N euroectodermal immunophenotype in uterine malignant mullerian tumors (MMT): Comparative immunohistochemical analysis with embryonal uterine development

Multidirectional differentiation of neoplastic cells in uterine MMT is still a subject of controversy. The present study was designed to assess the immunophenotype of 15 uterine MMT paying special attention to the markers of neural (neuroendocrine) differentiation. In addition, the same immunohistochemical study was performed on 20 human fetal specimens in order to establish possible relationships between the immunophenotype of MMT and the expression of the corresponding antigens in the fetal tissues of the embryonal female genital tract. Besides the typical immunohistochemical patterns in three cases the epithelial component showed simultaneous coexpression of vimentin and desmin. EMA and cytokeratin, whereas epithelial markers were coexpressed with vimentin in the sarcomatous component of one adenosarcoma. Moreover, both components were immunoreactive to the markers of neural differentiation (PGP 9.5, GFAP, HNK-1, N-CAM, HBA71). This aberrant expression was not correlated with morphological signs of neural differentiation at either light microscopy or ultrastructural levels. Regarding the analysis of fetal tissues, both epithelial and mesenchymal elements in the fetal genital tract expressed the above-mentioned neural markers at different dates of gestation. The intensity of this expression diminishes as the fetus matures and at the end of antenatal life the immunophenotype characteristic for adult life is established. Taking into consideration the capacity of uterine tissue to reproduce embryonal phenotype during neoplastic transformation, we studied this abnormal immunoprofile and its hypothetic value for the diagnosis and prognosis of MMT.

Uterine MMT; Immunophenotype of carcinosarcomas; Antigen coexpression; Neural d市erentiation; Immunophenotype of embryonal uterus

[1] Iwasa Y., Haga H., Konishi I. et al.: "Prognostic factors in uterine carcinosarcoma. A clinicopathologic study of 25 patients". Cancer, 1998, 85, 512.

[2] Kounelis S., Jones M.W., Papadaki H. et al.: "Carcinosarcomas (Malignant mixed mullerian tumors of the female genital tract: Comparative molecular analysis of epithelial and mesenchymal components". Hum. Pathol., 1998, 29, 82.

[3] Abeln E.C.A., Smit V.T.H.B.M., Wessels J.W. et al.: "Molecular genetic evidence for the conversion hypothesis of the origin of malignant mixed mullerian tumors". J. Pathol., 1997, 183, 424.

[4] Guarino M., Giordano F., Pallotti F. et al.: "Malignant mixed mullerian tumors of the uterus. Features favoring its origin from a common clone and an epithelial-to-mesenchymal transformation mechanism of histogenesis". Tumori, 1998, 84, 391.

[5] Silverberg S.G., Major F.J., Blessing J.A. et al.: "Carcinosarcoma (malignant mixed mesodermal tumor) of the uterus: A Gynecologic Oncology Group pathologic study of 203 cases". Int. J. Gynecol. Pathol., 1990, 9, 1.

[6] Bitterman P., Chun B.K., Kurman R.J.: "The significance of epithelial differentiation in mixed mesodermal tumors of the uterus: A clinicopathologic and immunohisto-chemical study". Am. J. Surg. Pathol., 1990, 14, 317.

[7] Sreenan J.J., Hart W.R.: "Carcinosarcomas of the female genital tract. A pathologic study of 29 metastatic tumors: Further evidence for the dominant role of the epithelial component and the conversion theory of histogenesis". Am. J. Surg. Pathol., 1995, 19 (6), 666.

[8] George E., Manivel J.C., Dehner L.P., Wich M.R. et al.: "Malignant mixed mullerian tumors: An immunohistochemical study of 47 cases, with histogenetic considerations and clinical correlation". Hum. pathol., 1991, 22, 215.

[9] Wick M.R.: "Immunohistology of neuroendocrine and neuroectodermal tumors". Semin. Diagn. Pathol., 2000, 17 (3), 194.

[10] Fukunaga M., Nomura K., Endo Y., Ushigome S., Aizawa S.: "Carcinosarcoma of the uterus with extensive neuroectodermal differentiation". Histopathology, 1996, 29, 565.

[11] Gersell DJ., Duncan D.A., Fulling K.H.: "Malignant mixed mullerian tumor of the uterus with neuroectodermal differentiation". Int. J. Gynecol. Pathol., 1989, 8, 169.

[12] Schultz D.M.: "A malignant melanotic neoplasm of the uterus resembling the "retinal anlage" tumors". Am. J. Clin. Pathol., 1957, 28, 524.

[13] De Brito P.A., Silverberg S.G., Orenstein J.M.: "Carcinosarcoma (malignant mixed Mullerian mesodermal tumor) of the female genital tract. Immunohistochemical and ultrastructural analysis of 28 cases". Hum. Pathol., 1993, 24, 132.

[14] Geisinger K.R., Dabbs D.J., Marshall RB.: "Malignant mixed mullerian tumors: An ultrastructural and immunohistochemical analysis with histogenetic considerations". Cancer, 1987, 59, 1781.

[15] Ramadan M., Goudie R.B.: "Epithelial antigens in malignant mixed mullerian tumors of the endometrium". J. Pathol., 1986, 148, 13.

[16] Costa M.J., Khan R., Judd R.: "Carcinosarcoma (malignant mixed mullerian meso-dermal tumor) of the uterus and ovary: Correlation of clinical pathologic and immunohistochemical features in 29 cases". Arch. Pathol. Lab. Med., 1991, 115, 583.

[17] Aumuller G., Renneberg H., Leonhardt M., Lilja H., Abrahamsson P.A.: "Localization of protein gene product 9.5 immunoreactivity in derivatives of the human Wolffian duct and in prostate cancer". Prostate, 1999, 38 (4), 261.

[18] Budka H.: "Non-glial specifities of immunocytochemistry for the glial fibrillary acidic protein (GFAP). Triple expression of GRAP, vimentin and cytokeratins in papillary meningioma and metastasizing renal carcinoma". Acta Neuropathol. Berlin, 1986, 72 (1), 43.

[19] Franca C.M., Jaeger M.M., Jaeger R.G., Araujo N.S.: "The role of basement membrane proteins on the expression of neural cell adhesion molecule (N-CAM) in an ade-noid cystic carcinoma cell line". Oral. Oneal., 2000, 36 (2), 248.

[20] Garin-Chesa P., Fellinger R.J., Huvos A.G., Beresford H.R., Melamed M.R., Triche T.J., Rettung W.J.: "Immunohistochemical analysis of neural cell adhesion molecules. Differential expression in small round cell tumors of childhood and adolescence". Am. J. Pathol., 1991, 139 (2), 275.

[21] Kapadia S.B., Meis J.M., Frisman D.M., Ellis G.L., Heffner D.K.: "Fetal rhabdomyoma of the head and neck; a clinicopathologic and immunophenotypic study of 24 cases". Hum. Pathol., 1993, 24 (7), 754.

[22] Martin R., Fraile B., Peinado F., Arenas M.I. et al.: "Immunohistochemical localization of protein gene product 9.5, ubiquitin and neuropeptide Y immunoreactivities in epithelial and neuroendocrine cells from normal and hyperplastic human prostate". J. Histochem. Cytochem., 2000, 48 (8), 1121.

[23] Konishi I., Fujii S., Okamura H., Mori T.: "Development of smooth muscle in the human fetal uterus: an ultrastructural study". J. Anat., 1984, 139 (Pt 2), 239.

[24] Ludvig K.S.: "The Mayer-Rokitansky-Kuster syndrome. An analysis of its morphology and embryology". Part 1, Morphology. Arch. Gynecol. Obstet., 1998, 262, 1.

[25] Ludvig K.S.: "The Mayer-Rokitabsky-Kuster syndrome. An analysis of its morphology and embryology". Part II, Embryology. Arch. Gynecol. Obst., 1998, 262, 27.

[26] Haley K.J., Drazen J.M., Osatanodh R., Sunday M.E.: "Comparison of the ontogeny of protein gene product 9.5 chromogranin A and proliferating cell nuclear antigen in developing human lung". Microsc. Res. Tech., 1977, 37 (1), 62.

[27] Goos N.P., Van Muijen, Dirk J., Ruiter, Sven 0., Warnaar: "Coexpression of intermediate filament polypeptides in human fetal and adult tissues". Lab. Invest., 1987, 57 (4), 359.

[28] Amant F., Moerman P., Davel G.H., De Vos R., Vergote I., Lindeque B.G., de Jonge E.: "Uterine carcinosarcoma with melanotic differentiation". Int. J. Gynecol. Pathol., 2001, 20 (2), 186.

[29] Cokelaere K., Michielsen P., De Vos R., Sciot R.: "Primary mesenteric malignant mixed mesodermal (Mullerian) tumor with neuroendocrine differentiation". Mod. Pathol., 2001, 14, 515.