Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2016 Mar 7.
Published in final edited form as: J Reprod Med. 2008 Nov;53(11):869–873.

Absence of progesterone receptors in a failed case of fertility-sparing treatment in early endometrial cancer: A case report

Anna V Hoekstra 1, J Julie Kim 2, Pacita Keh 3, Julian C Schink 1
PMCID: PMC4780569  NIHMSID: NIHMS282703  PMID: 19097521

Abstract

Background

Fertility-sparing treatment may be offered as an alternative to standard surgical management of early stage well-differentiated endometrial cancer in young women. Immunostaining for progesterone receptor (PR) status does not currently have a role in the standard workup before recommendations are made to patients.

Case

We describe the case of a 29-year-old woman on long-term oral contraceptive pills diagnosed with early stage well-differentiated endometrial cancer. She failed progestin therapy and her tumor was later found to be PR negative.

Conclusion

Tumor negativity for PR may represent a significant risk factor for the development of endometrial cancer, especially in young women on combination hormonal contraception. Consideration should be given to PR immunostaining prior to recommending fertility-sparing medical treatment due to the possibility of poor response rate of these tumors to progestins.

Keywords: Endometrial cancer, progesterone receptors, fertility-sparing treatment, progestins

Introduction

Endometrial cancer is the most commonly diagnosed gynecological malignancy in this country, with 41,200 new cases diagnosed in 2006. Most endometrial cancer occurs in postmenopausal women, however, approximately 5% of women with the disease are diagnosed under the age of 40 and 20–25% are diagnosed before menopause1. Options for conservative management have been developed for the preservation of fertility in young patients and for patients who are poor surgical candidates.

Standard treatment recommendations for endometrial cancer include total hysterectomy, bilateral salpingo-oophorectomy, and pelvic and paraaortic lymphadenectomy based on risk factors. However, conservative treatment with progestins in young patients with early stage well-differentiated tumors has been shown in multiple series to have a 60–75% response rate2–6.

Most well-differentiated tumors are estrogen receptor (ER) and progesterone receptor (PR) positive (ER-63%, PR-68%), which are used as markers of favorable prognosis. However, tumors with less than 10% immunostaining of PR (PR negative), in contrast to those with greater than 10% immunostaining (PR positive), respond very poorly to progestin therapy, with a response rate of 12–19%2–6.

We present the case of a 29-year-old woman with no risk factors for endometrial cancer who developed this malignancy while on prolonged oral contraceptives. She subsequently failed conservative treatment with megestrol. Receptor analysis found her tumor to be negative for PR.

Case Report

A 29-year-old G0 on long-term oral contraceptive pills presented with one episode of heavy bleeding in April of 2005. Physical exam revealed a body mass index of 26.3 and a completely normal abdominal and pelvic exam. She underwent transvaginal ultrasound which showed a polyp, and this was confirmed by sonohystogram. She underwent dilation and curettage, and pathology showed complex hyperplasia with focal atypia, and changes ranging from complex hyperplasia with atypia to grade I endometrioid adenocarcinoma. She began megestrol 20mg twice daily, discontinued oral contraceptive pills, and was referred to the Division of Gynecologic Oncology.

She was extensively counseled regarding surgical and conservative treatment options. Due to her young age and lack of commonly identified risk factors, she was referred for genetic counseling. She underwent counseling, a discussion of her family history, and subsequent testing for DNA mismatch repair gene mutations associated with hereditary nonpolyposis colorectal cancer (HNPCC). Her biopsy specimen was not sufficient to test for microsatellite instability. The results of her serum genetic testing were negative. She was interested in preserving fertility and elected to continue conservative management with megestrol, which was increased to 80mg twice daily for three months. She tolerated treatment well, reporting only minimal hot flashes and fatigue. Repeat sampling 3 months later revealed focal complex hyperplasia with atypia, but no endometrial adenocarcinoma. After 6 months of treatment she reported breakthrough bleeding lasting 1–2 days, and her endometrial biopsy revealed grade 1 endometrioid adenocarcinoma. Immunostaining at that time revealed 100% of tumor nuclei staining strongly for ER, 0% of tumor nuclei staining for PR and p53. Conservative management with megestrol was discontinued.

She was counseled at that time on continued conservative therapy, adding a GnRH agonist and an aromatase inhibitor to megestrol, versus definitive surgical treatment with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and possible pelvic and paraaortic lymphadenectomy. Imaging with ultrasound showed a 1.4 × 1cm tumor mass in the uterus and MRI of the pelvis showed the absence of disease in the myometrium and outside the uterus.

She elected definitive surgical treatment, and underwent total abdominal hysterectomy, pelvic and paraaortic lymphadenectomies, bilateral uterosacral ligament biopsies, right ovarian biopsies, and washings. Intraoperative findings revealed a small normal-appearing uterus and diffuse endometriosis implants on the uterosacral ligaments and ovaries with no bowel or abdominal abnormal findings. Final pathology showed foci of well differentiated endometrioid adenocarcinoma arising in a background of complex atypical hyperplasia confined to the endometrium. Endometriosis was found in the uterosacral ligaments and ovarian surface. Lymph nodes and washings were negative and she was surgically staged as Ia, grade 1 endometrial cancer. Hormone receptor and p53 immunostaining on the uterine specimen revealed positive staining for ER, <5% weakly positive staining for PR (compared to the strong staining of the control) and complete absence of p53 staining. PR immunostaining in the surrounding non-cancerous endometrium was positive (Figure 1). Her hospital course was uneventful and was discharged on postoperative day number 3. One year later she had no evidence of disease and was doing well.

Figure 1.

Figure 1

Open in a new tab

Progesterone receptor immunostaining of tumor (left), negative for PR staining, and normal endometrial gland (right), positive for PR staining (200x power).

Discussion

Conservative management with progestins was initially reviewed in the literature in 1985 as an alternative to surgical management as fertility-sparing surgery for young women diagnosed with early stage well-differentiated endometrioid cancer2,7. Since that time, multiple case reports and case series have supported this practice2–9. Current recommendations for workup prior to offering a patient of childbearing age conservative treatment include dilation and curettage for histologic diagnosis, as well as imaging with ultrasound or CT scan to evaluate the extent of disease. Treatment regimens include use of a progestin for 3 to 24 months, with endometrial sampling every 3 months to monitor for progression or persistence. The most commonly used progestin is medroxyprogesterone acetate. Patients with ER positive tumors have also been treated with aromatase inhibitors and GnRH agonists. Approximately 30% of women initially treated conservatively eventually undergo definitive surgical treatment due to lack of clinical response to progestins or recurrence after initial complete response to progestins.

The majority of patients (68%) with well-differentiated endometrioid endometrial cancer have positive immunostaining for uterine PR10. PR immunostaining has been suggested for use as a prognostic indicator and has been used to determine the extent of surgical staging, being triaged to either hysterectomy and bilateral salpingo-oophorectomy only or radical staging surgery. PR immunostaining has not previously been shown to have a role in the triage of patients to conservative versus surgical treatment, or in determining appropriate medical therapy.

The response rate with progestin treatment is decreased in PR negative tumors. Approximately 12–19% of women with PR negative tumors respond to progestins in contrast to 60–75% of women with PR positive tumors2–6. The response rate to progestins administered for recurrence after initially treated with progestins is estimated at 72%3. One series of 12 women undergoing fertility-sparing treatment with progestins reported only 1 patient who died of disease. ER/PR immunostaining in the 12 patients revealed the absence of PR in the one mortality in their series5. While it may be logical that PR negative tumors would have a poor response to treatment with progestins, the clinically observed decreased response rate supports the assertion that these tumors are generally progesterone-resistant. Patients with ER positive/PR negative tumors may instead benefit from conservative treatment with aromatase inhibitors or GnRH agonists.

Current recommendations for preoperative evaluation do not include ER/PR immunostaining of tissue retrieved from endometrial sampling. Dilation and curettage is the standard for preoperative evaluation from which to make therapeutic recommendations, as there is improved correlation between hysterectomy specimens and curettings when compared to tissue retrieved from endometrial biopsy (77% vs. 58%)3. If conservative management is being considered or advanced disease is suspected, imaging with ultrasound or CT scan is performed preoperatively as well. In a recent review of 81 patients with early stage, well-differentiated endometrial cancer undergoing fertility-sparing treatment by Ramirez et al, only 4 patients ever had hormone receptor immunostaining prior to treatment3. The poor response of PR negative tumors to progestins suggests consideration of PR immunostaining of curettings in the standard recommended workup for a patient who desires fertility-sparing treatment.

Investigation of tumor etiology in patients who lack the commonly identified risk factors often includes testing for HNPCC-related genetic mutations. HNPCC testing may be considered for patients such as the one presented here, regardless of the patient’s eligibility for the diagnosis based on the stringent Amsterdam II clinical criteria. Only 5–10% of cases of endometrial cancers are associated with HNPCC-related mutations, however the lifetime risk of endometrial cancer in patients affected by a mutation in DNA mismatch repair genes is estimated at 32–60%11. Increased risk for mutations in DNA mismatch repair genes may be detected by testing microsatellite instability in the tumor. If positive, the patient may undergo genetic counseling and serum genetic testing, which is 60% sensitive for the 2 most common mutations, MLH1 and MSH2. Five DNA mismatch repair genes have been identified (MSH6, PMS1, PMS2, MLH1 and MSH2), however 90% of mutations are attributable to MLH1 and MSH211,12. Therefore, laboratories test only for these two mutations in the absence of HNPCC-related research projects. The patient presented here not only had no commonly identified risk factors for the development of endometrial cancer, but underwent hormonal suppression of the endometrium for over 10 years in the form of combination oral contraceptive pills. The development of endometrial cancer in this hormonal milieu alone suggested benefit to both genetic testing for HNPCC-related gene mutations as well as hormone receptor immunostaining. This patient’s genetic testing was negative, which, in the context of no other family members testing positive for these gene mutations, is uninformative regarding the actual contribution of genetics to her disease. It is possible that the etiology of her cancer is genetic despite negative testing, but a hormonal etiology is likely.

Endometrial cancer is divided into two types by clinical behavior and etiology. Unopposed estrogen is implicated in type I tumors, while genetic mutations are implicated in type II tumors. Most young women with type I tumors have risk factors such as obesity, polycystic ovarian syndrome, infertility, chronic anovulation, and ovarian dysfunction. The patient presented here, however, had none of these risk factors. A low to absent level of uterine PR may be sufficient in young patients on oral contraceptive pills (OCPs) to create an environment of unopposed estrogen predisposing them to adenocarcinoma. Instead of protecting the endometrium, the OCPs may have actually led to the development of adenocarcinoma in this patient. In young women with no commonly identified risk factors for endometrial cancer, especially in the context of long-term hormonal endometrial suppression, immunostaining for PR is essential to determine the etiology of their tumor and prevent progression of their disease through inappropriate hormonal treatment.

This case highlights the value of PR immunostaining not only to determine the appropriate extent of surgical treatment, but to develop recommendations for fertility-sparing versus standard surgical treatment and which medical therapy to recommend. This case also suggests that low levels of PR, allowing unopposed estrogen stimulation to the uterus, represents a distinct risk factor for the development of type I endometrial cancer in women with no other risk factors. Especially in women with long-term combination oral contraceptive use, typically protective from the development of endometrial cancer, HNPCC genetic testing and hormone receptor testing contribute significantly to identification of the etiology and appropriate treatment options for their disease. For young women with early stage well-differentiated endometrial cancer being offered fertility-sparing treatment, consideration should be given to PR immunostaining of uterine curettings.

Synopsis.

Tumor negativity for progesterone receptors may represent a significant risk factor for the development of endometrial cancer, especially in young women on combination hormonal contraception.

References

  • 1.Di Saia P, Creasman W, editors. Clinical gynecologic oncology. St. Louis, MO: Mosby Inc; 2002. Adenocarcinoma of the uterus; pp. 289–350. [Google Scholar]
  • 2.Thornton J, Brown L, Wells M, Scott J. Primary treatment of endometrial cancer with progestogen alone. Lancet. 1985;2:207–8. doi: 10.1016/s0140-6736(85)91513-2. [DOI] [PubMed] [Google Scholar]
  • 3.Ramirez P, Frumovitz M, Bodurka D, Sun C, Levenback C. Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review. Gyn Onc. 2004;95:133–38. doi: 10.1016/j.ygyno.2004.06.045. [DOI] [PubMed] [Google Scholar]
  • 4.Randall T, Kurman R. Progestin treatment of atypical hyperplasia and well-differentiated carcinoma of endometrium in women under age 40. Obstet Gynecol. 1997;90:434–40. doi: 10.1016/s0029-7844(97)00297-4. [DOI] [PubMed] [Google Scholar]
  • 5.Ota T, Yoshida M, Kimura M, Kinoshita K. Clinicopathologic study of uterine endometrial carcinoma in young women aged 40 years and younger. Int J Gynecol Cancer. 2005;15:657–662. doi: 10.1111/j.1525-1438.2005.00129.x. [DOI] [PubMed] [Google Scholar]
  • 6.Erlich CE, Young PC, Stehman FB, Sutton GP, Alford WM. Steroid receptors and clinical outcome in patients with adenocarcinoma of the endometrium. Am J Obstet Gynecol. 1988;158:796–807. doi: 10.1016/0002-9378(88)90075-0. [DOI] [PubMed] [Google Scholar]
  • 7.Bokhman JV, Chepick OF, Volkova AT, Vishnevsky AS. Can primary endometrial carcinoma stage I be cured without surgery and radiation therapy? Gynecol Oncol. 1985;20:139–55. doi: 10.1016/0090-8258(85)90135-0. [DOI] [PubMed] [Google Scholar]
  • 8.Gotlieb WH, Beiner ME, Shalmon B, et al. Outcome of fertility-sparing treatment with progestins in young patients with endometrial cancer. Obstet Gynecol. 2003;102:718–25. doi: 10.1016/s0029-7844(03)00667-7. [DOI] [PubMed] [Google Scholar]
  • 9.Crissman J, Azoury R, Barnes A, Achellhas H. Endometrial carcinoma in women 40 years of age or younger. Obstet Gynecol. 1981;57:699–704. [PubMed] [Google Scholar]
  • 10.Bonfitto V, Andrade L. p53, estrogen and progesterone receptors in diagnostic curettage for endometrial adenocarcinoma and their correlation with morphologic data and disease stage at hysterectomy. Sao Paulo Med J. 2003;121:1–10. doi: 10.1590/S1516-31802003000400005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Renkonen-Sinisalo L, Butzow R, Leminen A, Lehtovirta P, Mecklin J, Jarvinen H. Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndrome. Int J Cancer. 2006;120:821–24. doi: 10.1002/ijc.22446. [DOI] [PubMed] [Google Scholar]
  • 12.Kaz A, Brentnall T. Genetic testing for colon cancer. Nature Clin Practice. 2006;3:670–79. doi: 10.1038/ncpgasthep0663. [DOI] [PubMed] [Google Scholar]

RESOURCES