Ovarian Cysts

INTRODUCTION

Background: An ovarian cyst is a sac filled with liquid or semi-liquid material arising in an ovary. The diagnosis of ovarian cysts has increased with the widespread use of regular physical examinations and ultrasound technology. The finding of an ovarian cyst causes considerable anxiety to women because of the fear of malignancy, but the vast majority are benign.

Pathophysiology: Each month, normally functioning ovaries develop small cysts called Graafian follicles. At midcycle a single dominant follicle up to 2.8 cm in diameter releases a mature oocyte.

The ruptured follicle becomes the corpus luteum, which at maturity is a 1.5-2.0 cm structure with a cystic center. In the absence of fertilization of the oocyte, it undergoes progressive fibrosis and shrinkage. If fertilization takes place, the corpus luteum initially enlarges and then gradually decreases in size during pregnancy.

Ovarian cysts arising in the course of ovarian function are called functional cysts and are always benign. They may be follicular and luteal, sometimes called theca-lutein cysts. These cysts can be stimulated by gonadotrophins including follicle stimulating hormone (FSH) and human chorionic gonadotrophin (HCG).

Multiple functional cysts can occur as a result of excessive gonadotrophin stimulation or sensitivity. In gestational trophoblastic neoplasia (hydatidiform mole and choriocarcinoma) and rarely in multiple and diabetic pregnancy HCG causes a condition called hyperreactio luteinalis. In infertility patients, ovulation induction with agents including gonadotrophin releasing hormone agonists, FSH, HCG, and clomiphene citrate may cause ovarian hyperstimulation syndrome.

Neoplastic cysts arise by inappropriate overgrowth of cells within the ovary and may be malignant or benign. Malignant neoplasms may arise from all ovarian cell types and tissues. By far the most frequent are those arising from the surface epithelium (mesothelium) and most of these are partially cystic lesions. The benign counterparts of these cancers are serous and mucinous cystadenomas. Other malignant ovarian tumors may contain cystic areas and these include granulosa cell tumors from sex cord-stromal cells and germ cell tumors from primordial germ cells. Teratomas are a form of germ cell tumor containing elements from all 3 embryonic germ layers ectoderm, endoderm, and mesoderm.

Endometriomas are cysts filled with altered blood arising from ectopic endometrium. In the polycystic ovary syndrome, the ovary often contains multiple cystic follicles 2-5 mm in diameter on ultrasound. The cysts themselves are never the main problem and the disease will not be discussed further.

Frequency:
　

• In the US: Ovarian cysts are found on transvaginal ultrasound in nearly all premenopausal women and in up to 14.8% of postmenopausal women. The majority of these cysts are functional in nature and benign.

  The mature cystic teratoma or dermoid represents more than 10% of all ovarian neoplasms.

  The incidence of ovarian carcinoma is about 15 per 100,000 women per year. In the year 2000, an estimated 23,100 new cases of carcinoma of the ovary will be diagnosed in the US, as well as 14,000 deaths.

  The majority of malignant ovarian tumors are epithelial ovarian cystadenocarcinomas. Tumors of low malignant potential make up approximately 20% of malignant ovarian tumors, malignant germ cell tumors less than 5%, and granulosa cell tumors approximately 2%.

Mortality/Morbidity:

• Benign cysts can cause pain and discomfort related to pressure on adjacent structures, torsion, rupture, hemorrhage (both within and outside of the cyst), and abnormal uterine bleeding. They rarely can cause death. Mucinous cystadenomas can cause a relentless collection of mucinous fluid within the abdomen, known as pseudomyxoma peritonei, which is frequently fatal.

• Mortality of malignant ovarian carcinoma is related to the stage at the time of diagnosis and it has a tendency to present late in the course of the disease. Five-year survival overall is 41.6%, varying between 86.9% for FIGO stage 1a to 11.1% for stage IV. Granulosa cell tumors have an 82% survival whereas squamous cell carcinomas arising in a dermoid cyst have a very poor outcome. Most germ cell tumors are diagnosed in early stage and have an excellent outcome. Advanced stage dysgerminoma has a better outcome than for non-dysgerminomatous germ cell tumors. A distinct group of less aggressive tumors of low malignant potential runs a more benign course but still with a definite mortality. The overall survival is 86.2% at 5 years.

• Malignant ovarian cystic tumors can cause severe morbidity ranging from pain, abdominal distension, bowel obstruction, nausea, vomiting, early satiety, wasting, cachexia, indigestion, heartburn, abnormal uterine bleeding, deep venous thrombosis, to dyspnea. Cystic granulosa cell tumors may secrete estrogen, which leads to postmenopausal bleeding and precocious puberty in the old and young, respectively.

Race: Malignant epithelial ovarian cystadenocarcinoma are the only ovarian cysts that have race differences.

Women from northern and western Europe and North America are most frequently affected, whereas those from Asia, Africa, and Latin America are the least affected.

Within the US, age-adjusted incidence rates in surveillance areas are highest among American Indian women, followed by white, Vietnamese, white Hispanic, and Hawaiian women. It is lowest among Korean and Chinese women.

Among women for whom there are sufficient numbers of cases to calculate rates by age, incidence in the age group 30-54 years is highest in whites, followed by Japanese, Hispanics, and Filipinos. For ages 55-69 years, the highest rates occur in whites, then Hispanics, and Japanese. Among women 70 years and older, the highest rate occurs among white women, followed by black and Hispanic women.

Age:

• Functional ovarian cysts occur at any age (including in utero), but are much more common in women of reproductive age. They are rare after the menopause. Luteal cysts occur after ovulation in the reproductive age. Most benign neoplastic cysts occur during the reproductive era but there is a wide age range and they may occur at any age.

• The incidence of epithelial ovarian cystadenocarcinoma, sex cord-stromal, and mesenchymal tumors rises exponentially with age until the sixth decade and then plateaus. Tumors of low malignant potential occur at a mean age of 44 years, with a span from adolescence to senescence. The average age is more than a decade less than that for invasive cystadenocarcinoma. Germ cell tumors are most common in adolescence and rare over the age of 30.

CLINICAL

History:

• The majority of ovarian cysts are asymptomatic. Even malignant ovarian cysts commonly remain silent until an advanced stage.

• Pain or discomfort may occur in the lower abdomen. Torsion or rupture may lead to more severe pain.

• Patient may experience discomfort with intercourse, particularly deep penetration.

• There may be difficulty with having bowel movements, or there may be pressure leading to a desire to defecate.

• Frequency of micturition due to pressure on the bladder

• Irregularity of the menstrual cycle and abnormal vaginal bleeding may occur. Young children may present with precocious puberty and early onset of menarche.

• Patient may experience abdominal fullness and bloating.

• Patient may experience indigestion, heartburn, or early satiety.

• Endometriomas are associated with endometriosis, which causes a classic triad of painful and heavy periods and dyspareunia.

• Polycystic ovaries may be part of the polycystic ovary syndrome, which include hirsutism, infertility, oligomenorrhea, obesity, and acne.

Physical:

• Advanced malignant disease may be associated with cachexia and loss of weight, lymphadenopathy in the neck, shortness of breath, and signs of pleural effusion.

• On abdominal examination, a large cyst may be palpable. Gross ascites may interfere with the palpation of an intra-abdominal mass.

• Although normal ovaries may be palpable on pelvic examination in thin, premenopausal patients, a palpable ovary should be considered abnormal in a postmenopausal woman. If a patient is obese, it may be difficult to palpate cysts of any size.

• It is sometimes possible to discern the cystic nature of an ovarian cyst and it may be tender to palpate. The cervix and uterus may be deviated to one side.

• Other masses may be palpable, including fibroids and nodules in the uterosacral ligament consistent with malignancy or endometriosis.

Causes:

• Multiple functional cysts can occur as a result of excessive gonadotrophin stimulation or sensitivity.

• In gestational trophoblastic neoplasia (hydatidiform mole and choriocarcinoma), and rarely in multiple or diabetic pregnancy, HCG is the gonadotrophin. The condition is called hyperreactio luteinalis.

• In infertility patients undergoing ovulation induction with hormonal manipulation, including gonadotrophin- releasing hormone agonists, FSH, HCG, and clomiphene citrate, the condition is called ovarian hyperstimulation syndrome.

• Tamoxifen and clomiphene citrate can cause benign functional ovarian cysts that usually resolve following discontinuation of treatment.

• Risk factors for ovarian cystadenocarcinoma include strong family history, advancing age, Caucasian ethnicity, infertility, nulliparity, a history of breast cancer, and BRCA gene mutations.

WORKUP

Lab Studies:
　

• There are no diagnostic laboratory studies for ovarian cysts.

• CA125 is a protein expressed on the cell membrane of normal ovarian tissue and ovarian carcinomas. A serum level of less than 35 u/mL is considered normal.

• While CA125 is raised in 85% of epithelial ovarian carcinomas, overall it is raised in only 50% of stage 1 lesions confined to the ovary. It is also raised in some benign conditions, other malignancies, and 6% of normal patients. A raised CA125 is most useful in conjunction with ultrasound in the assessment of a postmenopausal woman with an ovarian cyst.

• Other tumor markers may be raised in neoplastic ovarian cysts. They include serum inhibin in granulosa cell tumors, alpha-fetoprotein in endodermal sinus tumor, LDH in dysgerminoma, and alpha-fetoprotein and beta-hCG in embryonal carcinoma.

Imaging Studies:
　

• Ultrasound

  This is the primary imaging tool for a patient suspected of having an ovarian cyst. It can define morphologic characteristics of ovarian cysts.

• Simple cysts are unilocular and have a uniformly thin wall surrounding a single cavity that contains no internal echoes. These cysts have a very low chance of being malignant. Most commonly, they are functional follicular or luteal, or less commonly serous cystadenomas or inclusion cysts.

• Complex cysts may have more than 1 compartment (multilocular), thickening of the wall, projections (papulations) sticking into the lumen or on the surface, or abnormalities within the cyst contents. Malignant cysts usually fall within this category, as well as many benign neoplastic cysts.

• Hemorrhagic cysts, endometriomas, and dermoids tend to have characteristic features ultrasonically that may help to differentiate them from malignant complex cysts.

• Ultrasound may not be able to differentiate hydrosalpinx, paraovarian, and tubal cysts from ovarian cysts.

• Endovaginal ultrasound can give detailed morphologic examination of pelvic structures. It requires a hand-held probe to be inserted into the vagina. It is relatively non-invasive, well tolerated in women of reproductive age and those of post-reproductive age who are having intercourse. It does not require a full bladder.

• Transabdominal ultrasound is better than endovaginal for large masses and allows assessment of other intra-abdominal structures such as the kidneys, liver, and ascites. It requires a full bladder.

• Doppler flow studies

  These studies can identify blood flow within a cyst wall and adjacent areas, including tumor surface, septa, solid parts within the tumor, and peritumorous ovarian stroma. The principle is that new vessels within tumors have lower resistance to blood flow because they lack developed smooth muscle in the walls. This can be quantitated into a resistive or pulsatility index.

• Estimation of the resistive index has limited clinical value in the premenopause because of the great overlap of low resistance flow characteristics in functional tumors and early cancers.

• Determination of the presence or absence of any blood flow within certain cysts may be helpful in diagnosis. For instance, hemorrhagic cysts may contain fine internal septations that characteristically do not demonstrate blood flow on Doppler.

• MRI

• MRI with gadolinium allows clearer evaluation of lesions indeterminate on ultrasound. It demonstrates better soft tissue contrast than CT scan, particularly for identifying fat and blood products and can give a better idea of the organ of origin of gynecologic masses. It is unnecessary in most cases.

• CT scan

• CT scanning is inferior to ultrasound and MRI for the definition of ovarian cysts and pelvic masses. It does, however, allow examination of the abdominal contents and retroperitoneum in cases of malignant ovarian disease.

Procedures:
　

• Needle aspiration of fluid from a cyst for cytologic examination is inaccurate, and it is inappropriate for drainage of a cyst in most cases.

• Diagnostic laparoscopy may sometimes be necessary to inspect a suspected adnexal cystic mass but it may miss an intraovarian malignancy.

Histologic Findings: The definitive diagnosis of all ovarian cysts is made histologically. Each type has characteristic findings.

TREATMENT

Medical Care:

• Many patients with ultrasonically simple ovarian cysts do not require treatment.

• In a postmenopausal patient, a persistent simple cyst less than 5 cm in dimension in the presence of a normal CA125 may be followed with serial ultrasonography.

• Premenopausal women with asymptomatic simple cysts smaller than 8 cm on ultrasound in whom the CA125 is within the normal range may be followed with a repeat ultrasound examination at 8-12 weeks. Hormone therapy to suppress ovarian stimulation by gonadotrophins is not helpful.

Surgical Care:

• Persistent simple ovarian cysts larger than 5 cm and complex ovarian cysts should be removed surgically.

• A laparoscopic approach should be reserved for patients who have undergone thorough workup and are thought not to have malignant disease. Such patients include those considered to have a dermoid or endometrioma, those with functional or simple cysts that are causing symptoms and have not resolved with conservative management, and those presenting with acute symptoms.

  In all cases, the cyst should be able to be removed intact.

• A laparotomy should be performed for patients thought to have a significant risk for malignant disease and also for patients with benign-appearing cysts that cannot be removed intact laparoscopically.

• Whether performing a laparoscopy or laparotomy, the aims are as follows:

• Confirm the diagnosis of an ovarian cyst.

  　

• Assess whether the cyst appears malignant.

  　

• Take peritoneal washings for cytologic assessment.

• Remove the entire cyst intact for pathologic analysis, including frozen section. This may mean removing the entire ovary.

• Assess the other ovary and other abdominal organs.

• Excision of the cyst alone with conservation of the ovary may be performed in patients who desire retention of their ovaries for future fertility or other reasons. Included are endometrioma, dermoid, and functional cysts.

• If the ovarian cyst is benign, removal of the opposite ovary should be considered in postmenopausal women, in perimenopausal women, and in premenopausal women over 35 years of age who have completed their family and who are considered at increased risk for subsequent development of ovarian carcinoma. These issues should be discussed with the patient preoperatively.

• A gynecologic cancer specialist should be available to help with any patient who undergoes surgery for a potentially malignant ovarian cyst. This allows the appropriate surgery to be performed on patients found to have cancer.

  Whenever possible, the patient should have consulted with the specialist prior to the surgery to allow all issues to be addressed.

Consultations:

• Infertility and reproductive endocrinologist for endometrioma and polycystic ovary syndrome

• Gynecologic oncologist for any complex ovarian cyst or adnexal mass and for a patient with a strong family history of ovarian carcinoma

FOLLOW-UP

Deterrence/Prevention:
　

• Current use of the oral contraceptive pill protects against the development of functional ovarian cysts. Current and previous use within 15 years reduces the risk of epithelial ovarian cystadenocarcinoma.

• All women should undergo an annual gynecologic examination. There is no generalized screening test for ovarian cystadenocarcinoma, but women at high risk based on family history or previous history of breast cancer should undergo an annual ultrasound examination and CA125. Referral for genetic counseling should be considered.

• Women at high risk of ovarian cystadenocarcinoma may be offered prophylactic oophorectomy, which will prevent the development of ovarian cancer but not peritoneal carcinoma.

Complications:
　

• Torsion

• Rupture

• Hemorrhage

• Malignant change - The potential of benign ovarian cystadenomas to become malignant has been postulated but is unproven to date. Malignant change can occur in a small percentage of dermoid cysts and endometriomas.

Prognosis:
　

• The prognosis for benign cysts is excellent. All such cysts may occur in residual ovarian tissue or in the contralateral ovary.

• Mortality of malignant ovarian carcinoma is related to the stage at the time of diagnosis and it has a tendency to present late in the course of the disease. Five-year survival overall is 41.6%, varying between 86.9% for FIGO stage 1a to 11.1% for stage IV.

• Granulosa cell tumors have an 82% survival whereas squamous cell carcinomas arising in a dermoid cyst have a very poor outcome.

• Most germ cell tumors are diagnosed in early stage and have an excellent outcome. Advanced stage dysgerminoma has a better outcome than for non-dysgerminomatous germ cell tumors.

• A distinct group of less aggressive tumors of low malignant potential runs a more benign course but still with a definite mortality. The overall survival is 86.2% at 5 years.

MISCELLANEOUS

Medical/Legal Pitfalls:
　

• Any pelvic mass should be assumed to be a cancer until proven otherwise, particularly in a patient with a prior history of breast cancer or a family history of breast/ovarian cancer.

• An ultrasound of the pelvis should always be obtained if a patient is thought to have a pelvic mass on clinical examination.

• If a patient has large fibroids, it is possible to miss concomitant ovarian pathology both clinically and on ultrasound.

• Always be on the lookout for patients with an increased risk of ovarian cancer and arrange appropriate counseling.

Special Concerns:
　

• Ovarian cysts in pregnancy

• Because the routine use of ultrasonography, ovarian cysts are commonly diagnosed in pregnancy. Cysts should be evaluated in the same way as non-pregnant patients with ultrasound and CA125. MRI is preferable to CT scanning, but both modalities should be avoided in the first trimester.

• In addition to the normal complications of cysts, they may cause obstructed labor in pregnancy.

• Benign simple cysts can be followed and most will resolve spontaneously.

• Persistent cysts more than 5-10 cm or those that are symptomatic or have features concerning for malignancy may undergo surgery, preferably in the second trimester.

• Ovarian cysts occurring in children

• In a child found to have a symptomatic abdominopelvic mass, the ovary is the most common site of origin.

• Although such masses are infrequent, the percentage due to malignant tumors is thought to be higher than for older age groups. Most common are germ cell tumors followed by epithelial and granulosa cell. Such tumors may be partially cystic.