5\ Tumor Markers

CA-125, a glycoprotein antigen, is currently the most widely used tumor marker for ovarian cancer. However, elevation of CA-125 of more than 35 U/ml is not specific for epithelial ovarian cancer but can be observed as well in other malignant epithelial cancers, including pancreatic, lung, breast, and colon cancer, and in non-­Hodgkin’s lymphoma (Bairey et al. 2003). Furthermore, the list of benign conditions associated with an elevated CA-125 level is long and includes cirrhosis, peritonitis, pancreatitis, endometriosis, uterine fibroids, pregnancy, benign ovarian cysts, pelvic inflammatory disease, and even ascites. The level of CA-125 is associated with the menstrual cycle, and more than 90% of false-posi- tive findings are encountered in premenopausal women (Togashi 2003). This is why in premenopausal women, CA-125 is not useful as a single test, but its value is based upon the rise in serial measurements. In postmenopausal women, CA-125 is a better discriminator between benign and malignant diseases. More than 80% of women with advanced epithelial ovarian cancer present with CA-125 elevations. Of note, for early-stage disease, the sensitivity is only 25% (Togashi 2003). CA-125 is pivotal in the follow-­up of patients with ovarian cancer to monitor efficacy of treatment and tumor recurrence (Chen and Berek 2016). Multiple novel tumor markers using monoclonal antibodies are now tested in ovarian cancer. Currently they are used in combination with CA-125 in tumor marker panels but are still under investigation (Chen and Berek 2016).

Serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) have been helpful in recognizing preoperatively the presence of an endodermal sinus tumor, embryonal carcinoma, choriocarcinoma, or a mixed germ cell tumor. Serum lactate dehydrogenase (LDH) may be ­elevated in dysgerminomas, and anti-Mullerian hormone and inhibin have been used in the workup of granulosa cell tumors in postmenopausal age (Anthuber et al. 2014).

6\ Clinical Presentation

Ovarian cancer has been called a “silent killer” as it is in the majority of cases diagnosed only at an

advanced stage. In early stage symptoms are usually nonspecific or may mimic gastrointestinal or urinary symptoms (Carlson 2016; Chen and Berek 2016). Abdominal bloating or abdominal swelling may indicate ascites. Vaginal discharge and vaginal bleeding are rare symptoms and have been associated with tubal origin of the cancer (Chen and Berek 2016). Rarely, hormonal effects causing abnormal uterine bleeding, virilization, or paraneoplastic effects may be seen and may also precede the diagnosis. Paraneoplastic syndromes include neurologic disorders, e.g., limbic encephalitis or subacute cerebellar degeneration, and collagen vascular diseases, e.g., dermatomyositis and polymyositis, hypercalcemia, or Cushing’s syndrome (Lorraine et al. 2010).

7\ Imaging of Ovarian Cancer

7.1\ Imaging Findings in Ovarian

Cancer

7.1.1\ Imaging Characteristics

of Malignant Ovarian Tumors

Imaging features used for prediction of malignancy include lesion size larger than 4 cm, thickness of wall or septa exceeding more than 3 mm, papillary projections, necrosis, partially cystic and solid architecture, a lobulated solid mass, presence of tumor vessels, and patterns and dynamics of contrast enhancement (Table 1) (Fig. 1) (Hricak et al. 2000; Tsili et al.

Table 1  Imaging findings suggesting malignancy in an adnexal mass

Primary findingsa

Lesion size >4 cm

Wall/septal thickness >3 mm

Papillary projections

Lobulated mass

Necrosis

Solid and cystic architecture

Type 3 time-intensity curve

Ancillary findings

Lymph node enlargement

Peritoneal lesions

Ascites

aNot specific as single factors

Fig. 1  Imaging characteristics of bilateral ovarian cancer. Transaxial T2WI (a) demontrates a right cystic and solid adnexal mass. Intermediate SI on T2WI (a), avid contrast enhancement (b), and high SI on DWI using b 1000 mm2 (c) of the solid elements support the

findings of malignancy. Ascites is seen adjacent to the right mass (*). Note similar architecture and SI characteristics of the normal-­sized left ovary (arrow). At surgery bilateral high-grade serous ovarian cancer was found

2008; Buy et al. 1991; Sohaib et al. 2003; Stevens et al. 1991; Komatsu et al. 1996; Jung et al. 2002). None of these imaging criteria, however, were found specific enough as a single factor to reliably diagnose ovarian cancer. The likelihood of malignancy increases with solid nonfibrous elements, thickness of septa, and presence of necrosis (Hricak et al. 2000; Khasper et al. 2012). Ancillary findings such as the presence of lymphadenopathy, peritoneal lesions, and ascites improve the diagnostic confidence to diagnose ovarian cancer. The combination of tumor size and architecture with ancillary signs improves prediction of malignancy and yields an accuracy of 89–95% (Hricak et al. 2000; Tsili et al. 2008; Buy et al. 1991; Sohaib et al. 2003; Stevens et al. 1991; Komatsu et al. 1996; Jung et al. 2002).

Solid nonfatty nonfibrous tissue with or without necrosis has been reported as a valuable predictor of malignancy (Jung et al. 2002). Thus T2 WI signal intensity of solid aspects in adnexal masses may be used to predict malignancy. Masses that are as low or lower than skeletal muscle typically present benign entities, whereas lesions displaying a T2 intermediate SI or higher SI than skeletal muscle comprise a heterogenous group and include benign, borderline, and malignant lesions (Khasper et al. 2012). Thick walls and septations are less reliably signs of malignancy, as they may also occur in abscesses, endometriomas,

and benign neoplasms such as cystadenofibromas and mucinous cystadenomas (Jung et al. 2002; Khasper et al. 2012).

Papillary projections present folds of the proliferating neoplastic epithelium growing over a stromal core. Identification of papillary projections is important because they are typical for an epithelial neoplasm. They are most often associated with epithelial cancers of low malignant potential (Fig. 2) and may also be found in 38% of invasive carcinomas. In the latter, the gross appearance is usually dominated by a solid component (Buy et al. 1991; Jung et al. 2002). Small papillary projections ranging in the size of less than 3 mm with low-contrast enhancement are a feature of mucinous cystadenomas (Kaijser et al. 2014).

Psammoma bodies, which are tiny calcifications, are found in CT in approximately 10% of serous epithelial ovarian cancers (Fig. 3). Calcifications may also occur in benign teratomas and in benign ovarian stromal tumors, e.g., Brenner tumors or thecomas. These tumors are typically solid and tend to show extensive coarse calcifications.

In CT and MRI, assessment of contrast enhancement is a cornerstone of tumor characterization. It improves assessment of papillary projections and necrosis and visualizes patterns of vascularization (Hricak et al. 2000; Buy et al. 1991; Thomassin-Naggara et al. 2008b, 2012, 2013; Bernardin et al. 2012; Dilks et al. 2010)

c

Fig. 2  Serous borderline cancer of the right ovary. Coronal T2WI (a) displays a thin septation and a low SI mural papillary projection (arrow). Transaxial FSGd T1 demonstrates two papillary projections (b, c) (arrow). The

larger nodule displays a type 2 contrast enhancement curve (b, d), which is commonly found in borderline tumors

Fig. 3  Calcifications in ovarian cancer. Multiple plaquelike calcifications are demonstrated within a mixed solid and cystic bilateral ovarian tumor. They also cloak the peritoneal surface of the uterus (U). These small calcifications present psammoma bodies and are found in low-­ grade serous ovarian adenocarcinomas in CT. B bladder

(Figs. 1 and 2). DWI alone is limited due to overlap in benign and malignant adnexal lesions, and evidence is lacking supporting ADC quantification for reliable prediction of malignancy (Forstner et al. 2016a). DWI is most beneficial in adnexal mass characterization by excluding malignancy if a solid adnexal mass displays low SI using a high b value (Forstner et al. 2016a; Thomassin-Naggara et al. 2009). DCE using semiquantitative multiphase-dynamic contrast-­ enhanced MRI has become an important imaging tool for risk assessment in adnexal masses (Thomassin-Naggara et al. 2008b, 2012, 2013). Time-intensity curves are acquired of the solid areas within the adnexal lesion and the myometrium­ during multiphase-dynamic

Table 2  MR Adnex score

MR Adnex score (Adapted from Thomassin-Naggara et al. 2013)

aAssessed from solid tissue within the ovarian mass

contrast­ -­enhanced series. Using the myometrial­ enhancement as reference, three types of enhancement curves can be identified which correlate with benign, borderline, and malignant tumors (Fig. 4) (Tsili et al. 2008; Thomassin-­ Naggara et al. 2008a). Type 1 time-intensity curves are characterized by a gradual uptake of contrast. It was more frequently encountered in

benign than borderline lesion and never in malignant lesions. Type 2 time-intensity curves describing an early uptake of gadolinium – but less than myometrium – followed by a plateau were typical of borderline lesions (Fig. 2). Type 3 time-intensity curves describing an avid and early contrast uptake, followed by a washout, are typical of malignant tumors (Thomassin-Naggara et al. 2012, 2013). This technique is also pivotal in the MRI Adnex score system, a standardized MR imaging and reporting system for complex adnexal masses (Thomassin-Naggara et al. 2013). The MRI Adnex score assigns masses into five categories from score 1 correlating of no mass to score 5 that describes a probably malignant mass (Table 2). A feasibility study demonstrated excellent reproducibility and interobserver agreement for various levels of expertise (Thomassin-­ Naggara et al. 2013).

PET/CT is limited in prediction of malignancy of adnexal masses by false-positive findings, particularly in premenopausal ovaries due to physiologic uptake of the corpus luteum. It is more reliable in postmenopausal age, but false positives­