In this installment of Second Opinion, we are presenting two cases of tumors of the female genital tract, specifically, the ovary and uterus, which contain both epithelial and mesenchymal components and therefore have unique diagnostic and therapeutic implications. The first has an unusually poor prognosis and the second is notoriously difficult to diagnose.
A 64-year-old nulliparous woman who had been postmenopausal for 12 years presented to the emergency room with vague right lower quadrant pain, early satiety, and constipation for 1 week. She denied anorexia, nausea or vomiting, and weight loss. Review of systems was otherwise negative. Gynecologic history was significant for the use of hormone-replacement therapy, which had been discontinued for 2 years, and a bilateral tubal ligation 6 years ago. A Pap smear, mammogram, and colonoscopy were up-to-date and reportedly normal. An abdominal computed tomography (CT) scan showed a 6-cm right lower quadrant mass, omental cake, and ascites. Pertinent blood work included an elevated CA-125 level of 329 microL/mL. She was referred to Dr. Davidson at University of Colorado Health Sciences Center (UCHSC) for a surgical consultation.
On physical examination, the patient's abdomen was notable for hypoactive bowel sounds, lower right quadrant tenderness, and a palpable fluid wave. Bimanual pelvic examination revealed a mass causing posterior uterine displacement. Posterior cul-de-sac nodularity was noted on rectal-vaginal examination. A repeat CT scan did not demonstrate periaortic adenopathy. These findings were consistent with ovarian cancer.
The patient underwent comprehensive staging. The surgical procedure consisted of total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), rectosigmoid colon resection and primary anastomosis, appendectomy, omentectomy, and optimal tumor debulking.
Operative and Pathologic Findings
Dr. Ramona Evans: What were the operative findings?
Dr. Susan A. Davidson: Intraoperative exploration revealed a friable, nodular, pelvic mass arising from/attached to the right ovary. The tumor was adherent to the uterus, cecum, appendix, and distal ileum. Extensive tumor implants ranging in size from 0.1 to 5 cm were evident throughout the pelvic peritoneum, omentum, mesentery, distal ileum, cecum, appendix, transverse and sigmoid colon, and right side of the diaphragm. The left ovary was small but appeared to have surface disease. The stomach, spleen, pancreas, and porta hepatis were all normal in appearance, and enlarged lymph nodes were not identified.
Dr. Evans: What were the pathology findings? Was the perioperative diagnosis confirmed in the TAH/BSO specimen?
Dr. Meenakshi Singh: A friable, solid, tan with translucent areas, 11-cm mass was arising from/attached to the right ovary (Figures 1A, 1B). Tumor was scattered through the residual parenchyma of the right ovary and was macroscopically evident on the serosal surfaces of the uterus, left adnexa, and peritoneum. The omental cake showed multiple tumor nodules of variable size.
Microscopic examination of the right ovarian/pelvic mass revealed a biphasic, high-grade, malignant neoplasm with carcinomatous epithelium and sarcomatous mesenchymal tissues (Figures 1C-F). The carcinoma displayed solid sheets, glands, and focal papillary architecture as well as squamous differentiation (Figure 1C). The sarcomatous component showed spindle cells with increased cellularity and frequent mitoses (Figure 1F). Focal heterologous elements, predominantly chondrosarcoma-like, were noted (Figures 1D, 1F). Areas of hemorrhage and necrosis were present throughout the tumor.
Additionally, the tumor involved the surface and parenchyma of the left ovary. Serosal tumor deposits were observed on the uterus, peritoneum, colon, and appendix. The omental cake was due to tumor. Metastatic tumor was present in five of five regional lymph nodes examined as well as in the pelvic wash fluid. The tumor was diagnosed as a carcinosarcoma (also known as malignant mixed mullerian tumor) and was staged as American Joint Committee on Cancer (AJCC) stage IIIC.
Dr. Evans: What is the differential diagnosis for a tumor with this appearance?
Dr. Singh: A tumor with this histology is classic for carcinosarcoma. However, an additional biphasic tumor in this location and with infiltrative properties includes an ovarian endometrioid adenosarcoma (see discussion for patient 2).
Dr. Evans: What is the current thinking regarding the clonal origin of carcinosarcoma?
Dr. Singh: The majority of studies have actually been done on uterine carcinosarcomas, but the histology and pathogenesis of ovarian carcinosarcomas are thought to be similar. Immunohistochemical, ultrastructural, and molecular studies provide convincing evidence supporting a monoclonal origin for the majority of carcinosarcomas. Ovarian carcinosarcomas are believed to arise from either ovarian surface epithelium or foci of endometriosis and can be regarded as endometrioid adenocarcinomas in which malignant stromal differentiation has occurred. A small percentage of carcinosarcomas are not of monoclonal origin, but rather, represent true collision tumors. One study suggests that 8% to 16% of carcinosarcomas actually arise within, or in the endometrial tissue adjacent to, an adenosarcoma.
Dr. Evans: What are the clinical features of carcinosarcomas?
Dr. Davidson: Carcinosarcomas occur almost exclusively in postmenopausal women.[2,4,5] The clinical presentation of ovarian carcinosarcoma is similar to that of other ovarian carcinomas. Approximately 90% of ovarian carcinosarcomas are bilateral. The tumor marker CA-125 is usually elevated.
Dr. Evans: What is the epidemiology of carcinosarcoma?
Dr. Davidson: Carcinosarcomas of the ovary are very rare, constituting only 1% of all ovarian tumors. Studies suggest a higher incidence of uterine carcinosarcomas in blacks. Risk factors include age and low parity.[2,5] Exposure to radiation has long been considered to play a role in the development of carcinosarcoma.[2,4,6]
Dr. Evans: What are the treatment options for patients diagnosed with carcinosarcoma?
Dr. Davidson: Surgery is the mainstay of treatment. A number of postoperative treatment modalities have been utilized, but a significantly effective adjuvant therapy regimen has yet to be established. A recent study of uterine carcinosarcoma suggests that combination chemotherapy followed by whole-pelvic irradiation after optimal tumor debulking surgery may incur a significant decrease in mortality when compared to postoperative chemotherapy alone. Of the various chemotherapy regimens available, platinum-based combinations seem to be the most efficacious.[2,7] The overall response rate is reported at 20%, which is similar to that seen in the uterine counterpart. Clinical studies under the auspices of the Gynecologic Oncology Group are under way and shall provide more information when their data are analyzed.
Dr. Evans: What is the prognosis for these tumors, how are they followed up, and what factors influence prognosis?
Dr. Davidson: The prognosis for carcinosarcoma of the ovary is dismal, with a median survival of only 19 months and a 5-year survival rate of 18% to 27%.[2,5] The single most important prognostic indicator is the stage of tumor at the time of initial treatment, which unfortunately is advanced for this patient. There are no other histopathologic features that significantly predict outcome.