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]. Patients in this group were 27 to 74 years old (mean age, 45.1±13.7 years), among whom 32 cases (72.7%) were premenopausal and 12 cases (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. It is worth noting that one patient received toremifene citrate after breast cancer surgery for 5 years. There were 7 cases with 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]. B-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, adenomyosis, uterine adenofibroma and malignant mixed Mullerian tumours. APA can be combined with endometrial precancerous lesions and endometrial cancer[16]. Therefore, hysteroscopy must be performed for patients with clear indications such as abnormal uterine bleeding, abnormal intrauterine echo and infertility. 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. We also found that hysteroscopy plays an important role in the identification of lesions of APA.
Among the patients in this group, 40 had single lesions. The diameters of the lesions were 0.5 to 6 cm, with the average diameter being 2.83±0.73 cm, which was consistent with the literature[17]. APA does not have a unique appearance under hysteroscopy, and it is often confused with endometrial polyps or submucosal fibroids. However, the diameter of APA is larger than 1 cm in most cases, with the 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. 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[18]. 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[19]. Zhang et al[20]. 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 rates of APA in patients range from 28.9–35.1%[14, 16, 21], 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[22].
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 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 applied against 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 indicate that the best treatment for APA is hysteroscopy, as you correctly mention. Medications in particular progestogens are not a treatment but eventually a prevention of recurrence of APA. The metanalysis clearly shows that progestogens are useless for this [23].
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. B-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 tumor (MMMT) and EC1 [24]. In some cases, it is also difficult to distinguish APA from cervical polyp 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 mass or endogenous infiltrative lesions. 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 of component of fibrous tissue. Squamous metaplasia occurs in more than 90% cases of APA while it is uncommon in other benign lesions, so, squamous metaplasia is another useful marker for the differential diagnosis.
It has been confirmed that 2 to 5 years after surgical treatment is the peak time of APA recurrence among patients[25, 26]. To avoid APA relapse, close follow-up should be conducted within 5 years. Hysteroscopy and endometrial biopsy were performed within 3 to 6 months after treatments. 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 B-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 endometrial cancer 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 still some limitations in our study. This is a retrospective study. The sample size of patients was small, and conservative treatment was not unified. A large sample size is required for observation and verification of conservative treatment and follow-up of APA patients.