Introduction

Many common gynaecologic conditions, such as endometriosis or endometrial polyps, are associated with infertility [1, APA association with follow-up

The patients were followed up for 6–174 (62.5 ± 45.3) months, and there was no recurrence among the patients who received conservative treatment. (1) Among 15 patients who desired to give birth, 3 with ovulation disorders gave up on attempts to conceive after assisted reproduction technology failed. However, 12 patients became pregnant after hysteroscopic resection of their uterine cavity-occupying lesions, including 7 with spontaneous conception and 5 with increased odds of a successful pregnancy by ovulation induction or assisted reproductive technology. (2) Seven patients with abnormal uterine bleeding and ovulatory dysfunction experienced abnormal menstruation. Among them, 3 received progestin treatment in the second half of the menstrual cycle, 3 underwent an insertion of the levonorgestrel-releasing intrauterine system, and 1 who was followed up for 52 months after hysteroscopic conservative surgery had post-hysteroscopy and endometrial biopsy pathology results that revealed mild atypical hyperplasia of the endometrium, leading to total laparoscopic hysterectomy and sal**ectomy.

Discussion

The incidence of APA is low, and the cause of the disease is currently unclear. It has been reported that the age of onset of APA is 18 to 81 years [11] and that APA occurs mostly in premenopausal women [14]. The patients in the current study were 27 to 74 years old (mean age, 45.1 ± 13.7 years) 32 (72.7%) of these patients were premenopausal, and 12 (27.3%) were postmenopausal. The most common clinical manifestation was abnormal uterine bleeding (35/44). The second most common characteristic of the patients in our group was the B-ultrasound finding of no obvious symptoms in terms of an intrauterine echo (8/44). Other clinical complications, including infertility (7/44), AUB-O (10/44) and diabetes (4/44), were found in this group. Notably, one patient received toremifene citrate for 5 years after breast cancer surgery. Seven patients had mild or moderate atypical hyperplasia, considering that the occurrence of APA is related to continuous oestrogen stimulation.

Patients with APA do not have typical specific clinical manifestations. The most common symptom is abnormal uterine bleeding [15]. Auxiliary tools such as gynaecological ultrasonography for pelvic examination can be performed in sexually active women; otherwise, transrectal ultrasonography is considered [16]. Ultrasound techniques are now routine methods for first-level screening in patients with suspected endouterine disease because of their low cost, reproducibility and absence of complications [17]. Transvaginal ultrasound can indicate heterogeneous endometrial thickening, abnormal intrauterine echoes, and blood flow changes without specificity. Therefore, it is necessary to differentiate APA from endometrial polyps, endometrial cancer (EC), adenomyosis, uterine adenofibroma and malignant mixed Mullerian tumours. APA can be combined with precancerous endometrial lesions and EC [18]. Additionally, hysteroscopy should be performed for patients with clear indications, such as abnormal uterine bleeding, abnormal intrauterine echo and infertility. 3D sonohysterography has been reported to be a good method of screening for hysteroscopic confirmation, especially in patients with suspected polyps, myoma, mucus accumulation and Mullerian anomalies [17]. During hysteroscopy, endometrial thickness, texture, vascular morphology, intrauterine lesions, size, location, texture and surface vascular characteristics of the lesions should be carefully evaluated. The reliability of hysteroscopy in diagnosing focal intrauterine lesions even in precancerous cases has been shown in many previous studies. Data and statistical analyses in our study showed that the combination of transvaginal ultrasound and hysteroscopy plays an important role in the identification of APA lesions.

Among the patients in this group, 40 had single lesions. The diameters of the lesions were 0.5 to 6 cm, with an average diameter of 2.83 ± 0.73 cm, which was consistent with the literature [19]. APA does not have a unique appearance under hysteroscopy, and it is often confused with endometrial polyps or submucosal fibroids. However, the diameters of APAs are larger than 1 cm in most cases, with the lesion surface consisting of abundant and thick blood vessels. Therefore, during surgery, uterine space-occupying lesions with diameters greater than 1 cm should be completely resected according to the four-step diagnosis and treatment method used in this study. Additionally, corresponding biopsies of the endometrium and superficial muscular layer at the base and its surrounding area should be performed. It is indispensable to follow-up the pathological diagnosis to decrease the possibility of a misdiagnosis.

Wong et al. found that progesterone may have a protective effect in APA patients during pregnancy [20]. Chen et al. demonstrated that APA patients who desired to give birth and were treated with progestin had no recurrence after undergoing hysteroscopic resection of the lesion [21]. Zhang et al. [22] revealed that the four-step diagnosis and treatment method is the most effective treatment for APA patients, as it completely reduces the recurrence rate. However, other research has indicated that the recurrence rate of APA in patients ranges from 28.9% to 35.1% [14, 18, 23], as deeper invasion into the uterine muscle is easily induced. A multicentre study revealed that the malignant transformation rate of APA is up to 0.8%, which is much higher than that of endometrial polyps [24].

Therefore, APA treatments can be individualized according to age, fertility requirements and postoperative pathological diagnosis. Total hysterectomy is recommended for menopausal or perimenopausal patients with APA-H. Additionally, in determining precise treatments for patients with APA-L, physicians need to consider the patient’s age and desire to become pregnant or to preserve the uterus. High-efficiency progesterone therapy is recommended for patients of childbearing age with APA-H. Moreover, patients of childbearing age with APA-L should undergo regular follow-up. In this study, patients with APA-H or APA-L combined with atypical hyperplasia of the endometrium were treated with high-efficiency progesterone. Patients with APA-L were treated with progestin in the second half of the menstrual cycle and with short-acting oral contraceptives and then followed up regularly without medication so that there would be no recurrence in this group. Regular postoperative follow-up measures were performed for APA. Patients with APA-H or atypical hyperplasia of the endometrium tend to undergo uterine preservation or give birth, so this group should receive regular and close follow-up. Hysteroscopy and endometrial biopsy are the basis of treatment schemes and decrease the misdiagnosis rate of endometrial diseases. A recent metanalysis indicated that the best treatment for APA is hysteroscopy. Medications, in particular progestogens, are not the first-line treatment but could prevent APA recurrence [5].

Forty-four patients were confirmed to have no recurrence by regular hysteroscopy and endometrial biopsy during follow-up. There are many reasons for this outcome. First, complete resection of the lesion according to the principles of the four-step diagnosis and treatment method is the main treatment for APA patients, as this reduces the rate of misdiagnosis and provides an effective foundation for clinical treatments. Second, follow-up is of great significance for patients with conservative treatments. Transvaginal ultrasound, hysteroscopy and endometrial biopsy were combined during follow-up to avoid false negatives and improve the accuracy of endometrial biopsy. One patient in this group was found to have mild atypical hyperplasia of the endometrium by hysteroscopy and endometrial biopsy during follow-up. Surgery was performed in this patient to avoid malignant transformation of the endometrium. Finally, continuous stimulation with oestrogen and a lack of progesterone are the main pathological mechanisms of APA. Therefore, a levonorgestrel-releasing intrauterine device is the first choice for the treatment of APA patients with abnormal uterine bleeding and ovulatory dysfunction. In addition, these patients need long-term clinical management.

The differential diagnosis includes benign endometrial polyps, adenofibroma, adenosarcoma, complex atypical endometrial hyperplasia (CAH), malignant endometrial mixed tumour (MMMT) and EC [25]. In some patients, it is difficult to distinguish APA from cervical polyps when the lesions protrude from the cervix into the vagina. APA occurs in young, nulliparous and premenopausal women, and the sectioned surface is solid, polypoid, firm, rubbery or lobulated, whereas adenofibroma, adenosarcoma, MMMT and EC typically occur in postmenopausal women with large exophytic masses or endogenous infiltrative lesions. According to the literature, EC arising from adenomyosis is associated with significantly younger onset ages and better survival than other cases where adenomyosis coexists with EC. This distinctive behaviour between the two conditions may suggest that when EC arises from the adenomyotic microenvironment, the degenerated stromal cells could have a less aggressive phenotype and could be more susceptible to hormonal influence [26]. Vascular ultrasound is easy to perform and interpret and may improve the detection rate of EC in perimenopausal and postmenopausal women [27]. In contrast to the increased cellularity, cytological atypia and short interlacing fascicles of stroma in APA, typical endometrial polyps and adenomyomas comprise benign endometrial glands, myomatous stroma and a minor component of fibrous tissue. Squamous metaplasia occurs in more than 90% of patients with APA, while it is uncommon in those with other benign lesions, so squamous metaplasia is another useful marker for the differential diagnosis.

Two to 5 years after surgical treatment is the peak time of APA recurrence among patients [28, 29]. To avoid APA relapse, close follow-up should be conducted for 5 years. Hysteroscopy and endometrial biopsy should be performed within 3 to 6 months after treatment. If endometrial abnormalities are not diagnosed during two consecutive examinations and if the patient has fertility requirements, is of reproductive age and does not have any infertility factors, it is recommended that the patient actively attempt natural conception or conception by assisted reproductive technology. Therefore, the patient should be followed up by regular transvaginal ultrasound examinations to monitor changes in the endometrium. Moreover, once the patient develops abnormal uterine bleeding, an abnormal intrauterine echo and other symptoms, she needs to undergo both hysteroscopy and endometrial biopsy to obtain evidence of endometrial abnormalities. On the other hand, if precancerous endometrial lesions or EC are found during two consecutive examinations, the effective treatment plans should be further determined according to age, pathological diagnosis and fertility requirements.

However, there are some limitations in our study. This was a retrospective study. The sample size of patients was small, and conservative treatment was not uniform. A large sample size is required for observation and verification of conservative treatment and follow-up of APA patients.

Conclusions

For patients with intracavitary lesions > 1 cm, the hysteroscopic four-step diagnosis and treatment strategy and pathological diagnosis are the basis of clinical treatment. More than 30% of APA surface glands have complex structures characterized by branching and budding or other high-risk factors, such as endometrial hyperplasia, which are indications for hysterectomy. For patients who desire to become pregnant or preserve the uterus, hysteroscopy with complete excision of the lesions should be the preferred treatment. The patients should be treated individually and undergo close follow-up, and they should be followed up by regular hysteroscopy and endometrial biopsy.