Two case reports of ovarian clear cell carcinoma with central necrosis representing a mille-feuille-like appearance on contrast-enhanced MRI.

We have received written informed consent from the two patients to publish this case report and related images.

We reported two cases of entirely solid CCC with pT1a and pT1c3 stages in women aged 50 and 75 years, respectively; the origin of the tumors in both cases could not be traced to endometriosis or clear cell adenofibroma. Moreover, the mechanism underlying the appearance of central necrosis in solid-type CCC remains unknown. The findings in this case suggest that MRI can provide valuable insights into the differential diagnosis of epithelial ovarian carcinomas. Further studies are necessary to clarify the pathological structure and origin of CCC.

Two distinct but related developmental pathways are involved in the pathogenesis of ovarian CCC; the endometriotic cyst and adenofibromatous pathways [ 11 ] . The endometriotic cyst pathway arises from cystic endometriosis, and atypical endometriosis develops within the cyst wall, and subsequently progressing to CCC. The adenomatous pathway is believed to originate from noncystic endometriosis associated with fibromatous stromal proliferation, processing a stepwise from clear cell adenofibroma to borderline tumor and finally to carcinoma [ 12 ]. Although the two pathways are morphologically distinct, they are not mutually exclusive. In some cases, both endometriotic and adenofibromatous components coexist within the same lesion, indicating that these processes are pathogenetically related and may converge toward the development of ovarian CCC [ 13 ]. Several MRI features of CCC arising from endometriosis- and adenofibroma-associated tumors have been reported. CCC developing from endometriosis is frequently depicted as a unilocular cystic lesion with mural nodules in a “polypoid, focal, or eccentric” growth pattern with hyperintense cystic contents on T1WI [ 14 , 15 ], compared with endometrioid carcinoma and high-grade serous carcinoma. In cases of CCC arising in the background of adenofibroma, the tumor typically contains solid components with low signal intensity on T2WI [ 9 ], intermingled with numerous small cysts that exhibit a “black sponge-like” appearance [ 16 ]. Within this pattern, malignant transformation (CCC component) in clear cell adenofibromas showing mild hyperintensity on T2WI, hyperintensity on DWI with low ADC values, and intense early and prolonged contrast enhancement on dynamic studies can be identified [ 17 ]. However, when the proportion of malignant cells is small, the cancerous areas may not be discernible on imaging. In an ultrasound study by Pozzati et al. [ 6 ], 25% (19/76) of CCC cases without evidence of endometriosis on histology were of the solid-type. Of the patients with CCC, 22.2% (12/54) of CCC with evidence of endometriosis were of the solid type; however, only three reports have described the MRI findings of solid-type CCC. Takeyama, et al. [ 18 ] recently described two cases of entirely solid CCC with a renal corticomedullary contrast-like appearance, which revealed cancer cell proliferation accompanied by increased stromal fibrous tissue in the peripheral portion; edematous stroma and fibrosis were predominantly observed with minimal cancer cells in the central portion. Wang et al. reported two cases of solid-type CCCs with cysts or necrosis. Elsherif, et al. reported a case of solid-type CCC presenting with heterogeneous hyperintensities on T2WI [ 19 ]. In this case, the MRI finding of the solid-type CCC with extensive central necrosis differed from those reported in previous cases [ 20 ]. The mille-feuille sign is a recently described MRI feature characterized by a finely layered structure within cystic ovarian masses, measuring several millimeters in thickness and more than 10–20 mm in width or length [ 10 ]. Histopathologically, it corresponds to alternating layers of tumor cells, fibrous stroma, and intraluminal necrotic debris. Kurokawa et al. first reported this sign as highly specific for ovarian metastases from colorectal carcinoma [ 10 ], whereas Watanabe et al. subsequently described similar findings in ovarian carcinosarcoma [ 21 ]. In clinical practice, we have occasionally observed a comparable striped or finely layered appearance at the interface between the central necrosis and viable solid components of ovarian tumors, resembling the mille-feuille sign. We termed this finding the “mille-feuille-like appearance” on delayed-phase contrast-enhanced T1WI, and defined it as a striped or finely layered pattern oriented perpendicular to the tumor wall at the interface between central necrosis and viable solid components. This mille-feuille-like appearance is different from the classic mille-feuille sign in that layered structure is thinner and less well defined, with a minimum width and length of ≥2 mm and ≥20 mm, respectively, rather than ≥10 mm and ≥20 mm, respectively, for the original sign [ 10 ]. This imaging feature may also be observed in ovarian CCC and, if validated in larger studies, could serve as a valuable MRI finding for the preoperative diagnosis. The linear hypointense streaks of the peripheral solid component of the tumor on T2WI did not correspond with fibrous septa. They may have represented with hemorrhagic or necrotic component, as these areas showed mild hyperintensity on unenhanced T1WI and no contrast enhancement. Tumor microstructure is associated with the ADC value (mm 2 /second) as a potential imaging marker [ 22 ]. The mean (range) ADC value for the solid component was 1.20 (1.03-1.53) ×10 −3 mm 2 /second and 1.18 (1.05-1.33) × 10 −3 mm 2 /second in cases 1 and 2, respectively. These values were consistent with those reported in previous studies using a 1.5 T MRI scanner, which showed values ranging from 0.98 to 1.87 × 10 −3 mm 2 /second in patients with CCC [ 23 , 24 ]. The mean (range) ADC value for central necrosis was 1.98 (1.56-2.60) ×10 −3 mm 2 /second and 2.09 (1.82-2.33) × 10 −3 mm 2 /second in cases 1 and 2, respectively; low cellularity with an extracellular space was associated with a high ADC value [ 22 ]. Endometriotic cysts are found in 50%-74% of patients with CCC and CCC is associated with background pelvic endometriosis in up to 68% of cases [ 1 , 2 ]. In our two cases, neither background ovarian nor pelvic endometriosis was identified in either tumor. Furthermore, adenofibromatous components were not observed in any of the cases. However, we believe that these tumors originated from adenofibroma rather than from an endometriotic cyst. According to Kato et al., who analyzed four clear cell adenofibroma-associated, 21 endometriosis-associated, and 19 indeterminate CCCs, solid tumors were observed exclusively in the indeterminate group. They suggested that indeterminate CCCs constitute a distinct entity from adenofibroma- and endometriosis-associated CCCs, and should not be considered a true histological subtype [ 9 ]. The imaging and pathological features in our two cases appeared to correspond to the indeterminate form described by Kato et al.

Ovarian clear cell carcinoma (CCC) is a histological subtype of epithelial ovarian cancer characterized by clear, eosinophilic, and hobnail cells [ 1 ]. The prevalence of CCC varies geographically, accounting for approximately 10% and 20%-25% of all ovarian cancers in North America and Japan, respectively [ 2 ]. CCC typically presents as a large, unilateral pelvic mass and is frequently associated with mildly to moderately elevated serum carbohydrate antigen (CA) 125 levels (approximately 200 U/mL) [ 3 ]. Patients with CCC have a higher incidence of paraneoplastic hypercalcemia and venous thromboembolic events than those with other histological subtypes [ 4 ]. More than half of ovarian CCCs have been diagnosed at FIGO stage I; however, CCC is frequently resistant to conventional chemotherapy, including platinum-based regimens, and its prognosis is poor when residual disease remains after primary surgery [ 5 ]. Therefore, maximal surgical effort should be made to achieve complete resection (zero residual disease) when CCC is suspected, and preoperative recognition of CCC may be clinically valuable for optimizing surgical management [ 6 ]. Variable magnetic resonance imaging (MRI) findings of CCC have been reported to range from solid to cystic characteristics because the MRI features reflected the diversity of tissue structures arranged in tubulocystic, papillary, and solid architectures, which frequently coexist within the tumors [ 1 , 7 ]. The morphology of MRI finding in CCC has been described as multilocular cystic, unilocular with a single nodule, unilocular with multiple nodules, multilocular with solid, or solid [ [8] , [9] , [10] ]; the solid-type has been relatively rare, ranging from three of the 53 cases (5.7%) to three of the 44 cases (6.8%) [ 8 , 9 ]. To the best of our knowledge, no previous reports have described MRI features of solid-type CCCs with extensive central necrosis, displaying a striped or finely layered appearance at the interface between the central necrosis and solid components, resembling the mille-feuille sign. In this report, we describe two cases of solid-type CCC with extensive central necrosis presenting with a mille-feuille-like appearance and the correlation between their MRI features and corresponding pathological findings. A 50-year-old woman presented with swelling in the left inguinal area and lower abdominal pain for 2 months. Blood coagulation tests revealed abnormal results, with a Prothrombin Time (PT) of 13.9 seconds, PT-international normalized ratio of 1.22, and Activated Partial Thromboplastin Time of 46.3 seconds. The other laboratory tests revealed no abnormalities. Biochemical tests revealed no abnormalities, except for serum C-reactive protein (CRP) and CA 125 level. A high serum CRP level of 3.6 mg/dL (normal value: < 0.3 mg/dL) and CA125 level of 154.8 IU/mL (normal value: < 37 IU/mL) were observed. The patient had undergone a cesarean section 12 years prior. The patient’s family history was unremarkable. A well-circumscribed, oval tumor, 14 cm in diameter, was observed in the left adnexal region ( Fig. 1 ). The solid component, predominantly located at the periphery of the tumor, appeared mildly hyperintense with linear hypointense streaks on T2-weighted imaging (T2WI), and isointense on unenhanced T1-weighted imaging (T1WI), with gradual enhancement on dynamic contrast-enhanced T1WI relative to the myometrium. It displayed hyperintensity on diffusion-weighted imaging (DWI) and hypo- to isointensity on the apparent diffusion coefficient (ADC) map. The interface between the central necrosis and the viable solid component showed a striped or finely layered appearance resembling the mille-feuille sign [ 10 ]. We therefore termed this finding the “mille-feuille-like appearance” during delayed phase contrast-enhanced T1WI, and defined it as a striped or finely layered pattern at the interface between central necrosis and viable solid components in ovarian tumors. In this case report, the fine layered structures were operationally defined as linear layers separated by several millimeters, with a minimum width and length of ≥2 mm and ≥20 mm , respectively. Fig. 1 Case 1: Clear cell carcinoma of the left ovary of a 50-year-old woman. T2-weighted imaging in the sagittal (A) and axial (B) planes reveal that the tumor comprises an isohyperintense solid component with multiple linear hypointense streaks (arrows) and hypo-isointense necrotic component at the central portion of the tumor. Compared with the myometrium, the solid component in the anterior wall of the tumor appears hyperintense on diffusion-weighted imaging (DWI) (C), iso-hypointense on an apparent diffusion coefficient (ADC) map (D), isointense on unenhanced T1-weighted imaging (T1WI) (E), and gradual enhancement with a striped or finely layered appearance (arrows) on early (F) and delayed phases (G and H) of multiphasic contrast-enhanced T1WIs. The extensive necrotic component (asterisks) appears iso hyperintense on DWI, hypo-hyperintense on the ADC map, and hypoisointense on unenhanced T1WI (E) without enhancement (G). The ADC value ranged from 1.03 to 1.53 mm 2 /second and 1.56 to 2.60 mm 2 /second for the solid component of the tumor and central necrosis. The cut surface of the resected specimen (I) reveals a solid grayish-white mass measuring 14×14×7 cm. Extensive necrosis (asterisks) is observed in the central portion of the tumor. Hematoxylin and eosin (H&E) staining of the solid component (J) showing tumor cell proliferation with eosinophilic to clear cytoplasm and hobnail morphology (arrow). A low-power view of H&E staining (K) shows extensive necrotic debris in the central portion of the tumor. A high-power view of H&E staining (L) demonstrates alternating layers of fibrous stroma (asterisks) and tumor cells (star marks) at the interface between the necrotic and viable solid components. Fig 1 – dummy alt text Case 1: Clear cell carcinoma of the left ovary of a 50-year-old woman. T2-weighted imaging in the sagittal (A) and axial (B) planes reveal that the tumor comprises an isohyperintense solid component with multiple linear hypointense streaks (arrows) and hypo-isointense necrotic component at the central portion of the tumor. Compared with the myometrium, the solid component in the anterior wall of the tumor appears hyperintense on diffusion-weighted imaging (DWI) (C), iso-hypointense on an apparent diffusion coefficient (ADC) map (D), isointense on unenhanced T1-weighted imaging (T1WI) (E), and gradual enhancement with a striped or finely layered appearance (arrows) on early (F) and delayed phases (G and H) of multiphasic contrast-enhanced T1WIs. The extensive necrotic component (asterisks) appears iso hyperintense on DWI, hypo-hyperintense on the ADC map, and hypoisointense on unenhanced T1WI (E) without enhancement (G). The ADC value ranged from 1.03 to 1.53 mm 2 /second and 1.56 to 2.60 mm 2 /second for the solid component of the tumor and central necrosis. The cut surface of the resected specimen (I) reveals a solid grayish-white mass measuring 14×14×7 cm. Extensive necrosis (asterisks) is observed in the central portion of the tumor. Hematoxylin and eosin (H&E) staining of the solid component (J) showing tumor cell proliferation with eosinophilic to clear cytoplasm and hobnail morphology (arrow). A low-power view of H&E staining (K) shows extensive necrotic debris in the central portion of the tumor. A high-power view of H&E staining (L) demonstrates alternating layers of fibrous stroma (asterisks) and tumor cells (star marks) at the interface between the necrotic and viable solid components. The necrotic component occupying the central portion of the tumor appeared hypointense and hypo- to hyperintense on DWI and the ADC map, respectively. It showed heterogeneous and hyperintensity on T2WI, hypo-isointensity on T1WI, and less enhancement on dynamic contrast-enhanced T1WI. By placing a region of interest measuring 25 mm 2 , the ADC value ranged from 1.03 to 1.53 mm 2 /second and 1.56 to 2.60 mm 2 /second for the solid component of the tumor and central necrosis, respectively. Simple total hysterectomy, bilateral salpingo-oophorectomy, partial omentectomy, and para-aortic and pelvic lymph node dissection were performed. The cut surface of the resected specimen revealed a solid mass with extensive central necrosis. Hematoxylin and eosin (H&E) staining of the solid component of the tumor showed that cancer cells proliferated in solid architectures, with partial areas showing papillary and tubulocystic patterns. Predominant necrotic tissue with fibrosis was observed in the central portion of the tumor. The interface between the necrotic and viable solid components in the central portion of the tumors revealed alternating layers of tumor cells and necrotic or fibrotic tissues. No histopathological evidence of endometriosis and adenofibroma were observed. The final diagnosis was a left ovarian CCC (pT1a). The patient did not undergo adjuvant chemotherapy. No residual tumors or distant metastases were observed for 1 years after the treatment. A 75-year-old woman presented with urinary retention and was diagnosed with a pelvic mass using abdominal ultrasonography. Her obstetric history was gravida 2 and para 2, and she experienced menopause at 53 years of age. Her medical history included hypertension, diabetes mellitus, and hyperlipidemia. The patient’s family history was unremarkable. Laboratory tests revealed a high serum CRP level of 5.2 mg/dL (normal value: < 0.3 mg/dL) and a CA-125 level of 154.8 IU/mL (normal value: < 37 IU/mL). A well-contoured oval tumor with a diameter of approximately 14 cm in the left adnexal region was observed on T2WI ( Fig. 2 ). Compared with the myometrium, the peripheral area of the tumor appeared isointense, isointense, hyperintense, and hypoisointense on T2WI, unenhanced T1WI, DWI, and ADC maps, respectively, and it showed gradually increasing enhancement on dynamic contrast-enhanced T1WI. The “mille-feuille-like appearance,” which showed the striped or finely layered appearance at the interface between the central necrosis and solid components, was observed on delayed-phase contrast-enhanced T1WI. The central area of the tumor appeared hyperintense, hypointense, hypointense, hyperintense, and less enhanced on T2WI, T1WI, DWI, ADC maps, and dynamic contrast-enhanced T1WI, respectively. By placing a region of interest measuring 25 mm 2 , the ADC value ranged from 1.05 to 1.33 mm 2 /second and 1.82 to 2.33 mm 2 /second for the solid component of the tumor and central necrosis, respectively. Fig. 2 Case 2: Clear cell carcinoma of the left ovary of a 75-year-old woman. T2-weighted imaging of the sagittal (A) and axial (B) planes reveal that the tumor comprised an isohyperintense solid component at the periphery, and a heterogeneously hypo-isointense necrotic component at the central portion of the tumor. Compared with the myometrium, the solid component of the tumor appears hyperintense on diffusion-weighted imaging (DWI) (C), isohypointense on an apparent diffusion coefficient (ADC) map (D), and isointense on unenhanced T1-weighted imaging (T1WI) (E). Multiphasic contrast-enhanced T1WIs in the early (F) and delayed (G and H) phases show gradual enhancement with a striped or finely layered appearance (arrows). The extensive necrotic component (asterisks) appears iso hyperintense on DWI, hypo-hyperintense on the ADC map, and hypo-isointense on unenhanced T1WI (E) without enhancement (G). The ADC value ranged from 1.05 to 1.33 mm 2 /second and 1.82 to 2.33 mm 2 /second for the solid component of the tumor and central necrosis, respectively. The cut surface of the tumor shows an extensive necrotic area (I) on the right side and an extensive fibromatous area (J) on the left side of the tumor. A low-power view of hematoxylin and eosin (H&E) staining (K) shows extensive necrotic debris and exudate (asterisks) and viable clear cell carcinoma (star marks) in the central portion of the tumor. Tumor cells (L) with clear or eosinophilic cytoplasm and atypical nuclei, including hobnail cells, proliferated in tubular, papillary, and solid patterns. Low- (M) and high (N)-power views of H&E staining demonstrate alternating layers of fibrous stroma (asterisks) and tumor cells (star marks) at the interface between the necrotic and viable solid components. Fig 2 – dummy alt text Case 2: Clear cell carcinoma of the left ovary of a 75-year-old woman. T2-weighted imaging of the sagittal (A) and axial (B) planes reveal that the tumor comprised an isohyperintense solid component at the periphery, and a heterogeneously hypo-isointense necrotic component at the central portion of the tumor. Compared with the myometrium, the solid component of the tumor appears hyperintense on diffusion-weighted imaging (DWI) (C), isohypointense on an apparent diffusion coefficient (ADC) map (D), and isointense on unenhanced T1-weighted imaging (T1WI) (E). Multiphasic contrast-enhanced T1WIs in the early (F) and delayed (G and H) phases show gradual enhancement with a striped or finely layered appearance (arrows). The extensive necrotic component (asterisks) appears iso hyperintense on DWI, hypo-hyperintense on the ADC map, and hypo-isointense on unenhanced T1WI (E) without enhancement (G). The ADC value ranged from 1.05 to 1.33 mm 2 /second and 1.82 to 2.33 mm 2 /second for the solid component of the tumor and central necrosis, respectively. The cut surface of the tumor shows an extensive necrotic area (I) on the right side and an extensive fibromatous area (J) on the left side of the tumor. A low-power view of hematoxylin and eosin (H&E) staining (K) shows extensive necrotic debris and exudate (asterisks) and viable clear cell carcinoma (star marks) in the central portion of the tumor. Tumor cells (L) with clear or eosinophilic cytoplasm and atypical nuclei, including hobnail cells, proliferated in tubular, papillary, and solid patterns. Low- (M) and high (N)-power views of H&E staining demonstrate alternating layers of fibrous stroma (asterisks) and tumor cells (star marks) at the interface between the necrotic and viable solid components. Simple total hysterectomy, bilateral salpingo-oophorectomy, partial omentectomy, and para-aortic and pelvic lymph nodes dissections were performed. Macroscopic examination of the resected specimen revealed an entirely solid component with a central necrosis. In the histopathological analysis, H&E staining of the solid component showed that cancer cells proliferated in a tubular, papillary, and solid patterns. In the central area of the tumor, necrotic tissue and fibrous stroma were observed with minimal cancer cell proliferation. The interface between the necrotic and viable solid components in the central portion of the tumors revealed alternating layers of tumor cells and fibrotic stroma. No histopathological evidence of endometriosis and adenofibromas was observed. Ascitic fluid cytology was positive for malignant cells (class V), and the final pathological stage was determined to be pT1c3. The patient received adjuvant chemotherapy with six cycles of paclitaxel and carboplatin, followed by surgery. Moreover, additional chemotherapies were administered because peritoneal and hepatic metastases were observed for 1.6 years and 2.5 years after surgery, respectively.