Indian J Gynecol Oncolog DOI 10.1007/s40944-016-0042-8
CASE REPORT
Advanced Endometrial Carcinoma with Polycystic Ovarian Syndrome Ahmed Samy El-Agwany1 • Tamer Mamdouh Abdeldayem1
Received: 25 November 2015 / Revised: 30 January 2016 / Accepted: 22 February 2016 Ó Association of Gynecologic Oncologists of India 2016
Abstract Introduction Endometrial cancer is the most common cancer in Europe and North America and the second most common gynecological malignancy world wide according to WHO. It is a disease of postmenopausal women. The disease is rare in young women. However, patients with anovulatory polycystic ovarian syndrome are at risk of developing endometrial carcinoma. The disease may be advanced when diagnosed, thereby depriving the woman of the option for fertility-sparing conservative approach. Case report A case of endometrial cancer in 34-year-old Asian female, treated at Department of Obstetrics and Gynaecology, Alexandria University, Egypt (2012), is presented. This case highlights the need for endometrial sampling in young women with anovulatory cycles so that hyperplasia can be diagnosed and treated before frank invasion. Progesterone conservative therapy is an alternative in women with a strong desire for fertility, who have been explained the risks and given fully informed consent. This case report highlights the fact that endometrial cancer may be very advanced at diagnosis, even at young age. In such cases, fertility preservation attempts would not only fail, but there would be disease progression. Keywords Endometrial adenocarcinoma Polycystic ovaries Asian Hysterectomy Uterus Ultrasound
& Ahmed Samy El-Agwany
[email protected] 1
Department of Obstetrics and Gynecology, El-shatby Maternity Hospital, Alexandria University, Alexandria, Egypt
Introduction Endometrial cancer is the most common cancer in Europe and North America. It is a disease of postmenopausal women. The mean age at diagnosis is 61 years. It is relatively rare in the young age group (younger than 40 years old) and accounts only for 2.1–14.4 %. Only few cases younger than 30 years old were published [1–4]. Lack of clinical suspicion and reluctance to do an endometrial evaluation may delay diagnosis of endometrial cancer in young women. This is highlighted in this case report where an advanced endometrial cancer was encountered in a young woman. Endometrial cancer can be represented as a tumour with two different aetiologies. The first one is related with obesity, hypertension and diabetes, and associated with oestrogen therapy. The second type of tumour is rare and is not associated with oestrogen therapy [5]. Risk factors for endometrial cancer are: increasing age, long-term exposure to unopposed oestrogens, residence in North America or Europe, high concentrations of oestrogens postmenopausally, metabolic syndrome (obesity, diabetes), years of menstruation, nulliparity, history of breast cancer, long-term use of tamoxifen, HNPCC family syndrome, hormone-replacement therapy with\12–14 days of progestogens with estrogen therapy and first-degree relative with endometrial cancer [6]. In general, endometrial carcinoma arising from young patients tends to be well differentiated and have favourable histologic type, infrequent myometrial invasion and lack of extra uterine spread [7]. Women with endometrial carcinoma may be treated with progestin therapy as an alternative in women with a strong desire for fertility, who have received information regarding the risks and given fully informed consent. In operative work-up of patient, one
123
Indian J Gynecol Oncolog
thing should be clearly highlighted that conservative management in cancer endometrium in young women is feasible with atypical hyperplasia, focal adenocarcinoma or stage 1a Grade 1 [8].
Case Report A 34-year-old divorced Asian woman, G0P0, was referred to the outpatient clinic for investigation and treatment with complain of menstrual irregularity. An endometrial biopsy was performed since 2 month. Histopathology report was consistent with atypical endometrial hyperplasia. Longterm, high-dose progesterone for 3 month and follow-up endometrial biopsy was done. But continuous irregular bleeding persisted and so she was referred. Her menarche was at the age of 12 years and her menstrual cycles were irregular. On examination, she was neither hirsute nor obese with a body mass index of 23 (in Asian women, normal range is 18.5–23 kg/m2) [4]. Abdomino-pelvic examination was normal. Blood tests for thyroid function and prolactin concentrations were normal. Her glucose tolerance test values were within normal limits. She was normotensive. Her lipid profile was normal. A transvaginal ultrasound scan showed an endometrial thickness of 20 mm and bilateral polycystic ovaries. This history and examination was enough for confirming the diagnoses of polycystic ovarian syndrome. Repeat endometrial biopsy was done and analysed in our department that revealed well-differentiated adenocarcinoma of the endometrium. Contrast CT scan of the abdomen and pelvis was done that revealed bulky uterus with myometrial invasion but no lymph node spread or metastasis.
The patient accepted to proceed with laparotomy after counselling regarding hysterectomy with no fertility preservation because of invasion on imaging methods. At laparotomy, the uterus was bulky and ovaries appeared normal, but both fallopian tubes were dilated and tortuous. There was no free fluid in the pelvis. The pelvic and paraaortic lymph nodes were not enlarged. A total abdominal hysterectomy with bilateral salpingo-oophorectomy and pelvic lymphadenectomy was performed due to advanced surgical staging (Figs. 1, 2). Histopathology was consistent with well-differentiated adenocarcinoma endometrium stage III, grade 2 with fallopian tube involvement, and nodes were positive for malignancy. Patient received post-operative adjuvant radiation therapy and chemotherapy as platinum and Taxol compounds for lymph node metastasis due to advanced stage. After a follow-up for 1 year the patient was free of disease.
Discussion In young nulliparous women, endometrial cancer poses a challenge for the diagnosis and management. This case report illustrates that young women with PCOS are at risk of developing endometrial carcinoma. Physicians must be aware for signs of endometrial disease in these young women. Signs and symptoms such as treatment failure and abnormal vaginal bleeding should be thoroughly investigated. One of the effects of oestrogen on the endometrium is its growth-stimulating effect, which can produce a progression of changes from benign proliferation to atypical hyperplasia and adenocarcinoma [9]. Obesity has strong association with PCOS. Obesity increases the risk to two-
Fig. 1 Total abdominal hysterectomy and bilateral salpingoophrectomy with dilated and tortuous both tubes (left). Uterus with abnormal endometrium (right)
123
Indian J Gynecol Oncolog
Fig. 2 Posthysterectomy tubes revealed dilated lumens and malignant tissues invading and extruded out
to threefold. Moreover, two- to threefold increased risk has been documented in nulliparous women. Women with PCOS are about three times more likely to develop EC compared with women without it. This translates into a 9 % lifetime risk of EC in Caucasian women with PCOS compared with 3 % in women without it. Women with PCOS have several risk factors for EC and may be at increased risk of developing EC as unopposed oestrogen stimulation of the endometrium in anovulatory PCOS women, obesity, insulin resistance, insulin-like growth factors, diabetes, nulliparity, and progesterone resistance. The exact strength of the association between PCOS and EC is, however, unclear, and the evidence for an increased risk of endometrial carcinoma in PCOS was incomplete and contradictory [9–11]. Unopposed oestrogen that results from anovulation contributes to this situation. The endometrium of PCOS is unusually prone for malignancies. On the other hand, progesterone induces regular sloughing of the endometrium, thereby removing endometrial tissue that might otherwise become hyperplastic. Furthermore, progesterone can reverse various degrees of hyperplasia to normal endometrial histology also. Endometrial morphological changes with progestogens vary from the suppression of endometrial glandular growth, through stromal decidualization and leucocyte infiltration to glandular atrophy and stromal focal necrosis [10]. The standard treatment for endometrial carcinoma is type 1 extrafascial hysterectomy and BSO ± pelvic lymphadenectomy according to histopathology and stage of the disease. In young women with low histological grade and early stage of the disease, conservative hormonal therapy has been tried with close follow-up. There is no consensus regarding the ideal progestin agent that is most effective in treating endometrial cancer.
The most commonly used agents are medroxyprogesterone acetate (MPA) and megestrol acetate. In a multicentre prospective trial of fertility-sparing treatment with progestin, MPA was used as oral dose of 600 mg given daily [11]. This treatment is not without side effects. Additionally there are reports of successful treatment with levonorgestrel intrauterine devices (Mirena). Some publications have also mentioned hysteroscopic resection of localised endometrial carcinoma. Among patients who do respond, a majority will do so by 16 weeks. Hence, it is recommended that assessment of response should be in the form of endometrial sampling at 4–6 months after initiating progestin therapy. But one must remember that the duration for which the hormonal therapy will be successful is unknown [11–13]. There are reports of endometrial carcinoma progressing to advanced stages in those treated conservatively with Megace and levonorgestrel intrauterine device. Women with endometrial cancer who want fertility preservation should be counselled regarding the possible risk of advanced disease if surgical therapy is delayed [13]. Conservative therapy is feasible only in carefully selected young women with endometrial cancer. Recurrence rates were high during long-term observations even after pathologically complete remissions. Therefore, close follow-up is recommended [14, 15]. Metformin is a first-line drug in treatment of type 2 diabetes that is widely used, easy to take orally and has few side effects. Administration of metformin also reduces the risk of carcinogenesis, has preventive effects on several types of cancer and inhibits proliferation of cancer cells. In endometrial cancer, metformin shows in vitro effects of cell cycle arrest; decreased hTERT mRNA levels; inhibition of phosphorylation of S6PR, a downstream effector in the mTOR pathway, by AMPK; promotion of PR expression in opposition to IGF-2; and enhancement of the antitumor
123
Indian J Gynecol Oncolog
effects of MPA in combination therapy. These effects suggest that clinical use of metformin as an anticancer agent is possible. However, almost all of the effects have only been shown in vitro, and many occur at a metformin concentration that is much higher than that normally used for type 2 diabetes. Therefore, side effects may be problematic in clinical use of metformin as an antitumor agent. So, metformin could be used in management [16–18].
Conclusion This case highlights the need for endometrial sampling in young women with anovulatory cycles so that hyperplasia can be diagnosed and treated before frank invasion. PCOS patients should have withdrawal bleeding regularly monthly but not exceeding 2 months. Progesterone conservative therapy is an alternative in women with a strong desire for fertility, who have been explained the risks and given fully informed consent. This case report highlights the fact that endometrial cancer may be very advanced at diagnosis. In such cases, fertility preservation attempts would not only fail, but there would be disease progression.
References 1. Fadhlaoui A, Hassouna JB, Khrouf M. Endometrial adenocarcinoma in a 27-years old women. Clin Med Insights Case Rep. 2010;3:31–9. 2. Shyamala G, Lavanya R, Prashanth A. An unusual case of endometrial cancer in a young lady. Int J Oncol. 2008;5:1. 3. Gupta M, Malik TR, Wani ML. Endomerial carcinoma in a 20 years old female: a rare presentation. J Clin Case Rep. 2012;2:9. 4. Duska LR, Garrett A, Rueda BR. Endometrial cancer in women 40 years old or younger. Gynecol Oncol. 2001;83:388–93. 5. Amant F, Moerman P, Neven P. Endometrial cancer. Lancet. 2005;366:491–505.
123
6. Crissman JD, Azoury RS, Barnes AE. Endometrial carcinoma in women 40 years of age or younger. Obstet Gynecol. 1981;57: 699–704. 7. Kim MK, Seong SJ, Lee TS. Treatment with medroxyprogesterone acetate plus levonorgestrel-releasing intrauterine system for early-stage endometrial cancer in young women: single-arm, prospective multicentre study: Korean gynaecologic oncology group study. Jpn J Clin Oncol. 2012;42:1215–8. 8. Choo V. WHO reassesses appropriate body- mass index for Asian population. Lancet. 2002;360:235. 9. Murphy LJ, Ghahary A. Uterine insulin-like growth factor-1: regulation of expression and its role in oestrogen-induced uterine proliferation. Endocr Rev. 1990;11:443–53. 10. Ota T, Yoshida M, Kimura M. Clinicopathologic study of uterine endometrial carcinoma in young women aged 40 years and younger. Int J Gynecol Cancer. 2005;15:657–62. 11. Ushijima K, Yahata H, Yoshikawa H, et al. Multicentre phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women. J Clin Oncol. 2007;25:2798–803. 12. Ramirez PT, Frumovitz M, Bodurka DC. Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review. Gynecol Oncol. 2004;95:133–8. 13. Popli K, Singhal G, Batta N. Endometrial carcinoma presenting as infertility in young woman. J Obstet Gynaecol India. 2005;55: 367–8. 14. Dursun P, Erkanli S, Gu¨zel AB. A Turkish gynecologic oncology group study of fertility-sparing treatment for early-stage endometrial cancer. Int J Gynaecol Obstet. 2012;119:270–3. 15. Kesterson JP, Fanning J. Fertility-sparing treatment of endometrial cancer: options, outcomes and pitfalls. J Gynecol Oncol. 2013;23:120–4. 16. Lu KH, Wu W, Dave B, Slomovitz BM, Buruke TW, Munsell MF, Broaddus RR, Walker CL. Loss of tuberous sclerosis complex-2 function and activation of mammalian target of rapamycin signaling in endometrial carcinoma. Clin Cancer Res. 2008;14:2543–50. doi:10.1158/1078-0432.CCR-07-0321. 17. Cantrell LA, Zhou C, Mendivil A, Malloy KM, Gehrig PA, BaeJump VL. Metformin is a potent inhibitor of endometrial cancer cell proliferation: implications for a novel treatment strategy. Gynecol Oncol. 2010;116:92–8. doi:10.1016/j.ygyno.2009.09. 024. 18. Zhou C, Gehrig PA, Whang YE, Boggess JF. Rapamycin inhibits telomerase activity by decreasing the hTERT mRNA level in endometrial cancer cells. Mol Cancer Ther. 2003;2(8):789–95.
