Incidental finding of endometrial carcinoma in a first-trimester miscarriage mimicking molar pregnancy: a case report and review of literature

Endometrial cancer has become the most common gynecological cancer in developed countries. The life time risk of endometrial cancer is around 3% and the median age at diagnosis is 61 years [1]. 4.2% of all low-grade endometrial cancer cases occur in women under the age of 40 years and the incidence of endometrial cancer in this age group has increased most significantly [2]. These patients usually present with abnormal uterine bleeding [3] with or without risk factors such as family history, obesity, polycystic ovarian syndrome, diabetes mellites, early menarche, late menopause, exogenous estrogen exposure, use of estrogen receptor modulator such as tamoxifen [4]. Progesterone is considered as a protective factor against endometrial cancer [5]. As a result, endometrial cancer is very rare during pregnancy when progesterone level is elevated. There are 34 cases reported to date (Table 1), 30 of which were diagnosed during first trimester when patients had a miscarriage or termination of pregnancy (Table 1). Endometrial cancer was also diagnosed at advanced gestation or during the postpartum period in a few case reports [7] (Table 1). The majority of patients underwent surgical treatment and recovered well after. In this case report, we present a patient with a suspected molar pregnancy who underwent evacuation of uterus. The histology showed endometrial carcinoma. She subsequently underwent staging scans and definitive surgery. She remained well post-surgery at 21-months review.

A 39-year-old gravida 3 para 1 lady presented in December 2022 for per vaginal spotting in pregnancy. She denied any abdominal pain. She was 5 weeks and 3 days amenorrheic. Prior to pregnancy, she reported regular menses every 3 weeks. She had a body mass index of 17.6 kg/m². The patient had one previous full-term vaginal delivery in 2013 and one miscarriage. Her past medical history included tuberculosis which was treated in 2018 and supraventricular tachycardia since 2010 with infrequent recurrent episodes.

Her serum beta-HCG was 14,634 IU/L and ultrasound pelvis showed an empty uterus. The endometrial thickness was 13 mm. There were echogenic materials 2.5 × 1.4 × 0.9 cm within the cavity with no significant vascularity (Fig. 1A). Beta-HCG trending was performed 48 h later and showed a suboptimal rise to 22,546 IU/L (54% rise). A follow-up ultrasound showed multiple cystic spaces in the endometrial cavity, with some cystic spaces showing hypervascularity (Fig. 1B and C). These findings raised the question of a possible molar pregnancy.

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The patient underwent an evacuation of uterus using suction vacurette followed by gentle curettage under ultrasound guidance. The definitive histopathological exam confirmed product of conception (Fig. 2A) and also showed focal well-differentiated endometrioid adenocarcinoma (Fig. 2C) with background of endometrial hyperplasia with and without atypia (Fig. 2B). Staging MRI pelvis and CT chest and abdomen were performed which showed 1.5 × 0.7 × 0.7 cm lesion confined to the lower endometrial cavity (Fig. 3A and B) with no loco-regional involvement. Options of definitive surgery versus fertility sparing management were discussed with patient. The patient opted for definitive surgery as she had completed her family and was not keen for future fertility. The case was discussed at a multidisciplinary tumor board meeting and the board recommended to proceed with definitive surgery as patient was not keen for fertility preservation. She underwent total laparoscopic hysterectomy (TLH), bilateral salpingectomy and bilateral sentinel lymph node (SLN) biopsy with ovarian conservation. She recovered well and was discharged on post-operative day 2. The final histology showed no evidence of residual adenocarcinoma. There was a focus of complex hyperplasia without atypia and a focus of complex atypical hyperplasia. Immunological staining reveled positive staining for ER and wild type P53. Peritoneal washing was negative and lymph nodes were not involved. Ancillary studies were performed on the original specimen from dilatation and curettage as endometrial carcinoma was absent on the final hysterectomy specimen. Immunohistochemistry for DNA mismatch repair protein returned normal and there was no microsatellite instability. The case was discussed at the multidisciplinary tumor board and was staged as stage 1 A grade 1 endometrioid adenocarcinoma of the uterus. Patient remained disease-free at 21-months follow-up.

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Our case is the first case reported so far of endometrial cancer mimicking a molar pregnancy. The ultrasound findings of cystic spaces and thickened endometrium can be contributed by both endometrial hyperplasia or malignancy as well as molar pregnancy. Moreover, the patient did not have the classical risk factors of endometrial cancer as she had regular menses, was lean and without exogenous or unopposed estrogen exposure. As such, it is essential to have detailed histological examination and a high level of suspicion if the histology does not correlate to the clinical picture.

A review of the literature was shown in Table 1. There are 34 cases of endometrial cancer in pregnancy reported so far with majority detected in first trimester after a miscarriage. Majority are low grade adenocarcinoma, with one reporting high grade clear cell carcinoma [10] and one adenosquamous carcinoma [6, 8]. Almost all patients were diagnosed with stage 1 disease with one patient diagnosed at stage IVB [11]. Majority of the patients underwent definitive surgery including a total hysterectomy and bilateral salpingo-oophorectomy (BSO). 5 patients had pelvic lymph node dissection (PLND) as well. A few patients decided for expectant management or hormonal treatment with repeat endometrial biopsies. The three cases with clear cell carcinoma, adenosquamous carcinoma and stage IVB adenocarcinoma respectively, did not survive the surveillance period. All patient with early-stage low grade adenocarcinoma remained disease free during the surveillance period and two had successful pregnancies and deliveries subsequently. Interestingly, although some patients had risk factors such as obesity, anovulatory cycles and diabetes, most of the patients including our patient had no identifiable risk factors. This raises the question on the pathophysiology of developing endometrial cancer during pregnancy.

Pregnancy is considered as a protective factor against endometrial cancer and ovarian cancer. The mechanisms leading to the protection include both endocrine and non-endocrine factors [5]. The lack of ovulation and pregnancy shift the hormonal balance to decreased estrogen levels and increased progesterone levels. Estrogen promotes growth of all endometrial cell types while progesterone promotes terminal differentiation of epithelium, induces apoptosis and prevents estrogen-induced proliferation [12, 13]. Therefore, progesterone-dominant pregnancy state leads to reduced mitotic activity and reduced risk of malignant transformation [14]. Fetal antigen hypothesis offers an explanation from a non-endocrine aspect. Fetal/placental cells release certain antigens into maternal circulation during pregnancy, which share some similarities to cancer cells. These antigens are believed to stimulate the maternal immune system to produce protection or natural immunity against tumors expressing the same antigens [15, 16]. There is also an interesting similarity between the placenta and tumors. Trophoblasts migrate away from the basement membrane, lose their polarized structures, penetrate the endometrium and remodel the maternal uterine spiral arteries without being detected by the maternal immune system. Although it is highly invasive like tumors, growth of the human placenta is strictly controlled both spatially and temporally [17]. The underlying mechanism remains to be elucidated with one possibility involving extracellular vesicles (EVs) [17] It is possible that the fetal antigens carried by placental EVs produce the lasting cross-reactive anti-cancer cell antibody responses.

Despite the protective effect of pregnancy against endometrial cancer, some patients did develop endometrial cancer during pregnancy. The underlying pathogenesis is complex and remains to be elucidated. The concept of progesterone unresponsiveness was described decades ago that certain part of the endometrium may not be responsive to progesterone and these progesterone refractory areas may become malignant over time [18]. A similar theory described by Novak and Matzloff in 1924 introduced the idea of “unripe endometrium” which were progesterone-unresponsive [19]. The portion of the endometrium which becomes neoplastic in pregnancy may be sensitive to estrogen but unresponsive to progesterone [20]. Progesterone unresponsiveness may occur in patients with no risk factors such as obesity and anovulation. More research is required to better delineate the pathophysiology of endometrial malignancy during pregnancy.

Assessment of the endometrial gland architecture and cytological details in a gravid uterus is often difficult due to pregnancy related changes. However, in our case, the areas concerned in the curettings showed atypical glands with confluent growth pattern and back-to-back gland arrangement allowing the pathologist to make a confident diagnosis.

In conclusion, our case report and review of the literature highlights the importance of careful histological examination in miscarriages even in women without any risk factors to exclude malignancy. Once detected and managed appropriately, majority of the cases will have excellent prognosis. More research is required to elucidate the mechanism underlying the development of endometrial cancer during pregnancy.