare tumour called a ‘granulosa cell tumour’; in this case, serum inhibin levels are useful in tracking the course of disease.

Ultrasound

The techniques of transabdominal and transvaginal ultrasound are discussed in detail in Chapter 6. Ultrasound is the single most important investigation and can demonstrate the presence of an ovarian mass with 81% sensitivity and 75% specificity. Most ovarian masses are cystic, whilst the presence of solid areas makes a malignancy more likely. Reporting of an ultrasound finding of an ovarian cyst has been standardized in order to allow for the allocation of a scoring system to assist in the preoperative assessment of the risk of any ovarian cyst being malignant. The ultrasound is awarded a U score of 0 if no cyst is present, 1 if only one characteristic is found, and 3 if two or more characteristics are found:

Computed tomography (CT) scanning has no significant advantages over ultrasound in cyst assessment, but can be useful in the presence of obvious extrapelvic disease to assess tumour bulk prior to chemotherapy. Magnetic resonance imaging (MRI) has a marginal advantage over CT in determining if a cyst is more likely to be benign or malignant, but both have no benefit over good transvaginal ultrasound and should not be used routinely. Initial studies using colour flow Doppler were promising but, once again, its use has not been proven to improve cyst assessment.

Risk of malignancy index

There is good evidence that primary surgery undertaken by a gynaecological oncologist improves survival in ovarian cancer by allowing for adequate staging and optimal debulking. It is not practical for all cysts to be managed by gynaecological oncologists; thus, in order to triage cysts for the appropriate surgeon, the Royal College of Obstetricians and Gynaecologists (RCOG) recommend use of the risk of malignancy index (RMI). In order to calculate the RMI, the menopausal status is also taken into account, with premenopausal being awarded a score of 1 and postmenopausal being awarded a score of 3. This simple formula is used:

A score below 25 can be managed by any gynaecologist, a score of 25–250 should be managed by a cancer unit lead, and a score above 250 should be referred to a cancer centre. This assessment allows for 70% of ovarian cancers to be managed in a cancer centre. The specificity is 90%. The cysts most likely to result in confusion regarding their benign or malignant nature are endometriomas. The clinical history and examination may better inform the clinician but, as a general principle, a significantly raised CA125 (>300 u/ml) is almost always associated with malignant disease.

The Scottish Collegiate also uses an RMI scoring system but gives different weightings to the ultrasound findings and menopausal status. If there are two or more abnormal ultrasound features, they award a U score of 4, whilst a postmenopausal status also has a score of 4. In addition, referral to a cancer centre is recommended when the RMI score is above 200. These adaptations increase the sensitivity of the RMI for prediction of malignant disease from 70% to 80%, and increase the specificity from 89% to 92%. Many centres in the UK also apply this RMI.

Ultrasound-guided diagnostic ovarian cyst aspiration

This investigation has been introduced gradually into gynaecological practice without the benefit of appropriate trials to indicate its potential efficacy. Unfortunately, this technique has a false-negative rate of up to 71% and a false-positive rate of 2% for the cytological diagnosis of malignancy (Diernaes et al 1987). The degree of risk of dissemination of malignant cells along the needle track or into the peritoneal cavity is not established. Most simple cysts will resolve, and most complex cysts require definitive management. Thus, due to its poor prognostic value and the potential for upstaging an early malignancy, cyst aspiration is not recommended for the assessment or management of ovarian cysts.

The asymptomatic patient

This includes women whose cysts were diagnosed incidentally during investigation of another problem or during investigation of lower abdominal symptoms that may or may not be related to the cyst.

Simple cysts less than 8 cm in diameter with normal CA125 levels

A normal follicular cyst up to 3 cm in diameter requires no further investigation. A simple cyst which is unilocular, echo-free without solid parts or papillary formations less than 8 cm in diamater with a normal CA125 level should have a repeat ultrasound in 3–6 months. If the cyst persists or grows, laparoscopic removal is advised. Premenopausal women under 40 years of age are more likely to want the option of further children and less likely to have a malignant epithelial tumour. In a study by Ekerhovd et al (2001), only three (0.73%) of 413 premenopausal women who underwent surgery for simple echo-free cysts without solid parts or papillary formations had borderline (n = 2) or malignant (n = 1) tumours.

The use of a combined oral contraceptive is unlikely to accelerate the resolution of a functional cyst (Steinkampf and Hammond 1990). Hormonal treatment of endometriosis does not usually benefit an endometrioma, the mainstay management of which is surgical.

The older woman

Women over 50 years of age are far more likely to have a malignancy and have less to gain from the conservative management of a pelvic mass. However, the capacity of the postmenopausal ovary to generate benign cysts is greater than previously thought, occurring in up to 17% of asymptomatic women (Levine et al 1992). Over 50% of simple cysts will resolve spontaneously and almost 30% will remain static (Levine et al 1992, Bailey et al 1998, Saasaki et al 1999).

Considerable efforts have been made to safely avoid unnecessary surgery in this older age group. However, one group found malignant tumours in 8.9% of 112 postmenopausal women with monolocular simple cysts studied between 1987 and 1993 with transvaginal ultrasound (Osmers et al 1998). They did not find internal echoes helpful in identifying malignancies. They found malignancies in 4.6% of cysts less than 40 mm in diameter, 10.8% of cysts 40–69 mm in diameter, and 18.2% of cysts more than 69 mm in diameter. Their view was that only cysts less than 3 cm in diameter could be managed conservatively. The results of other studies are more reassuring. In particular, a more recent study running from 1992 to 1997 found that only 1.6% of 247 echo-free cysts in postmenopausal women were malignant and that all of these were more than 7.9 cm in diameter (Ekerhovd et al 2001). It was only cysts with small solid areas or papillary formations on the internal side of the cyst wall or echogenic cyst content that carried a 10% risk of malignancy in the 130 cysts studied. Of the nine invasive cancers detected in this group, five were in cysts less than 8 cm in diameter.

This suggests that simple, echo-free, unilateral cysts without solid parts or papillary formations and less than 8 cm in diameter are very likely to be benign, and may safely be managed conservatively with 3–6-monthly ultrasound and CA125 estimation (Goldstein 1993, Ekerhovd et al 2001).

All other cysts

Echo-free ovarian cysts more than 7.9 cm in diameter are unlikely to be physiological or to resolve spontaneously, and will be malignant in approximately 5% of premenopausal women and approximately 15% of postmenopausal women (Ekerhovd et al 2001). These are probably better removed or, at the very least, rescanned 3 months later if the woman is unwilling to undergo surgery.

If the cyst is not echo-free, unilocular or unilateral, or if the CA125 level is raised, surgical removal must be advised to all postmenopausal women regardless of the size of the lesion. In premenopausal women, a corpus luteum or an endometrioma will have a complex appearance on ultrasound and the CA125 level is often slightly raised. When these are suspected, a repeat scan in 3 months is reasonable, with surgery advised if the tumour persists. Otherwise, surgical removal should be advised.

The patient with symptoms

If the patient presents with severe, acute pain or signs of intraperitoneal bleeding, an emergency laparoscopy or laparotomy will be required. More chronic symptoms of pain or pressure may justify pelvic ultrasound if no mass can be felt.

The pregnant patient

An ovarian cyst in a pregnant woman may undergo torsion or may bleed. There is said to be increased incidence of these complications in pregnancy, although the evidence for this is poor. Very occasionally, it can prevent the presenting fetal part from engaging. An ovarian cyst is usually discovered incidentally at the antenatal clinic or on ultrasound. These are usually physiological and resolve by the time of the midtrimester scan.

A recent RCOG publication in The Obstetrician and Gynaecologist (2006) has clarified the position somewhat:

• If the cyst is more than 5 cm in diameter and complex in nature, arrange an MRI and MDT discussion:

If thought to be benign, remove post natally.

If thought to be malignant (7–11%), remove in the midtrimester.

The pregnant woman with an ovarian cyst is a special case because of the dangers of surgery to the fetus. These have probably been exaggerated in the past and no urgent operation should be postponed solely because of a pregnancy. Thus, if the patient presents with acute pain due to torsion or haemorrhage into an ovarian tumour, or if appendicitis is a possibility, the correct course is to undertake a laparotomy regardless of the stage of the pregnancy. The likelihood of labour ensuing is small; however, the operation should be covered by tocolytic drugs and performed in a centre with intensive neonatal care when possible.

The tumour marker CA125 is not useful in pregnant women, since elevated levels occur frequently as an apparent physiological change.

Cysts found by chance at caesarean section can also have a variety of management options. In summary:

• If the cyst is complex or more than 5 cm in diameter, consider the following options:

Perform an ovarian cystectomy and open cyst. If any atypical feature (inclusions), remove ovary. Counsel patient of a 10% chance of a second operation if cystectomy only performed.

Perform oophorectomy and staging.

If there is a high clinical suspicion of malignancy, advice from an appropriately trained consultant colleague should be sought.

Physiological ovarian cysts

These are included here because they can present as tumours when increased in size. However, most are asymptomatic, being found incidentally as a result of pelvic examination or ultrasound scanning. Although they may occur in any premenopausal woman, they are most common in young women. They are an occasional complication of ovulation induction, when they are commonly multiple. They may also occur in premature female infants and in women with trophoblastic disease.

Corpus luteum cyst

Sometimes, corpora lutea undergo central cystification, often associated with haemorrhage into their lumen. Not uncommonly, these will present as an acute haemorrhagic abdominal episode. The degree of cystic dilatation exceeding 2 or 3 cm (according to different authors) justifies the designation of ‘corpus luteum cyst’.

Macroscopic identification is straightforward due to the intense yellowish colour resulting from mature luteinized theca cells (Figure 44.1).

Figure 44.1 Cyst of corpus luteum. Note luteinized theca cells. Haematoxylin & eosin, original magnification ×20.

Pathological ovarian cysts

The diagnosis of ovarian tumours ultimately depends upon histological examination.

Benign epithelial tumours

Most ovarian tumours (approximately two-thirds of all benign tumours and up to 90% of all malignant tumours) are classified as surface epithelial tumours. Most of these are derived from the ovarian surface epithelium, which in turn develops from the mesothelium–coelomic epithelium that covers the embryonic gonad. It is important to note that in the embryo, this epithelium is continuous with the coelomic epithelium that penetrates the underlying mesenchyme to form the Müllerian duct. This proximity is, in turn, reflected in the various directions of differentiation: towards fallopian tube epithelium in serous neoplasms, endometrial epithelium in endometrioid and clear cell tumours, and endocervical epithelium in some of the mucinous and transitional tumours.

The majority of these tumours are thought to derive from precursor lesions such as serosal inclusions, surface proliferations, metaplasias and endometriosis in the ovary. Although benign epithelial tumours tend to occur at a slightly younger age than their malignant counterparts, they are most common in women over 40 years of age.

Benign serous tumours

Serous tumours are most commonly endophytic (serous cystadenoma), but they may grow to the surface in the form of papillomas.

Serous cystadenomas are the most common type of benign epithelial tumour. Approximately 10% are bilateral. They can occasionally attain huge dimensions (Figure 44.2) and can be uni- or multilocular. Characteristically, the cysts are thin walled and feature watery contents. The cysts may have a smooth lining, but not uncommonly polypoid excrescences can be seen.

Figure 44.2 Macrophotograph of a serous cystadenoma. This specimen measured 40 cm in diameter and weighed over 5 kg.

Serous surface papillomas appear as polypoid excrescences on the outer surface of the ovaries. Serous adenofibromas are hard and white due to a predominance of the fibromatous component.

Histologically, all three variants are typically lined by epithelium similar to that of the fallopian tube, with variable degrees of ciliation. Psammoma bodies are usually absent.

When papillae are found, these are made almost entirely of stroma. In cystadenofibromas, the fibromatous stroma is prominent. By definition, none of these tumours show cellular atypia.

Benign mucinous tumours (mucinous cystadenoma)

These are the second most common type of ovarian epithelial tumour and tend to be the largest, some of them exceeding 30 cm in diameter and weighing more than 4 kg. The lining epithelium consists of columnar mucus-secreting cells. The most common type is referred to as of intestinal-type lining, in which goblet cells are almost always found. Less frequently, the epithelial lining is of endocervical type. The cyst fluid is generally thick and gelatinous.

A rare complication is pseudomyxoma peritonei which is more often present before the cyst is removed rather than following intraoperative rupture. Pseudomyxoma peritonei is most commonly associated with mucinous tumours of the ovary or appendix. Synchronous tumours of the ovary and appendix are common. There is, however, strong evidence that ovarian mucinous tumours associated with pseudomyxoma peritonei are almost all metastatic rather than primary.

Benign endometrioid tumours

These are ovarian tumours with histological features of benign glands or cysts lined by well-differentiated cells of endometrial type. They are very rare, usually unilateral and have no specific clinical symptoms. The histological diagnosis of an endometrioid adenoma or cystadenoma is based on the presence of well-differentiated glands lined by endometrial-type cells with scanty or absent surrounding endometrial stroma. When the latter is prominent, the lesion is classified as endometriosis.

Transitional cell (Brenner) tumours

These are neoplasms composed of epithelial elements histologically resembling urothelium (transitional epithelium). They account for only 1–2% of all ovarian tumours, and are bilateral in 10–15% of cases.

The tumour consists of nests and islands of transitional-type epithelial cells with characteristically grooved nuclei and abundant amphophilic cytoplasm set in a dense fibrotic stroma, giving a largely solid appearance. The nests show central lumina containing mucin and may be lined by columnar cells with a mucinous or ciliated appearance (Figure 44.3).

Figure 44.3 Transitional cell (Brenner) tumour showing bland epithelial cells with well-formed lumina. Haematoxylin & eosin, original magnification ×20.

Despite the transitional appearance of the epithelium, immunohistochemical studies have demonstrated that it lacks a urothelial phenotype, and it closely resembles that of ovarian surface epithelium. As with the other ovarian tumours of epithelial derivation, the whole spectrum from benign to malignant is possible.

Clear cell (mesonephroid) tumours

These arise from serosal cells showing little differentiation, and are only rarely benign. The typical histological appearance is of clear or ‘hobnail’ cells with varying proportions of fibromatous component. Other cells that may be present include cuboidal, flat, oxyphilic and, rarely, signet ring.