Sparing fertility in young patients with endometrial cancer

doi:10.1016/j.ygyno.2008.07.056

Gynecologic Oncology

Volume 111, Issue 2, Supplement, November 2008, Pages S101-S104

https://doi.org/10.1016/j.ygyno.2008.07.056 Get rights and content

Abstract

The objective of this review is to recognize the characteristics of endometrial adenocarcinoma in young patients and to evaluate the published experience with conservative approach in patients with endometrial adenocarcinoma.

We searched MEDLINE articles describing patients with endometrial adenocarcinoma who were treated with hormonal therapy. The search included articles published between January 1966 and January 2007.

Endometrial carcinoma in patients under 45 years of age is an unusual condition that shows a more favorable pattern than in older patients. One hundred thirty three patients were found in the search. The average duration of hormonal therapy was approximately 6 months. The average response time was 12 weeks. Seventy six percent of patients treated with hormonal therapy had a complete response and the other 24% never responded to treatment. Of those who initially responded, 66% didn't show recurrence of disease. The other 34% had a relapse. There have been published 4 deaths of patients conservatively managed.

A conservative approach in these patients can offer reasonable oncological security and the opportunity of fulfilling their maternal desires in selected cases. However, consideration should be taken regarding the potential adverse outcomes that have been recently published in the literature.

Introduction

Endometrial cancer is the most common gynecological malignancy [1]. The 5-year survival rate in Spain is almost 85% for all stages [2]. This malignancy does not often appear in young patients, accounting for probably less than 5% of all cases [3]. However, the issue of sparing fertility emerges as a challenge in some cases, especially in patients who have been diagnosed at a very early stage and who have not already had children.

For decades, the initial therapeutic approach to an early-stage endometrial cancer has been a staging laparotomy, including a total hysterectomy and bilateral salpingo-oophorectomy, pelvic washings, and lymphadenectomy (pelvic and para-aortic), depending on findings.

In some exceptional cases, surgery is avoided due to a poor medical condition [4]. As for the conservative management of early endometrial cancer in young patients, worldwide experience and data are lacking [5], [6].

The objectives of this article include outlining the characteristics of endometrial cancer in young patients, assessing the feasibility of a fertility-sparing approach in select cases of young women with endometrial cancer, and summarizing the reproductive outcomes in these patients.

Section snippets

Endometrial cancer in young women

In 1999, Ibañez et al., on behalf of the Section of Gynecologic Oncologists of SEGO (Spanish Society of Gynecologists), conducted a national survey studying endometrial cancer in Spain [2]. The study consisted of 1054 patients from 70 Spanish institutions diagnosed with invasive endometrial cancer in 1993. The average age of patients in the study group was 64 years. Of these patients, only 11% were premenopausal. Only 2.3% of these patients were under 45 years of age. These data were consistent

Patient selection for sparing fertility

According to the international literature, it appears that the most important factor is selecting the “appropriate” patient for conservative treatment. The first criterion for conservative treatment is an accurate diagnosis of a well-differentiated endometrial carcinoma by an expert pathologist (Fig. 1) [7].

The following are other criteria that should be adhered to when selecting a patient for conservative treatment:

A well-differentiated carcinoma
The tumor does not deeply invade the myometrium,

Medical treatment as a conservative approach

Taking advantage of this tumor's hormonal sensitivity, most authors have used hormone-based treatments as a conservative approach [8]. Exceptionally, some authors have proposed a local surgical excision by hysteroscopy or repeated curettage as well as progesterone IUD as local treatment. The literature contains case reports reporting initial experiences with hysteroscopic resections of localized endometrial carcinomas before starting hormonal therapy [9]. Interestingly, there have been

Reproductive outcome

Among these young women who underwent conservative treatment for endometrial cancer, 53 achieved pregnancy. Eighty women were nulliparous. In 96% of these patients, the tumor was well differentiated. There were 35 pregnancies as a result of assisted reproductive techniques. At least 70 of these patients underwent a hysterectomy after completing gestation [18], [19], [20], [21]. We also found three cases of residual carcinoma in the surgical specimen 6, 8, and 22 months after delivery. In

Follow-up of these patients

We still do not have enough experience to establish a reliable follow-up protocol for these patients. It would be wise to take advantage of the published experience by doing a first biopsy after 12 weeks of hormonal treatment, considering that this period is the average response time. In the case of a positive biopsy, we could offer our patients the option to maintain treatment another 12 weeks. A positive biopsy, however, is an indication that a patient will not respond. We would take another

Conclusions

•
Endometrial carcinoma in young patients is not common
•
A conservative management is a therapeutic challenge
•
Selecting patients through meticulous pathologic and imaging studies is crucial for the oncological outcome of these patients
•
Approximately 50% of well-differentiated tumors show a complete response to hormonal treatment
•
On the other hand, 25% of patients will suffer a relapse after a temporary response
•
Once reproductive desires have been fulfilled, a standard surgical treatment must be

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Resultados de la Encuesta Nacional sobre Carcinoma de Endometrio Diagnosticado en 1993

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Endometrial hyperplasia is primarily caused by estrogen excess. Understanding the clinical situations in which excess unopposed estrogen may exist helps the clinician better predict which women are at risk for endometrial hyperplasia and cancer. In addition, such knowledge provides windows of opportunity for implementation of prevention strategies. The obesity epidemic has certainly contributed to the rising incidence of endometrial cancer in the United States and other developed countries. Delays in childbearing in combination with a younger age of diagnosis has also led to more women with pre-malignant or malignant endometrial lesions wishing to preserve fertility. Treatment of gynecological cancers may have a significant impact on women and their quality of life due to early menopause. In addition, many female cancers contain estrogen receptors. The question of the role of hormone replacement therapy in developing or stimulating cancers and its use for cancer survivors remains confusing, conflicting, and controversial. Understanding menopause and the benefits and risk of menopausal hormone use will help clinicians work with oncologists to respond to women’s menopausal concerns and improve quality of life for women at risk of or having survived cancer.
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To determine whether progestin type or number of dilation and curettage procedures (D&Cs) were associated with intrauterine synechiae (IS) or pregnancy outcomes in patients conservatively treated for endometrial intraepithelial neoplasia (EIN) or endometrial cancer (EC).
We evaluated patients conservatively treated for EIN or EC from 2000 to 2017 at an academic center. IS were identified hysteroscopically. We calculated proportions for categorical variables and tested associations between D&C number, progestin, and pregnancy outcomes using Pearson chi-squared and Fisher’s exact tests. A post-hoc power analysis indicated sufficient power to detect livebirth.
We analyzed 54 patients, 15 with EIN (28 %) and 39 with EC (72 %), with a mean age of 34 ± 1.2 years. Progestin treatment types included megestrol acetate (MA) (n = 24), MA with levonorgestrel intrauterine device (LngIUD) (n = 10), MA followed by LngIUD (n = 3), and LngIUD alone (n = 6). Mean number of D&Cs was 3.9 ± 0.9. Overall, 53 subjects underwent hysteroscopy; 10 (19 %) had IS. When D&Cs were grouped into 0−2, 3−4 and ≥5, each increase in D&C group had a 2.9 higher odds of IS (OR: 2.91, p = 0.04, CI: 1.05–10.02). LngIUD was associated with a nonsignificant 46 % decrease in the odds of IS (OR: 0.54, p = 0.66, CI: 0.08–2.87). Twenty-two women attempted pregnancy; 14 women achieved a total of 20 pregnancies and 9 women had total of 15 livebirths (41 % livebirth rate). The number of D&Cs and progestin treatment type were not associated with pregnancy outcomes.
Among 54 patients conservatively treated for EC/EIN, nearly 20 % developed IS. However, hysteroscopic and/or fertility treatments may improve pregnancy outcomes.
CNR1 may reverse progesterone-resistance of endometrial cancer through the ERK pathway
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Endocrine therapy is a promising treatment for endometrial cancer (EC) that preserves fertility, however, progesterone-resistance is currently the major challenges. The Cancer Genome Atlas (TCGA) database analysis showed that CNR1 was closely have a negative correlation with overall survival (OS) and relapse-free survival (RFS) in endometrial cancer. To explore the role of CNR1 in progesterone resistance and possible molecular regulation mechanism, we established stable progesterone-resistant cell lines (IshikawaPR) via progesterone tolerance of ordinary cancer cells (Ishikawa). The difference of CNR1 level in two cell lines was assessed by MTT, RT-PCR, Western blot, immunofluorescence. Then, lentiviruses constructed CNR1-knockdown with GV248 as the tool vector were used to transfect IshikwaPR cells, and the changes of biological behavior and progesterone sensitivity was verified respectively through plate cloning experiment, EdU assay, flow cytometry cycle analysis, transwell, Scratch test, etc. We founded after CNR1 was knocked down, the proliferative activity and ability to migrate of IshikawaPR cells decreased, progesterone-response sensitivity could be improved. Moreover, knockdown of CNR1 can also down-regulate ERK and NFκ B expression and activation. Furthermore, subcutaneous xenograft in nude mice was tested similarly in vivo.
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We aimed to investigate the effectiveness of continuing medical therapy in patients who did not achieve complete response (CR) despite 9 months of progestin treatment. We also sought to determine the prognostic factors associated with achieving CR among these patients.
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Sparing fertility in young patients with endometrial cancer

Abstract

Introduction

Section snippets

Endometrial cancer in young women

Patient selection for sparing fertility

Medical treatment as a conservative approach

Reproductive outcome

Follow-up of these patients

Conclusions

Obstet. Gynecol.

Gynecol. Oncol.

Am. J. Obstet. Gynecol.

Gynecol. Oncol.

Gynecol. Oncol.

Gynecol. Oncol.

Fertil. Steril.

Fertil. Steril.

Gynecol. Oncol.

Resultados de la Encuesta Nacional sobre Carcinoma de Endometrio Diagnosticado en 1993