Differentiation of epithelial ovarian cancer subtypes by use of imaging and clinical data: a detailed analysis

The results for each parameter, the univariate analysis, and the multivariate analysis are listed in Tables 2, 3, and 4, respectively.

The Result of the each parameter in each subtype

The result of each parameter is tabulated in this table

 

All 4 subtypes

Serous vs Mucinous

Serous vs Clear cell

Serous vs Endometrioid

Mucinous vs Clear cell

Mucinous vs Endometrioid

Clear cell vs Endometrioid

P value

P??0.05 ?

P??0.05 ?

P??0.05 ?

P??0.05 ?

P??0.05 ?

P??0.05 ?

Age

N.S.

N.S.

N.S.

N.S.

N.S.

N.S.

N.S.

Largest tumor diameter

0.0001

^***

^***

^*

N.S.

^*

N.S.

Largest solid part diameter

0.0016

N.S.

N.S.

N.S.

***

N.S.

N.S.

Ratio of the solid part

0.0001

^***

^**

N.S.

^**

^*

N.S.

T2 signal ratio

N.S.

N.S.

N.S.

N.S.

N.S.

N.S.

N.S.

DWI signal ratio

0.0100

N.S.

^**

N.S.

N.S.

N.S.

N.S.

Contrast Ratio

0.0263

N.S.

N.S.

N.S.

N.S.

N.S.

N.S.

Bilaterality

0.0001

^**

^***

^***

N.S.

N.S.

N.S.

Morphology

0.0001

^***

^***

^**

N.S.

N.S.

N.S.

Calcification

0.2328

N.S.

N.S.

N.S.

N.S.

N.S.

N.S.

Dissemination

0.0001

N.S.

^***

^***

N.S.

N.S.

N.S.

LNs mets

0.0116

N.S.

^*

N.S.

N.S.

N.S.

N.S.

Staging

0.0001

N.S.

^***

^**

N.S.

N.S.

N.S.

Endometriosis

0.0051

N.S.

N.S.

^*

N.S.

N.S.

N.S.

Thrombosis

0.2465

N.S.

N.S.

N.S.

N.S.

N.S.

N.S.

CA125

0.0502

N.S.

N.S.

N.S.

N.S.

N.S.

N.S.

CA19-9

0.0003

^***

N.S.

N.S.

^***

^*

N.S.

CEA

0.0001

^*

N.S.

N.S.

^*

N.S.

N.S.

Hypercalcemia

0.0096

N.S.

^**

N.S.

N.S.

N.S.

N.S.

Parametric factors were analyzed with one-way ANOVA, followed by a Bonferroni multiple comparison test was applied for a post hoc -test

Nonparametric factors were analyzed with the Kruskal-Wallis test, followed by a Dunn post hoc test

^*significant with low p values, ^** significant with lower p values, and ^***significant with the lowest p values

Multivariate analysis was performed using binary logistic regression. The tables indicate only independent variables that showed multicollinearity for each subtype

Serous carcinoma showed a strong prediction for bilateral disease (p?=?.040, multivariate analysis; the same shall apply hereinafter), smaller tumor size (p?=?.001), and restricted diffusion (p?=?.016), especially when compared with CCC. It also tended to appear as predominantly solid masses, although this difference was not significant on multivariate analysis (Fig. 2). In addition, hypercalcemia was observed significantly less often (p?=?.013).

A case with serous carcinoma. Small almost entirely solid small masses are replacing the bilateral ovaries (arrows, a: axial T2-weighted image, b: axial contrast-enhanced and fat-saturated T1-weighted image). Both masses show strong restricted diffusion on diffusion-weighted image (c, arrowheads). Note the massive ascites and thickened parietal peritoneum with a mass in the cul-de-sac (arrowhead) on sagittal and contrast-enhanced and fat-saturated T1-weighted image (d), reflecting the extensive peritoneal dissemination

CA19-9 levels were significantly higher in MC (p?=?.009). Twelve of the 13 MC appeared as multilocular cystic masses, although this difference was not statistically significant and only the smaller ratio of the solid portion was evident (p?=?.039) (Fig. 3).

A case with mucinous carcinoma. A multilocular cystic mass with varying signal intensity, so called stained-glass tumor, is seen on sagittal T2-weighted image (arrow heads, a). After administration of contrast material, we can see some small solid parts along the septa enhanced by contrast material (arrow heads, b: sagittal T1-weighted image, c: contrast-enhanced and fat-saturated T1-weighted image)

Clear cell carcinoma tended to appear as unilateral disease (p?=?.000) with a larger solid portion (p?=?.031) in younger patients (p?=?.002). Hypercalcemia was also commonly seen in CCC (p?=?.011, Fig. 4).

A case with clear cell carcinoma. A solitary large unilocular cystic mass with a mural nodule is demonstrated on the uterus on sagittal T2-weighted image (a). The lack of adipose tissue between the mass and the uterus suggest adhesion, which evoke co-existing endometriosis. In addition, the content of the cyst shows high signal intensity on sagittal fat-saturated T1-weighted image is another evidence of hemorrhagic material included within an endometriotic cyst (b). After administration of contrast material, the mural nodule is weakly enhanced (arrow heads, b: sagittal T1-weighted image, c: contrast-enhanced and fat-saturated T1-weighted image)

Only intraperitoneal dissemination was significantly less common in EC (p?=?.051). CCC and EC are subtypes well known as complicated by endometriosis (Fig. 5) [13, 14]; however, in this study neither subtype showed any significant increase in endometriosis in the multivariate analysis.

A case with endometrioid carcinoma. A multilocular cystic mass with mural nodules is seen in the cul-de-sac adhering to the uterus on sagittal T2-weighted image (a). The content of the cyst also shows high signal intensity on sagittal fat-saturated T1-weighted image  (b), suggesting co-existing endometriosis. The mural nodules are also well enhanced (arrow heads, c: contrast-enhanced and fat-saturated T1-weighted image). As these imaging characteristics share those of serous and clear cell carcinoma, the specific diagnosis with imaging findings seems the most difficult among 4 subtypes

Primary epithelial ovarian tumors are sub-classified into serous, mucinous, clear cell, and endometrioid carcinomas [1, 2]. Primary debulking surgery followed by chemotherapy is an established standard treatment for epithelial ovarian carcinoma, having achieved excellent therapeutic results with the use of cytotoxic agents [6, 7]. These excellent results may be due to the fact that the vast majority of ovarian carcinoma are of the serous subtype, particularly in the United States and Europe. On the other hand, in the past couple of decades, the number of primary ovarian cancers accompanied by endometriosis has rapidly increased [13, 15]. It is well known that CCC and EC are common subtypes arising from ovarian endometriotic cysts [13, 15]. As the incidence of ovarian cancer accompanied by endometriosis has become higher, the incidence of CCC has become much higher in Japan than in the United States and Europe [15]. CCC is also known as a chemotherapy-resistant subtype of ovarian carcinoma [4, 5]. Therefore, clinicians want to avoid NAC in patients with this subtype.

Although the imaging findings of ovarian carcinoma have been rarely reported, we can speculate on its morphological characteristics on the basis of the macroscopic findings reported in the pathology literature. Serous carcinoma has been characterized by psammomatous calcification on CT [16], peritoneal carcinomatosis, relatively small ovaries, and a highly elevated serum CA-125 level [17]. Our findings revealed that bilateral disease with a smaller tumor size is also common in SC; however, calcification and intraperitoneal dissemination were not significantly frequent in our results. It has also been reported that intratumoral calcification may be observed in ovarian carcinomas other than SC [18] and that on CT psammomatous calcification could not be differentiated from other calcifications [19]. Therefore, our findings may not be surprising. Recently, SC has been subdivided into low-grade and high-grade subtypes [20]. Low-grade serous carcinoma (LGSC) is considered to arise from serous borderline tumors. Serous surface papillary borderline tumors (SSPBTs) are characterized by a papillary architecture and internal branching pattern, like that of a sea anemone [21]. Therefore, LGSC may resemble SSPBTs that tend to make larger tumors. Our findings might have included a few LGSCs, as the incidence of the LGSC has been reported as far lower than those of high-grade serous carcinomas [22]. We speculate that this inhomogeneity in the SC group might have influenced the present findings.

Mucinous carcinoma is also a chemotherapy-resistant subtype of ovarian carcinoma [3]. MRI findings characteristic of MC have been reported as a large multilocular cystic mass with varying signals [23, 24], and its so-called stained glass-like appearance may be a hallmark of the tumor. In this study, we classified the morphological subtypes into 5 categories, and 12 of the 13 MC showed multilocular cystic with and without a solid portion. However, we could not reveal that the multilocular cystic mass was characteristic of MC because many of the cases of the other subtypes also had a multilocular cystic morphology with solid masses. The former WHO classification of ovarian tumors classified MC into intestinal and endocervical-like subtypes [1]. In the latest version of the WHO classification, endocervical-like MC is defined as seromucinous carcinoma [2]. However, our study was performed following the former version of the WHO classification [1] and thus included endocervical-like MC. Endocervical-like MC usually appears as mural nodules of endometriotic cysts [2]. Our results also revealed a high incidence of endometriosis in MC. This high incidence might suggest that endocervical-like MC is difficult to differentiate from CCC or EC.

Clear cell carcinoma and endometrioid carcinoma are commonly complicated by endometriosis [13, 15]. Therefore, coexistent endometriosis may be the key finding for these subtypes [14, 25, 26]. In our study, however, only CCC showed a significantly higher incidence of endometriosis when compared with SC in the univariate analysis. In addition, CCC was reported to appear as a larger unilocular cystic mass with eccentric mural nodules [27, 28], whereas in our study a large number of CCC had multilocular cystic masses. Therefore, differentiating CCC from EC based only on the imaging findings seems to be difficult. On the other hand, as in previous reports, coexistent hypercalcemia was more commonly seen in CCC in our study [29], which may be helpful for the differential diagnosis. Venous thrombosis was also reported as a frequently seen paraneoplastic syndrome of CCC [30]; however, our study could only reveal that the incidence of venous thrombosis was lower in SC.

Endometrioid carcinoma, a chemosensitive subtype of ovarian carcinoma, only showed a significantly lower incidence of peritoneal dissemination. In other words, it did not show any unique characteristics in its morphology.

Some limitations in our study should be pointed out. First, we could analyze only the morphological characteristics of the ovarian carcinomas, whereas numerous histological types of tumors affect the ovaries. Therefore, the process of differential diagnosis in daily practice may be more complex. Second, the number of tumors that we analyzed was limited. We included relatively larger number of CCC as our study population included a lot of ovarian cancer coexisting endometriosis. However, a bigger number of tumors need to be analyzed, in particular MC and EC.