Surgical staging and differential protein expression in endometrial cancers

Purpose of Investigation: The benefit of comprehensive surgical staging in type I versus type II tumors is investigated and translationally associated with differentially expressed proteins. Materials and Methods: A single institutional database was queried for all uterine cancer patients and sample data was abstracted. Proteins identified from microarray data were further investigated at the immunohistochemical (IHC) level and correlated with sample data. Results: Lymph node dissection did not result in a survival benefit for either type I or type II uterine cancer. L1CAM is differentially expressed between tumor types. GRB7 was found to correlate with stage in type II cancers. Thrombomodulin was expressed at higher levels in all lymph node (LN) positive cancers. Conclusions: LN dissection did not provide a therapeutic benefit in endometrial cancers, especially type II cancers. Protein correlations with stage and histology demonstrate specific biologic profiles. Novel diagnostic and therapeutic targets for differentially expressed tumor proteins are identified.

Immunohistochemistry; Lymph node; Uterine cancer.

[1] Siegel R.L., Miller K.D., Jemal A.: “American Cancer Society. Cancer Facts & Figures 2018”. Atlanta: American Cancer Society, 2018.

[2] Mendivil A., Schuler K.M., Gehrig P.A.: “Non endometrioid adenocarcinoma of the uterine corpus: a review of selected histological subtypes”. Cancer Control, 2009, 16, 46.

[3] Hendrickson M., Ross J., Eifel P., Martinez A., Kempson R.: “Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma”. Am. J. Surg. Pathol., 1982, 6, 93.

[4] Kitchener H., Swart A.M., Qian Q., Amos C., Parmar M.K.: “Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomized study”. Lancet, 2009, 373, 125.

[5] Benedetti Panici P., Basile S., Maneschi F., Alberto Lissoni A., Signorelli M., Scambia G., et al.: “Systemic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial”. J. Natl. Cancer Inst., 2008, 100, 1707.

[6] Goff B.A.: “Uterine papillary serous carcinoma: What have we learned over the past quarter century?” Gynecol. Oncol., 2005, 98, 341.

[7] Kelly M.G., O’Mally D.M., Hui P., McAlpine J., Yu H., Rutherford T.J., et al.: “Improved survival in surgical stage I patients with uterine papillary serous carcinoma (USPC) treated with adjuvant platinum- based chemotherapy”. Gynecol. Oncol., 2005, 98, 353.

[8] Risinger J.I., Maxwell G.L., Chandramouli G.V., Jazaeri A., Aprelikova O., Patterson T., et al.: “Microarray analysis reveals distinct gene expression profiles among different histologic types of endometrial cancer”. Cancer Res., 2003, 63, 6.

[9] Santin A.D., Zhan F., Cane’ S., Bellone S., Palmieri M., Thomas M., et al.: “Gene expression fingerprint of uterine serous papillary carcinoma: identification of novel molecular markers for uterine serous cancer diagnosis and therapy”. Br. J. Cancer, 2005, 92, 1561.

[10] Santin A.D., Diamandis E.P., Bellone S., Marizzoni M., Bandiera E., Palmieri M., et al.: “Overexpression of kallikrein 10 (hK10) in uterine serous papillary carcinomas”. Am. J. Obstet. Gynecol., 2006, 194, 1296.

[11] Konecny E., Agarwal R., Keeney G.A., Winterhoff B., Jones M.B., Mariani A., et al.: “Claudin-3 and claudin-4 expression in serous papillary, clear-cell, and endometrioid endometrial cancer”. Gynecol. Oncol., 2008, 109, 263.

[12] Morrison C., Zanagnolo V., Ramirez N., Cohn D.E., Kelbick N., Copeland L., et al.: “HER-2 Is an Independent Prognostic Factor in Endometrial Cancer: Association With Outcome in a Large Cohort of Surgically Staged Patients”. J. Clin. Oncol., 2006, 24, 2376.

[13] Havrilesky L.J., Cragun J.M., Calingaert B., Synan I., Secord A.A., Soper J.T., et al.: “Resection of lymph node metastases influences survival in stage IIIC endometrial cancer”. Gynecol. Oncol., 2005, 99, 689.

[14] Chan J.K., Cheung M.K., Huh W.K., Osann K., Husain A., Teng N.N., Kapp D.S.: “Therapeutic role of lymph node resection in endometrioid corpus cancer: a study of 12,333 patients”. Cancer, 2006, 107, 1823.

[15] Lutman C.V., Havrilesky L.J., Cragun J.M., Secord A.A., Calingaert B., Berchuck A., et al.: “Pelvic lymph node count is an important prognostic variable for FIGO stage I and II endometrial carcinoma with high-risk histology”. Gynecol. Oncol., 2006, 102, 92.

[16] Goldstein H., Miller R.C., Abdah-Bortnyak R., Steiner M., Yildiz F., Meirovitz A., et al.: “Outcome after combined modality treatment of uterine papillary serous carcinoma: A study by the Rare Cancer Network (RCN)”. Gynecol. Oncol., 2008, 108, 298.

[17] Boo Y.J., Park J.M., Kim J., Chae Y.S., Min B.W., Um J.W., Moon H.Y.: “L1Expression as a Marker for Poor Prognosis, Tumor Progression, and Short Survival in Patients with Colorectal Cancer”. Ann. Surg. Oncol., 2007, 14, 1703.

[18] Gavert N., Sheffer M., Raveh S., Spaderna S., Shtutman M., Brabletz T., et al.: “Expression of L1-CAM and ADAM10 in Human Colon Cancer Cells Induces Metastasis”. Cancer Res., 2007, 67, 7703.

[19] Heuberger J., Birchmeier W.: “Interplay of Cadherin-Mediated Cell Adhesion and Canonical Wnt Signaling”. Cold Spring Harb. Perspect. Biol., 2010, 2, 1.

[20] Gutwein P., Stoeck A., Riedle S., Gast D., Runz S., Condon T.P., Marmé A., et al.: “Cleavage of L1 in exosomes and apoptotic membrane vesicles released from ovarian carcinoma cells”. Clin. Cancer Res., 2005, 11, 2492.

[21] Mechtersheimer S., Gutwein P., Agmon-Levin N., Stoeck A., Oleszewski M., Riedle S., Postina R., et al.: “Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins”. J. Cell Biol., 2001, 155, 661.

[22] Vihinen P., Veli-Matti K.: “Matrix metalloproteinase’s in cancer: Prognostic markers and therapeutic targets”. Int. J. Cancer, 2002, 99, 157.

[23] Cao Q.J., Jones J.G., Li M.: “Expression of calretinin in human ovary, testis, and ovarian sex cord-stromal tumors”. Int. J. Gynecol. Pathol., 2001, 20, 346.

[24] AlHilli M.M., Podratz K.C., Dowdy S.C., Bakkum-Gamez J.N., Weaver A.L., McGree M.E., et al.: “Risk-scoring system for the individualized prediction of lymphatic dissemination in patients with endometrioid endometrial cancer”. Gynecol. Oncol., 2013, 131, 103.

[25] Bendifallah S., Genin A.S., Naoura, I., Chabbert Buffet N., Clavel Chapelon F., Haddad B., et al.: “A nomogram for predicting lymph node metastasis of presumed stage I and II endometrial cancer”. Am. J. Obstet. Gynecol., 2012, 207, 197.e1