Staging ovarian cancer: role of imaging

Radiol Clin N Am 40 (2002) 609 – 636

Staging ovarian cancer: role of imaging Fergus V. Coakley, MD Abdominal Imaging, Department of Radiology, University of California San Francisco, Box 0628, L-308, 505 Parnassus Avenue, San Francisco, CA 94143, USA

Ovarian cancer is the commonest cause of death from gynecologic malignancy, and is the fifth commonest cause of cancer deaths in women [1]. The lifetime risk of ovarian cancer in women is 1.5%, and the overall mortality is approximately 60%. As with other tumors, it is important to distinguish the separate radiological roles of detection, characterization, and staging, although in practice these are often combined. Ultrasound is the primary modality used for the detection and characterization of adnexal masses, and these issues are discussed in a separate chapter. CT is the primary modality used for staging of ovarian cancer, and CT is the main modality discussed in this chapter. MRI is useful in the characterization of ovarian masses and for the elucidation of certain equivocal CT findings, and these applications are also described. The role of imaging in the staging of ovarian cancer is reviewed under the following headings:     

Radiologically relevant pathology Staging and management Typical CT findings Atypical CT findings Clinical role of imaging in ovarian cancer

Radiologically relevant pathology The pathology of ovarian cancers is complex, but only a few basic concepts are essential for the practicing radiologist. The germinal epithelium is

E-mail address: [email protected] (F.V. Coakley).

the single layer of columnar cells that line the ovary. Approximately 90% of ovarian cancers are of epithelial origin [2 – 4]. Epithelial cancers are graded as well (10%), moderately (25%), or poorly (65%) differentiated. More differentiated tumors have a better prognosis. Epithelial tumors are subtyped as serous (50%), mucinous (20%), endometrioid (20%), clear cell (10%), or undifferentiated (1%). The current consensus is that histologic subtype is not of independent prognostic significance, allowing for tumor grade and stage, and should not affect treatment planning [2]. Clear cell cancer is a possible exception, and may have a worse prognosis independent of other factors. Epithelial cancers are typically cystic and have a propensity to spread within the peritoneal cavity. Non-epithelial cancers include malignant granulosa cell tumor, dysgerminoma, immature teratoma, endodermal sinus tumor, and metastases to the ovary.

Staging and management Ovarian cancer is staged surgically, based on the International Federation of Obstetrics and Gynecology (FIGO) system introduced in 1964 and most recently revised in 1985 [5]. The FIGO system reflects the three primary mechanisms of spread of ovarian cancer, i.e., local, peritoneal, and lymphatic [6]. The FIGO staging system is summarized in Table 1. Stage I ovarian cancer refers to tumor confined to the ovaries. Stage II consists of ovarian cancer with peritoneal metastases confined to the true pelvis. Stage III consists of ovarian cancer with extrapelvic peritoneal metastases or abdominopelvic nodal metastases. Stage IV consists of ovarian cancer

0033-8389/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 3 3 - 8 3 8 9 ( 0 1 ) 0 0 0 1 2 - 4

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Table 1 FIGO staging system for ovarian cancer Stage

Approximate percentage at diagnosis

I

25%

II

25%

III

25%

IV

25% a

5 year survival [2]

Description Grossly confined to one or both ovaries. IA: Intracapsular and unilateral IB: Intracapsular and bilateral IC: Actual or potential microscopic peritoneal contaminationa Local extension; grossly confined to the true pelvis IIA: Involvement of Fallopian tubes or uterus IIB: Involvement of other pelvic tissues, eg, sigmoid, pelvic implants IIC: Actual or potential microscopic peritoneal contaminationa Nodal metastases, or peritoneal implants outside the pelvis. IIIA: Microscopic abdominal implants IIIB: < 2 cm abdominal implants IIIC: > 2 cm abdominal implants or positive nodes Distant spread, for example malignant pleural effusion, intrahepatic metastases

80%

60%

20%

10%

Based on the presence of surface tumor, tumor rupture, ascites containing malignant cells, or positive washings.

with metastases outside of the abdomen and pelvis. The distinction of stage III and IV disease contributes to treatment planning and prognosis, and there are two important related issues in imaging. First, the

commonest finding to result in the assignment of stage IV disease at presentation is a malignant pleural effusion. However, the radiological detection of an effusion is not of itself sufficient to constitute stage

Fig. 1. Axial contrast-enhanced CT section of the chest in a 56-year-old woman with epithelial ovarian cancer. A right pleural effusion can be confidently characterized as malignant, because of co-existent pleural metastases (arrows). A pleural effusion is an indication of stage IV disease only if the effusion is proven to be malignant.

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IV disease; the effusion must be demonstrated to be malignant. CT rarely contributes to the determination of whether an effusion is benign or malignant, except when pleural thickening or nodules are identified

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(Fig. 1). Another similarly important distinction is the differentiation of liver surface implants (peritoneal spread; stage III) from true intraparenchymal metastases (hematogenous spread; stage IV). Surface

Fig. 2. Axial contrast-enhanced CT sections in two different patients with ovarian cancer, illustrating the differences between perihepatic (A) and intrahepatic (B) metastases. Perihepatic metastases are surface peritoneal implants and are a feature of stage III disease. Intrahepatic metastases are hematogenous intraparenchymal deposits and indicate stage IV disease.

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Fig. 3. Axial contrast-enhanced CT section in a 56-year-old woman with stage I well-differentiated mucinous adenocarcinoma of the right ovary. The large right cystic adnexal mass demonstrates the characteristic imaging features of malignancy in a cystic lesion; the presence of thick septa (white arrow) and solid components (black arrow).

implants are usually well defined, biconvex, and peripheral, and indent the liver rather than replace liver parenchyma. True intraparenchymal implants are often ill-defined, circular, and partially or completely surrounded by liver tissue (Fig. 2). The management of ovarian cancer is closely related to stage. The standard of care for suspected early ovarian cancer is a comprehensive staging laparotomy [7]. The established elements of a comprehensive staging laparotomy, based on the known patterns of disease spread, are total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), infracolic omentectomy, random sampling of multiple peritoneal sites (including pelvic side walls, paracolic gutters, cul-de-sac, and surface of bladder, rectum, and diaphragm), and pelvic and para-aortic lymphadenectomy. Inspection and palpation are also performed, but in isolation are inadequate for the detection of peritoneal or nodal metastases. The standard of care for operable advanced ovarian cancer is primary optimal surgical cytoreduction (ie, debulking) followed by adjuvant combination chemotherapy with a platinum com-

pound and paclitaxel [7]. Optimal debulking refers to the reduction of all tumor sites to a maximal diameter of less than 1 to 2 cm. The 1 to 2 cm threshold has been established empirically. Cytoreduction with residual tumor over 1 to 2 cm confers no benefit, while more aggressive cytoreduction to less than 1 cm has no incremental benefit. Optimal cytoreduction improves survival, and probably improves quality of life. Debulking is believed to act by removing hypovascular tumor which would receive inadequate chemotherapy, by increasing the number of actively proliferating cells which are highly chemosensitive, and by reducing the number of cancer cells from which chemoresistant clones might develop.

Typical CT findings Primary tumor The majority of malignant epithelial tumors appear as cystic masses lateral to the uterus. Because of the mobility of the ovary, ovarian masses may also be seen in the midline above the bladder or anterior to

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Fig. 4. Fifty-four-year-old woman with stage II poorly differentiated papillary serous carcinoma of the left ovary. Axial T2-weighted MR image (A) shows large predominantly solid adnexal masses (asterisks) is inseparable from the sigmoid colon (arrow). Sagittal T2-weighted MR image (B) confirms the sigmoid colon (arrow) is encased and compressed by tumor (asterisks). At surgery, the sigmoid colon was extensively involved by tumor, and a sigmoid resection was required.

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the rectum [8]. Ovarian cancer is frequently bilateral, and it is thought that in about half these cases the contralateral tumor represents a synchronous second malignancy (multicentric origin) while in the remaining cases contralateral involvement is due to metastatic spread from the primary tumor in the other ovary [4]. Cystic adenocarcinomas are usually over 4 cm in diameter, and may be very large. Features that suggest malignancy in a cyst are thick (>3 mm) walls or septa, nodules, vegetations, or papillary projections (Fig. 3) [9,10]. Malignancy in a solid lesion

is suggested by necrosis. While these features are usually detectable by contrast-enhanced CT, gadolinium-enhanced MRI is slightly superior to both contrast-enhanced CT and Doppler US in the characterization of adnexal masses [11]. The administration of gadolinium is important, because it may reveal solid elements not appreciated on the pre-contrast T1 and T2 weighted images. It is sometimes possible to suggest the histologic subtype of epithelial cancer based on imaging findings. Calcification suggests a serous tumor, but only 12% of serous tumors have

Fig. 5. Axial contrast-enhanced CT sections in three different patients with ovarian cancer, illustrating peritoneal implants (arrows) in the left paracolic gutter (A), greater omentum (B), and perihepatic space (C). These are all frequent sites of peritoneal metastases in ovarian cancer. The finding of confluent metastatic disease in the greater omentum is known as omental cake, and is virtually diagnostic of ovarian cancer.

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Fig. 5 (continued ).

calcification that is visible at CT [12]. High density within the locules of a multilocular tumor is suggestive of proteinaceous fluid in a mucinous tumor [13]. Endometrioid carcinomas are associated with hyperplasia or carcinoma of the endometrium in 20 to 30% of cases. The endometrial pathology is thought to represent an independent lesion, rather than metastatic disease [13]; however, the primary radiological distinction in the imaging of an adnexal mass is the characterization of the mass as likely benign or malignant, rather than identification of the histological subtype. Local spread In addition to peritoneal implantation, ovarian cancer also spreads by local continuity. Spread to the opposite ovary occurs in 6 to 13% of patients with disease that would otherwise be stage IA [14,15]. Tumor spread to the uterus occurs in 5 to 25% of cases, possibly by a retrograde lymphatic route [16]. Surgically important local spread that may be detected by imaging are invasion of the pelvic sidewall, rectum, sigmoid colon, or urinary bladder [16]. Pelvic sidewall invasion should be suspected when the primary tumor lies within 3 mm of the pelvic sidewall or when the iliac vessels are surrounded or distorted by tumor [17]. Imaging criteria for bladder or rectosigmoid involvement have not been systematically described, but focal obliteration of the fat plane between these structures and the tumor is concerning, particularly when there is associated tumor encasement (Fig. 4), and frank tumor invasion is essentially diagnostic.

Peritoneal spread Intraperitoneal dissemination is the commonest route of spread of ovarian cancer, and likely occurs when free tumor cells shed from gross or microscopic tumor excrescences on the surface of the ovary [16]. These exfoliated cells are distributed by gravity into the pouch of Douglas, and by the normal flow of peritoneal fluid throughout the peritoneal cavity. The normal peritoneal cavity contains less than 100 ml of serous fluid, which circulates in the cavity and is preferentially drawn upwards in the paracolic gutters to the right subphrenic space, where it is absorbed [18]. The mesothelial cells of the right subphrenic peritoneum have wide intercellular gaps (stomas) that facilitate absorption into the terminal lymphatics of the mediastinum. These mechanisms explain the commonly seen sites of peritoneal metastases in ovarian cancer (Fig. 5):      

Pouch of Douglas Paracolic gutters Surface of the small and large bowel Greater omentum Surface of the liver (perihepatic implants) Subphrenic space (right greater than left)

Other less common sites of peritoneal metastases include (Fig. 6):    

Porta hepatis Fissure for the ligamentum teres Lesser sac Gastrosplenic ligament

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Splenic hilum Gastrohepatic ligament

As noted, such peritoneal implants should not be mistaken for intraparenchymal metastases in the liver or spleen. Peritoneal metastases appear as nodular or plaque-like enhancing soft tissue masses of varying size, and may occur anywhere in the peritoneal cavity. Delayed enhancement of perihepatic implants has been described at MRI [19], though this may actually represent contrast retention in the lesion with washout in the adjacent liver. In either case, delayed

images may help. Ascites is a nonspecific finding, but in a patient with ovarian cancer, usually indicates peritoneal metastases [20]. Ascitic fluid may outline small implants, which facilitates detection [8]. Previous studies examining the accuracy of CT in the diagnosis of peritoneal metastases in ovarian cancer have reported a sensitivity of 63% to 79% and a specificity of 100% [21 – 23]. A more recent study of 64 patients at Memorial Sloan-Kettering Cancer Center, using spiral CT, demonstrated a sensitivity of 85% to 93% and specificity of 91% to 96% for the detection of peritoneal metastases outside the

Fig. 6. Axial contrast-enhanced CT sections in five different patients with ovarian cancer, illustrating peritoneal implants (arrows) in the porta hepatis (A), fissure for the ligamentum teres (B), superior recess of the lesser sac (C), gastrosplenic ligament (D), and splenic hilum (E). These are uncommon sites of metastatic disease in ovarian cancer, but are important to recognize, because they may constitute unresectable disease. In addition, peritoneal implants (stage III) in the fissure for the ligamentum teres, superior recess of the lesser sac, or splenic hilum should not be mistaken for intraparenchymal metastases (stage IV).

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Fig. 6 (continued ).

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Fig. 7. Axial contrast-enhanced CT sections in two different patients with ovarian cancer, illustrating nodal metastases (arrows) in the obturator chain (A) and retroperitoneum (B).

true pelvis [24]. This increased accuracy likely reflects the increasing use of thinner sections and the absence of slice misregistration artifact on spiral CT, which aid the detection of small implants and help in the distinction of unopacified bowel from tumor implants. However, implants measuring 1 cm or less in diameter remain difficult to detect, and CT sensitivity falls from 25% to 50% for such small volume disease [24]. While CT is the primary modality for the demonstration of metastatic disease [11,17], MRI may be equally or more accurate [17,25]. The use of MRI is currently limited by expense, availability, prolonged duration of scanning, and lack of widespread reader experience. Nodal spread The ovarian lymphatic vessels are another important route of metastatic spread. The ovary has three routes of lymphatic drainage [16]. The main pathway ascends with the ovarian vessels to the retroperitoneal nodes of the upper abdomen. The second pathway passes laterally in the broad ligament to reach the internal iliac and obturator nodes in the pelvic sidewall. The third group passes with the round ligament to the external iliac and inguinal nodes, and explains the occasional spread of ovarian cancer to the groin. The frequency of nodal metastases in patients with what would otherwise be stage I or II disease is 15 to 17%, and rises to 64% in stage IV disease [26]. In a study of 71 unselected patients with ovarian cancer, 20 (28%) had pathologically proven nodal metastases [17]. Using a size threshold of greater than 1 cm in

short axis to define adenopathy, the sensitivity and specificity of preoperative CT for nodal staging was 50% and 95%, respectively. Therefore, while enlarged nodes are likely to be involved (Fig. 7), CT is unable to exclude disease in non-enlarged nodes. This emphasizes the importance of lymphadenectomy as part of the routine surgical staging of suspected early stage disease. Occasionally, patients are encountered who have predominantly nodal rather peritoneal spread. Disproportionate nodal disease may be seen in dysgerminoma (see later), and this should be suggested as a possible diagnosis, particularly in younger patients. However, in our experience, disproportionate nodal disease is more frequently encountered in the setting of poorly differentiated adenocarcinoma (Fig. 8). Interestingly, while nodal involvement indicates at least stage III disease, there is evidence that patients with ‘‘node only’’ stage III disease have a better prognosis than patients with stage III disease due to the presence of peritoneal metastases [27]. Distant metastases (stage IV disease) The term ‘‘distant metastases’’ in the setting of ovarian cancer refers to metastases beyond the status of stage III disease, ie, metastases outside of the peritoneal cavity and abdominopelvic lymph nodes (Fig. 9). Such metastases are rare at presentation, but are increasingly recognized during treatment because of the sophistication of imaging technology and because therapy is increasingly successful at controlling peritoneal disease, so patients live longer and die of distant disease which would not otherwise have

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Fig. 8. Axial contrast-enhanced CT sections in a 55-year-old woman with stage III poorly differentiated adenocarcinoma of the right ovary. The primary tumor (asterisk) is predominantly cystic with mural nodules (A). A large nodal deposit (arrow) is seen in the retroperitoneum (B), without visible peritoneal deposits or ascites. Disproportionate nodal disease is unusual, and may be seen in poorly differentiated primary epithelial cancer, and dysgerminoma. An extra-ovarian primary cancer with nodal and adnexal metastases is also a consideration.

become evident [28]. The common sites of distant metastases at autopsy are listed in Table 2 [28 – 30]. Manifestations of stage IV disease, such as parenchymal hepatic metastases, pleural or pulmonary nodules, and superior diaphragmatic adenopathy, are important to recognize but do not necessarily contraindicate cytoreduction.

cake, and ascites. Other sites of peritoneal disease may also be present; however, a significant proportion of patients has atypical findings. These are important to recognize, because they may have important pathologic or clinical implications. In addition, several pathologic entities may result in unusual or potentially confusing imaging findings. These issues are described in this section.

Atypical CT findings

Non-epithelial ovarian cancer Ovarian cancers other than primary epithelial cancers include malignant sex-cord stromal tumors, malignant germ cell tumors, and metastases to the ovary. Malignant germ cell and malignant sex-cord

The typical CT findings in a patient with advanced ovarian cancer are cystic adnexal masses with irregular internal solid components, omental

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Fig. 9. Axial contrast-enhanced CT sections in a 45-year-old woman with recurrent ovarian adenocarcinoma, 6 years after initial surgery and chemotherapy for stage III disease. Two separate metastases (arrows) are seen in the mid (A) and lower (B) right kidney. Hematogenous metastases are increasingly detected in patients with ovarian cancer, due to modern imaging technology and better control of peritoneal disease. Such metastases may be seen in a wide variety of sites.

stromal tumors account for approximately 7% of primary ovarian cancers [3]. Of the many subtypes of sex-cord stromal tumors, only granulosa cell tumors are seen with significant frequency [16]. Granulosa cell tumors are characterized histologically by a significant content of granulosa cells, which are the cells that surround the ovarian follicles. During ovulation, these cells mature from pregranulosa cells to granulosa cells, and finally granulosa lutein cells. The latter secrete estrogens and progesterone, and accordingly granulosa cell tumors are often functional (ie, hormonally active). Granulosa cell tumors are divided into adult and juvenile types. The later are almost always benign [31]. Adult granulosa cell tumors usually present in pre- or post- menopausal patients with menstrual disturbance or uterine bleeding, due to estrogen-induced endometrial hyperplasia. Endome-

Table 2 Frequency of distant metastases in ovarian cancer at autopsy by site Site

Frequency

Liver Lung Pleura Adrenal glands Spleen Bone and bone marrow Kidney Skin and subcutaneous tissues Brain

45 – 48% 34 – 39% 25% 15 – 21% 15 – 20% 11% 7 – 10% 5% 3 – 6%

trial hyperplasia progresses to endometrial carcinoma in 5 to 25% of patients. The wide variation in the reported incidence of secondary endometrial carcinoma may be partially due to histologic difficulty in distinguishing atypical hyperplasia and endometrial carcinoma [32]. Occasionally, granulosa cell tumors are androgenic and present with virilization. At imaging, granulosa cell tumors are large encapsulated multicystic masses that are predominantly solid with variable cystic components [33,34]. The tumors may have a characteristic ‘‘spongelike’’ appearance on T2-weighted MRI. The masses are usually unilateral and confined to the ovary. Associated endometrial thickening or mass may be seen. Unilateral salpingo-oophorectomy is the standard treatment [16]. The histological appearance of granulosa cell tumors does not correlate with biological behavior, so prolonged follow-up is required to detect evidence of malignancy, such as peritoneal metastases (Fig. 10). Granulosa cell tumors have a particular predisposition to hemorrhage. Hemorrhage may be intratumoral or intraperitoneal. The latter is due to tumor rupture and may result in an acute clinical presentation with hemoperitoneum. Malignant germ cell tumors account for less than 5% of all ovarian cancers [16], but are more frequent in younger women, and account for two-thirds of ovarian cancers in women less than 20 years of age [35]. The commonest subtypes are dysgerminoma, immature teratoma, and endodermal sinus tumor, and these subtypes account for approximately 90% of malignant germ cell tumors [4]. Dysgerminoma is the female equivalent of seminoma. The tumor is fre-

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Fig. 10. Axial contrast-enhanced CT sections in a 46-year-old woman with recurrent granulosa cell tumor, 4 years after initial surgery for stage I disease. A predominantly solid peritoneal implant (arrow) is seen between the liver, right kidney, and duodenum (A). Four weeks later, the patient complained of right upper quadrant pain, and a repeat CT scan (B) showed a large hematoma (asterisk) adjacent to the implant, secondary to tumor rupture and hemorrhage. Granulosa cell tumors have a particular predilection to hemorrhage, either within the tumor or into the peritoneal cavity.

quently unilateral and solid, but be partially cystic and contain areas of hemorrhage and necrosis [36]. The finding of a multi-lobulated mass with prominent enhancing septa has been described as a characteristic feature on MRI [37]. The tumor is often localized at presentation (stage I or II) [38]. If present, metastatic disease tends to be nodal rather than peritoneal. Many patients can be successfully treated by unilateral oophorectomy and combination chemotherapy [16]. Immature (malignant) teratoma of the ovary is also usually unilateral and solid, though cystic areas are common [39]. About 70% of patients have stage I or II disease at presentation. Calcification and small amounts of fat may be seen within

mature teratoma [40]. In addition, a co-existent mature teratoma is present in the ipsilateral ovary in 26% of patients and in the contralateral ovary in 10% of patients [41]. Metastases, if present, are usually peritoneal in location (Fig. 11). Endodermal sinus tumor or yolk sac tumor of the ovary is a malignant germ cell tumor characterized histologically by papillary projections that resemble the yolk sac endodermal sinus of the rodent placenta [32]. The tumor usually presents as rapidly growing unilateral adnexal mass in a young woman. The imaging features are variable, and the tumors may range from predominantly solid to predominantly cystic [42]. A co-existent mature teratoma (dermoid cyst) is seen in

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Fig. 11. Axial contrast-enhanced CT sections in a 28-year-old woman with stage III immature teratoma. Relatively small and predominantly solid ovarian masses (arrow) are seen in pelvis (A). Two larger additional masses (asterisks) lying in the pouch of Douglas and superior to the bladder were found to be extra-ovarian peritoneal implants at surgery. (B) Tumor implants (arrows) are also seen in the greater omentum (arrows). Solid ovarian masses in young women with suspected ovarian malignancy are suggestive of primary non-epithelial cancer.

up to 15% of cases (Fig. 12). Hemorrhage and hypervascular enhancement have been suggested as imaging findings that may suggest the histologic diagnosis, in the setting of a complex ovarian mass in a young woman. Metastases to the ovary usually arise from primary malignancy in the stomach or colon, though other primary sites such as the breast, lung, and pancreas are also recognized [43]. The term Krukenberg tumor is sometimes used as a synonym for metastases to the ovary. However, this term is correctly used for a metastasis consisting of mucin signet-ring cells in a cellular stroma, usually arising from a carcinoma of the gastric antrum [32]. Using this definition, only 30% to 40% of ovarian metastases are Krukenberg tumors [4]. Metastases to the ovary are typically bilateral, solid, and strongly enhancing [43,44]. Cystic and necrotic areas are common (Fig. 13). Mucinous tumors may result in areas of increased T2 signal on MRI, while fibrous stromal may result in areas of reduced T2 signal [43]. The primary tumor is often clinically overt, with other evidence of widespread metastatic disease [45]. Superior diaphragmatic adenopathy The superior diaphragmatic (or cardiophrenic) nodes lie on the superior surface of the diaphragm, and are divided into two groups [46,47]. The anterior diaphragmatic (or paracardiac) nodes lie behind the seventh costochondral junction and ster-

num. The lateral diaphragmatic (or juxtaphrenic) nodes lie close to the entrance of the phrenic nerve into the diaphragm, adjacent to the inferior vena cava on the right and the cardiac apex on the left. The diaphragmatic nodes are the principal drainage site of the entire peritoneal cavity, and enlarged superior diaphragmatic nodes are seen in approximately 15% of patients with advanced ovarian cancer (Fig. 14) [48]. Because these nodes are usually small, enlargement is defined as a short axis diameter greater than 5 mm [47,48]. In a study of FIGO stage III ovarian cancer at the Royal Marsden Hospital, anterior diaphragmatic adenopathy was seen at baseline CT scanning in 15 (28%) of 53 patients [48]. This finding was an independent predictor of disease recurrence and death. This suggests anterior diaphragmatic adenopathy should be considered indicative of stage IV disease, but such radiologic findings are not currently incorporated in the surgically-based FIGO staging system. One limitation of the Marsden study was that the pathological status of the nodes was not directly assessed, but the inaccessible location of these nodes is such that they are rarely biopsied or resected. Mesenteric root disease The small bowel mesentery may be involved by surface peritoneal implants, such as in the greater omentum or on the bowel wall. These implants are usually peripherally located with respect to the small

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Fig. 12. Axial contrast-enhanced CT sections in a 34-year-old woman with stage I endodermal sinus tumor. The tumor forms a lobulated layer of enhancing tissue at the periphery of a dermoid cyst. The tumor was confined within the capsule of the ovary at histopathologic examination. Approximately 15% of endodermal sinus tumors arise in association with a pre-existing dermoid cyst.

bowel mesentery. Occasionally, tumor is present at the root of the mesentery, and may be unresectable and result in suboptimal debulking [17]. The frequency and mechanism of mesenteric root involvement has been poorly described. There are two plausible mechanisms; tumor may seed along the surface of the mesentery, spreading centrally towards the mesenteric root, or malignant cells may be absorbed from the greater omentum and mesenteric surface, resulting in true mesenteric adenopathy (Fig. 15). Whatever the mechanism, it is important to scrutinize the mesenteric root at imaging, since this is a clinically important disease site that may be overlooked, particularly if there is extensive disease elsewhere in the abdomen and pelvis. Complex histology The classification of ovarian cancers is complex, and many tumors contain mixed histologic patterns [4]. In general, treatment is determined by the most malignant tissue pattern [16]. These

complexities indicate that attempts to assign a histologic subtype to a malignant ovarian mass based on radiological findings will be of somewhat limited accuracy, and the primary aims of imaging are the detection of malignant characteristics and the assessment of stage. However, two histologic issues are important to radiologists; malignant transformation of benign tumors and cancer arising in association with endometriosis. Malignant transformation may occur in benign epithelial tumors, and is a topic of considerable interest in the pathogenesis of epithelial ovarian cancer [49]. The most frequently encountered form of malignant transformation in clinical practice, however, is the development of cancer in a mature cystic teratoma (dermoid cyst). Between 0.2% and 2% of dermoid cysts undergo malignant transformation [4,50]. The risk of malignant transformation is higher in postmenopausal women. A variety of cancers may arise in dermoid cysts with malignant transformation, but squamous cell carcinoma is the single commonest

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Fig. 13. Axial contrast-enhanced CT section in a 69-year-old woman with widely metastatic pancreatic cancer, including a metastasis to the left ovary (arrow). The mass is heterogenous and hypodense, but predominantly solid.

malignancy. The imaging findings in a series of six patients with malignant transformation in dermoid cysts have been reported [51]. A large nonfatty solid component was seen in four cases, and this mass invaded adjacent structures in three cases. Therefore, these findings may indicate malignancy when seen in a dermoid cyst, particularly in a postmenopausal patient. The co-existence of endometriosis and endometrial cancer was initially considered coincidental [4], but is now generally accepted as a real association [52,53]. The reported relative risk of ovarian cancer in patients with long-standing endometriosis is 4.2 [54]. The mechanism of the association remains obscure. The commonest histologic types of ovarian cancer seen in association with endometriosis are clear cell, endometrioid, and serous carcinoma [53]. The radiological appearances of ovarian cancer arising in endometriosis have not been systematically described, but the detection of solid tissue in an endometriotic cyst should be considered suspicious (Fig. 16).

Primary papillary serous carcinoma of the peritoneum Occasionally, a female patient presents with peritoneal carcinomatosis, an elevated CA-125, but without large adnexal masses [55,56]. While this may represent peritoneal spread from a non-ovarian primary site, the constellation of findings should raise the possibility of primary papillary serous carcinoma of the peritoneum (Fig. 17). Papillary serous peritoneal carcinomatosis is usually secondary to ovarian papillary serous carcinoma. However, in about 10% of cases, the ovaries appear grossly normal, or are only superficially involved by tumor. In such cases, it is postulated that the tumor has arisen from the extraovarian peritoneum, and the term papillary serous carcinoma of the peritoneum is used [57]. A primary origin from the extraovarian peritoneum is supported by the occurrence of the tumor many years after bilateral oophorectomy for benign disease [58], and by one reported case in a man [59]. Other terms that have been used to refer to this condition include serous surface papillary

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Fig. 14. Axial contrast-enhanced CT section (A) in a 59-year-woman with ovarian cancer showing an enlarged superior diaphragmatic node (arrow). These nodes are rarely biopsied, because of the inaccessible location. In this case, a PET scan (B) was performed, and confirmed increased metabolic activity (arrow) in the node.

carcinoma, papillary tumor of the peritoneum, and normal-sized ovary carcinoma syndrome. Imaging

findings resemble those of peritoneal carcinomatosis due to ovarian carcinoma, except that the ovaries are

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Fig. 16. Axial gadolinium-enhanced T1 axial MR image with fat suppression in a 41-year-old woman. A left ovarian cystic lesion is of high T1 signal intensity (asterisk), despite fat saturation. This is suggestive of hemorrhage in an either endometriotic cyst or a hemorrhagic ovarian cyst. However, in addition, an enhancing mural nodularity is visible (arrow). The lesion was resected and histopathologic analysis showed a focus of clear-cell carcinoma arising in an endometriotic cyst.

typically less than 4 cm in size. The presence of peritoneal masses, extensive omental calcification, and the absence of an ovarian mass on CT have been reported as highly suggestive of primary papillary serous carcinoma of the peritoneum, particularly in postmenopausal women [55,60]. The distinction from ovarian papillary serous carcinoma is largely academic, since both are treated with cytoreductive surgery and platin-based chemotherapy, and the prognosis is similar in both conditions [56,57]. The distinction from primary peritoneal mesothelioma can be difficult histologically, but is important to make, since prognosis and management are dif-

ferent. The median survival for patients with papillary serous carcinoma of the peritoneum is 2 years, whereas patients with peritoneal mesothelioma rarely survive for more than a year. Calcified ovarian tumors Calcification in an ovarian mass usually suggests a benign etiology, such as mature teratoma, fibroma, or Sertoli-Leydig cell tumor [61 – 63], but calcification can also be seen in ovarian malignancies. Most calcified ovarian cancers are serous carcinomas [12]. Other rare malignancies such as malignant Brenner

Fig. 15. Axial contrast-enhanced CT sections in two different patients with ovarian cancer, illustrating mesenteric root involvement. Disease in the mesenteric root may appear as soft tissue nodules (arrow) adjacent to the superior mesenteric vessels (A), which may represent nodal spread after absorption of malignant cells from the greater omentum or mesenteric surface, or as soft tissue masses (arrows) distributed more randomly within the mesentery (B), which may represent peritoneal implants on the mesenteric surface.

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Fig. 17. Axial contrast-enhanced CT sections (A and B) in a 52-year-old woman with primary serous papillary carcinoma of the peritoneum, showing the typical radiologic constellation of ascites, peritoneal implants (straight arrows) and non-enlarged ovaries (curved arrows).

tumors and gonadoblastoma may also calcify [64,65]. Calcification in peritoneal metastases is helpful in the

detection of implants around the liver and spleen. Calcified disease more inferiorly in the abdomen may

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require careful scrutiny to allow distinction from contrast-filled bowel (Fig. 18). Pseudomyxoma peritonei Pseudomyxoma peritonei is a form of peritoneal neoplasia that is characterized by the progressive accumulation of mucinous ascites, and is usually due to rupture of an ovarian or appendiceal mucinous adenoma or low-grade mucinous adenocarcinoma [66]. In practice, the primary site is often unclear, and cases of apparent pseudomyxoma peritonei secondary to ovarian tumors may represent metastatic disease to the ovaries and peritoneum from an unrecognized primary tumor in the appendix or elsewhere [67,68]. Two forms can be recognized, depending on whether the histological appearance suggests an adenomatous or adenocarcinomatous origin [69]. These have been designated disseminated peritoneal adenomucinosis (approximately 60% of cases of pseudomyxoma peritonei) and disseminated peritoneal mucinous carcinomatosis, respectively. This pathologic distinction is of major clinical importance; disseminated peritoneal

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adenomucinosis has an age-adjusted 5-year survival of 84% compared to 7% for disseminated peritoneal mucinous carcinomatosis. At CT, the condition may superficially resemble simple ascites; however, the mass-like nodular nature of the gelatinous material in pseudomyxoma peritonei may result in suggestive findings such as hepatic, splenic, and mesenteric scalloping, and visible septations or locules (Fig. 19). Benign mimics of metastatic ovarian cancer Benign mimics of peritoneal metastatic disease are rare. The major differential diagnosis for peritoneal malignancy is infectious peritonitis, especially tuberculous peritonitis. There is considerable overlap between the CT findings in peritoneal carcinomatosis and tuberculous peritonitis [70], and definitive differentiation is histological. Other reported non-cancerous mimics of peritoneal carcinomatosis include mesenteric panniculitis, leiomyomatosis peritonealis disseminata, extramedullary hematopoiesis, and chronic leak from an ovarian dermoid cyst with granulomatous peritonitis [71 – 74]. Prominent diaphragmatic

Fig. 18. Axial contrast-enhanced CT sections of the upper abdomen (A) and pelvis (B) in a 53-year-old woman with stage III ovarian serous adenocarcinoma. Calcification within peritoneal metastases facilitates the detection of perihepatic (black arrow) and gastrosplenic ligament (white arrow) implants. Conversely, calcified omental cake (curved arrow) could potentially be mistaken for contrast-filled bowel.

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Fig. 18 (continued ).

slips should not be mistaken for perihepatic implants [75] (Fig. 20).

Clinical role of imaging in ovarian cancer The previous sections have described the typical and atypical imaging findings in ovarian cancer. The ultimate role of the radiologist is to integrate these findings with the clinical setting in order to optimize patient care and develop a tailored patient-specific management plan. The imaging observations that are critical to management may be divided into those related to characterization of the primary tumor, identification of metastatic disease to prevent understaging, and identification of disease that may be an indication for neoadjuvant chemotherapy. Most ovarian malignancies are epithelial cancers and appear as cystic adnexal masses with irregular internal solid components. This is often accompanied by omental cake, peritoneal implants, and ascites. The clinical and imaging findings in non-epithelial cancers have been described previously, and are

summarized in Table 3. These diagnoses are important considerations in the appropriate setting, because in young patients some of these tumors (granulosa cell tumor, dysgerminoma, immature teratoma, and endodermal sinus tumor) may be treated by unilateral oophorectomy in order to preserve fertility. Conversely, metastatic disease to the ovary may be more appropriately treated by systemic chemotherapy rather than resection. In practice, up to 90% of patients with apparent stage I or II ovarian cancer do not have optimal surgical staging, often because of failure to perform a selective retroperitoneal lymphadenectomy [76]. As a result, approximately 30% of such patients are under-staged [77]. Accurate identification of ovarian metastases by imaging helps prevent such understaging, and may guide subspecialist referral in patients in whom the diagnosis of ovarian cancer was not considered, or considered unlikely. In practice, the percentage of women with advanced ovarian cancer who are successfully (optimally) debulked varies from 17% to 87% [7]. This wide variation likely reflects differences in surgical

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Fig. 19. Axial contrast-enhanced CT sections in a 45-year-old woman with pseudomyxoma peritonei. Mucin in the peritoneal cavity resembles simple ascitic fluid, but the presence of scalloping (arrow) of the liver surface (A) and mass-like separation of bowel loops (B) indicates the true diagnosis.

expertise, but indicates that even in specialist centers a significant fraction of patients will have

inoperable disease and will gain no benefit from primary cytoreduction. The optimal management of

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Fig. 20. Axial contrast-enhanced CT section of the upper abdomen, showing a prominent diaphragmatic slip (arrow). This should not be interpreted as a perihepatic implant.

patients with inoperable ovarian cancer is not established, but review of the clinical and radiological literature suggests: 

Neoadjuvant chemotherapy (ie, preoperative) with interval (or delayed) cytoreductive surgery after tumor shrinkage is a viable management option, and merits a randomized controlled trial [78,79].  Cross-sectional imaging can help treatment planning by identifying, with a high degree of accuracy, those patients with inoperable disease [17,80,81]. The concept of using imaging to identify patients with inoperable disease who may be more appropriately managed by neoadjuvant chemotherapy appears straightforward, but the problem is that there are no clearly established surgical criteria for inoperable disease. Some institutions consider radical surgery appropriate to achieve optimal debulking, even if this involves including resection of the liver, spleen, or kidneys [7,82]. Therefore, the role of the radiologist is not to describe disease as resectable or unresectable, but rather to alert the clinician to disease that may complicate surgery. Depending on the institu-

tion, this may be an indication for neoadjuvant chemotherapy. Findings that may indicate inoperable disease include: 

Invasion of the pelvic sidewall, rectum, sigmoid colon, or bladder  Tumor deposits greater than 1 to 2 cm in size in the gastrosplenic ligament, gastrohepatic ligament, lesser sac, fissure for the ligamentum teres, porta hepatis, subphrenic space, small bowel mesentery, or retroperitoneum above the renal hila [17,80,81,83].

Summary Ovarian cancer is relatively common, and often presents at an advanced stage with widespread intraperitoneal metastases. The constellation of complex pelvic masses, ascites, omental cake, and other peritoneal implants is virtually diagnostic. All patients are potential surgical candidates, since suspected early stage disease is treated by a comprehensive staging laparotomy including total abdominal hysterectomy, bilateral salpingo-oophorectomy,

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Table 3 Clinicoradiological clues to the diagnosis of non-epithelial ovarian cancer. Diagnosis

Frequency (% of all cancers)a

Malignant granulosa cell tumor

<10%

Metastases to the ovary

6%

Dysgerminoma

1%

Immature teratoma

<1%

Endodermal sinus tumor

<1%

a

Clinical and radiological clues Perimenopausal patient with estrogenic symptoms Large encapsulated solid mass with variable cystic (may be spongelike) components Usually unilateral and confined to the ovary ± Endometrial hyperplasia/carcinoma ± Intratumoral hemorrhage/hemoperitoneum Older woman with known primary malignancy, including gastric, colonic, breast, lung, and pancreatic Bilateral solid strongly enhancing masses ± Cystic and necrotic areas ± Increased (mucin) or decreased (stromal reaction) T2 signal intensity Young woman Unilateral solid multi-lobulated mass ± Nodal metastases Young woman Unilateral predominantly solid mass ± Peritoneal metastases Young woman with a rapidly growing mass Predominantly solid to cystic unilateral mass with hemorrhage and hypervascular enhancement ± Co-existent dermoid cyst

Scully.

and omentectomy. Operable advanced disease is treated by surgical debulking and adjuvant combination chemotherapy. The role of imaging is to detect and characterize adnexal masses as likely malignant, recognize unusual findings that may suggest atypical pathology, demonstrate metastases in order to prevent under-staging, and detect specific sites of disease that may be unresectable. These aims are directly related to clinical management; characterization of an adnexal mass as malignant guides appropriate surgical referral, recognition of atypical pathology such as malignant granulosa cell tumor in a young woman may be an indication for fertilitypreserving surgery. Demonstration of metastatic sites assists surgical planning, and detection of unresectable disease may be an indication for neoadjuvant (ie, preoperative) chemotherapy with interval debulking rather than primary debulking with adjuvant (postoperative) chemotherapy.

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