Fertility preservation in young patients with endometrial cancer!
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1 Fertility preservation in young patients with endometrial cancer! ISFP Vienna 17. November 2017 Assoc.Prof.PD.Dr.med Kazem Nouri Medizinische Universität Wien Universitätsklinik für Frauenheilkunde, Klinische Abteilung für Endokrinologie und Reproduktionsmedizin Dr. Kazem Nouri Medizinische Universität Wien, UFK
2 Epidemiology Endometrial cancer is the most common gynecologic malignancy typically in the postmenopausal women. 1-Benshushan A. Endometrial adenocarcinoma in young patients: evaluation and fertility-preserving treatment. Eur J Obstet Gynecol Reprod Biol 2004; 117: Crissman JD, Azoury RS, Barnes AE, et al. Endometrial carcinoma in women 40 years of age or younger. Obstet Gynecol 1981; 57: Gallup DG, Stock RJ. Adenocarcinoma of the endometrium in women 40 years of age or younger. Obstet Gynecol 1984; 64: Lowe MP, Bender D, Sood AK. Two successful pregnancies after conserva- tive treatment of endometrial cancer and assisted reproduction. Fertil Steril 2002; 77: Randall TC, Kurman RJ. Progestin treatment of atypical hyperplasia and well differentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol 1997; 90:
3 Dr. Kazem Nouri Medizinische Universität Wien, UFK
4 Dr. Kazem Nouri Medizinische Universität Wien, UFK
5 Dr. Kazem Nouri Medizinische Universität Wien, UFK
6 Dr. Kazem Nouri Medizinische Universität Wien, UFK
7 Dr. Kazem Nouri Medizinische Universität Wien, UFK
8 Risk factors! Infertility and nulliparity hyperestrogenic state Hypertension and diabetes Endometrial cancer Tran BN, Connell PP, Waggoner S, et al. Characteristics and outcome of endometrial carcinoma patients age 45 years and younger. Am J Clin Oncol 2000; 23:
9 Hyperestrogenic state 1. Obesity 2. PCO 3. Anovulation 4. Irregular menses 5. Functional ovarian tumors Presence of two or more polyps in patients with polycystic ovary syndrome increases the probability of premalignant and malignant changes! 1-Montz FJ, Bristow RE, Bovicelli A, et al. Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol 2002; 186: Kilicdag EB, Haydardedeoglu B, Cok T, Parlakgumus AH, Simsek E, Bolat FA. Polycystic ovary syndrome and increased polyp numbers as risk factors for malignant transformation of endometrial polyps in premenopausal women. Int J Gynaecol Obstet 2011; 112:
10 Key Symptoms? 1. Abnormal bleeding! 2. Prolonged anovulation Duska LR, Garrett A, Rueda BR. Endometrial cancer in women 40 years old or younger. Gynecol Oncol 2001; 83:
11 Subset of young women with endometrial cancer are slim with regular menses! In the current study the normal-weight woman does seem to be at higher risk to develop higher stage disease and is more likely to have high-risk histology! Duska LR, Garrett A, Rueda BR. Endometrial cancer in women 40 years old or younger. Gynecol Oncol 2001; 83:
12 Other malignancy! Ovarian malignancy Young women with endometrial cancer are at significant risk for concomitant adnexal disease: 1- Synchronous primary ovarian tumors ( 10-29,4 %) 2- Endometrial metastases to the ovary (5%) Lynch/HNPCChe Gitsch G, Hanzal E, Jensen D, et al. Endometrial cancer in premenopausal women 45 years and younger. Obstet Gynecol 1995; 85: Walsh C, Holschneider C, Hoang Y. Coexisting ovarian malignancy in young women with endometrial cancer. Obstet Gynecol 2005; 106: Morice P, Fourchotte V, Sideris L. A need for laparoscopic evaluation of patients with endometrial carcinoma selected for conservative treatment..gynecol Oncol 2005; 96:
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14 Endometrial Hyperplesia Precursor 0f EM-Ca! Simple hyperplasia without atypia -1 % Complex hyperplasia without atypia 3 % Simple atypical hyperplasia 8 % Complex atypical hyperplasia 29 %
15 Staging FIGO 2010 Carcinoma of the Endometrium IA Tumor confined to the uterus, no or < ½ myometrial invasion IB Tumor confined to the uterus, > ½ myometrial invasion II Cervical stromal invasion, but not beyond uterus IIIA Tumor invades serosa or adnexa IIIB Vaginal and/or parametrial involvement IIIC1 Pelvic node involvement IIIC2 Para-aortic involvement IVA Tumor invasion bladder and/or bowel mucosa IVB Distant metastases including abdominal metastases and/or inguinal lymph nodes ER+/PR+ (by either ligand binding or immunohisto- chemistry)
16 Grade Grade 1 tumors have 95% or more of the cancerous tissue forming glands. Grade 2 tumors have between 50% and 94% of the cancerous tissue forming glands. Grade 3 tumors have less than half of the cancerous tissue forming glands. Early endometrial carcinoma is defined as lowgrade cancer limited to the uterus!
17 Good prognosis The available data suggest relative safety and efficacy of progestin treatment for a short window to allow the woman to achieve her reproductive goals! early stage and low grade hysterectomy, bilateral salpingooophorectomy assessment of the retroperitoneal lymph nodes 5-year disease-specific survival rate of 93%in younger patinets, in contrast to older patients (86%) Fertility Preservation! complete resolution rates ranging from 65.8% to 74% for CAH and 48.2% to 72% for EM Cancer patients Duska LR, Garrett A, Rueda BR, Haas J, Chang Y, Fuller AF. Endometrial cancer in women 40 years old or younger. Gynecol Oncol 2001;83: Lee NK, Cheung MK, Shin JY, et al. Prognostic factors for uterine cancer in reproductive-aged women. Obstet Gynecol 2007;109(3):
18 Staging of endometrial carcinoma 1. Pelvic exam 2. Pap smear 3. D&C / Endometrial Biopsy 4. Hysteroscopy 5. Transvaginal ultrasound 6. CT/MRI 7. CA LSK Larson DM, Johnson KK, Broste SK, et al. Comparison of D&C and office endometrial biopsy in predicting final histopathologic grade in endometrial cancer. Obstet Gynecol 1995; 86:38 42.
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20 simple endometrial biopsy?
21 Only D & C? Jadoul P, Donnez J. Conservative treatment may be beneficial for young women with atypical endometrial hyperplasia or endometrial adenocarcinoma. Fertil Steril 2003; 80: Larson DM, Johnson KK, Broste SK, et al. Comparison of D&C and office endometrial biopsy in predicting final histopathologic grade in endometrial cancer. Obstet Gynecol 1995; 86:38 42.
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23 Underdiagnose!
24 Incorrectly grading : 25% Missing higher-grade tumors : 10% Jadoul P, Donnez J. Conservative treatment may be beneficial for young women with atypical endometrial hyperplasia or endometrial adenocarcinoma. Fertil Steril 2003; 80: Larson DM, Johnson KK, Broste SK, et al. Comparison of D&C and office endometrial biopsy in predicting final histopathologic grade in endometrial cancer. Obstet Gynecol 1995; 86:38 42.
25 Hysteroscopy with D&C 1-Hysteroscopy with directed biopsies and D&C 2-Following the lesion during the course of therapy 3-Sensitivity and specificity of hysteroscopy in diagnosis of endometrial carcinoma: 86.4% and 99.2% Huang SY, Jung SM, Ng KK, et al. Ovarian metastasis in a nulliparous woman with endometrial adenocarcinoma failing conservative hormonal treatment. Gynecol Oncol 2005; 97:
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30 1- Removal of the tumor
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32 2-Removal of the endometrium adjacent to the tumor
33 3-Removal of the myometrium underlying the tumor. Successful surgery: If the results of the first pathologic analysis are positive (neoplastic lesion) and the other two are negative!
34 Hysteroscopy with D&C Fluid based hysteroscopy could cause retrograde seeding of the peritoneal cavity with malignant cells, the prognostic significance of positive peritoneal cytology in clinical stage I endometrial adenocarcinoma remains controversial! Bradley WH, Boente MP, Brooker D. Hysteroscopy and cytology in endo- metrial cancer. Obstet Gynecol 2004; 104: Egarter C, Krestan C, Kurz C. Abdominal dissemination of malignant cells with hysteroscopy. Gynecol Oncol 1996; 63: Revel A, Tsafrir A, Anteby SO, Shushan A. Does hysteroscopy produce intra- peritoneal spread of endometrial cancer cells? Obstet Gynecol Surv 2004; 59:
35 Imaging? MR CT VS
36 Grade 1 Endometrial carcinoma Pelvic lymphnode involvement (3%) Para-aortic lymph node involvement (1.7%) Grad 1 Deep myometrial invasion (9%) Spread of tumor to the adnexa (6%) coexisting ovarian neoplasms (19%)
37 MRI? 1-For the detection of myometrial invasion, contrast-enhanced MRI, is superior to ultrasonography and computed tomography scan ( Sensitivity and specifity of 74% ) 2-MRI can also be used to evaluate lymph nodes. Lymph nodes over 1 cm and with central necrosis are suspicious. Zarbo G, Caruso G, Caruso S, Mangano U, Zarbo R. Endome- trial cancer: Preoperative evaluation of myometrial infiltration magnetic resonance imaging versus transvaginal ultrasonography. Eur J Gynaecol Oncol 2000; 21:
38 The Role of Laparoscopy Extrauterine disease Peritoneal cytology Laparoscopy Pelvic lymphadenectomy Benshushan A. Endometrial adenocarcinoma in young patients: evaluation and fertility-preserving treatment. Eur J Obstet Gynecol Reprod Biol 2004; 117: Morice P, Fourchotte V, Sideris L. A need for laparoscopic evaluation of patients with endometrial carcinoma selected for conservative treatment. Gynecol Oncol 2005; 96:
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40 Coexisting ovarian malignancy Retrospective analysis of 102 subjects ages 24 to 45 years Ovarian malignancies were identified in 26 subjects (25%) 23 S. synchronous primaries, 3 S. metastases 18 (69%) had grade 1 endometrial cancer on final pathology 4 (15%) had normal preoperative imaging 4 (15%) had benignappearing ovaries during surgery
41 Coexisting Ovarian Malignancy Stage I ovarian cancer Excelent prognosis 2-4,6% In Women > % in Women <45 Higher stage tumors and poorer prognosis Walsh C, Holschneider C, Hoang Y. Coexisting ovarian malignancy in young women with endometrial cancer. Obstet Gynecol 2005; 106:
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43 Conservative management : 1-With what? 2-How lang?
44 Uses of gonadotrophin-releasing hormone agonists, anti-estrogens and aromatase inhibitors have also been reported! Medroxypro -gesterone acetate (MPA) mg/d Megestrolacetate mg/d Progestin IUD Benshushan A. Endometrial adenocarcinoma in young patients: evaluation and fertility-preserving treatment. Eur J Obstet Gynecol Reprod Biol 2004; 117: Montz FJ, Bristow RE, Bovicelli A, et al. Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol 2002; 186:
45 Risks of conservative management! 1-The risk of disease progression during conservative management of grade 1 endometrial carcinoma: 6% 2-Clinical understaging of a more advanced cancer 3- Presence or development of a simultaneous primary ovarian malignancy 4- Fertility options? Deferral of definitive surgery to achieve childbearing, but no replacement!! Pinto AB, Gopal M, Herzog TJ, et al. Successful in vitro fertilization preg- nancy after conservative management of endometrial cancer. Fertil Steril 2001; 76: Vinker S, Shani A, Open M, et al. Conservative treatment of adenocarcinoma of the endometrium in young patients. Is it appropriate? Eur J Obstet Gynecol Reprod Biol 1999; 83:63 65.,
46 Complications of Progestin therapy? 1-thrombophlebitis 2-weight gain, 3-mood or libido changes 4-headaches, 5-breast tenderness 6-sleep disorders 7-leg cramps 8-Lever dysfunction 9- Thrombus formation 600 mg MPA A-thromboembolism history, B-breast cancer C- hepatic dysfunction Kaku T, Yoshikawa H, Tsuda H. Conservative therapy for adenocarcinoma and atypical endometrial hyperplasia of the endometrium in young women: central pathologic review and treatment outcome. Cancer Lett 2001; 167: Ushijima K, Yahata H, Yoshikawa H, Konishi I, Yasugi T, Saito T, et al. Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women. J Clin Oncol 2007;25:
47 IUD? 1- high-risk surgical patients with grade I endometrial cancer and no evidence of extrauterine disease. 2- It releases 20 mcg of levonorgestrel per day, generating a localized effect within the endometrium! 3- higher concentrations of progestin to the uterine mucosa compared to oral MA, 4-Superior results in endometrial hyperplasia compared with oral MA
48 How long? 10 weeks to 12 Months! Surveillance? Sampling or D & C or HSC every 3 to 6 months Regression : Conception (3 Months reevaluation)
49 Dr. Kazem Nouri Medizinische Universität Wien, UFK
50 Dr. Kazem Nouri Medizinische Universität Wien, UFK
51 Other options? Gestational carrier!. 1- egg/embryo freezing prior to hysterectomy, 2- Hysterectomy with lymph node dissection and preservation of ovaries with the future use Disadvantages: 1- Diminish ovarian reserve or reduce accessibility to the ovaries for oocyte retrieval. 2- Risk of microscopic metastatic or concurrent disease to the ovaries or development of metachronous ovarian cancer Am J Obstet Gynecol Mar;210(3):255.e1-4. doi: /j.ajog Reproductive and oncologic outcomes after progestin therapy for endometrial complex atypical hyperplasia or carcinoma. Kudesia R 1, Singer T 2, Caputo TA 1, Holcomb KM 1, Kligman I 2, Rosenwaks Z 2, Gupta D 3.
52 Reproductive Endocrinology Gynecologic Oncology Multidisciplinary management team Maternal Fetal Medicine
53 Conclusiones 1- Detailed informed consent 2-Both physician and patient should be aware of the potential risks of deviation from standard therapy. Current recommendations are based on a small number of case series and case reports, but no prospective data! 3-Careful oncologic, psychotherapeutic, genetic and reproductive counseling is essential before starting conservative management
54 Thank you for your attention!
55 Complete remission? A thinning of the endometrium as seen on transvaginal ultrasound is associated with an increased chance of responding to progestin therapy. Total absence of tumor cells during the follow-up diagnostic hysteroscopy with biopsy after hormone therapy! If the patient does not respond on the first assessment, recomendation to switch to traditional surgery should be performed.
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58 Reavaluating the safty? Concomitant Ovarian disease at Laparoscopy! 4 Patients with endometrium. ca persistent to progestin Yang YC, Wu CC, Chen CP, et al. Reevaluating the safety of fertility-sparing hormonaltherapy for early endometrial cancer. Gynecol Oncol 2005; 99: Morice P, Fourchotte V, Sideris L. A need for laparoscopic evaluation of patients with endometrial carcinoma selected for conservative treatment. Gynecol Oncol 2005; 96:
59 1-Medexyprogesterone acetate 30 mg twice daily for 6 months 2- Hysteroscopy and D&C was 3- Well-differentiated adenocarcinoma with no myometrial invasion. 4- HE Cum Adenxe + LN The patient has since requested that her sister-in-law acts as a host to her frozen embryos from the IVF cycle
60 2 Questions! Medically complicated cases!
61 No evidence of disease by post-partum serial endometrial samplings or hysterectomy.
62 Worst case senario synchronous ovarian malignancy Persistence Poor outcome Progression
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64 Epidemiology Endometrial cancer is the most common gynecologic malignancy in the United States, with over 40,000 cases diagnosed each year, typically in the postmenopausal women. In 2013, the National Cancer Institute estimates 49,560 new cases in the United States and 8190 deaths. 25% of cases affect premenopausal women. 14% of endometrial cancers are diagnosed in women younger than 45 years old 5% of these tumors are diagnosed in women younger than 40 years old 1-Benshushan A. Endometrial adenocarcinoma in young patients: evaluation and fertility-preserving treatment. Eur J Obstet Gynecol Reprod Biol 2004; 117: Crissman JD, Azoury RS, Barnes AE, et al. Endometrial carcinoma in women 40 years of age or younger. Obstet Gynecol 1981; 57: Gallup DG, Stock RJ. Adenocarcinoma of the endometrium in women 40 years of age or younger. Obstet Gynecol 1984; 64: Lowe MP, Bender D, Sood AK. Two successful pregnancies after conserva- tive treatment of endometrial cancer and assisted reproduction. Fertil Steril 2002; 77: Randall TC, Kurman RJ. Progestin treatment of atypical hyperplasia and well differentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol 1997; 90:
65 25 % premenopausal 14% younger than 45 5% younger than 40
66 Disease free window! The available data suggest relative safety and efficacy of progestin treatment for a short window to allow the woman to achieve her reproductive goals!
67 Majority of women had stage I and grade I disease, Howhever 19 of 95 patients (20%) had disease beyond the uterus, including 10 with advanced disease. Four women died as a result of their disease!
68 Regression rate! Metaanalysis of the 32 studies (408 women) of women with EC managed with fertility-sparing treatment found that 301 women regressed with a pooled regression rate of 76.2% (95% CI, ) Regression, relapse, and live birth rates with fertilitysparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis Ioannis D. Gallos, MD; Jason Yap, MBChB; Madhurima Rajkhowa, MD; David M. Luesley, MD; Arri Coomarasamy, MD; Janesh K. Gupta, MD AJOG
69 Relapse rate! In 29 studies (267 women), women were followed up over time with the median ranging from 11 to 76.5 months, 89 women after an initial regression of the EC relapsed during follow-up, which amounts to a pooled relapse rate of 40.6% (95% CI, ) Regression, relapse, and live birth rates with fertilitysparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis Ioannis D. Gallos, MD; Jason Yap, MBChB; Madhurima Rajkhowa, MD; David M. Luesley, MD; Arri Coomarasamy, MD; Janesh K. Gupta, MD AJOG
70 Hysteroscopy and direct resection hysteroscopy in the presence of endometrial cancer Disadvantages Advantages Tumor grade extent of myometrial invasion Mazzon I, Corrado G, Morricone D, Scambia G. Reproductive preservation for treatment of stage IA endometrial cancer in a young woman: hysteroscopic resection. Int J Gynecol Cancer 2005; 15:
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