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Malignant Ovarian Tumors (Serous/ Mucinous/Endometrioid/Clear Cell Carcinoma): Clinical Setting and Ultrasound Appearance Juan Luis Alcázar and Jesús Utrilla-Layna

Abstract

Epithelial ovarian cancer remains as the most deadly gynecological malignancy and it is the seventh leading cause of cancer in women in developed countries. Worldwide more than 200,000 new cases are diagnosed annually, resulting in more than 140,000 deaths. Histologically, ovarian malignancies are classified in two broad groups: epithelial and nonepithelial ovarian cancer. Epithelial ovarian cancers are subclassified based on hystotype, with serous, endometrioid, clear cell, and mucinous carcinomas accounting for 96 % of all cases. In this chapter we shall review the origin, clinical setting, and ultrasound appearance of serous, endometrioid, and mucinous carcinomas. Keywords

Serous carcinoma • Mucinous carcinoma • Endometrioid carcinoma • Clear cell • Imaging • Ultrasound

Introduction Epithelial ovarian cancer remains as the most deadly gynecological malignancy and it is the seventh leading cause of cancer in women in developed countries. Worldwide more than 200,000 new cases are diagnosed annually, resulting in more than 140,000 deaths [1]. Histologically, ovarian malignancies are classified in two broad groups: epithelial and non-epithelial ovarian cancer [2]. Epithelial ovarian cancers account more than 90 % of all ovarian malignancies [2].

J.L. Alcázar, MD, PhD (*) Department of Obstetrics and Gynecology, Clínica Universidad de Navarra, University of Navarra, Avenida Pio XII, 36, 31008 Pamplona, Spain e-mail: [email protected] J. Utrilla-Layna, MD Department of Obstetrics and Gynecology, Clínica Universidad de Navarra, Pamplona, Spain

Epithelial ovarian cancers are subclassified based on hystotype, with serous, endometrioid, clear cell, and mucinous carcinomas accounting for 96 % of all cases [3]. In this chapter we shall review the origin, clinical setting, and ultrasound appearance of serous, endometrioid, and mucinous carcinomas.

Origin of Epithelial Ovarian Cancer Currently, recent morphologic, immunohistochemical, and molecular genetic studies have led to a new theory for the pathogenesis and origin of epithelial ovarian cancer (EOC): the dualistic model of EOC carcinogenesis [4]. According to this model, EOCs are divided into two categories: type I and type II. EOC type I include low-grade serous, low-grade endometrioid, clear cell, and mucinous carcinomas, as well as transitional cell cancers. These tumors are usually indolent and slow-growing tumors. Generally they are diagnosed at early stage and they are characterized by some specific mutations. They account about 25 % of ECOs.

L. Saba et al. (eds.), Ovarian Neoplasm Imaging, DOI 10.1007/978-1-4614-8633-6_14, © Springer Science+Business Media New York 2013

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Table 1 Genetic alterations in EOC HGSC LGSC Clear cell Endometrioid Mucinous

p53 (95 %), BRCA (50 %) KRAS (70 %), BRAF (68 %), HER-2 (9 %) ARID1 A (50 %), PIK 3CA (50 %), PTEN (20 %) ARID1 A (36 %), PTEN (20 %), CTNNBI (38–50 %) KRAS (75–85 %), HER-2 (15–20 %)

Type II EOCs compromise high-grade serous, high-grade endometrioid carcinosarcomas and undifferentiated carcinomas. Generally, these tumors are aggressive, present in advanced stage, and harbor different mutations than EOC type I. They account about 75 % of ECOs.

Serous Ovarian Cancer Ovarian serous carcinoma is the most frequent EOC (60 % of all cases). As stated above serous EOCs are divided into lowgrade (LGSC) and high-grade (HGSC) carcinomas. About 10 % of serous EOCs are diagnosed at stage I, 8 % at stage II, 55 % at stage III, and 27 % at stage IV [5]. HGSCs constitute 90 % of all serous EOCs, whereas LGSCs account for 10 % of serous EOCs. Current evidence suggests that HGSC actually arise from the epithelium from the fimbriated end of the fallopian tube [4]. These lesions implant on the ovary surface resembling a primary ovarian origin at gross examination. HGSC are characterized by p53 mutations (more than 95 % of the cases) and BRCA1 and BRCA2 mutations (about 80 % of the cases) (Table 1). Most BRCA-related ovarian cancers (60–100 %) are HGSCs. Mutations of BRCA1 and BRCA 2 are found in 40–50 % of sporadic HGSCs. They are genetically unstable. These features confer a high aggressiveness and high cellular proliferation. In contrast to HGSC, LGSC EOCs rarely contain p53 mutations but they are characterized by KRAS, BRAF, and HER-2 mutations (Table 1) and they are much more genetically stable. There is evidence that LGSC EOCs develop in a stepwise fashion from a benign epithelium from ovarian or tubal origin to borderline tumor, ending in an invasive cancer [4].

Endometrioid and Clear Cell Carcinomas Endometrioid and clear cell carcinomas constitute about 15–20 % of all EOCs. The most frequent genetic mutations of these EOCs are shown in Table 1. Endometrioid carcinomas are also subclassified into lowgrade endometrioid carcinoma (LGEC) and high-grade endo-

metrioid carcinoma (HGEC); morphologic studies and more recently molecular studies have shown that both, endometrioid and clear cell carcinomas, arise from endometriosis [4].

Mucinous Carcinomas Mucinous carcinomas account for less than 5 % of all EOCs. The most frequent mutations are KRAS and HER-2 (Table 1). Current evidence support that these cancers develop also in a stepwise fashion from a benign epithelium to a borderline lesion, leading to an invasive carcinoma [4]. The origin of mucinous carcinomas is rather intriguing, because unlike serous, endometrioid, and clear cell carcinomas, they do not show a müllerian phenotype. It seems that mucinous tumors could have the same histogenesis than transitional cell tumors, arising from microscopic transitional cell nets at the tuboperitoneal junction [4]. Histologically, there are two variants: intestinal type and endocervical type, the former being the most frequent one.

Clinical Setting Current knowledge about EOC carcinogenesis and pathogenesis highlights the heterogeneity of this disease. From the clinical point of view, there are some differences in clinical presentation of EOC depending on the hystotype.

High-Grade Serous Carcinomas Mean patient age at diagnosis is 55.5 years old, or even earlier in BRCA-related carcinomas [6]. Up to 85 % of these patients present intra-abdominal spread of the disease at diagnosis. Extra-abdominal disease at presentation, such as liver, lung, or brain metastases, is not common at diagnosis (2–3 %). For this reason symptoms related to intra-abdominal spread such as abdominal swelling, bloating, constipation, or dyspepsia are common in these women. Some studies have shown that the most of these women referred symptoms suggestive for EOC several months before diagnosis [7]. Thus, paying attention to those symptoms could lead to an earlier diagnosis or the so-called minimal volume disease diagnosis [8].

Low-Grade Serous Carcinomas Mean patient age at diagnosis is 62.6 year old, being younger (40 year) in borderline serous tumors [6].

Malignant Ovarian Tumors (Serous/Mucinous/Endometrioid/Clear Cell Carcinoma): Clinical Setting and Ultrasound Appearance

Most of these tumors present at early stage although a small proportion could present with intraperitoneal or visceral metastases. These tumors generally are slow growing and do have an indolent course, so a significant proportion of women are asymptomatic at diagnosis.

Endometrioid Carcinomas These tumors usually appear in the fifth and sixth decades of life [6]. Association with endometriosis is frequent and past history of complaints related to endometriosis such as pelvic pain and infertility is common. About 30 % of these tumors are diagnosed at stage I.

Clear Cell Carcinomas Patient’s mean age at presentation is 57 years old [6]. Association with endometriosis is also common. These tumors generally manifest as large unilateral adnexal masses with nonspecific symptoms. About 50 % of these carcinomas are diagnosed at stage I.

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The content of the cystic portion generally is anechoic. The presence of ascites (Fig. 3) and abdominal metastases is also a common finding in most of the cases (Figs. 4 and 5). Color or power Doppler ultrasound generally shows moderation or abundance within solid components (Figs. 6 and 7). Septations may be present (Fig. 8). The size of the lesion may vary significantly but is not rarely found out as small adnexal lesions (Fig. 9).

Ultrasound in Low-Grade Serous Cancer Low-grade serous cancers appear as large cystic adnexal masses with septation and solid components (Figs. 10 and 11). The cyst’s content also is anechoic in most cases. Bilaterally it is found in 60–75 % of cases, and abdominal carcinomatosis and ascites can also be found out in advancedstage cases. Small lesions and solid lesions are not common in this type of EOC. With color or power Doppler ultrasound, the tumor generally exhibits a moderate or abundant amount of flow. In cases of borderline tumor, the mass typically appears as a cystic mass with large vascularized papillary projections (Figs. 12 and 13).

Mucinous Carcinomas Mucinous carcinomas are usually diagnosed during the fourth to fifth decades of life. Only 20 % are invasive carcinomas whereas 80 % are borderline tumors at diagnosis. Most of the tumors present as large unilateral adnexal masses. About 80 % of mucinous carcinomas are diagnosed at stage I.

Ultrasound Features of Epithelial Ovarian Cancer In spite of the significant amount of published studies addressing the role of ultrasound for predicting ovarian malignancy in adnexal or pelvic tumors, there is a paucity of studies describing the specific features of epithelial ovarian cancers [9–14].

Ultrasound in High-Grade Serous Cancer It could be considered that the “typical” sonographic features of HGSC are the presence of cystic–solid or solid irregular adnexal masses [6] (Figs. 1 and 2). Bilaterally it is frequently found out (60–84 %).

Ultrasound in Endometrioid and Clear Cell Carcinomas Endometrioid and clear cell ovarian cancers usually appear as unilateral (65–72 % of cases) cystic masses with solid components (Figs. 14 and 15). Cyst’s content generally is low level – resembling that of endometriotic cysts (Fig. 16) – and tumor size may vary. Septations are a frequent finding. Like serous carcinomas, color or power Doppler examination will show a significant amount of blood flow within the tumor (Fig. 17).

Mucinous Carcinomas Mucinous carcinoma usually appears as significantly large (>10 cm) unilateral adnexal masses. Their typical finding is the multilocularity (>10 locules) (Fig. 18). Solid components may be present (Fig. 19) or not. Content of the cystic area may be different from one locule to another (Fig. 20) and blood flow is usually seen within septations (Fig. 21). Since most of these tumors are early-stage cancers, ascites or carcinomatosis is not a frequent finding.

232 Fig. 1 Transvaginal sonogram of an HGSC showed as a large irregular cystic–solid adnexal mass

Fig. 2 Transvaginal sonogram of an HGSC showed as an irregular solid adnexal mass


Malignant Ovarian Tumors (Serous/Mucinous/Endometrioid/Clear Cell Carcinoma): Clinical Setting and Ultrasound Appearance Fig. 3 Transabdominal ultrasound showing a significant amount of ascites in a patient with stage IIIc high-grade ovarian serous ovarian cancer

Fig. 4 Transvaginal ultrasound showing carcinomatosis involving the peritoneum of the bladder

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234 Fig. 5 Transabdominal ultrasound showing omentum involvement in a woman with intra-abdominal spread for ovarian cancer

Fig. 6 Transvaginal ultrasound showing an irregular solid mass with abundant vascularization


Malignant Ovarian Tumors (Serous/Mucinous/Endometrioid/Clear Cell Carcinoma): Clinical Setting and Ultrasound Appearance Fig. 7 Transvaginal ultrasound showing a cystic–solid mass with abundant vascularization within the solid portions of the tumor

Fig. 8 Transvaginal ultrasound showing a predominantly cystic mass with a solid area and septations. Histology revealed an HGSC stage II

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236 Fig. 9 Transvaginal ultrasound showing a small, highly vascularized, solid mass that corresponded to HGSC stage III

Fig. 10 Transvaginal ultrasound showing a multilocular cystic–solid mass. Histology confirmed an LGSC stage II


Malignant Ovarian Tumors (Serous/Mucinous/Endometrioid/Clear Cell Carcinoma): Clinical Setting and Ultrasound Appearance Fig. 11 Transvaginal ultrasound showing a multilocular solid mass. Histology revealed an LGSC, stage III

Fig. 12 Transvaginal ultrasound showing a regular cystic mass with solid components and septations. Histology confirmed a stage I borderline serous tumor

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238 Fig. 13 Transvaginal ultrasound showing a regular cystic mass with thick papillary projections from a borderline serous tumor

Fig. 14 Transvaginal ultrasound showing an irregular cystic–solid mass that corresponds to a clear cell ovarian carcinoma


Malignant Ovarian Tumors (Serous/Mucinous/Endometrioid/Clear Cell Carcinoma): Clinical Setting and Ultrasound Appearance Fig. 15 Another cystic mass with a thick papillary projection. It corresponded to a stage I endometrioid carcinoma

Fig. 16 Unilocular cystic mass with a focal wall irregularity. Cyst’s content is homogeneous low level. Histology revealed a stage I endometrioid carcinoma

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240 Fig. 17 Transvaginal ultrasound from an endometrioid ovarian carcinoma showing moderate vascularization at power Doppler examination

Fig. 18 Multilocular cystic mass with more than 10 locules, characteristic for mucinous carcinoma


Malignant Ovarian Tumors (Serous/Mucinous/Endometrioid/Clear Cell Carcinoma): Clinical Setting and Ultrasound Appearance Fig. 19 Similar image than previous figure corresponding to a mucinous carcinoma. In this case solid components are present

Fig. 20 Three-dimensional ultrasound from a mucinous carcinoma showing a multilocular mass. Note different content is different locules

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Fig. 21 Multilocular cystic mass with more than 10 locules, characteristic for mucinous carcinoma. Note blood flow within septations

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