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Conservative Medroxyprogesterone Acetate Therapy in Early Stage of Endometrial Carcinoma Associated with Phosphatase and Tensin Homolog Expression

DOI: 10.4236/ojpathology.2017.71001, PP. 1-12

Keywords: Endometrial Cancer, Medroxyprogesterone Acetate, Conservative Therapy, High Relapse Rate, PTEN Retain

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Young patients with the endometrial cancer IA who desire to preserve fertility, can select the conservative therapy with progestin. However, the therapy involves risks of progression and relapse. We examined immunohistochemical analyses of phosphatase and tension homolog (PTEN) and p53 expressions to predict the early relapse, and pregnancy and delivery. Twenty women with endometrial cancer, FIGO IA (1988) (FIGO staging was essentially defined post-surgically), instead of the pathogical specimen before surgery without myometrial invasion were estimated by MRI under 40 years at Gifu University Hospital, Japan from 1988 to 2009. Patients were treated with medroxyprogesterone acetate (MPA, 400 - 600 mg/day) for 4 - 10 months, with whole wall endometrial curettage performed every four weeks. Response to the therapy, pregnancy, delivery and relapse of disease during follow-up over a 72-month period. Immunohistochemical expression of PTEN and p53 was also evaluated with pregnancy, delivery and relapse rate. All patients had pathological complete remissions within 4 - 10 months. Relapse rate was high (60%) in more than 72 months. Immunohistochemical PTEN retain in tumor cells before MPA treatment (8/10) was significant better correlation with pregnancy and delivery rate than of lost cases (1/5) in non-obese women (P < 0.05). Conservative therapy is feasible in carefully selected young women with endometrial cancer without myometrial invasion. However, the relapse rate was high. In cases who desire to be a pregnant, an earlier infertility treatment may be considered especially for PTEN loss especially in nonobese cases.


[1]  Kaku, T., Yoshikawa, H., Tsuda, H., Sakamoto, A., Fukunaga, M., Kuwabara, Y., Hataeg, M., Kodama, S., Kuzuya, K., Sato S., Nishimura, T., Hiura, M., Nakano, H., Iwasaka, T., Miyazaki, K. and Kamura, T. (2001) Conservative Therapy for Adenocarcinoma and Atypical Endometrial Hyperplasia of the Endometrium in Young Women: Central Pathologic Review and Treatment Outcome. Cancer Letters, 167, 39-48.
[2]  Zheng, W., Baker, H.E. and Mutter, G.L. (2004) Involution of PTEN-Null Endometrial Glands with Progestin Therapy. Gynecologic Oncology, 92, 1008-1013.
[3]  Ramirez, P.T., Frumovitz, M., Bodurka, D.C., Sun, C.C. and Levenback, C. (2004) Hormonal Therapy for the Management of Grade 1 Endometrial Adenocarcinoma: A Literature Review. Gynecologic Oncology, 95, 133-138.
[4]  Niwa, K., Tagami, K., Lian, Z., Onogi, K., Mori, H. and Tamaya, T. (2005) Outcome of Fertility-Preserving Treatment in Young Women with Endometrial Carcinomas. BJOG, 112, 317-320.
[5]  Ushjima, K., Yahata, H., Yoshikawa, H., Konishi, I., Yasugi, T., Saito, T., Nakanishi, T., Sasaki, H., Saji, F., Iwasaki, T., Hatase, M., Kodama, S., Saito, T., Terakawa, N., Yaegashi, N., Hiura, M., Sakamoto, A., Tsuda, H., Fukunaga, M. and Kamura, T. (2007) Multicenter Phase II Study of Fertility-Sparing Treatment with Medroxyprogesterone Acetate for Endometrial Carcinoma and Atypical Hyperplasia in Young Women. Journal of Clinical Oncology, 25, 2798-2803.
[6]  Park, J.Y. and Nam, J.H. (2015) Progestins in the Fertility-Sparing Treatment and Retreatment of Patients with Primary and Recurrent Endometrial Cancer. Oncologist, 20, 270-278.
[7]  van Gent, M.D., Nicolae-Cristea, A.R., de Kroon, C.D., Osse, E.M., Kagie, M.J., Trimbos, J.B., Hazelbag, H.M., Smit, V.T. and Bosse, T. (2016) Exploring Morphologic and Molecular Aspects of Endometrial Cancer under Progesterone Treatment in the Context of Fertility Preservation. International Journal of Gynecological Cancer, 26, 483-490.
[8]  Fournier, D.B., Chisamore, M., Lurain, J.R., Rademaker, A.W., Jordan, V.C. and Tonetti, D.A. (2001) Protein kinase C alpha Expression Is Inversely Related to ER Status in Endometrial Carcinoma: Possible Role in AP-1-Mediated Proliferation of ER-Negative Endometrial Cancer. Gynecologic Oncology, 81, 366-372.
[9]  Salvesen, H.B., Carter, S.L., Mannelqvist, M., Dutt, A., Getz, G., Stefansson, .M., Raeder, M.B., Sos, M.L., Engelsen, I.B., Trovik, J., Wik, E., Greulich, H., Bø, T.H., Jonassen, I., Thomas, R.K., Zander, T., Garraway, L.A., Oyan, A.M., Sellers, W.R., Kalland, K.H., Meyerson, M., Akslen, L.A. and Beroukhim, R. (2009) Integrated Genomic Profiling of Endometrial Carcinoma Associates Aggressive Tumors with Indicators of PI3 Kinase Activation. Proceedings of the National Academy of Sciences of the United States of America, 106, 4834-4839.
[10]  Cheung, L.W., Henessy, B.T., Li, J., Yu, S., Myers, A.P., Djordjevic, B., Lu, Y., Stemke-Hale, K., Zhang, F., Ju, Z., Cantley, L.C., Scherer, S.E., Liang, H., Lu, K.H., Broaddus, R.R. and Mills, G.B. (2011) High Frequency of PI3KR1 and PI3KR2 Mutations in Endometrial Cancer Elucidates a Novel Mechanism for Regulation of PTEN Protein Stability. Cancer Discovery, 1, 170-185.
[11]  Kong, D., Suzuki, A., Zou, T.T., Sakurada, A., Kemp, L.W., Wakatsuki, S., Yokoyama, T., Yamakawa, H., Furukawa, T., Sato, M., Ohuchi, N., Sato, S., Yin, J., Wang, S., Abraham, J.M., Souza, R.F., Smolinski, K.N., Meltzer, S.J. and Horii, A. (1997) PTEN1 Is Frequently Mutated in Primary Endometrial Carcinomas. Nature Genetics, 17, 143-144.
[12]  Risinger, J.I., Hayes, A.K., Berchuck, A. and Barrett, J.C. (1997) PTEN/MMAC1 Mutations in Endometrial Cancers. Cancer Research, 57, 4736-4738.
[13]  Tashiro, H., Blazes, M.S., Wu, R., Cho, K.R., Bose, S., Wang, S.I., Li, J., Parsons, R. and Ellenson, L.H. (1997) Mutations in PTEN Are Frequent in Endometrial Carcinoma But Rare in Other Common Gynecological Malignancies. Cancer Research, 57, 3935-3940.
[14]  Minaguchi, T., Nakagawa, S., Takazawa, Y., Nei, T., Horie, K., Fujiwara, T., Osuga, Y., Yasugi, T., Kugu, K., Yano, T., Yoshikawa, H. and Taketani, Y. (2007) Combined Phospho-Akt and PTEN Expressions Associated with Post-Treatment Hysterectomy after Conservative Progestin Therapy in Complex Atypical Hyperplasia and Stage Ia, G1 Adenocarcinoma of the Endometrium. Cancer Letters, 248, 112-122.
[15]  Fata, J.E., Debnath, S., Jenkins Jr., E.C. and Fournier, M.V. (2012) Nongenomic Mechanisms of PTEN Regulation. International Journal of Cell Biology, 2012, Article ID: 379685.
[16]  Minaguchi, T., Yoshikawa, H., Oda, K., Ishino, T., Yasugi, T., Onda, T., Nakagawa, S., Matsumoto, K., Kawana, K. and Taketani, Y. (2001) PTEN Mutation Located Only Outside Exons 5, 6, and 7 Is an Independent Predictor of Favorable Survival in Endometrial Carcinomas. Clinical Cancer Research, 7, 2636-2342.
[17]  Dellas, A., Jundt, G., Sartorius, G., Schneider, M. and Moch, H. (2009) Combined PTEN and p27kip1 Protein Expression Patterns Are Associated with Obesity and Prognosis in Endometrial Carcinomas. Clinical Cancer Research, 15, 2456-2462.
[18]  Mackay, H.J., Gallinger, S., Tsao, M.S., McLachlin, C.M., Tu, D., Keiser, K., Eisenhauer, E.A. and Oza, A.M. (2010) Prognostic Value of Microsatellite Instability (MSI) and PTEN Expression in Women with Endometrial Cancer: Results from Studies of the NCIC Clinical Trials Group (NCIC CTG). European Journal of Cancer, 46, 1365-1373.
[19]  Kanamori, Y., Kigawa, J., Itamochi, H., Sultana, H., Suzuki, M., Ohwada, M., Kamura, T., Sugiyama, T., Kikuchi, Y., Kita, T., Fujiwara, K. and Terakawa, N. (2002) PTEN Expression Is Associated with Prognosis for Patients with Advanced Endometrial Carcinoma Undergoing Postoperative Chemotherapy. International Journal of Cancer, 100, 686-689.
[20]  Salvesen, H.B., Stefansson, I., Kalvenes, M.B., Das, S. and Akslen, L.A. (2002) Loss of PTEN Expression Is Associated with Metastatic Disease in Patients with Endometrial Carcinoma. Cancer, 94, 2185-2191.
[21]  Terakawa, N., Kanamori, Y. and Yoshida, S. (2003) Loss of PTEN Expression Followed by Akt Phosphorylation Is a Poor Prognostic Factor for Patients with Endometrial Cancer. Endocrine-Related Cancer, 10, 203-208.
[22]  Athanassiadou, P., Athanassiades, P., Grapsa, D., Gonidi, M., Athanassiadou, A.M., Stamati, P.N. and Patsouris, E. (2007) The Prognostic Value of PTEN, p53, and Beta-Catenin in Endometrial Carcinoma: A Prospective Immunocytochemical Study. International Journal of Gynecological Cancer, 17, 697-704.
[23]  Westin, S.N., Ju, Z., Broaddus, R.R., Krakstad, C., Li, J., Pal, N., Lu, K.H., Coleman, R.L., Hennessy, B.T., Klempner, S.J., Werner, H.M., Salvesen, H.B., Cantley, L.C., Mills, G.B. and Myers, A.P. (2015) PTEN Loss Is a Context-Dependent Outcome Determinant in Obese and Non-Obese Endometrioid Endometrial Cancer Patients. Molecular Oncology, 9, 1694-1703.
[24]  Stambolic, V., MacPherson, D., Sas, D., Lin, Y., Snow, B., Jang, Y., Benchimol, S. and Mak, T.W. (2001) Regulation of PTEN Transcription by p53. Molecular Cell, 8, 317-325.
[25]  Mayo, L.D., Dixon, J.E., Durden, D.L., Tonks, N.K. and Donner, D.B. (2002) PTEN Protects p53 from Mdm2 and Sensitizes Cancer Cells to Chemotherapy. The Journal of Biological Chemistry, 277, 5484-5489.
[26]  Kurman, R.J. and Norris, H.J. (1982) Evaluation of Criteria for Distinguishing Atypical Endometrial Hyperplasia from Well-Differentiated Carcinoma. Cancer, 49, 2547-2559.<2547::AID-CNCR2820491224>3.0.CO;2-0
[27]  Garg, K., Broaddus, R.R., Soslow, R.A., Urbauer, D.L., Levine, D.A. and Djordjevic, B. (2012) Pathologic Scoring of PTEN Immunohistochemistry in Endometrial Carcinoma Is Highly Reproducible. International Journal of Gynecological Pathology, 31, 48-56.
[28]  Risinger, J.I., Hayes, K., Maxwell, G.L., Carney, M.E., Dodge, R.K., Barrett, J.C. and Berchuck, A. (1998) PTEN Mutation in Endometrial Cancers Is Associated with Favorable Clinical and Pathologic Characteristics. Clinical Cancer Research, 4, 3005-3010.
[29]  Simoncini, T., Hafezi-Moghadam, A., Brazil, D.P., Ley, K., Chin, W.W. and Liao, J.K. (2000) Interaction of Oestrogen Receptor with the Regulatory Subunit of Phosphatidylinositol-3-OH Kinase. Nature, 407, 538-541.
[30]  Maxwell, G.L., Risinger, J.I., Gumbs, C., Shaw, H., Bentley, R.C., Barrett, J.C., Berchuck, A. and Futreal, P.A. (1998) Mutation of the PTEN Tumor Suppressor Gene in Endometrial Hyperplasias. Cancer Research, 58, 2500-2503.
[31]  Kanamori, Y., Kigawa, J., Itamochi, H., Shimada, M., Takahashi, M., Kamazawa, S., Sato, S., Akeshima, R. and Terakawa, N. (2001) Correlation between Loss of PTEN Expression and Akt Phosphorylation in Endometrial Carcinoma. Clinical Cancer Research, 7, 892-895.
[32]  Mitchell, A. and Fantasia, H.C. (2016) Understanding the Effect of Obesity on Fertility among Reproductive-Age Women. Nursing for Women's Health, 20, 368-376.
[33]  Kester, H.A., Sonneveld, E., van der Saag, P.T. and van der Burg, B. (2003) Prolonged Progestin Treatment Induces the Promoter of CDK Inhibitor p21Cip1, Waf1 through Activation of p53 in Human Breast and Endometrial Tumor Cells. Experimental Cell Research, 284, 264-273.
[34]  Brooks, C.L. and Gu, W. (2003) Ubiquitination, Phosphorylation and Acetylation: The Molecular Basis for p53 Regulation. Current Opinion in Cell Biology, 15, 164-171.
[35]  Vereide, A.B., Kaino, T., Sager, G., Arnes, M. and Ørbo, A. (2006) Effect of Levonorgestrel IUD and Oral Medroxyprogesterone Acetate on Glandular and Stromal Progesterone Receptors (PRA and PRB), and Estrogen Receptors (ER-Alpha and ER-Beta) in Human Endometrial Hyperplasia. Gynecologic Oncology, 101, 214-223.


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