Preservation of fertility in patients with uterine didelphus and endometrial carcinoma: a case report | BMC Women’s Health

The parenchyma of the female reproductive system develops from the epithelium of the Mullerian duct and the urogenital sinus [5]. Muller’s duct is derived from the intermediate mesoderm and composed of epithelial and mesenchymal cells [1]. The development of Muller’s canals includes specification, invagination and elongation. Around the 8th week of gestation, the terminal ends of the Mullerian ducts come together. A median epithelial septum temporarily separates the lumen of two adjacent Mullerian ducts. In the 9th week, the median septum disappears, largely leading to the formation of the median uterovaginal duct. At around 12 weeks gestation, the disappearance of the basement membranes creates the uterus. At around 14-15 weeks, gland formation in the uterine body and cervix initially appears. The primary glands are located far from the uterine fundus, which proves that the first glands to form may be cervical glands. The uterine and cervical glands that are initially lined with a simple columnar epithelium are elongated and branched into the stroma at 20 weeks [6, 7]. Based on embryological observations, it can be assumed that both uterine cavities of the double uterus have the same risk of pathological changes.

We reviewed articles published on uterus didelphys combining endometrial cancer in PubMed from 1990 to 2020 [8,9,10,11,12,13,14,15,16,17,18,19,20,21,22]. There are 15 cases included, the age of onset ranged from 33 to 75 years. Among them, 4 cases [11, 12, 15, 16] were under 45 years old. Only 1 case had finished childbearing before the operation [12], 3 cases had a multistage operation, and only 1 case had a reserved bilateral appendix [11]. Many guidelines and experts have reached consensus on fertility preservation treatment for endometrial cancer at home and abroad. There is no discussion on the preservation of fertility function in young patients with uterine didelphysis and endometrial carcinoma due to the rare occurrence.

In this case, an infertile woman with didelphys uterus was diagnosed with endometrial cancer in the left uterine cavity at the age of 28. The patient’s endometrium did not reverse after conventional high-efficacy progesterone treatment which resulted in the removal of the left uterus. According to embryological observations, the uterus didelphys is due to the failure of the fusion of Muller’s ducts to form the uterus. Whether to keep the uterus contralateral deserves more discussion and attention.

Looking at the previous 15 cases of double uterine malformation with endometrial cancer, we concluded that 7 cases (7/15) occurred in the right uterus with cancer stage Ia-II and differentiation types of G1-G3. Among the 7 cases, only 1 case was associated with atypical hyperplasia of the left endometrium. 4 cases (4/15) occurred in the left uterus with cancer stage Ia-IIIc and type of differentiation from G1 to G3, 1 in 4 cases was associated with atypical hyperplasia of the right endometrium. 4 cases (4/15) occurred in the bilateral uterus with 1 case in stage IA (type of differentiation G1), 1 case in stage II (type of differentiation G2), 1 case in stage IIIA (type of differentiation G1) and 1 case in stage IV (type of differentiation G3).

From a limited data perspective, most patients (11/15) with didelphys uterus had endometrial cancer on one side of the uterus, two cases had atypical endometrial hyperplasia on the uterus contralateral. Atypical endometrial hyperplasia is the precancerous lesion of adenocarcinoma of the endometrium. 29% of complex atypical hyperplasias without treatment will develop into cancer [23]. Advanced endometrial carcinoma was more common in bilateral uterus, only one case of advanced endometrial cancer occurred in left uterine cavity with differentiation type G3 [14].

Returning to our case, the patients were diagnosed as stage IA of moderately differentiated endometrial carcinoma in the left uterus. No cancer or precancerous lesion was detected in the contralateral uterus based on the results of the previous hysteroscopy. Only the affected side of the uterus and the appendix were removed during the surgery. It is certain that the patient should revisit the transvaginal ultrasound, MRI and hysteroscopy of the uterus reserved in the follow-up treatment.

In order to ensure the safety of preserving the fertility of this patient, we wish to search for prognostic biomarkers to predict progression among normal endometrium, atypical endometrial hyperplasia and cancer of the endometrium. PTEN is the most commonly studied biomarker in endometrial cancer. However, PTEN is expressed normally in proliferative endometrial glands and stroma, but decreasingly expressed in the secretion cycle, which can result in variable staining. [24]Recently, scientists have become more interested in PAX2 which is less frequently lost in the normal proliferative and secretory endometrium than PTEN [25].

PAX2 can be expressed by immunohistochemistry inside the nucleus of normal endometrial glandular cells. In 2018, Emma saw a gradual decrease in PAX2 expression from proliferative endometrium to endometrial intraepithelial neoplasia (EIN) to endometrioid carcinoma of the endometrium (EEC) which is also seen in previous studies. It is recognized that it can take 30 to 40 years between a normal endometrium and endometrial cancer. Despite the small sample size, this study is very popular since its long follow-up of these patients. In Emma’s study, they presented a method and cutoff with a PAX2 expression H-score of 75. EIN lesions with a PAX2 expression H-score less than or equal to 75 (high risk ) had significantly lower progression-free survival than those with an H-score greater than 75 (low risk). In addition, more EIN patients with high-risk PAX2 showed progression (73%; 8/11) compared to low-risk patients (8%; 2/25) [26].

In this study, our patient underwent 4 hysteroscopic surgeries at Peking University First Hospital, of which the right uterine endometrium was examined 3 times. To better understand the risk of pathological development on the reserved side of the uterus, our pathologist examined PTEN and PAX2 on three pathological sections of the patient’s right endometrium. The results showed that the right endometrium obtained from three hysteroscopic operations showed strong positive expression of PTEN and PAX2. This may indicate to clinicians that the possibility of endometrial damage on the right side is not significant from start to last operation. In the follow-up process, PTEN and PAX2 immunohistochemical analysis of the endometrium can be performed. If possible, the PAX2 H score can be used to better complement the monitoring of endometrial lesions, in order to adjust the treatment plan over time.

Endometrial cancer occurring in patients with a didelphyseal uterus is quite rare in published articles, especially in young patients in need of childbearing. In this case report, the patient had the unilateral uterus removed with endometrial cancer due to the lack of response to the drugs. According to the IHC analysis of the uterine endometrium on the reserved side, there is no pathological progression until the last hysteroscopic surgery. However, with less evidence, it takes more follow-up later to trace the patient’s tumor and fertility results. In order to shorten the time needed for fertility, the patient chose assisted reproduction technology in our hospital. During the ovarian hyperstimulation process and after obtaining the fertility result, we will continue to monitor the patient’s transvaginal ultrasound, MRI and hysteroscopy. The application of the PAX2 H score will be considered to assess the risk of reserving the contralateral uterus.


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