Ritu Salani and Christa Nagel
Uterine adnexae are defined as the areas adjacent to the uterus that are occupied by the fallopian tubes and ovaries. The embryologic origin of the fallopian tubes and ovaries are 2 distinct events in the development of a female embryo. Development of the ovaries begins before the development of the remainder of the genital tract. The origin of the male and female gonads are similar up until the seventh week of gestation, at which time the primitive sex cords begin to break up in the female embryo. The developing ovary eventually has 3 layers: the surface epithelium, primitive germ cells, and sex cord epithelium. These layers give rise to the 3 main types of ovarian tumors: (1) epithelial tumors, which comprise approximately 70% of all ovarian neoplasms; (2) germ cell tumors, which comprise 15% to 20% of ovarian tumors; and (3) sex cord–stromal tumors, which account for 5% to 10% of ovarian tumors. The remainder of the masses are a result of metastatic or secondary involvement to the ovary.1
It is estimated that 289,000 women will undergo surgical intervention for an adnexal mass in the United States every year.2 This represents one of the most common indications for gynecologic surgery.3 The determination of whether a mass represents a condition that requires immediate surgical intervention, or is likely to be malignant or benign, is of paramount importance. A patient’s demographics, presenting symptoms, physical examination, imaging, laboratory studies, and family history can provide invaluable insights in determining the appropriate treatment plan. Given this information, a physician can form an accurate differential diagnosis and establish an appropriate management plan.
DIAGNOSIS
Key Points
1. Ultrasound characteristics of malignant adnexal masses include presence of complex or solid components, presence of ascites, bilaterality, and size greater than 10 cm.
2. Serum tumor markers useful in the evaluation of adnexal masses include CA125, alpha-fetoprotein, lactate dehydrogenase, human chorionic gonadotropin, and inhibin A and B.
3. Novel markers, including human epididymis 4 protein (HE4), transthyretin, transferrin, β-microglobulin, and apolipoprotein A1 may improve preoperative assessment of the risk of malignancy in adnexal masses.
Symptoms
Not all patients with an adnexal mass initially present with symptoms. Some masses are found incidentally on imaging ordered for the evaluation of unrelated conditions. However, when patients do present with symptoms, detailed evaluation and characterization of the reporting signs can provide insight into the etiology of the mass. Physicians should question patients regarding the duration, intensity, location, and radiation of their pain to determine whether immediate surgical intervention is needed for conditions such as ovarian torsion or ectopic pregnancy. Physicians should also perform a complete review of systems focusing on symptoms that can help elucidate the etiology of an adnexal mass such as the following: fevers, chills, vaginal discharge, vaginal bleeding, weight loss, abdominal bloating, changes in bowel or bladder function, and early satiety.4
Abdominal pain is a common presenting symptom for the majority of patients who are diagnosed with an adnexal mass. The first step in treating a patient who presents with abdominal pain is to differentiate those who will ultimately be diagnosed with conditions that require emergent surgical intervention, such as ectopic pregnancy, adnexal torsion, or a ruptured tubo-ovarian abscess (TOA). A pregnancy test should be performed in any woman of reproductive age whose symptoms include abdominal pain and abnormal bleeding. In the case of a ruptured TOA, a patient may have signs and symptoms of an acute abdomen and/or hemodynamic instability, requiring emergent surgical intervention.5 Similarly, adnexal torsion may be an operative emergency. Torsion is defined as the twisting of an ovarian mass around the infundibulo-pelvic ligament, which results in compromise of the arterial and venous blood flow. This is a condition that is often difficult to diagnose and requires a high suspicion from the patient’s initial presentation. Findings consistent with adnexal torsion include acute onset of abdominal pain (< 8 hours), vomiting, and absence of bleeding or leukorrhea. Thus, particularly in premenopausal women, prompt recognition and treatment is paramount in preserving the involved ovary.6 Another entity that commonly presents with abdominal pain, a pelvic mass, and fever is a TOA. Leukorrhea combined with a previous diagnosis of pelvic inflammatory disease (PID) or sexually transmitted infection should also raise the suspicion of TOA, as 30% of patients admitted with PID will go on to develop a TOA.7
Once emergent situations are excluded, the focus of the evaluation of an adnexal mass turns to determination of its etiology. A patient’s presenting symptoms may initially help determine the likelihood that a mass is malignant. In 2000, Goff et al8 evaluated the symptoms of 1725 women with ovarian cancer and found that 95% had previously presented with symptoms before their diagnosis. The most commonly reported symptoms were related to abdominal and gastrointestinal complaints. They also found that 89% of patients with stage I/II disease had symptomatic complaints before their diagnosis. In supplementary studies, further characterization of symptoms most indicative of malignancy, accounting for duration, intensity, and frequency, was conducted. The Early Ovarian Cancer Detection Study, which comprised a 23-item symptom index in an exploratory group of patients, found that the symptoms that strongly correlated with an ultimate diagnosis of ovarian cancer were pelvic pain, abdominal pain, increased abdominal size or bloating, early satiety, and difficulty eating. Further assessment of a modified symptom index in women with at least 1 symptom for less than a year and occurring greater than 12 times per month had an accuracy of 56.7% in women with early-stage ovarian cancer and in 79.5% in women with advanced-stage disease.9
In addition to the symptoms discussed in the preceding paragraph, other presenting complaints, when combined with the finding of an adnexal mass, may point to less common types of ovarian neoplasms. Estrogen-secreting tumors, such as granulosa cell tumors or a thecomas, should be considered in women with an adnexal mass, abnormal uterine bleeding, and breast tenderness, or precocious puberty in prepubertal females.10-12 In contrast, Sertoli-Leydig tumors, which secrete testosterone, often present with symptoms such as hirsutism and deepening of the voice.13 Other rare findings may include symptoms of hyperthyroidism in patients with a struma ovarii or symptoms such as flushing, diarrhea, and palpitations in women with a carcinoid tumor of the ovary.
Physical Examination
A thorough physical examination is advocated for the assessment of an adnexal mass, whether detected incidentally in an asymptomatic patient, or for the evaluation of symptoms. The health care provider should note general appearance. This includes assessment for signs of cachexia, such as temporal wasting, which may be found in women with advanced malignancies. Patients with a functional tumor may have signs of virilization, including hirsutism, male pattern balding, clitoromegaly, and acne indicating a hyperandrogenic state, or breast tenderness and vaginal bleeding, possibly suggesting a hyperestrogenic state.
In addition to a general examination, emphasis should be placed on a comprehensive evaluation of supra clavicular, axillary, and inguinal lymph nodes. Abdominal examination is a critical portion of the physical examination, allowing for palpation of large masses and assessment of pain. Tenderness, particularly with fever, may indicate an infectious process, such as a TOA. Presence of a fluid wave or omental caking may be indicative of advanced ovarian cancer.4,14
The pelvic examination affords assessment of the uterus and the adnexae. Speculum examination provides evaluation for signs of recent bleeding or displacement of the cervix secondary to the presence of a pelvic mass. Furthermore, characteristics of the mass, such as contour (smooth vs. irregular), firmness (solid, cystic, or mixed), and mobility should be assessed on examination. The rectovaginal examination allows for palpation of the uterosacral ligaments and the culde-sac, where nodularity or obliteration may suggest the presence of endometriosis or metastatic cancer. If a primary colonic malignancy is suspected, a stool guaiac should be performed.4
Studies have shown that examiners, regardless of experience, tend to underestimate the size of a mass on pelvic examination.15 In a pooled analysis of studies evaluating the ability of pelvic examination to detect a pelvic mass, sensitivity was 45%.14 Therefore, one must recognize the limitations of the pelvic examination, which can be further compromised by the presence of a small adnexal mass or in the obese patient.14,15 Thus a normal examination does not eliminate the need for further evaluation.
Radiographic Imaging
Once an adnexal mass is suspected, the proper imaging modality must be determined. Ultrasound uses high-frequency ultrasonic waves to create a picture of the internal and external structures of a mass (Figure 11-1). Used either transvaginally and/or transabdominally, it is both an inexpensive and accurate way to determine the origin of an adnexal mass and allows further characterization of the mass as benign, malignant, or indeterminate.16 Table 11-1provides an overview of common characteristic appearances on ultrasound for benign and malignant ovarian masses.17
Table 11-1 Ultrasound Characteristics for Common Adnexal Masses
FIGURE 11-1. A simple ovarian cyst on transvaginal ultrasound.
In 2009, Sokalska et al18 studied the ability of ultrasound to provide a specific diagnosis of an adnexal mass that was compared with final pathology after surgical management. In 800 women with benign processes, the sensitivity of diagnosing dermoid cysts (86%), hydrosalpinges (86%), and endometriomas (77%) were the highest among all ovarian pathologies. In addition to the detection of benign conditions, certain ultrasound findings can also raise the suspicion of a malignant origin. The size, location, locularity, echogenicity, and blood flow of a mass are characteristics used to determine the malignant potential of a pelvic mass. In an evaluation of symptoms in combination with ultrasound findings, the factors that raised the probability of malignancy were a personal history of ovarian cancer, older age, presence of ascites, presence of blood flow within a solid papillary projection, increasing diameter of the solid component of the mass, and irregular internal cyst walls. Factors that decreased the probability of malignancy were the presence of pain during the ultrasound examination, current use of hormonal therapy, and the presence of acoustic shadows. The ultimate sensitivity and specificity of this model were 93% and 76%, respectively.19 McDonald et al20 also looked at ultrasound characteristics of adnexal masses that conferred a probability of malignancy. This study confirmed that older age (> 55 years), presence of complex or solid components, presence of ascites, bilateral tumors, and a mass greater than 10 cm were all associated with an increased risk of malignancy at the time of surgical intervention.
The use of color flow Doppler, which evaluates the blood flow of a mass, has also been studied for the evaluation of an adnexal mass. However, this technique has been found to be inconsistent in the differentiation between various etiologies and not recommended for routine use at this time.17 The introduction of 3-dimensional (3D) ultrasound and its utility in the evaluation of a pelvic mass has been less clearly defined. Recent studies have compared the use of 3D ultrasound with conventional ultrasound for the evaluation of a pelvic mass. However, results are premature, and given the limited data, high costs, and availability of 3D ultrasound, its routine use for evaluation of an adnexal mass is not yet recommended.21
Though not ideal for initial imaging, the use of magnetic resonance imaging (MRI) may be helpful in further assessing those masses that have an indeterminate malignant potential on ultrasound. The differential diagnosis of an indeterminate adnexal mass on MRI is determined by its dominant signal characteristic. Mature teratomas, hemorrhagic cysts, endometriomas, mucinous cystadenomas, and melanoma metastasis are characterized by a “bright” T1 signal. The T1 signal helps to further define components of blood, blood clots, fat, and proteinaceous material that suggest a benign lesion, but are not always clearly delineated with ultrasonography. These images are especially helpful in defining heme-filled masses that may appear to be solid in nature on ultrasound. In addition, fat-suppressed T1 images are used to identify small amounts of fat within an adnexal mass that most often signify a mature teratoma.22 In contrast to this, lesions demonstrating a solid T2 signal may be either malignant or benign. Masses that are homogenously dark, well circumscribed, and smooth are most often leiomyomas or an ovarian fibroma/thecoma. A mixed signal solid mass on T2 imaging should raise an increased suspicion of malignancy. These are usually demonstrated by tumors that express both dark and bright signals. Lastly, tumors that have a predominantly cystic-solid appearance may be aided by further evaluation by MRI. Multilocular benign ovarian cysts, hydrosalpinx, and cystadenomas may appear to have “pseudo-solid” areas on ultrasound that are truly opposed folds of an otherwise cystic mass and that are able to be delineated by MRI. Further characterization of solid-cystic masses can be performed using contrast-enhanced MRI. The addition of contrast helps to more accurately identify solid components, such as mural nodules, areas of necrosis, and vegetations, which are concerning for malignancy.16,22 Although MRI is expensive, its use to determine the appropriate therapeutic modality in patients with an indeterminate adnexal mass may be warranted. Because the majority of these masses will ultimately be benign in nature, the cost of an MRI may be indicated, as it may prevent patients from undergoing an unnecessary surgical procedure.22
In past decades, the use of computed tomography (CT) has been reserved for pre- and postoperative treatment planning for patients with ovarian cancer and not for detailed characterization of adnexal masses. This was mostly secondary to the inadequate characterization of soft tissue densities and the added exposure to radiation.23 In 1998, the introduction of sub-millimeter spatial resolution and 2- and 3D spatial reconstruction resulted in the ability of CT scans to provide more accurate staging, evaluate disease volume, and determine resectability of metastatic ovarian cancer. In 2008, Tsili et al23 conducted a prospective study that evaluated the use of CT in the detection and characterization of adnexal masses in patients diagnosed with an adnexal mass on physical exam or ultrasound. Characteristics examined on preoperative CT that were thought to be consistent with a malignant process included a diameter greater than 4 cm, presence of bilateral ovarian masses, cystic and solid components, necrosis present within a solid lesion, and a cystic lesion that contained thick (> 3 mm) or irregular walls, septa, or papillary projections, as well as extra-ovarian disease (Figure 11-2). CT scanning correctly identified the origin of the adnexal mass in 96% of patients, with an overall diagnostic accuracy of 89%,23 thus concluding that CT scans can provide an accurate characterization of adnexal masses.
FIGURE 11-2. Large mucinous cystadenoma with multi-loculations (depicted by arrows) on CT scan.
The preferred imaging strategy of an adnexal mass is to start with the least expensive and readily available test, which, in most cases, is an ultrasound. For masses that are highly suspicious for malignancy on ultrasound, use of a CT scan may be considered for preoperative staging and determination of disease resectability. If a mass is indeterminate on ultrasound, either an MRI or CT may be used for further evaluation; however, the diagnostic test chosen should take into consideration the availability of resources, costs to the patient, and the implications of radiation exposure.
Tumor Markers
The use of tumor markers may aid in determining the malignant potential and histology of an adnexal mass. Typically elevated in patients who are ultimately diagnosed with cancer, the utility of tumor markers may be helpful in the initial diagnosis, monitoring of response to treatment, and triaging to the appropriate specialist. However, tumor markers should be ordered selectively, and physicians should take into account the patient’s age, presentation of symptoms, findings on physical examination, and imaging.
Though currently there are no validated biomarkers for ovarian cancer screening, the use of CA-125 level has been extensively studied. CA-125 is a glycoprotein that is produced by the ovary, peritoneal, and pleural linings. Although it is frequently elevated in malignant conditions, it can also be increased with benign processes, such as endometriosis and PID. In contrast, patients with early-stage epithelial ovarian carcinoma or borderline tumors may present with a normal CA-125 value.24 However, when assessing a patient’s risk of malignancy, this value may contribute to management decisions.
Germ cell tumors are most commonly associated with secretion of tumor markers. α-Fetoprotein (AFP) is an oncofetal protein that was initially characterized in the fetal liver and yolk sac, and elevation of this protein is often seen in hepatocellular carcinoma, gastric cancer, colon cancer, and pancreatic cancer.25 Because the fetal liver and yolk sac produce AFP, tumors that resemble these tissues are often associated with increased serum levels. Kawai et al26examined at the association of 7 tumor markers with malignant germ cell tumors of the ovary. One hundred percent of patients with endodermal sinus tumors, 61.9% of patients with immature teratomas, and 11.8% of patients with dysgerminomas had elevated serum levels of AFP. More commonly, dysgerminomas, and to a lesser degree other germ cell tumors, are associated with an elevation in lactate dehydrogenase (LDH). Another commonly expressed tumor marker in germ cell tumors is human chorionic gonadotropin (hCG). This glycoprotein hormone, which is produced in pregnancy, is also secreted by germ cell tumors such as choriocarcinoma, embryonal carcinoma, and dysgerminoma (low levels).26,27
Inhibin A and B, which belong to heterodimeric glycoproteins of the transforming growth factor β family of growth factors, are the most common tumor markers associated with sex cord–stromal tumors, specifically granulosa cell tumors. In 2007, Mom et al28 looked at the prevalence of elevations in both inhibin A and B in patients diagnosed with granulosa cell tumors. They found that 89% of patients had an elevated inhibin B level at the time of diagnosis, but only 67% had elevations in inhibin A. More patients were also noted to have an increase in inhibin B at the time of recurrence when compared with inhibin A. The conclusion from this study was that inhibin B levels more accurately reflect disease status in patients with granulosa cell tumors than inhibin A and should be used for diagnosis and monitoring.
Other biomarkers have also been evaluated in the work-up of a pelvic mass. CA 19-9, a monosialoganglioside, is commonly used for mucinous tumors of the gastrointestinal tract, most notably of the pancreas and biliary tract; however, it has also been found to be associated with mucinous tumors of the ovary. Unfortunately, CA 19-9 has not been helpful in separating benign from malignant tumors and is not recommended for use in triaging patients.29Another marker is carcinoembryonic antigen (CEA), which is an oncofetal antigen most often found in the colon. In the evaluation of an adnexal mass, CEA has limited potential; however, it may be useful for detection of a colonic primary or metastatic disease involving the adnexa.30
The routine use of tumor markers in the evaluation of an adnexal mass can be helpful in determining the risk of malignancy, and therefore, the need for surgical intervention or referral. Table 11-2 lists the recommended tumor markers in the initial evaluation of an adnexal mass based on age at presentation. Caution should be used in placing a high degree of emphasis on the results of these laboratory values, and the entire clinical picture should be evaluated when determining a patient’s ultimate treatment plan.
Table 11-2 Tumor Marker Recommendations Based on Age
Assessing for Risk of Malignancy
When further work-up has confirmed the presence of an adnexal mass, assessment for malignancy is a top priority. Although surgical management may be warranted, the appropriate triage of patients to an oncologist is critical. Studies have shown that women with ovarian malignancies are more likely to undergo optimal cytoreductive surgery and have improved overall survival of more than 1 year when under the care of a gynecologic oncologist rather than a general gynecologist or surgeon.31,32 Unfortunately, more than 50% of patients diagnosed with ovarian cancer are never seen by a gynecologic oncologist during their care.31 If suspicious is high or the patient has a strong family history for genetic predisposition for ovarian cancer, referral may reduce the risk of reoperation and increase the rate of optimal cytoreduction, improving survival outcomes.
To help delineate which patients are at higher risk for the presence of an epithelial ovarian malignancy, multiple tests and guidelines have been proposed. In patients with adnexal masses, one of the most widely studied is the use of CA-125 levels. The CA-125 level is elevated in 80% of patients with epithelial cancer; however, this test is often elevated in benign conditions, such as leiomyomas, endometriosis, and diver-ticulitis. Although it is widely used, more precise methods exist for discrimination between benign and malignant adnexal masses.24
In 2005, the American Congress of Obstetricians and Gynecologists (ACOG), along with the Society of Gynecologic Oncologists (SGO), devised guidelines for referral of the adnexal mass.33 These guidelines, which are stratified by menopausal status, include assessment of CA-125 levels, presence of extraovarian disease or ascites, and family history. In a retrospective validation study, these guidelines showed that 70% of premenopausal and 94% of postmenopausal women with epithelial ovarian cancer were appropriately identified.34 These guidelines have been further confirmed by other investigators and provide a simple assessment for referral.35 It is important to remember that these guidelines assess predominantly for epithelial ovarian cancer. When evaluating a younger patient, in addition to the above assessment, consideration should be given to tumor markers for germ cell tumors, such as AFP, hCG, and LDH.36
In 1990, investigators reported on the use of the Risk of Malignancy Index (RMI), incorporating menopausal status, ultrasound characteristics, and CA-125 level, to discriminate between benign and malignant ovarian tumors to triage patients appropriately. Using a simple mathematical formula, an RMI at a value of ≥ 200 was able to detect women with a more than 40-fold risk of cancer compared with the background risk.37 Since this time, modifications to the RMI have been studied, such as increasing the cut-off value to ≥ 450 or incorporating tumor size, which resulted in improvements in referral rates of malignant processes and a reduction in the number of benign tumors.32,38,39
Unfortunately, the RMI uses ultrasound as part of the analysis, which is operator dependent. Additionally, many patients are noted to have the presence of an adnexal mass on radiographic imaging such as CT scans, eliminating the need for ultrasonic evaluation. Thus, after a mass has been detected, several studies have examined the use of additional biomarkers. In addition to CA-125 values, the use of human epididymis 4 protein (HE4) has demonstrated potential. In a series of more than 500 women, the use of CA-125 and HE4 in combination successfully classified 94% of patients with epithelial ovarian cancer as high risk.40 In a study of 65 biomarkers, the combination of CA-125 and HE4 provided the highest level of discrimination between malignant and benign ovarian tumors.41 When using the Risk of Malignancy Algorithm, which combined the use of HE4 and CA-125 with the presence of an adnexal mass, sensitivity for malignancy was noted to be significantly increased over that of the RMI.42
Women with ovarian cancer frequently have a constellation of vague, yet persistent symptoms, including difficulty eating, early satiety, bloating, pain, and gastrointestinal and urinary symptoms. When using a specific symptom index in women with an adnexal mass, the sensitivity of predicting ovarian cancer was 64%. However, when the symptom index was combined with CA-125 and HE4, and 2 of the 3 tests were positive, the rate of detection increased to 84%. When the symptom index was used to triage high-risk patients for further study with CA-125 and HE4 levels, the specificity exceeded 98%.43 Thus the authors concluded that the symptom index may be used to select for the use of CA-125 and HE4 in high-risk patients.
In early 2010, the US Food and Drug Administration approved the use of the OVA1 test (Vermillion). This test combines 5 immunoassays of CA-125, transthyretin, transferrin, β-microglobulin, and apolipoprotein A1 into a single numerical unit. In an evaluation of 516 women with an adnexal mass, the OVA1 test increased the sensitivity of preoperative assessment from 72.5% to 91.7% for a nongynecologic oncologist and from 77.5% to 98.9% for a gynecologic oncologist. The purpose of this test is to determine which patients should be referred to a gynecologic oncologist and supplements, but does not replace, clinical assessment.44,45
Development of the ideal test to distinguish benign from malignant pelvic masses continues to elude practitioners. Currently, using a combination of tumor markers and imaging, along with a thorough review of symptomatology and family history, provides the best assessment. Table 11-3 lists the sensitivity and specificity of the most commonly used tests to assess the risk of malignancy. Health care providers should always assess each patient individually and evaluate the entire clinical picture when determining which patients require referral to a gynecologic oncologists.
Table 11-3 Summary of Studies Assessing for Risk of Malignancy in an Adnexal Mass
PATHOLOGY
Key Points
1. Menopausal status, symptomatology, and risk factors for malignancy influence the differential diagnosis of adnexal masses.
2. The most common epithelial tumor presenting as an adnexal mass is the serous cystadenoma, followed by the mucinous cystadenoma, borderline tumor, mature teratoma, and endometrioma.
Differential Diagnosis
Once the presence of an adnexal mass has been detected, differential diagnoses should consider gynecologic and nongynecologic processes, as well as both benign and malignant entities. The differential for each patient should consider several factors to help tailor the most probable causes. First, identifying the menopausal status of the patient will narrow the possibilities. First, in young women, consideration should be given to pregnancy-related conditions, functional ovarian cysts, germ cell tumors, and entities such as endometriosis. In postmenopausal women, although the risk of malignancy is much higher than for their younger counterparts, the differential should also include cystadenomas and diverticular disease. Second, although many masses are found incidentally, symptomatology should be thoroughly reviewed.8,9 This includes assessing for the presence of abdominal bloating and pain, as well as abnormal bleeding, suggesting uterine pathology, and evaluation of bowel symptoms, indicating gastrointestinal disease. Third, patient risk factors should be taken into account. Patients with a suspected or known genetic predisposition to ovarian malignancy, such as BRCA mutations or Lynch II syndrome, should be assessed appropriately.33 This may result in favoring surgical management over conservative therapy as well as specific recommendations for surgery, such as a bilateral salpingo-oophorectomy or hysterectomy at the time of intervention. Furthermore, patients with a previous history of malignancy, particularly breast or colorectal cancers, are at risk for metastatic disease to the adnexae, and one should be aware of this possibility.46 A differential diagnosis of an adnexal mass is provided in Table 11-4.
Table 11-4 List of Differential Diagnoses of an Adnexal Mass
Benign Epithelial Neoplasms
Epithelial tumors comprise the largest subgroup of ovarian tumors. The most common histology within this subgroup is the serous cystadenoma, which accounts for almost a quarter of benign ovarian neoplasms. These masses are characterized by a smooth cyst wall and are bilateral in 15% of cases.47 Loculations may be present, along with the presence of psammoma bodies (calcifications). The second most common histologic subtype is the mucinous cystadenoma. These are often multi-loculated and often unilateral. Rarely, these tumors can be associated with the presence of peritoneal implants and gelatinous ascites, known as pseudomyxoma peritonei. Less common epithelial tumors may also be encountered. These include Brenner tumors and benign mesotheliomas; the former is characterized by a transitional cell-like epithelium and is a rare ovarian tumor often found incidentally.47
Borderline Tumors
Borderline tumors, also known as tumors of low malignant potential, were first described in 1929.48 These tumors were defined by the presence of proliferative activity, nuclear atypia, and presence or absence of stromal invasion. Histologically, they are classified based on epithelial characteristics, which are also found in their malignant counterparts. Serous and mucinous borderline tumors are the most common subtype encountered, comprising 95% of all borderline tumors.48,49 These tumors are classically associated with surface papillations and exophytic growth. Less commonly seen subtypes include endometrioid, clear cell, or even Brenner borderline tumors.48
Serous borderline tumors are more often bilateral, which occurs in approximately 40% of cases, and more often associated with the findings of extraovarian disease, ranging from 25% to 35% of cases. In comparison, mucinous tumors are bilateral in only 10% of cases and are more often associated with foci of malignancy. Therefore, surgical staging and extensive pathology sampling is warranted.48
Recently, more detailed description has been given to the serous subgroup. Kurman et al49 classified serous borderline tumors into 2 groups based on natural course of the disease process. The first group is defined as the atypical proliferative serous tumors, which behave similarly to benign serous tumors of the ovaries. The second group is the micropapillary serous carcinoma or intraepithelial serous carcinomas. This finding is associated with a poorer outcome and often accompanied by noninvasive implants. If invasive implants are encountered, the tumors may be classified as a low-grade serous carcinoma.49 Although these terms may not be universally used, careful assessment of the histology will allow for better counseling of these patients.
Mature Teratomas
Although germ cell tumors are discussed in greater detail in Chapter 14, mature teratomas remain one of the most commonly encountered ovarian neoplasm. They account for 20% of all ovarian neoplasms in adults and approximately 50% in the pediatric/adolescent population.50 These tumors are defined by presence of all 3 pluripotential germ cell layers: (1) ectoderm—such as hair and skin elements; (2) mesoderm—including fat, cartilage, and bone; and (3) endoderm—such as gastrointestinal and thyroid tissue. Rates of bilaterally exceed 10%, and although the mature classification suggests a benign nature, these tumors can, albeit rare, undergo malignant transformation.50
Endometriosis/Endometriomas
Endometriosis is an inflammatory condition stimulated by estrogen and is associated with infertility, chronic pelvic pain, and dyspareunia. Although symptoms vary in severity, endometriosis is estimated to affect 5% to 10% of reproductive age women.51 One of the most common locations is on the ovary, known as an endometrioma, which is a cyst wall lined with endometrioid mucosa. Often these tumors have a complex appearance on ultrasound and are associated with an elevated CA-125 level. Additionally, malignant degeneration, typically clear cell or endometrioid carcinoma, is associated with this disease.51 Thus clinical suspicion and appropriate evaluation will help determine the best management approach.
TREATMENT
Key Points
1. Women with adnexal masses with a high suspicion of malignancy should undergo surgical evaluation either via exploratory laparotomy or laparoscopy with care to avoid intraperitoneal rupture of the mass.
2. Conservative management with close surveillance is appropriate for masses suspected to be benign and are asymptomatic.
The management of an adnexal mass depends highly on the suspicion of malignancy. Presently, the lifetime risk of undergoing surgery for an ovarian neoplasm is 5% to 10%, although it is estimated that less than a quarter of these will be malignant.4 Clinical decision making regarding a patient with an adnexal mass will result in observation with follow-up or operative management.52 Patients with adnexal masses can be divided into 3 categories: (1) high suspicion of ovarian cancer, irrespective of symptoms; (2) suspected benign mass with symptoms; and (3) asymptomatic mass with low suspicion of malignancy.
When a patient falls into the first category, surgical intervention is warranted. These patients should be referred to a gynecologic oncologist or have a contingency plan in the event that malignancy is confirmed. Typically, this requires a midline vertical incision to allow for access to pelvic structures as well as the upper abdomen. The use of intraoperative frozen section, which has accuracy rates approaching 95% in the evaluation of ovarian tumors, may help identify a clinically early ovarian cancer and determine the need for surgical staging.53,54
Although aspiration of cyst fluid is contraindicated in postmenopausal women secondary to the risk of malignancy, occasionally patients are encountered who have a high likelihood of malignancy but who are not surgical candidates as a result of comorbidities. To establish a diagnosis, biopsy or cytology of an ovarian mass may be required to confirm diagnosis and allow for commencement of therapy. However, this should be used judiciously, as cytology has poor sensitivity (25%-82%) and is considered a diagnostic tool and not a therapeutic measure.33
The management of symptomatic women with a pelvic mass with a low suspicion of malignancy may have an option of management modalities. First, physiologic cysts in women of reproductive age must be excluded. Certain conditions, such as endometriosis and TOAs, may be amenable to medical therapy, such as hormonal manipulation and antibiotics, respectively.33 However, if symptoms are severe, or the patient declines or is unsuccessfully managed with medical therapy, surgery is often indicated. The extent of surgery should be further tailored by the patient’s preference for future fertility and ovarian function. Often patients who are premenopausal may be managed with an ovarian cystectomy or unilateral salpingo-oophorectomy. However, patients should be counseled on the need for performing a bilateral salpingo-oophorectomy, particularly women at high risk for ovarian cancer.55 Other possibilities for this procedure include bilateral involvement of the ovaries or in women with endometriosis and/or chronic pelvic pain, as rates for repeat operation approach 30%.55 In patients who have completed child-bearing, the option of undergoing a hysterectomy at the time of surgery to reduce risk of pelvic surgery in the future may be discussed, although benefits of this practice are unclear at this time.
A more complicated scenario is the asymptomatic patient with an adnexal mass that appears to be at low risk for malignancy. In these situations, the risks and costs of surgical intervention often outweigh the benefit of surgery, and often expectant management is the treatment of choice. Several large studies have shown that asymptomatic women with simple, unilocular masses can be managed conservatively, as rates of malignancy are less than 1%.14,33 Even in the postmenopausal setting, with a normal CA-125 level, expectant management of simple cysts up to 10 cm is recommended. In this scenario, more than two-thirds of these cysts respond without intervention.56
In addition to simple cysts of the ovaries, a series evaluating septated tumors, without solid areas or papillary projections, reported a spontaneous resolution rate of almost 40%, and no cases of ovarian cancer were reported with more than 6 years of follow-up.57 Thus continued surveillance without surgical intervention may be appropriate for this group of patients. However, it is important to conduct follow-up with repeat imaging and CA-125 levels within 6 months to confirm improvement/resolution. If the mass persists, symptoms develop, or CA-125 level becomes abnormal, operative intervention should be considered.52
In a woman of reproductive age, findings of an asymptomatic mass often represent functional cysts. These cysts rarely exceed 7 cm, and resolution occurs in more than 70% of cases within 6 weeks.4 Thus these tumors should be monitored conservatively with repeat imaging after 6 weeks, allowing for potential resolution with the menstrual cycle. Once a cyst is present, the use of oral contraceptives will not result in quicker resolution, but their use may prevent the formation of new cysts.58 Occasionally, the incidental finding of a small adnexal cyst in the premenopausal woman will be discovered. If the cyst measures ≤ 2.5 cm, and there are no other concerning signs or symptoms, no further management is warranted.4 Figures 11-3 and 11-4 provide general management schemas for premenopausal and postmenopausal patients with an adnexal mass.
FIGURE 11-3. Schema for the management of a complex adnexal mass in a postmenopausal woman.
FIGURE 11-4. Schema for the management of a complex adnexal mass in a premenopausal woman.
Once the decision to proceed with surgery has been made, the surgical approach must then be addressed. For any patient with an obvious advanced malignancy, exploratory laparotomy with a vertical midline incision, allowing access to pelvis and upper abdomen, is recommended. In the patient with a suspected benign adnexal mass, laparoscopic management is preferred. Although rates of complications from laparoscopic ovarian procedures are low, ranging from 0% to 30%, and mortality is less than 1%, each decision should be individualized, taking into account the size of the mass, surgeon skill, and other factors, such as surgical and medical history of the patient.14 Every effort should be made to avoid rupture, which, if encountered, can result in upstaging of malignancy. Additionally, every patient should be counseled and prepared for a laparotomy, in the event that minimally invasive surgery cannot safely be performed or an unsuspected malignancy is encountered.52 Regardless of approach, it is important to obtain cytology, assess all peritoneal surfaces, and thoroughly inspect the abdominopelvic cavity.
SPECIAL MANAGEMENT PROBLEMS
Management of Borderline Tumors
When epithelial ovarian cancer is encountered, surgical staging is recommended; when benign disease is found, either cystectomy or oophorectomy, depending on the patient’s age, is warranted. However, when borderline tumors are diagnosed, the management options are varied. If diagnosed on frozen section, complete surgical staging is recommended due to the possibility of identifying invasive cancer on final pathology. For patients desiring fertility-sparing treatment, conservative staging with ovarian cystectomy or unilateral salpingo-oophorectomy with preservation of the contralateral ovary and uterus are acceptable. Patients should be aware that rates of recurrence range from 10% to 30% with this approach.59 Because frozen section has a notoriously high rate of inaccuracy for the diagnosis of borderline tumors or if not performed, the diagnosis may not be apparent until final pathology.54 Survival differences were not noted in patients who underwent a restaging operation that resulted in a higher stage of disease.60 Other studies have supported this finding and reported that complete surgical staging for serous borderline tumors may not be necessary if the intracystic growth pattern has less than a 10% borderline change, as these typically behave like benign serous cystadenomas.61
Adnexal Mass in Pregnancy
Due to a delay in child-bearing and improvement in technology, the findings of a pelvic mass at the time of pregnancy are not uncommon, with rates ranging from 2% to 10%.62 Fortunately, most masses are benign, and spontaneous resolution occurs in a majority of cases, allowing for expectant management. Typically, this includes ultrasound assessment each trimester and repeat assessment in the postpartum period or at the time of caesarean delivery (reserved for obstetrical indications). However, surgical management may be warranted in several clinical situations. First, torsion is reported to occur in 0% to 7% of cases and may require emergent surgery; less common is a mass effect, causing pain or obstructing labor.62,63 Lastly, clinicians should be aware for the potential of a malignant process, which occurs in approximately 2% to 6%, although some reports indicate the incidence to be as high as 10%.62 Most often, these malignancies are early-stage epithelial tumors, borderline tumors (51%), or germ cell tumors (39%).62,63 Because tumor markers are elevated secondary to pregnancy, intervention is based on imaging and clinical suspicion. Although surgery is safe, it should be reserved for surgical emergency or high suspicion of malignancy, as most patients can be managed expectantly.
Adnexal Mass in the Pediatric/Adolescent Population
The finding of an ovarian mass in the pediatric and adolescent population is not uncommonly encountered. An ovarian mass may be discovered as an incidental finding on examination, imaging, or at the time of an operation such as an appendectomy or detected during the evaluation of symptoms, such as abdominal pain or, less commonly, signs of hormone excess such as precocious puberty from a functional tumor. Reports indicate that more than 90% of adnexal tumors are benign in this population, and most patients can be managed with serial evaluation and avoid surgical intervention.64 However, if a germ cell tumor or other malignancy is suspected, or if surgical emergencies such as torsion occur, surgery may be indicated. As ovarian function is critical to development at this stage, careful evaluation and management are warranted.
FUTURE DIRECTIONS
Over the past several decades, many advances have been made in the assessment of adnexal masses. The improvement in imaging has resulted in the ability to diagnose pelvic masses and evaluate for specific characteristics. Additionally, when appropriate, the use of imaging characteristics may allow for continued surveillance and allow for patients to be conservatively managed, avoiding risks of surgery. Although currently there is no imaging modality that can distinguish benign from malignant lesions perfectly, progress is occurring. This has resulted in improved sensitivity, ultimately allowing for triage of patients with a high suspicion of malignancy to be referred to gynecologic oncologists. Ideally, the ability to distinguish a benign adnexal mass that does not require surgery from a malignant mass should be done with confidence. The use of biomarkers continues to be evaluated for this purpose. Tests such as the use of HE4, OVA1, and combinations have shown potential. Developing algorithms to triage patients appropriately may result in better outcomes for women with pelvic masses.
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