Ovarian carcinosarcoma

Incidence and mortality

Carcinosarcoma (also known as malignant mixed Müllerian tumor) of the gynecologic tract is a rare and highly aggressive malignancy. Carcinosarcomas are dedifferentiated (metaplastic) carcinomas comprised of both carcinomatous and sarcomatous elements. While the exact mechanism by which these two phenotypes arise within a single tumor remains yet to be elucidated, current molecular evidence with whole-exome sequencing indicates that the epithelioid and spindle-cell components share a single malignant epithelial clonal origin.

Ovarian cancer is the most common cause of cancer death in women with gynecologic malignancy and the fifth leading cause of cancer death in the United States. It is projected that there will be approximately 22,000 new cases and 14,000 cancer-related deaths in the United States. Ovarian carcinosarcomas account for 1%–4% of all ovarian malignancies. As such, an estimated 220–880 cases of ovarian carcinosarcoma will be diagnosed in the United States with up to 90% of cases initially presenting with spread to other organs at the time of diagnosis. The median age at diagnosis is 75 years, and patients typically present with advanced stage disease often with a large tumor that has abundant hemorrhage and necrosis. Nevertheless, the prognosis for even localized ovarian carcinosarcoma is also dismal with a high risk of recurrence, both local and distant, occurring within 1 year. Due to the aggressive nature of carcinosarcoma, the survival of women with this disease is worse than the survival of those with other histologic subtypes such as endometrioid and high-grade serous (formerly known as high-grade papillary serous). In fact, women with ovarian carcinosarcoma have a significantly worse five-year, disease-specific survival rate than those with high-grade serous ovarian carcinoma 28.2% vs 38.4% ( P < 0.001). This difference persists for each FIGO disease stage with 5-year survival consistently being worse for women with ovarian carcinosarcoma when compared to those with high-grade serous ovarian cancer ( Table 3.1 ).

Etiology and risk factors

Ovarian carcinosarcomas are composed of both malignant epithelial and sarcomatous elements. The sarcomatous component may resemble uterine sarcomas (i.e., homologous) such as leiomyosarcoma, endometrial stromal sarcoma, fibrosarcoma, or heterologous differentiation such as rhabdomyosarcoma, chondrosarcoma, liposarcoma, or osteosarcoma. The epithelial component most commonly consist of serous carcinoma whether this may be in a pure or mixed form with other carcinoma types. Molecular studies suggest that carcinosarcomas are predominantly monoclonal in that they arise from the carcinoma component through an epithelial–mesenchymal transition.

Risk factors for ovarian carcinosarcomas are similar to those of epithelial ovarian carcinoma which include increasing age, early age at menarche or late menopause, and nulliparity. However, demographic factors associated with worse mortality for patient with ovarian carcinosarcoma include increasing age (HR 1.03), African-American race (HR 1.04), and unmarried status (HR 0.8 for married status) and have been found to be more commonly associated with ovarian carcinosarcoma. Such findings that ovarian carcinosarcoma was more common in unmarried women and that it may be associated with a higher disease-specific mortality warrant further investigation as it perhaps suggests that reproductive history may be more relevant in patients with ovarian carcinosarcoma than those with serous carcinoma.

Gross description

Ovarian carcinosarcoma are large (> 10 cm) and mostly solid with areas of cystic degeneration, hemorrhage and necrosis. Rarely cartilage and bone maybe grossly identified in tumors with heterologous elements.

Microscopic features

Similar to the more commonly encountered uterine counterpart, ovarian carcinosarcoma is a biphasic tumor composed of high-grade carcinoma and high-grade sarcoma components ( Fig. 3.2 A ). The carcinoma component is usually serous, and less commonly, other histologic subtypes of epithelial ovarian cancer. When derived from a high-grade serous carcinoma, it may be associated with serous tubal intraepithelial carcinoma (STIC) in the fallopian tube. The sarcoma component is classified as homologous when it exhibits a nonspecific spindled appearance, or heterologous, when it exhibits non-gynecologic tissue differentiation. Rhabdomyosarcoma is the most common heterologous element, though chondrosarcoma, and rarely liposarcoma, osteosarcoma or other sarcoma subtypes may be present ( Fig. 3.2 B and C). Rarely other components such as yolk sac tumor or primitive neuroectodermal tumor may be present.

Ancillary testing

Immunohistochemical stains may not be necessary for diagnosis, though desmin staining ( Fig. 3.2 D) may be used to confirm myogenic differentiation, while myogenin or MyoD1 can be more specific to confirm the presence of a rhabdomyosarcoma component. Carcinosarcomas often exhibit an aberrant p53 expression pattern (diffuse staining, or complete absence of staining) in both carcinoma and sarcoma components. A CK7 +/CK20 −/PAX8 + immunoprofile can confirm Müllerian epithelial origin, when metastasis from another site is under diagnostic consideration.

Pathogenesis and molecular features

Carcinosarcomas are derived from transdifferentiation of high-grade carcinoma through epithelial–mesenchymal transition. Most originate as high-grade serous carcinomas, and as such, harbor TP53 mutations and numerous chromosomal gains and losses. However, the carcinoma component may also be high-grade endometrioid or clear cell carcinoma, or a carcinoma with ambiguous morphologic features.