46-year-old female with ovarian mass

Gynecological

Author
Shelia Segura, MD

Summary of clinical history
46-year-old G2P1 female presents with a pelvic mass and an elevated CA-125 level of 142.3 U/mL. Cross-sectional imaging with CT of the abdomen and pelvis reveals a large cystic mass measuring up to 19.5 cm located in the lower abdomen and pelvis. The mass demonstrates multiple thin septations and areas of soft tissue density, particularly in the left lateral and inferior portions. These radiologic features raise concern for a primary ovarian neoplasm. Additionally, mild to moderate ascites is noted, further supporting the suspicion of a malignant process.

Gross findings
The specimen labeled as left fallopian tube and ovary consists of a 19.0 × 15.0 × 8.0 cm ovarian mass. No fallopian tube is grossly identified. The external surface of the mass is purple-pink, wrinkled, nodular, and focally disrupted, with areas of focal adhesions. On sectioning, the mass appears tan and heterogeneous, demonstrating both cystic and solid components. The cystic areas contain hemorrhagic, watery fluid, while the solid portions are tan to red, focally hemorrhagic, and markedly heterogeneous. Approximately 50% of the solid component shows necrosis and hemorrhage. No normal ovarian stroma is identified.

Microscopic findings
Histologic examination of the ovarian mass reveals an adenocarcinoma characterized by a biphasic architecture, consisting of both glandular and corded/hyalinized components. These two morphologic patterns merge seamlessly and share similar cytologic features. Notably, there is squamous and spindle cell differentiation throughout the tumor.

Incidentally, a separate endometrial carcinoma is identified. This lesion is a well-differentiated tumor with squamous morules, confined to the endometrial cavity, with no evidence of myometrial invasion or lymphovascular space invasion (LVSI). The tumor extends into the lower uterine segment and focally involves the cervical mucosa.

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Figure 1: H&E, 4x- Ovarian carcinoma with glandular growth.

Figure 2: H&E, 20x- Ovarian carcinoma with glandular growth and squamoid differentiation.

Figure 3: H&E, 10x- Ovarian carcinoma with spindle cells and a hyalinized stroma.

Figure 4: H&E, 40 x- Single neoplastic cells infiltrating a dense hyaline matrix with a corded and vague trabecular patterns.

Figure 5: IHC, 40x- Immunohistochemical stains for beta-catenin shows aberrant nuclear and cytoplasmic staining pattern in the ovarian tumor.

Figure 6: H&E, 4x- Endometrial carcinoma without myometrial invasion.

Figure 7: H&E, 40x- Endometrial carcinoma with squamoid differentiation.

Immunohistochemical findings
Immunohistochemical analysis of the ovarian tumor reveals that the epithelial component is positive for CK7 and EMA, supporting its epithelial origin. The tumor is negative for WT-1, which helps distinguish it from serous carcinoma. CD10 is negative. Beta-catenin demonstrates an aberrant staining pattern with both nuclear and cytoplasmic localization, suggesting dysregulation of the Wnt signaling pathway. DNA mismatch repair proteins MLH1, PMS2, MSH2, and MSH6 are retained, indicating microsatellite stability. P53 exhibits a wild-type staining pattern, consistent with a non-mutant phenotype. Notably, beta-catenin shows the same aberrant nuclear and cytoplasmic staining pattern in the endometrial carcinoma, which also retains expression of all mismatch repair proteins and displays a wild-type P53 pattern.

Given the histologic and immunophenotypic features, the primary diagnosis is a corded and hyalinized endometrioid carcinoma (CHEC) of the ovary, a rare subtype of endometrioid carcinoma characterized by biphasic architecture, squamous and spindle cell differentiation, and aberrant β-catenin staining. The concurrent presence of a FIGO grade 1 endometrial carcinoma raises the possibility of metastatic disease; however, several factors favor the interpretation of synchronous primaries. The ovarian tumor is large, unilateral, and confined to the ovary, with no capsular invasion or surface involvement (equivalent to pT1a), and lacks identifiable normal ovarian stroma. Meanwhile, the endometrial carcinoma is low-grade, limited to the endometrial cavity, with no myometrial invasion, no lymphovascular space invasion (LVSI), and no evidence of extrauterine spread. Taken together, the morphologic, immunohistochemical, and staging features support the diagnosis of synchronous primary tumors rather than metastatic disease.

Key differential diagnosis

Ovarian carcinosarcoma.
Ovarian carcinosarcoma is a rare and highly aggressive neoplasm, accounting for less than 5% of ovarian malignancies. It is more commonly encountered in the uterus and only rarely involves the ovaries, fallopian tubes, or cervix. These tumors are characterized by the presence of both malignant epithelial and mesenchymal components, often admixed in a high-grade fashion. The epithelial component is most frequently high-grade serous adenocarcinoma, followed by endometrioid, clear cell, squamous, mixed, and undifferentiated carcinomas. The mesenchymal component may show homologous differentiation (e.g., fibrosarcoma, leiomyosarcoma) or heterologous elements (e.g., rhabdomyosarcoma, chondrosarcoma).

Histologically, carcinosarcomas display two distinct components — carcinomatous and sarcomatous — that are typically juxtaposed but do not merge, in contrast to endometrioid carcinomas with sex cord-like features and hyalinization. The sarcomatous areas exhibit overt pleomorphism, brisk mitotic activity, and frequent lymphovascular invasion. More than 90% of ovarian carcinosarcomas spread beyond the ovary, and approximately one-third are associated with peritoneal effusion.

Immunohistochemically, carcinosarcomas tend to show diffuse, strong p16 expression, p53 overexpression (mutant pattern), and reduced ER/PR expression. Cytokeratins and EMA are not particularly helpful in distinguishing carcinosarcoma from other epithelial tumors. In contrast, endometrioid carcinomas with sex cord-like features typically express ER/PR, show patchy p16 positivity, and retain wild-type p53 expression. Nuclear β-catenin expression has been reported in ECAs with sex cord-like formations and hyalinization, but not in carcinosarcomas.

In this case, although the ovarian tumor exhibits spindle cell and squamous differentiation, the overall architecture is biphasic in a more integrated fashion, consistent with corded and hyalinized endometrioid carcinoma (CHEC). The absence of overtly malignant mesenchymal features, lack of heterologous differentiation, and the presence of a wild-type p53 pattern argue against carcinosarcoma. While carcinosarcoma is considered in the differential, the histologic and immunophenotypic findings do not support this diagnosis.

Metastatic endometrial carcinoma to the ovary
Adnexal involvement by endometrial carcinoma has important prognostic implications and historically required distinction from synchronous primary tumors. In high-grade endometrial carcinomas, ovarian involvement is typically considered metastatic. However, in low-grade endometrioid endometrial carcinomas (EECs), the distinction is more nuanced. Molecular studies have demonstrated a clonal relationship between the endometrial and ovarian tumors in most cases, suggesting that the ovarian lesion may represent secondary spread from the endometrium. Interestingly, this molecular clonality does not always correlate with the clinical behavior expected of metastatic disease.

Recognizing this complexity, the 2020 WHO Classification and joint guidelines from ESGO, ESTRO, and ESP recommend conservative management (treating these as synchronous primaries) when specific favorable criteria are met. The 2023 revised FIGO staging system reflects this approach by introducing Stage IA3 for low-grade EECs with limited spread. This category applies when the following conditions are present: (1) superficial myometrial invasion (<50%), (2) absence of substantial lymphovascular space invasion (LVSI), (3) no additional metastatic disease, and (4) a unilateral ovarian tumor confined to the ovary without capsular breach (equivalent to pT1a). If these criteria are not met, the ovarian involvement should be interpreted as metastatic disease (Stage IIIA1).

In this case, both tumors meet the criteria for Stage IA3, supporting the interpretation of synchronous primaries rather than metastatic spread.

Endometrioid carcinoma with spindle cells
Endometrioid carcinoma with spindle cells is a recognized variant of endometrioid adenocarcinoma in which conventional glandular architecture merges with a cellular spindle cell component. Unlike corded and hyalinized endometrioid carcinoma (CHEC), this variant lacks stromal hyalinization, a corded growth pattern, and squamous differentiation. The spindle cells are typically low-grade and may exhibit abrupt keratinization, keratin pearls, or intercellular bridges, merging gradually with the glandular component. Immunohistochemically, these tumors often show ER and PR positivity, focal or patchy p16 expression, and a wild-type p53 pattern. These features help distinguish them from carcinosarcoma, which remains a common diagnostic pitfall.

In this case, the ovarian tumor demonstrates a biphasic architecture with glandular and corded/hyalinized areas, along with squamous and spindle cell differentiation. The presence of stromal hyalinization and a corded pattern, combined with cytologic continuity between components, supports a diagnosis of CHEC rather than conventional endometrioid carcinoma with spindle cells. The immunoprofile, positive CK7 and EMA, wild-type p53, and aberrant β-catenin staining, further reinforces this interpretation. Therefore, while endometrioid carcinoma with spindle cells is considered in the differential, the integrated histologic and immunophenotypic findings favor CHEC.

Ovarian low-grade endometrial stromal sarcoma
Endometrial stromal sarcoma is a rare mesenchymal neoplasm that most commonly arises in the uterus. Extrauterine manifestations are uncommon but have been reported in sites such as the ovary, fallopian tube, pelvic cavity, abdominal cavity, and retroperitoneum. When involving the ovary, LG-ESS may present as a solid-cystic mass, often mimicking epithelial tumors grossly.

Histologically, LG-ESS is characterized by a diffuse and infiltrative proliferation of uniform, small round to oval cells resembling proliferative-phase endometrial stromal cells. A hallmark feature is the presence of abundant small arterioles, often described as "spiral arteriole-like" vessels. The tumor typically shows low-grade cytologic atypia and a low mitotic index. In contrast, undifferentiated endometrial stromal sarcoma (UES) displays pleomorphic round to spindled cells, high mitotic activity, and areas of necrosis, reflecting its more aggressive behavior.

Immunohistochemically, LG-ESS usually expresses CD10, ER, PR, and may harbor JAZF1-SUZ12 gene fusions, which can aid in diagnosis. In this case, CD10 staining was not performed, and no molecular testing was conducted. However, the tumor’s epithelial marker expression (CK7, EMA), absence of classic vascular pattern, and lack of infiltrative growth argue against LG-ESS. Additionally, the presence of glandular, squamous, and spindle cell differentiation, along with aberrant β-catenin staining and wild-type p53, supports a diagnosis of corded and hyalinized endometrioid carcinoma (CHEC) rather than a stromal neoplasm.

References

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