{"paper_id":"4655aaeb-ac41-4f09-b59d-d9aa9330d7e1","body_text":"Submit Manuscript | http://medcraveonline.com\nBackground\nEndometrial cancer is the most common cancer of the female \nreproductive organs, the American Cancer Society estimates 63,230 \nnew cases in 2018 alone. 1 Although endometrial cancer is typically \na disease affecting post-menopausal women, a small percentage \nof woman are diagnosed before the age of 40. 2 These patients can \npresent without any symptoms or with abnormal uterine bleeding \ncharacterized by intermenstrual bleeding or prolonged menstruation. \nUterine cancer is classified into two main subtypes. Type 1 \nconsists of endometrioid cells that are commonly low grade, well \ndifferentiated, and typically hormone receptor positive. Risk factors \nfor Type 1 are associated with unopposed estrogen: early menarche, \nlate menopause, tamoxifen use, nulliparity, infertility, failure to ovulate \nand polycystic ovarian syndrome (PCOS). In addition hypertension, \ndiabetes and obesity also increases the risk of developing endometrial \ncancer.3 Type 1 cancer has a favorable prognosis since the likelihood \nof metastasis is low, and the cancer is typically defined to the uterus.3 \nType 2 cancers are common in non-obese females, typically high \ngrade, poorly differentiated, does not have hormone receptors, and \ncarries a poorer prognosis since it tends to metastasize.3\nThe gold standard treatment for endometrial cancer is total \nhysterectomy, bilateral salpingo-oophorectomy, pelvic and para-\naortic lymphadenectomy with peritoneal cytology. This eliminates \nchildbearing for young, reproductive age females. 3,4 Women who \ndesire a fertility sparing option may undergo medical management; \nObstet Gynecol Int J. 2018;9(5):338‒342. 338\n© 2018 Rezai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which \npermits unrestricted use, distribution, and build upon your work non-commercially.\nLong-term fertility-sparing, conservative \nmanagement of endometrial cancer with progestin, a \ncase report and review of literature\nVolume 9 Issue 5 - 2018\nShadi Rezai,1 Danielle Kochen,2 Neil D Patel,2 \nBhavin R Pandya,1 Mon-Lai Cheung,1 Omid \nHakimian,1 Sudha M Reddy,1 Janis A Penner,1 \nPaul N Fuller,1 Cassandra E Henderson3\n1Department of Obstetrics and Gynecology, Southern California \nKaiser Permanente, USA\n2St. George’s University, School of Medicine, Grenada\n3Maternal Fetal Medicine, Department of Obstetrics and \nGynecology, Lincoln Medical and Mental Health Center, USA\nCorrespondence: Shadi Rezai MD, Department of Obstetrics \nand Gynecology, Southern California Kaiser Permanente, Kern \nCounty, 1200 Discovery Drive, Bakersfield, California, 93309, \nUSA, Email rezsha@sgu.edu\nCassandra E. Henderson MD, Maternal Fetal Medicine, \nDepartment of Obstetrics and Gynecology, Lincoln Medical and \nMental Health Center, 234 East 149th Street, Bronx, New Y ork, \n10451, USA, Email mdwstmd@aol.com \nReceived: July 04, 2018 | Published: September 28, 2018\nAbstract\nBackground:  In premenopausal women, endometrial cancer presentation may be \nasymptomatic or present as abnormal uterine bleeding. The gold standard treatment \nfor endometrial cancer is total hysterectomy, bilateral salpingo-oophorectomy, pelvic \nand para-aortic lymphadenectomy with peritoneal cytology. However, this definitive \ntreatment eliminates childbearing for young reproductive age females. Confirmation of \na low-grade, well differentiated, Type 1 cancer, confined to the endometrium without \nmyometrial invasion or spread; supplemented with MRI to rule out metastasis may \nbenefit from medical management. Medical management includes hormone therapy \nprimarily with progestin analogs. \nCase:  42-year-old, Gravid 0, female with last menstrual period in February 2018 was \nevaluated for menorrhagia and irregular menstrual bleeding for 3 months. Her past \nmedical history was significant for two cases of endometrial carcinoma (2006-2007, \n2008-2011) treated with progestin therapy. \nIn 2006, the patient was diagnosed with early-stage endometrial cancer and declined \nhysterectomy to preserve her fertility. She was treated with progestin and returned \nin 2007 showing remission of endometrial cancer. In 2008 she presented again \nwith irregular vaginal bleeding; work-up revealed Grade 1 endometrial cancer with \nsquamous differentiation and progesterone effect; patient was treated with progestin. \nSubsequently, follow-up dilation and curettage in 2011 revealed no cancer present. \nIn May 2018, an endometrial biopsy performed for irregular bleeding, showed \nendometrial hyperplasia with atypia suspicious for adenocarcinoma; endocervical \ncurettage and endocervical polyp showed similar pathology. In the meantime, the \npatient was started on progestin therapy. She ultimately underwent hysterectomy and \nbilateral salpingo-oophorectomy with no complications. The patient declined the gold \nstandard treatment of hysterectomy, in order to preserve fertility. Alternatively, the \npatient underwent progesterone treatment and remained in early-stage endometrial \ncancer for a 10-year period. Unfortunately, the patient never conceived. \nConclusion:  Fertility preservation has always been a priority for many reproductive \nand perimenopausal age women. This juxtaposes the most effective treatment modality, \nhysterectomy, for patients who desire fertility preservation. Progestin and progestin \nderivative medical management now gives reproductive age females an opportunity to \ncombat endometrial cancer, while retaining the ability to conceive. However, the risk \nof resistance and recurrence still remain with medical management.\nKeywords: conservative, fertility-sparing, hormonal therapy, endometrial cancer, \nmegace, Megestrol, progestin\nObstetrics & Gynecology International Journal\nCase Report\n Open Access\n\n\nLong-term fertility-sparing, conservative management of endometrial cancer with progestin, a case report \nand review of literature\n339\nCopyright:\n©2018 Rezai et al.\nCitation: Rezai S, Kochen D, Patel ND, et al. Long-term fertility-sparing, conservative management of endometrial cancer with progestin, a case report and \nreview of literature. Obstet Gynecol Int J. 2018;9(5):338‒342. DOI: 10.15406/ogij.2018.09.00360\nkeeping in mind there is a risk of recurrence. 5 Patients confirmed to \nhave a low-grade, well differentiated, Type 1 cancer, confined to the \nendometrium without myometrial invasion or spread supplemented \nwith MRI to rule out metastasis may benefit from medical \nmanagement.4 Medical Management includes hormone therapy with: \noral progestin analogs such as medroxyprogesterone acetate (MPA) or \nmegestrol acetate (MA), progestin releasing IUD, selective estrogen \nreceptor modulators, aromatase inhibitors, gonadotropic releasing \nagonists and/or retinoid derivatives.2,6,7,8,9\nWe present a case report and literature review in which progestin \ntherapy is used for long-term fertility-sparing endometrial cancer \nmanagement.\nPresentation of the case\n42-year-old, Gravid 0, female with last menstrual period in \nFebruary 2018 was evaluated for menorrhagia and irregular menstrual \nbleeding for the past 3 months. Her past medical history was \nsignificant for two cases of endometrial carcinoma (2006-2007, 2008-\n2011) treated with Megace and Provera, respectively; and Type 2 \nDiabetes Mellitus; patient does not smoke or consume alcohol; family \nhistory is significant for Type 2 Diabetes Mellitus, patient denies any \nfamily history of breast, ovarian, or colon cancer. Past surgical history \nincludes dilation and curettage (2006, 2007, and 2011), dilation and \ncurettage with laparoscopy, right ovarian cystectomy and pelvic node \nbiopsy (2009). Upon presentation, vital signs were stable and within \nnormal limits; BMI 34.16 kg/m². \nIn 2006, at the age of 30, the patient was diagnosed by an alternate \nprovider with early-stage endometrial cancer with no myometrial \ninvasion and declined hysterectomy to preserve her fertility. She was \ntreated with Megace, in 2007 end of treatment dilation and curettage \nshowed remission of endometrial cancer. Patient was instructed \nto discontinue Megace. In 2008 she presented again with irregular \nvaginal bleeding to the same facility; endometrial biopsy showed \nGrade 1 endometrial cancer - patient was started on Provera for \ntreatment. Two months later, patient underwent dilation and curettage \nwith laparoscopy pelvic node biopsy and right ovarian cystectomy \nfor persistent irregular vaginal bleeding. Pathology revealed grade 1 \nendometrial cancer with squamous differentiation and progesterone \neffect confined to the uterus; patient was treated with Megace 40-mg \ndaily, for a total duration of 3 years. Due to patient non-compliance and \nincomplete follow up dilation and curettage could not be preformed \nevery 3 months. Subsequently, follow-up dilation and curettage \nin 2011, showed decidual effect, with no cancer present, ovulation \ninduction cycling was initiated with no success. Patient continued \nMegace until 2013, then discontinued. \nPatient was lost to follow-up until she presented in May 2018 \nfor irregular bleeding and endometrial biopsy showed endometrial \nhyperplasia with atypia suspicious for adenocarcinoma; endocervical \ncurettage and endocervical polyp showed similar pathology. Pap \nscreen and HPV were negative for intraepithelial lesion or malignancy; \nCA-125 was 43.4. Pelvic sonogram showed the uterus (11.3 by 7.6 \nby 8.5) with an endometrial mass (10.5 by 5.8 by 6.6) (Figure 1). \nIn addition, there was a 19-mm cyst in the right ovary (Figure 1). \nOn review of the sonogram, the endometrial mass is heterogenous \nand extended into the endocervical os (Figure 1). Concurrent chest \nx-ray was within normal limits with no abnormalities; CT of the \nchest, abdomen, and pelvis (Figure 2) was negative for chest and liver \nmetastasis and hydronephrosis; positive for 7-mm paraaortic node, \n9-mm pelvic node, right ovarian cyst (2.8-cm), and an endometrial \nmass (6.7 by 6.4-cm). Physical exam showed midline cervix 2.0 cm \nin diameter, soft but with 4 by 5 mm ass protruding from the cervical \nos. Uterus is 12 by 10 by 8 cm anterior not tender. Adnexa were not \nappreciated and no nodularity in the cul de sac. The patient was started \non Megace 40mg daily. At this time, hysterectomy, bilateral salpingo-\noophorectomy and staging were indicated. \nFigure 1 Pelvic Ultrasound, Transverse view (1A) and Sagittal view (1B) showing endometrial mass measuring 10.5×5.8×6.6cm, highly suspicious for endometrial \nneoplasia.\n\n\nLong-term fertility-sparing, conservative management of endometrial cancer with progestin, a case report \nand review of literature\n340\nCopyright:\n©2018 Rezai et al.\nCitation: Rezai S, Kochen D, Patel ND, et al. Long-term fertility-sparing, conservative management of endometrial cancer with progestin, a case report and \nreview of literature. Obstet Gynecol Int J. 2018;9(5):338‒342. DOI: 10.15406/ogij.2018.09.00360\nFigure 2 Computed tomography (CT) of Pelvis: sagittal View (2A); Coronal View (2B); and Transverse View (2C), showing 6.7×6.4×10cm hypodense mass in the \nendometrial cavity compatible with known uterine cancer.\nThe patient underwent hysterectomy and bilateral salpingo-\noophorectomy in May 2018. Her post-operative course was \nuncomplicated and uneventful. She was able to tolerate regular diet, \nambulate, pass flatus, and void on her own. Pain was well controlled \nand was afebrile with vital signs within normal limits. Incision site \nwas clean, dry and intact and patient was discharged post operation \nday 2 with follow up at the gynecology clinic. Pathology from \nhysterectomy showed Grade 1 endometrial carcinoma with less than \n1mm of myometrial invasion. \nTo summarize, the patient declined the gold standard treatment \nof hysterectomy, in order to preserve fertility. Alternatively, the \npatient underwent progesterone treatment and remained in early-stage \nendometrial cancer for a 10-year period. Unfortunately, the patient \nnever conceived. \nDiscussions\nEndometrial cancer is a disease of postmenopausal women; \ndiagnosis under the age of 40 is considered to be an unusual \npresentation and tend to have more favorable outcomes compared to \nolder patients. 10 Diagnosis of cancer is established through dilation \nand curettage or endometrial biopsy, supplemented with MRI to \nevaluate for invasion. \nHysterectomy with bilateral salpingo-oophorectomy with \nor without lymphadenotomy is the gold standard treatment. \nMedical management is an alternate option for early stage cancer \nfor reproductive age women who desire to conceive. 3 Fertility \nsparing treatment using progesterone is effective for early stage, \nwell differentiated, endometrioid type cancer with no evidence of \nextra uterine spread. 11,2 Progesterone therapy has shown favorable \ntherapeutic results for conceiving and successfully carrying a normal \npregnancy, however the risk of recurrence still remains, even after \nprogesterone therapy is completed.12,13,14 \nThere are four commonly used progesterone medications \ncombinations prescribed for conservative management of endometrial \ncancer. Table 1 demonstrates these treatment options, with associated \nsuccess rates, pregnancy rates, and live birth rates. 15 Studies have \nshown that the use of oral or intrauterine progestin is equally effective \nfor fertility sparing management of complex atypical endometrial \nhyperplasia.6,14,16−18 The average duration of hormonal therapy is \napproximately six months; with an average response time of twelve \nweeks. 76% of patients treated with hormonal therapy had a complete \nresponse and the other 24% never responded to treatment - Of those \nwho initially responded, 66% percent did not show recurrence of \ndisease; the other 34% had a relapse.10 One report supports increasing \nthe dose if the initial response is not achieved, or when disease \nrecurs.19 Serious complications were not observed with the use \nof higher doses. 9,19 Upon initiation of therapy, follow up screening \nand surveillance through dilation and curettage, every 3 months is \nrecommended for evaluation.3,11 \n\nLong-term fertility-sparing, conservative management of endometrial cancer with progestin, a case report \nand review of literature\n341\nCopyright:\n©2018 Rezai et al.\nCitation: Rezai S, Kochen D, Patel ND, et al. Long-term fertility-sparing, conservative management of endometrial cancer with progestin, a case report and \nreview of literature. Obstet Gynecol Int J. 2018;9(5):338‒342. DOI: 10.15406/ogij.2018.09.00360\nT able 1 Comparison of success rate, pregnancy rate and live birth rate of four \nprogestin interventions used for early stage endometrial cancer22\nDrug Success \nrate\nPregnancy \nrate\nLive birth \nrate\nMedroxyprogesterone \nacetate (Provera) oral 71% (63-77) 34%(30-38) 20%\nMegestrol Acetate \n(Megace) oral 71% (63-77) 34%(30-38) 20%\nProgestin IUD 76 (67-83) 18% (7-37) 14%\nProgestin oral + IUD 87% (75-93)) 40% (20-63) 35%\nProgesterone treatment can begin to have an effect on endometrial \ntissue as early as 10 weeks from initiation. Therapy follow-up should \nbe done every 3 months in order to assess for pathologic response until \ncomplete response is achieved.5 Increased use of hysteroscopic biopsy \nis not recommended because of repeated damage to the basal layer \nby thermal injury, fibrosis, and trauma will decrease the success of \npregnancy in the future. Patients who desire to conceive immediately \nafter treatment should undergo ovulation induction once progestin \neffect is seen on histology. Patients, who want to delay pregnancy, \nshould be placed on low dose cyclic progestin or progestin IUD to \ncounteract the unopposed estrogen until they wish to conceive.5 After \ncompleting family planning, a prophylactic hysterectomy should be \nadvised due to the likelihood of recurrence. Patients with recurrent \ndisease, who have not achieved a successful pregnancy are able to \nundergo progestin retreatment since the histology of these tumors are \ntypically well differentiated, however; treatment outcomes have not \nbeen well studied. 5 If metastasis is suspected, hysterectomy along \nwith chemotherapy is suggested. \nOver time, patients may experience resistance to progestin therapy \nalone – up to 30% of women.8 New combination therapies have been \nintroduced in attempt to overcome the resistance. A case presentation \nproposed the use of MPA and anastrozole daily for 3 and 6 months \nrespectively for reversion to normal endometrium. 7 Progesterone \ncombined with the elimination of adipose estrogen production was \neffective for differentiated endometrial cancer, especially in obese pre-\nmenopausal women.7 Another combination trial consisted of MA with \nTamoxifen and Temsirolimus. However, while this combination did \nnot show enhanced activity, or improve resistance, it was associated \nwith an increased risk for venous thrombosis.20 \nAdvancements in progesterone therapy are being studied to \noptimize medical management. A fourth-generation progestin, \nDienogest, provides a fertility sparing alternative to patients who \nhave previously failed to respond to MPA. 21 Dienogest antitumor \neffects work by suppressing proliferation of endometrial cancer cells \nin-vitro; and is used for endometriosis-associated pain. 21 Additional \nnon-progesterone therapies include anti-cancer retinoid analogs. \nThe anti-cancer effect of Fenretinide, a retinoid derivative, was \nfound to decrease tumor size and have an anti-tumor effect against \nendometrial cancer. 8 Fenretinide acts to decrease cell viability, \nincrease apoptosis, and cause a decrease in tumor size. It is postulated \nthat Fenretinide induces apoptosis because of an increase in retinol \nuptake.8 \nConclusion\nFertility preservation has always been a priority for many \nreproductive age women. Even though endometrial cancer \nprimarily affects post-menopausal women, it is seen in younger \npremenopausal women. Treatment maintaining fertility juxtaposes \nthe most effective treatment modality, hysterectomy. Progesterone \ntherapy gives reproductive age females a non-surgical treatment \noption, while retaining the ability to conceive in the future. However, \nmedical management is not a wide-spread standard treatment \nopportunity; rather it is evaluated on individual circumstances, taking \ninto consideration the aggressiveness and staging of the cancer. \nProgestin therapy has shown to impact endometrial growth at all \nstages; endometrial hyperplasia has highest likelihood of favorable \nresponse, followed by Grade 1 endometrial carcinoma at 66% and \n48% respectively. However, the risk of resistance and recurrence still \nremain after completion of medical management for endometrial \ncancer.22\nAcknowledgments\nNone. \nConflicts of interest\nAuthors did not report any potential conflicts of interests.\nReferences\n1. American Cancer Society. Facts & Figures 2018 . Atlanta: American \nCancer Society; 2018.\n2. Park JY , Nam JH. Progestins in the fertility-sparing treatment and \nretreatment of patients with primary and recurrent endometrial cancer. \nOncologist. 2015;20(3):270−278. \n3. ACOG. Practice bulletin NO. 149: Endometrial cancer. Obstet Gynecol. \n2015;125(4):10006−10026.\n4. Kesterson JP, Fanning J. Fertility-sparing treatment of endometrial cancer: \nOptions, outcomes and pitfalls. J Gynecol Oncol. 2012;23(2):120–124.\n5. Park JY , Lee SH, Seong SJ, et al. Progestin retreatment in patients with \nrecurrent endometrial adenocarcinoma after successful fertility-sparing \nmanagement using progestin. Gynecol Oncol. 2013;129(1):7–11.\n6. Brown AJ, Westin SN, Broaddus RR, et al. Progestin intrauterine device \nin an adolescent with grade 2 endometrial cancer. Obstet Gynecol.  \n2012;19(2 Pt 2):423–426.\n7. Burnett AF, Bahador A, Amezcua C. Anastrozole, an aromatase inhibitor, \nand (progesterone acetate therapy in premenopausal obese women with \nendometrial cancer: A report of two cases successfully treated without \nhysterectomy. Gynecol Oncol. 2004;94(3):832–834.\n8. Mittal N, Malpani S, Dyson M, et al. Fenretinide: a novel treatment for \nendometrial cancer, PLoS One. 2014;9(10):e110410. \n9. Park JY , Kim DY , Kim TJ, et al. Hormonal therapy for women with stage \nIA endometrial cancer of all grades. Obstet Gynecol. 2013;122(1):7–14.\n10. Chiva de Agust´ın L, Lapuente Sastre F, Corraliza Gal´an V , et al. \nConservative management of patients with early endometrial carcinoma: \nA systematic review. Clin Transl Oncol. 2008;10(3):155–162.\n11. Dorais J, Dodson M, Calvert J, et al. Fertility sparing management of \nendometrial adenocarcinoma. Obstet Gynecol Surv. 2011;66(7):443–451.\n12. Gadducci A, Spirito N, Baroni E, et al. The fertility-sparing \ntreatment in patients with endometrial atypical hyperplasia and early \nendometrial cancer: A debated therapeutic option. Gynecol Endocrinol. \n2009;25(10):683–691.\n13. Gotlieb WH, Beiner ME, Shalmon B, et al. Outcome of fertility-sparing \ntreatment with progestins in young patients with endometrial cancer. \nObstet Gynecol. 2003;102(4):718–725.\n\nLong-term fertility-sparing, conservative management of endometrial cancer with progestin, a case report \nand review of literature\n342\nCopyright:\n©2018 Rezai et al.\nCitation: Rezai S, Kochen D, Patel ND, et al. Long-term fertility-sparing, conservative management of endometrial cancer with progestin, a case report and \nreview of literature. Obstet Gynecol Int J. 2018;9(5):338‒342. DOI: 10.15406/ogij.2018.09.00360\n14. Perri T, Korach J, Gotlieb WH, et al. Prolonged conservative treatment of \nendometrial cancer patients: More than 1 pregnancy can be achieved. Int \nJ Gynecol Cancer. 2011;21(1):72–78.\n15. Wei J, Zhang W, Feng L, et al. Comparison of fertility-sparing treatments \nin patients with early endometrial cancer and atypical complex \nhyperplasia A meta-analysis and systematic review. Medicine (Baltimore). \n2017;96(37):e8034.\n16. Baker J, Obermair A, Gebski V , et al. Efficacy of oral or intrauterine device-\ndelivered progestin in patients with complex endometrial hyperplasia \nwith atypia or early endometrial adenocarcinoma: A meta-analysis and \nsystematic review of the literature. Gynecol Oncol. 2012;125(1):263–270.\n17. Koskas M, Yazbeck C, Walker F, et al. Fertility sparing management \nof grade 2 and 3 endometrial adenocarcinomas. Anticancer Res.  \n2011;31(9):3047–3049.\n18. Montz FJ, Bristow RE, Bovicelli A, et al. Intrauterine progesterone \ntreatment of early endometrial cancer. Am J Obstet Gynecol.  \n2002;186(4):651–657.\n19. Eftekhar Z, Izadi-Mood N, Yarandi F, et al. Efficacy of megestrol \nacetate (Megace) in the treatment of patients with early endometrial \nadenocarcinoma: Our experiences with 21 patients. Int J Gynecol Cancer. \n2009;19(2):249–252.\n20. Fleming GF, Filiaci VL, Marzullo B, et al. Temsirolimus with or without \nmegestrol acetate and tamoxifen for endometrial cancer: a gynecologic \noncology group study. Gynecol Oncol. 2014;132(3):585−592. \n21. Banno K, Kisu I, Yanokura M, et al. Progestin therapy for endometrial \ncancer: The potential of fourth-generation progestin . Int J Oncol.  \n2012;40(6):1755–1762.\n22. Gunderson CC, Fader AN, Carson KA, et al. Oncologic and reproductive \noutcomes with progestin therapy in women with endometrial hyperplasia \nand grade 1 adenocarcinoma: A systematic review. Gynecol Oncol.  \n2012;125(2):477–482.","source_license":"CC0","license_restricted":false}