Final Diagnosis -- Malignant Müllerian Mixed Tumor

FINAL DIAGNOSIS:  MALIGNANT MÜLLERIAN MIXED TUMOR, HETEROLOGOUS TYPE.

FOLLOW-UP:

This patient later underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy. The final pathology report showed: 1) malignant müllerian mixed tumor, heterologous type; 2) multiple leiomyomas. The tumor had also metastasized to omentum, appendix, and pelvic lymph node by the time of surgery.

DISCUSSION:

Malignant müllerian mixed tumors (MMMTs) occur almost exclusively in postmenopausal women. The patients present with abnormal vaginal bleeding and an enlarged uterus in most cases. Pelvic or abdominal pain is also common. Grossly tumor often appears to be large, soft, polypoidal, and typically fill up the endometrial cavity. The cutting surface of the tumor is usually fleshy, hemorrhagic, necrotic, and with cystic degeneration. Microscopically, MMMTs are characterized by an intimate admixture of carcinomatous and sarcomatous components. The carcinomatous component is usually high-grade endometrioid or serous and less often clear cell, mucinous, nonspecific adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma, alone or in combination. The sarcomatous element can be homologous or heterologous. Homologous sarcoma is usually a nonspecific spindle cell sarcoma or may resemble high-grade endometrial stromal sarcoma, leiomyosarcoma, malignant fibrous histiocytoma, undifferentiated sarcoma, or any combination thereof. Heterologous sarcomas may contain or consist of rhabdomyoblasts; mature appearing cartilage or chondrosarcoma; osteoid, bone, or osteosarcoma; and liposarcoma. Histogenesis of MMMTs centers on two theories: 1. simultaneous formation of independent tumors (biclonal theory), 2. multidirectional differentiation of a single neoplasm (monoclonal theory). The results from one cytogenetic study of 43 MMMT cases favored monoclonal theory.

By immunohistochemistry, the carcinomatous components of MMMTs are always strongly and diffusely positive for cytokeratins and epithelial membrane antigen (EMA) and variably immunoreactive for vimentin in the minority of cases. The mesenchymal components are diffusely positive for vimentin and occasionally express muscle-specific actin and alpha-smooth muscle actin. In addition, there is often patchy staining for cytokeratins and EMA. When the mesenchymal component displays the histologic features of rhabdomyosarcoma, immunoreactivity of this component for desmin confirms the presence of this heterologous elements. Myoglobin appears to be the most specific but least sensitive marker for rhabdomyoblasts.

MMMT is a high-grade aggressive malignant neoplasm. As many as one third of the patients have clinical evidence of extrauterine spread at the time of presentation; in some series, as many as half of the patients thought to have Stage I disease clinically are found to have higher stage disease at surgery. No adjuvant therapy has been shown to be effective in randomized trial, and treatment of persistent or recurrent tumor by chemotherapy or radiation practically never results in cure. There are no consistent differences in survival between patients whose sarcomatous element is homologous or heterologous, but important prognostic features are the stage, size of the tumor, and depth of myometrial invasion. Essentially, the only patients who have long-term survival are those with small tumors that are at most minimally invasive. However, even tumors that seem to be confined to the endometrium or to an endometrial polyp can metastasize. The types of sarcoma, the mitotic index, and the grade of the sarcoma have not been shown to be significantly related to survival. There are conflicting reports about the significance of vascular invasion, cervical involvement, and the subtype of carcinoma. Moreover, metastases from almost all carcinosarcomas are composed exclusively of the carcinomatous element.

MMMTs should be differentially diagnosed with the following entities:

1. Adenosarcoma versus carcinosarcoma
   Adenosarcoma and carcinosarcoma are distinguished by determining whether the epithelial component is benign or malignant. Ambiguous cases are unusual, but when there is uncertainty in a curettage or biopsy specimen, resolution may have to await hysterectomy.

2. Carcinosarcoma versus proliferations of malignant undifferentiated cells
   This not uncommon problem revolves around whether undifferentiated or poorly differentiated areas of a malignant neoplasm are carcinoma or sarcoma. In one scenario, unequivocal carcinoma is identified but it is associated with areas of undifferentiated tumor cells that are not definitely sarcoma or carcinoma. Immunohistochemical stains have been advocated in this situation, but some high-grade carcinomas will not react with keratin antibodies and the cells in morphologically unequivocal sarcomatous areas of carcinosarcoma may express keratin. If the uncertainty persists after many sections have been taken from the hysterectomy specimen, it is useful to know that in clinical terms very little depends on distinguishing between carcinosarcoma and high-grade anaplastic carcinoma. The second situation involves an endometrial sample composed of sheets of undifferentiated malignant cells with neither a discernible carcinomatous component nor a sarcomatous one. Five different entities need to be considered: pure high-grade carcinoma, pure sarcoma, lymphoma or leukemia, carcinosarcoma in which the undifferentiated areas have been sampled, and metastatic carcinoma.

The prognosis of MMMT is universally bad, ranging from 12 to 20% five-year survival. Associated with a good prognosis are a limited extent of the disease in relation to myometrial and cervical involvement and absence of vascular invasion within the endometrium. Five-year survival of around 50% has been reported in women with stage 1 disease. In stage I, positive peritoneal cytology is of greater prognostic importance than the depth of the invasion.

REFERENCES

1. Kempson RL, Hendrickson MR. Smooth muscle, endometrial stromal, and mixed Mullerian tumors of the uterus. Modern Pathology. 13(3):328-42, 2000.
2. Clement PB, Young, RH. Atlas of gynecologic surgical pathology. 1st Edition, 177-210, 2000.
3. Kurman RJ. Blaustein's pathology of female genital tract. 5th Edition, 583-605, 2002.
4. Robboy SJ, Anderson MC, Russell P. Pathology of the female reproductive tract. 1st Edition, 370-80, 2002.
5. Kounelis S, Jones MW, Papadaki H, Bakker A, Swalsky P, Finkelstein SD. Carcinosarcomas (malignant mixed mullerian tumors) of the female genital tract: comparative molecular analysis of epithelial and mesenchymal components. Human Pathology. 29(1):82-7, 1998.
6. Kanbour AI, Buchsbaum HJ, Hall A, Kanbour AI. Peritoneal cytology in malignant mixed mullerian tumors of the uterus. Gynecologic Oncology. 33(1):91-5, 1989.

Contributed by Lei Chen, MD, PhD, Rovena L Kessinger, MD, Anisa I Kanbour, MD