Update on Imaging of Ovarian Cancer.

The concept of ovarian cancer as a single disease has been revised. Epithelial ovarian cancer is now understood as a subsumption of diverse cancer entities that vary significantly clinically as well as pathologically and on a molecular level [ 7 – 9 ]. It comprises the following main cancer subtypes: high-grade serous, low-grade serous, endometrioid, clear cell and mucinous ovarian cancer [ 6 , 11 ]. high-grade serous, low-grade serous, endometrioid, clear cell and mucinous ovarian cancer [ 6 , 11 ]. Differentiation of these subtypes is pivotal with regards to several aspects, such as biomarkers, precursor lesions, clinical presentation at diagnosis, prognosis, and response to treatment [ 5 – 11 ] (Table  1 ). Furthermore, considerable heterogeneity even within the same epithelial ovarian cancer subtype has been identified on a macroscopic and molecular level. This has also been attributed to the dedifferentiation within different implants of the same primary and thus the problem of tumor recurrence after initial response to therapy [ 3 , 12 ]. Table 1 Clinico-pathological and radiological characteristics of ovarian cancer subtypes Carcinoma subtype HG-serous LG-serous Mucinous Endometrioid Clear cell Percentage (%) 70–80 <5 3 10 5–10 Gene mutations TP53, BRCA1/2 BRAF; KRAS KRAS PTEN;CTNNB-1 KRAS, PTEN, PIK3CA Precursor STIC Serous cystadenoma borderline tumor Mucinous cystadenoma borderline tumor Endometriosis Endometriosis, clear cell adenofibroma Tumor morphology Cystic and solid; solid; irregular contour Solid and cystic; papillary projections; Psammoma bodies; Large, cystic or solid; smooth contour Smooth contour; solid and cystic; solid nodule in endometrioma Large, thick wall; cystic with mural nodules protruding into lumen Uni- or bilateral Bilateral Bilateral Unilateral Unilateral Rarely bilateral Dissemination Diffuse abdominal Abdominal Ovary Pelvic Pelvic Platinum-based-chemotherapy response High Intermediate Low High Low Prognosis Poor Intermediate Good Good Intermediate Adapted from references [ 3 , 5 , 11 , 13 ] Clinico-pathological and radiological characteristics of ovarian cancer subtypes Adapted from references [ 3 , 5 , 11 , 13 ] From the radiological perspective, it is pivotal to understand that these subtypes of EOC may manifest with distinct radio-morphology of the primary ovarian mass and peritoneal metastatic traits at diagnosis may differ (Table  1 ) [ 7 , 13 ]. The two serous cancer subtypes [high-grade (HGSC) and low-grade serous cancer (LGSC)] are fundamentally distinct neoplasms including molecular pathogenesis, their response to chemotherapy as well as prognosis [ 11 ]. Typical for HGSC is diffuse peritoneal dissemination at diagnosis, usually presenting with large amounts of ascites and peritoneal deposits throughout the abdominal cavity [ 13 ] (Fig.  1 ). Moreover, Vargas et al. reported an association between patterns of spread on CT imaging in different subtypes of HGSC based on the classification of ovarian cancer (CLOVAR) gene signatures. The mesenchymal CLOVAR subtype was found to be significantly more often associated with both diffuse mesenteric infiltration and peritoneal enhancement and adverse survival than the other genetic subtypes [ 14 ]. Fig. 1 High-grade serous cancer FIGO stage IIIC with a bilateral solid adnexal mass, enlarged retroperitoneal lymph nodes ( arrowhead ), and large amounts of ascites and peritoneal implant ( arrow ) at the right diaphragm High-grade serous cancer FIGO stage IIIC with a bilateral solid adnexal mass, enlarged retroperitoneal lymph nodes ( arrowhead ), and large amounts of ascites and peritoneal implant ( arrow ) at the right diaphragm High-grade serous epithelial ovarian cancer is promoted by TP53 and BRCA1/2 mutations and seems to develop de novo and within only several months [ 13 ]. Conversely, low-grade serous ovarian cancer develops in a stepwise fashion from serous cystadenoma to serous Borderline cancer. In these tumors, KRAS and BRAF mutations are frequently identified, rather than BRCA1/2 mutations as in high-grade serous cancers [ 11 ]. The gradual malignant degeneration from a benign precursor lesion and slow growth is a feature that LGSC shares with the subtypes mucinous, endometrioid, and clear cell cancer. For the latter two cancer types, endometriosis has been identified as precursor [ 15 ]. High-grade serous ovarian cancer accounts for the vast majority (70–80 %) of ovarian cancers. There is increasing evidence that many of these cancers derive from tubal intraepithelial cells. This so called “serous tubal intraepithelial carcinoma” (STIC) theory proposes that high-grade serous ovarian cancer, tubal cancer, and primary peritoneal cancer share the common origin from serous tubal intraepithelial cancer [ 8 , 9 , 16 , 17 ]. BRCA1 and BRCA2 mutation carriers have a 30–50 % life-time risk of developing ovarian cancer, mainly high-grade serous cancers [ 11 ]. Identification of these gene mutations, which occur in approximately 10 % of HGSCs, is important, as these patients have a better prognosis, and new therapeutic options can be offered [ 18 ].

Ovarian cancer is surgically staged according to the FIGO or TNM staging classification. The FIGO system, which is most commonly used world-wide, has updated its classification, effective from 2014 on. Of note, this classification applies not only for EOC but also for sex-cord stromal and germ cell malignancies [ 5 , 43 •]. A revision of the classification seemed warranted in the light of new concepts in ovarian cancer biology, including immunohistochemical and molecular genetic analysis, overlap of histopathological features, new prognostic factors, differences in chemotherapy response, and the need for new treatment protocols [ 17 , 43 •, 44 , 45 ]. In this new staging classification system, not only the tumor stage should be documented, but also the histological subtypes and grade. Acknowledging the concept of a common origin of high-grade serosal tumors from tubal cells, the most important revision in the new staging classification includes that now ovarian, fallopian, and primary peritoneal cancer are seen as one entity. The other major change is the further subdivision of the stages III and IV. The rationale for subcategorization of stage IIIA1 is that according to evidence patients with isolated retroperitoneal lymph node metastases have a better prognosis than those who have extrapelvic peritoneal spread (now FIGO IIIB) [ 45 , 46 ]. The findings in the various FIGO stages are seen in Table  3 . Table 3 FIGO classifications of ovarian cancer FIGO stage Subcategory and findings I A  Tumor one ovary or fallopian tube B  Both ovaries or fallopian tubes C  One or both ovaries or fallopian tubes and   C1: surgical spill   C2: capsule ruptured or tumor on surface   C3: malignant cells in ascites or peritoneal washings II A  Extension/implants on uterus and/or ovaries and/or fallopian tubes B  Extension to other pelvic intraperitoneal tissues III A  A1 Positive retroperitoneal lymph nodes (LN) only   A1(i): metastasis ≤10 mm   A1(ii): metastasis >10 mm  A2 Microscopic extrapelvic peritoneal spread   ±   LN B  Peritoneal implants outside pelvis up to 2 cm ± retroperitoneal LN C  Peritoneal implants outside pelvis > 2 cm ± retroperitoneal LN; liver and/or spleen surface metastasis included IV A   Pleural effusion with positive cytology B  Parenchymal metastasis, metastasis to extraperitoneal organs, inguinal LN and LN outside abdominal cavity Changes made to the version from 1998 are highlighted FIGO classifications of ovarian cancer Changes made to the version from 1998 are highlighted Imaging findings in CT and MRI have also been adapted to the FIGO classification system [ 47 , 48 ]. Thus, changes and key features relevant for pre-therapeutic imaging are highlighted in the following paragraph. Of utmost importance is the understanding of merging of ovarian, fallopian tube, and primary peritoneal cancer in staging. This results in major ramifications for radiological reporting: fallopian tube and primary peritoneal cancers are no longer regarded as single entities and thus they are no longer staged differently than ovarian cancer [ 8 , 9 , 17 ]. In a malignant adnexal mass, differentiation of fallopian from ovarian origin has often been challenging. The classical findings of a sausage like adnexal mass or fallopian tube distension and a focal solid mass are only rarely visualized [ 49 ]. This needs no longer to be differentiated, which will facilitate radiological reporting. The other major change is that primary ovarian cancer no longer exists as a separate entity. The findings previously indicative of this disease, e.g., peritoneal metastases and normal ovaries constitute now a subtype of ovarian cancer. Stage I primary peritoneal cancer does not exist [ 17 ]. If it is limited to the pelvis, it has to be classified as stage II, but more often, it will present with stage III B or C with ascites and spread outside the pelvis at diagnosis. The new staging classification also leads to the clarification of the lymph node status. Regional lymph nodes in ovarian cancer remain pelvic (internal and external iliac, obturator, and common iliac), presacral, and paraaortic and paracaval nodes. Conversely, inguinal lymph nodes are now considered as distant metastases (IVB). In contrast to other sites, smaller lymph node thresholds are used to assess CLNM (cardiophrenic lymph node metastases). A short axis cut-off of 5 mm has been suggested as normal cardiophrenic lymph nodes size [ 50 ]. A recent study reported 86 % positive predictive value for histologically proven CLNM using a short axis diameter of >7 mm in preoperative CT [ 51 ]. CLNM are associated with peritoneal dissemination and are found in approximately 30 % of advanced ovarian cancer [ 52 ]. These metastases occur typically in the anterior prepericardiac region, more commonly on the right than on the left side [ 51 ]. Stage IVA1 is characterized by pleural metastases proven either by positive cytology or biopsy. Stage IVB characterizes parenchymal metastases in the abdomen or extraabdominal lymph node metastases. Peritoneal implants on surface of liver and spleen (stage IIIC) have to be differentiated from parenchymal metastases in these organs. Umbilical metastases, Sister Mary Joseph nodes, are classified as metastases corresponding to stage IV B [ 5 ]. Transmural bowel invasion with mucosal involvement is also assigned to this category [ 5 ]. Conversely, rectum invasion defined as stage IIB, since it represents spread within the pelvis [ 5 ]. Quantification of ascites as small, moderate, or large should be included in the report, because it has shown to be related with survival [ 53 ].

Advances in immunohistochemistry and molecular genetics are the basis of new concepts in ovarian cancer. Imaging is integral in various aspects in assessing ovarian cancer. It is not only used as a diagnostic tool but is also a major determinant in triaging to personalized treatment. Sonography is an excellent modality to predict malignancy in adnexal masses and thus assists in reducing unnecessary surgeries. The use of functional MRI techniques is further improving characterization of sonographically indeterminate masses of which the vast majority will be benign. The MRI ADNEX score provides standardized assessment and reporting of complex adnexal masses. In MDC, imaging plays a central role for treatment stratification in ovarian cancer. It serves as a roadmap for surgery and is one of the major predictors for successful primary cytoreductive surgery. Currently, CT is the standard of care for staging patients with ovarian cancer. However, MRI using functional techniques is emerging as technique that may be able to overcome limitations of staging CT. The revised FIGO classification has introduced some major changes radiologists have to be familiar with. This includes the fusion of fallopian tube and primary ovarian cancer, and new concepts regarding lymph node dissemination as well as distant metastases.

Comprehensive staging laparotomy and cytoreductive surgery followed by chemotherapy has been the standard of care in newly diagnosed advanced ovarian cancer [ 17 ]. There is evidence that cytoreduction is associated with increased survival in ovarian cancer. In the last years, the ultimate goal of cytoreduction has continuously been changed [ 17 , 54 ]. Currently, a cut-off of 1 cm of residual tumor size is defined as optimal cytoreduction [ 55 ]. However, a trend toward ultraradical surgery with complete resection of all gross tumor deposits can be noted [ 55 ]. A recent meta-analysis of 18 studies with more than 13,000 patients proved positive impact of complete cytoreduction on median survival [ 56 ]. The best treatment for the advanced cancer stages IIIC and IV has been a subject of ongoing debate and much controversy over the last years [ 54 , 57 , 58 ]. Supporters of neoadjuvant chemotherapy refer to cancer biology and to the issue of high perioperative complications [ 54 , 59 ]. Debulking rates differ significantly between different sites and countries. Optimal cytoreduction broadly ranges from 15 to 85 %, with high-volume oncologic centers attaining rates of 60–75 % [ 17 , 60 , 61 ]. To improve treatment stratification, particularly to select patients amenable or not for successful cytoreduction, various predictive tests have been published. Major determinants include clinical risk factors (e.g., age, performance status, obesity, and comorbidity), tumor markers (CA-125), and imaging, most commonly CT [ 33 , 60 , 61 ]. However, the problem in the preoperative assessment of resectability is that there is no general accepted model and that reproducibility is a major challenge due to different clinical practice. Other limitations include complexity of scoring systems and prediction models. Different resection rates are also attributed to subjective assessment of resectability based on surgeons experience and preference, on anesthesia support and different departmental policies [ 33 ]. Multidisciplinary consensus conferences (MDC) are the platform to define individualized optimal treatment regimen. If a patient with ovarian cancer will benefit from upfront surgery or rather from a neoadjuvant approach has to be discussed in the context of patient-related factors and surgical technical issues [ 33 , 62 •]. In this setting, the accurate mapping of tumor burden and distribution of disease by imaging plays a central role in treatment stratification and will thus also influence patient outcome [ 47 , 48 , 62 •]. Site, size, and distribution of metastases have been used as radiological predictors for the outcome of cytoreductive surgery. CT images need to be scrutinized for subtle findings of peritoneal spread since these can change treatment decision (Fig.  3 ). Various CT criteria assessing different sites throughout the abdomen and CT scores without and with the incorporation of CA-125 or other clinical criteria have been proposed [ 33 , 60 , 61 , 63 , 64 ]. In the ESUR guidelines for staging ovarian cancer, large disease (>2 cm) in the upper abdomen around the liver and spleen, mesenteric deposits and lymph node metastases above the renal hilum were summarized as sites likely to be not optimally resectable [ 47 ] (Fig.  4 ). However, it was emphasized that resectability criteria may differ from center to center, and that predictive parameters have to be specified and agreed on in MDC [ 47 ]. Two recent publications of high-volume tumor centers addressed the value of CT for prediction of cytoreduction in ovarian cancer. A multi-center prospective trial of two major US cancer centers analyzed features to predict suboptimal cytoreduction. In 350 patients with surgically treated ovarian cancer, three clinical and six radiological criteria were significantly associated with suboptimal debulking [ 60 ]. Borley et al. analyzed radiological predictors associated with debulking success and requirement for bowel resection by logistic regression models. In their study, the presence of lung metastases >7 mm, pleural effusion, deposits >10 mm in size on large and small bowel mesentery, and infrarenal paraaortic lymph node metastases were associated with low success rate with debulking [ 61 ]. Despite advanced surgical techniques in both studies, bowel involvement was a major limitation for optimal cytoreduction. Thus, signs of bowel and mesenteric involvement have to be carefully analyzed in CT, like e.g., bowel wall thickening, adhesions, and mesenteric tethering [ 14 , 48 ]. Since small size (<5 mm) peritoneal deposits are hard to see in CT, complementary laparoscopy may play a role in the preoperative assessment of ovarian cancer [ 57 ]. It seems that currently the role of PET/CT for primary ovarian cancer staging is limited, as it is not superior to CT alone, and treatment regimen is not changed [ 41 ]. There is a paucity of data of advanced MRI techniques for staging of ovarian cancer [ 33 ]. Low and Barone used the peritoneal cancer index based on MRI/DWI and DCE in 35 patients (5 with ovarian cancer) with peritoneal carcinomatosis. Radiological–surgical correlation yielded a high match of tumor sites [ 65 ]. Recently, these authors also reported the superiority of this advanced MRI technique compared to CT [ 66 ]. In a prospective comparative study with surgery as standard of reference whole-body MRI using DWI was superior to CT and to PET/CT in the challenging assessment of bowel serosal and mesenteric disease. Furthermore, metastases outside the abdomen could be detected similarly to PET/CT [ 67 •]. Conversely, another comparative study found no significant differences between MRI, CT, and PET/CT for staging. However, PET/CT was more accurate for supradiaphragmatic metastases [ 68 ]. Fig. 3 Subtle imaging findings indicative of advanced ovarian cancer spread: ascites in omental bursa ( a , asterisk ) lymph node ( b , arrow ) with a short axis diameter of >7 mm in the cardiophrenic fat above the diaphragm. In all ovarian cancer staging exams, mesentery and omentum should be scrutinized for band-like and reticular pattern ( c , arrows ) presenting peritoneal spread Fig. 4 Excessive peritoneal metastases in the upper abdomen in high-grade serous cancer. Sites as in the omental bursa ( arrow ) and large deposits along the gastrocolic ligament ( arrowhead ) are findings indicative of non-optimal cytoreduction in most centers. These may synonymously also be termed as “difficult to resect” Subtle imaging findings indicative of advanced ovarian cancer spread: ascites in omental bursa ( a , asterisk ) lymph node ( b , arrow ) with a short axis diameter of >7 mm in the cardiophrenic fat above the diaphragm. In all ovarian cancer staging exams, mesentery and omentum should be scrutinized for band-like and reticular pattern ( c , arrows ) presenting peritoneal spread Excessive peritoneal metastases in the upper abdomen in high-grade serous cancer. Sites as in the omental bursa ( arrow ) and large deposits along the gastrocolic ligament ( arrowhead ) are findings indicative of non-optimal cytoreduction in most centers. These may synonymously also be termed as “difficult to resect”

From a clinical perspective, ovarian cancer remains a major challenge. Despite advances in medicine over the past decades, only minor improvement in 5-year overall survival has been achieved in patients diagnosed with advanced epithelial ovarian cancer [ 1 ]. This cancer is the most lethal among the pelvic cancers, and cancer-associated mortality is as high as for cervical cancer and uterine cancer combined [ 2 ]. One of the reasons is its late diagnosis with more than 60 % of patients presenting already with metastatic spread beyond the pelvis. In this scenario, episodes of tumor recurrence will develop, followed by chemo resistance, and subsequently these patients will succumb to their disease [ 3 •]. Increased understanding of the molecular biology of ovarian cancer opens new perspectives, and targeted therapies are emerging [ 4 ]. Moreover, gene abnormalities have been identified in different cancers subtypes, which will provide the basis for a personalized management in patients with ovarian cancer [ 3 •]. This review will focus on the most common cancer type, epithelial ovarian cancer (EOC). The other primaries including germ cell and sex-cord stromal cell ovarian cancer are extremely rare (<5 %) and differ in many aspects, but share the same staging classification with EOC [ 5 , 6 ]. An update of recent advances regarding EOC will be provided with special emphasis on their impact on clinical radiological practice.