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.

(A) Carcinosarcoma with high-grade carcinoma and sarcoma components. Heterologous elements can include chondrosarcoma (B) and rhabdomyosarcoma (C). (D) Myogenic differentiation in rhabdomyosarcoma is highlighted by desmin immunohistochemical stain.

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.

Differential diagnosis

The differential diagnosis of ovarian carcinosarcoma depends on the histomorphologic features of the particular case in question. Some pure carcinomas are associated with desmoplastic stroma, which can mimic a sarcomatous component. However, in the latter, high-grade nuclear atypia and frequent mitotic figures are present. Immunohistochemical staining showing an aberrant p53 expression pattern in both epithelial and mesenchymal components could serve as confirmation. Sarcomatoid carcinoma can mimic carcinosarcoma; in the former the glandular component merges with the spindle component and the latter usually has diffuse expression of keratin markers. Dedifferentiated carcinoma is another consideration and consists of a low-grade endometrioid carcinoma juxtaposed with discohesive poorly differentiated tumor cells sometimes with rhabdoid morphology. The possibility of metastatic tumor from nongynecologic sites should be excluded. An example is gastric adenocarcinoma (i.e., Krukenberg tumor), which is commonly associated with highly cellular fibromatous stroma, however, predominant signet ring cell morphology is highly unusual in gynecologic primaries. In some carcinosarcomas, the sarcomatous component is predominant, with only focal residual carcinoma, and these cases can occasionally be misclassified as a pure high-grade sarcoma. Carcinosarcoma should be distinguished from other tumors showing multilineage differentiation. These include poorly differentiated Sertoli-Leydig cell tumor with heterologous elements, Müllerian adenosarcoma and immature teratoma. These tumors lack a true high-grade carcinomatous component, though benign or low-grade neoplastic epithelial elements may be present. Pertinent immunohistochemical stains for sex cord and germ cell tumors may be used to facilitate the diagnosis. Ovarian carcinosarcoma should also be distinguished from ovarian metastasis from a uterine primary. In a patient with synchronous endometrial and ovarian tumors, the presence of a large tumor in the uterine cavity would favor an endometrial primary.

Signs and symptoms

These patients typically present with advanced stage disease with a pelvic mass and peritoneal carcinomatosis. These tumors are typically large at presentation with abundant hemorrhage and necrosis. As with epithelial ovarian carcinoma, the clinical presentation can be either acute or subacute. Those that present in an acute fashion are those with advanced disease whose condition requires urgent evaluation and management (i.e., bowel obstruction, pleural effusion, acute abdominal pain). More often, patients present in a subacute fashion (i.e., vague abdominopelvic pain, bloating, early satiety, gastrointestinal (GI) or genitourinary symptoms) in patients with either early or advanced disease. Women with ovarian cancer frequently report symptoms prior to diagnosis but distinguishing these symptoms from those that normally occur in women remains problematic as they can be confused with other more common GI or genitourinary issues. To date, there is no effective screening modality which has been shown to reduce morbidity or mortality. The American College of Obstetricians and Gynecologists (the College) and the Society for Gynecologic Oncology (SGO) both endorse that the best method to diagnose ovarian cancer is for clinicians to have a high index of suspicion in a symptomatic patient.

Physical exam findings

As most women present with advanced stage disease, a large pelvic mass that is solid, immobile and with irregular borders is often found on physical examination ( Table 3.2 ). Malignancy-related ascites can result in abdominal distension as a consequence of tumor cell growth in the peritoneal cavity and metastatic spread to the omentum and diaphragm which prevents proper fluid circulation and results in obstruction in the reabsorption of fluid from the peritoneal cavity. Peritoneal carcinomatosis due to disease spread will also lead to accumulation of ascites due to blockage of draining lymphatic channels and increased vascular permeability. Some patients may present with shortness of breath due to a malignant pleural effusion whereas others may have severe nausea and vomiting due to the extent of their intraabdominal tumor burden obstructing the bowel.

Differential diagnosis

As ovarian carcinosarcomas are rare and highly aggressive malignancies that portend a worse prognosis than their more commonly found epithelial ovarian carcinomas accurate diagnosis is imperative in understanding the usual course of the disease. Typically, the diagnosis will be made on final pathologic review of an ovarian specimen after surgical cytoreduction (see Section “ Pathology ” ). Nonetheless, prior to operative management the differential diagnosis of an adnexal mass must include metastatic disease from endometrial, breast, and some GI malignant neoplasms. As such, one should assure that the patient is up to date with all health care maintenance (i.e., mammogram, colonoscopy).

Tumor markers

CA-125 is the most commonly used biomarker for the evaluation of adnexal masses and as a marker for response to treatment in epithelial ovarian cancer. CA-125 alone has a low sensitivity and low overall specificity for diagnosing malignancy. However, improved survival in women with ovarian carcinosarcoma has been associated with lower CA-125 levels. Therefore, CA-125 may be highly elevated in a subset of ovarian carcinosarcoma and can be used as a marker for response to treatment.

Imaging studies

One of the most important elements in initial evaluation is the finding of an adnexal mass on imaging. Often, this could initially be due to findings on ultrasound which include a mass with solids components, nodules, papillary excrescences, increased Doppler flow, irregularly thick septations and ascites ( Fig. 3.3 ). Once, there is either clinical or radiologic concern for malignancy, imaging studies to assess the extent of disease burden and to evaluate for metastatic disease include computed tomography (CT scan) of the chest, abdomen and pelvis with and without contrast. It must be noted that radiologic staging tends to underestimate the extent of disease, since the majority of clinical stage I tumors have been shown to have lymph node metastasis in up to 60% of cases. If the patient has a contrast allergy that precludes use of CT, magnetic resonance imaging (MRI) may be used instead. There is some data suggesting that positron emission tomography (PET) alone or combined with CT increases the detection of metastatic ovarian cancer compared with CT alone or MRI; however, further studies of the preoperative use of this imaging modality are needed. Typically, CT scan is the first-line imaging technique performed since it provides adequate anatomic delineation and detection of disease to assist with preoperative staging and surgical planning. The limitation of CT is the inability to use contrast in those with contraindications to contrast agents and the ionizing radiation exposure to the patient. The benefit of PET combined with CT over CT alone in preoperative staging of ovarian cancer has not yet been completely established. It could also potentially improve staging accuracy by improving detection of infra- and supradiaphragmatic metastasis. PET/CT scans may also help in cases of indeterminate lymph node appearance or when there is contraindication to contrast-enhanced CT. However, with PET alone false-positive may result by FDG accumulation in normal tissues (i.e., bowel loops and urinary system), in inflammatory lesions (i.e., diverticulitis) or in atherosclerotic plaques. Nonetheless, the costs of PET/CT are higher than those of ultrasound, CT and MRI. Nevertheless, as part of initial work-up, all women with newly diagnosed disease should undergo either CT scan of the chest, abdomen, and pelvis, PET scan from skull to thigh, or a combined PET/CT scan in order to guide appropriate treatment recommendations.

Findings on ultrasound of an adnexal mass suspicious for malignancy. Here you see multilocular mass with solid components, papillary excrescences, increased Doppler flow, increased irregular thick septations on the left (A). On the right, you see fluid in the posterior cul-de-sac which is ascites (B).

(Adapted from Sayasneh et al. The characteristic ultrasound features of specific types of ovarian pathology (review). Published online on: November 18, 2014. https://doi.org/10.3892/ijo.2014.2764 . https://www.spandidos-publications.com/10.3892/ijo.2014.2764 .)

Diagnostic testing

Diagnosis of ovarian carcinosarcoma is made pathologically with histologic confirmation (biopsy preferred). After assessment by a gynecologic oncologist, if the patient is deemed a surgical candidate primary surgical cytoreduction is performed after which pathological assessment of the tissue provides the diagnosis. If unsure of the feasibility of debulking surgery, laparoscopic evaluation may be performed and if the disease burden is deemed unlikely to be cytoreduced to CGR tissue biopsies can be obtained providing the diagnosis. If the patient is deemed a poor surgical candidate and there is a low likelihood of complete gross cytoreduction, image-guided biopsy can provide histologic confirmation. If biopsy is not feasible, cytopathology from ascites or pleural effusion could allow a diagnosis of malignancy of Müllerian origin but unlikely to provide the diagnosis of carcinosarcoma. Nevertheless, all women with a diagnosis of ovarian, fallopian tube, or peritoneal cancer should have genetic risk evaluation. However, further studies are needed to assess if ovarian carcinosarcoma is an associated hereditary malignancy. Additionally, the tissue used to make the diagnosis of ovarian carcinosarcoma should be assessed for HER2 positivity and sent for somatic testing for the use of potentially targetable treatment. A recent comprehensive analysis of HER2 expression in a large cohort of uterine and ovarian carcinosarcomas demonstrated that up to 13% of tumors (10/80) were positive; however, of the 15 ovarian carcinosarcoma tumors only one ovarian carcinosarcoma was HER2 positive. Additionally, the presence of a germline or somatic BRCA1 or BRCA2 mutation may have treatment implications in maintenance therapy and management of recurrent disease.