Carcinosarcoma of the uterine corpus is a rare neoplasm, accounting for less than 5% of all uterine malignancies [12]. It is characterized by the presence of both epithelial and stromal malignant components. Immunohistochemical and molecular studies have suggested that the sarcomatous component is actually a metaplastic component derived from the carcinoma (combination tumor theory) [34]. Therefore, carcinosarcoma is believed to have biological behavior similar to high-grade endometrial carcinoma [4]. The clinical course of uterine carcinosarcoma is aggressive, contributing to 30% of uterine cancer mortality [1]. Although many clinicopathological factors, including the presence of a heterologous component, histologic types of the carcinomatous component, grade of the carcinomatous component, depth of myometrial invasion, and lymphatic and vascular space invasion, have been reported to be prognostic factors [56789], stage of disease has been the only definite independent prognostic indicator of survival in patients with uterine carcinosarcoma [789].

Necrosis is a significant prognostic factor of endometrial carcinoma [10], but its prognostic impact on carcinosarcoma is unclear. The magnetic resonance (MR) findings of carcinosarcoma include a heterogeneous appearance, including unenhanced areas, which possibly indicate necrosis [11]. The aims of this study are to confirm if the unenhanced regions on MR imaging (MRI) represent pathological necrosis and to explore the clinicobiological significance of these regions in patients with uterine carcinosarcoma.

Although carcinosarcoma of the uterus has a poor prognosis, the best treatment for this carcinosarcoma has not yet been determined [13]. A carcinosarcoma exhibits characteristic findings on MRI. Tanaka et al. [11] reported that carcinosarcoma typically appears as a large, exophytic, heterogeneous, high signal intensity mass on T2WI, and mostly contains strongly enhanced areas and unenhanced regions within the mass on T1WI, which could indicate necrosis. However, they did not confirm the unenhanced regions on MRI as representing pathological necrosis. Others have reported the same MRI findings of uterine carcinosarcoma [1415]. Our results are compatible with their findings. All cases showed an exophytic uterine endometrial mass with heterogeneous signal intensity. In our study, 17 (77.3%) cases had unenhanced areas, which almost coincided with pathological necrosis. That means that the presence of unenhanced areas within the mass, which implies the existence of necrosis, could be a frequent MR finding of uterine carcinosarcoma.

The definitive prognostic factors for carcinosarcoma of the uterus have been controversial. Galaal et al. [8] identified depth of myometrial invasion, stage, and pelvic node metastasis to be associated with poor survival. Stage appears to be an independent prognostic indicator of survival in patients with uterine carcinosarcoma [67]. It is uncertain whether age, endometrioid adenocarcinoma as a carcinomatous component, or absence of a heterologous component in the sarcomatous area are favorable prognostic factors [7]. Matsuo et al. [5] demonstrated that high-grade and a heterologous pattern are correlated with the worst PFS. In our study, log-rank tests indicated that FIGO stage, histological grade of the carcinomatous component, positive cytology of ascites, LN metastasis, and the presence of an unenhanced region on MRI were associated with poor OS. The univariate analyses using a Cox regression model identified LN metastasis and more than 10% of the tumor being unenhanced on MRI as poor prognostic indicators in OS. Although the multivariate analyses determined that neither of these factors was an independent prognostic factor, our findings suggest that semi-quantification of an unenhanced region on MRI, indicating tumor necrosis, is a prognostic indicator for uterine carcinosarcoma, in addition to stage, histological grade, LN status, and sarcomatous component.

Few reports have investigated the prognostic impact of the presence of necrosis. Rovirosa et al. [6] reported that the existence of pathological necrosis did not have a significant influence on OS. However, the methodology for evaluating necrosis is uncertain. For example, it has poor reproducibility, and excluding the presence of necrosis requires adequate sampling [10]. Therefore, we attempted to quantify the extent of necrosis in tumors using the unenhanced region on MRI, because an unenhanced region on MRI corresponded highly with pathological necrosis in our study. When the extent of tumor necrosis was semi-quantitatively assessed as either absent, focal (≤10% of the tumor area), moderate (10%–30%), or extensive (≥30%), the necrosis showed significant impact on prognosis of colorectal cancer patients in a volume-dependent manner [16]. Because of small numbers of patients in this study, we used 10% unenhanced region as the cut off value because this value categorized them clearly into favorable and poor prognosis groups. As a result, semi-quantification of the necrotic region (>10%) using MRI successfully predicted worse OS.

Unfortunately, it is very difficult to identify microscopically which component contributes to necrosis, because viable cells disappear in the necrotic region. However, by MRI findings, the sarcomatous component is suspected to be more likely to have hemorrhagic necrosis. Takemori et al. [14] reported that the sarcomatous component was more strongly enhanced than the carcinomatous component on contrast-enhanced T1WI, and this might be related to the prominent vascularity of the sarcomatous component. Ohguri et al. [17] also reported that the portions with high signal intensity in the early phase dynamic study corresponded histologically to sarcomatous components with prominent vascularity. Matsuo et al. [5] reported that not only did the carcinoma component play a leading role in tumor progression and survival, but also that the sarcoma component contributed markedly. They suggested that the effect of chemotherapy seems to vary according to the histologic combination of carcinoma and sarcoma components. These findings suggest that tumors with large unenhanced regions, which are related to poor prognosis, might predominantly comprise sarcoma. It is hypothesized that tumor necrosis is caused by chronic ischemic injury due to rapid tumor growth [18]. Tanaka et al. [11] also reported that only 2 of the 8 tumors that included an unenhanced area were smaller than 8 cm in maximum diameter. In our study, the presence of an unenhanced region correlated with tumor size and clinical stage. Therefore, necrosis seems to indicate uterine carcinosarcomas that have developed into larger masses. Necrosis is often accompanied by hypoxia, leading to the induction of hypoxia-inducible factors [19]. Ischemic regions contribute to tumor progression by inducing overexpression of hypoxia-inducible factors under hypoxic conditions [20]. These findings imply that unenhanced regions caused by necrosis likely represent a highly aggressive tumor with active proliferation.

There are several limitations of this study. First, our findings are based on a single-center study with a small sample size, which might have hindered identification of independent prognostic factors. Second, unenhanced regions on MRI can represent hyalinization or a cyst as well as necrosis. In fact, 2 cases had hyalinization and cyst formation in our study. Five of the 22 cases with a high signal intensity area in the tumors on T1WI had intratumoral hemorrhage. Although intermediate-to-high signal intensity on T1WI is helpful for diagnosing hemorrhagic necrosis [21], MRI is unable to strictly quantify necrosis.

In summary, unenhanced regions on MRI represent pathological necrosis and aggressive biology. Semi-quantification of necrosis using MRI is useful to predict the prognosis of uterine carcinosarcoma. Multi-center or larger studies are needed to validate the impact of the presence of an unenhanced region on MRI on prognosis of this rare, aggressive disease.