3.1 Pathogenic characteristics. Polyp like intrauterine membrane endometriosis is different from the traditional type of peritoneal, ovary, and deep infiltrating endometriosis, at present, the PEM most cases reported in literatures in the rectum and sigmoid colon, followed by the ovaries, uterus serous and cervical and vaginal tract of department of gynaecology, individual in ureter, fallopian tubes, greater omentum and retroperitoneal region [3-6,7,9]. As shown in Table 1, ovarian PEM accounted for 4 of the 7 cases in this group, followed by uterine serosal and cervical PEM. PEM is characterized by multi-site and multi-focal lesions with different lesions in size, with the largest case increasing from 3cm to 20cm in 6 months [9], and small cysts in part of the section were honeycombed. In our cases, 3 cases were single lesions and 4 cases were multiple lesions. The size of the tumor ranged from 2.1cm to 11.7cm, but the size of the tumor had nothing to do with the duration of the disease. Parker [2] believed that PEM was common in elderly women, and 60% of the 24 PEM patients they observed were older than 50 years old (23-78 years old), with multifocal lesions, and most of the cases had a history of EMs. In addition, 13 international cases reported in the past 5 years, aged 20-62 (51.14±3.78) years old (as Table 4) [10-21], were summarized. Gunawardane DN reported a 50-year-old female had a hysterectomy and bilateral salpingo-oophorectomy for adenomyosis, uterine leiomyomas, ovarian and cervical endometriosis. Nine months later, a mass between the vagina and rectum was diagnosed the Pouch of Douglas PEM[22].But all of the 7 patients in our group were women of childbearing age, aged from 31 to 45 (38.00±1.72) years old. No such lesions were found in postmenopausal women, which may be due to the small sample size of the cases in this group or the difference in race. Some studies have shown that the average age of 10 cases with tumor pathomorphology similar to EMS is about 43.4 years old (29-58 years old), and the possible age of polyps with morphology similar to EMs tends to be postmenopausal, with an average age of 50.9 years old (42-74 years old) [23].
The clinical manifestations of PEM are related to the site and size of the disease, and the common manifestations are abnormal uterine bleeding, pelvic mass, and mass compression. Cervical and vaginal polypoid manifestations include irregular vaginal bleeding and contact bleeding in most cases, and there may be no symptoms in the pelvic and abdominal cavity, most of which are accompanied by adenomyosis and dysmenorrhea [6,8]. This is related to the fact that PEM belongs to a special type of EMs. In addition, the patient also had endometrial polyps, and the clinical manifestations of prolonged menstrual period of PEM may also be related to adenomyosis and endometrial polyps. Colin Jr performed intrauterine endometrial biopsy on 5 cases of PEM with pathomorphology similar to endometrial polyps, and the results found that 3 cases had endometrial polyps [23], suggesting that PEM was also closely related to endometrial polyps. In this group, there were 6 cases of severe pelvic adhesion, complete closure of the uterorectal fossa, and even frozen pelvis (Case NO. 6), which was another factor causing infertility. 4 out of 7 cases in this group were infertile, which also reflected that infertility was one of the clinical manifestations of EMs. Large PEM masses may present symptoms of compression at relevant sites, such as abdominal pain, nausea, vomiting, constipation, etc. The symptoms of urinary system [25] and digestive system [20] were mostly reported by related departments. In this group, 1 case of PEM invaded the ureter and resulted in left hydronephrosis (Case NO. 6).
3.2 Cause of disease. Endometriosis is a benign estrogen-dependent disease, and PEM belongs to a special type of EMS. Most of the case literature suggests that it is related to the use of sex hormones, such as tamoxifen, non-antagonistic estrogen or gonadotropin-releasing hormone [9,12,15,18]. Sex hormone drugs were used in 5 of the 13 cases reported in the last 5 years, as shown in Table 4. However, in this group of 7 cases, only 2 cases had a history of sex hormone use, and no correlation was suggested. One case had a history of mifepristone anti-progesterone use for 6 months, and one case had a history of drodrogesterone use for 10 days. Among the cases reported by Parker et al. [2], 45% were affected by exogenous or endogenous hormones, most of which were perimenopausal hormone replacement therapy, which is also the reason why the age of onset of the cases reported by Parker et al tended to be post-menopausal. Kaushal S reported a 27-year-old nulliparous woman who had no history of tamoxifen or oestrogen intake, but presented with large finger-like projections protruding from her vagina, and last was diagnosed multifocal PEM[3].
Syrcle et al. studied a 25-year-old vaginal PEM case and found that compared with normal vaginal tissue, the expression of ER-β in PEM polyp tissue was 10 times higher, while the expression of ER-α was 5 times lower. The expression of estrogen synthetase aromatase in polyps was 8 times higher, while the expression of 3β-hydroxysteroid dehydrogenase was 400 times higher. The cell type localization of PR in polyps was altered and stromal cell proliferation was increased. It is considered that vaginal PEM tissue may be caused by increased local estrogen production [26]. Combined with the pathogenesis of EMT [27], abnormal expression of local estrogen progesterone receptor could not be ruled out, and ER(+) and PR(+) were suggested by immunohistochemistry in most cases reported [6]. Incidence of 1 immunohistochemical also prompt the ER (+ +), PR (+ +), and most with ovulation dysfunction caused by abnormal uterine bleeding (AUB - O) and endometrial polyps, or associated with menstrual extension, 6 regular checks on the sex hormones, including 4 cases of serum estradiol tip increases (116-323 pg/ml), does not exclude the PEM morbidity associated with excessive estrogen in the body. The recent reserch Altay AY[7] included 15 cases of polypoid endometriosis, which were diagnosed between 2005 and 2019,and conclude that loss of stromal CD73 expression, due to its effect on the extracellular ATP/adenosine balance, may contribute to the pathogenesis of this rare form of endometriosis.
3.3 Auxiliary examination. Tumor marker monitoring was performed in PEM patients. As shown in Table 1, CA125 significantly increased (> 100 kU/L), which may be related to EMS. The clinical manifestations of adenomyosis, dysmenorrhea and infertility also support this reason. In addition, the cases reported internationally in the past 5 years also showed abnormal increase of CA125. Akiko Y reported 1 case of large ovarian PEM (tumor diameter was about 20cm), with serum CA125 level up to 3263 U/ml (normal < 35 U/ml)[9]. In this group, 6 cases showed a significant increase in CA125 by 103.8-762.6 (225.47±117.49) kU/L, and 1 case was found to be located in the fallopian tube during PEM operation, but imaging examination did not indicate it. CA125 was 15.3 kU/L, about 2.7 x 2.1cm in size, and the clinical symptoms were not specific. In conclusion, the abnormal increase of CA125 is helpful for the diagnosis of PEM, and the value of CA125 may be related to the size of the tumor.
At present, there is still a lack of ultrasonic and imaging research summary of this disease, and color ultrasound and intraoperative freezing manifestations are mostly similar to EMs without specificity. Color ultrasound may have difficulty in diagnosis. Jacquot A[6] thought that MRI findings were useful for preoperative diagnosis and is the preferred imaging modality for these lesions.There was no functional sign of malignancy (no diffusion restriction, pronounced tumor enhancement, or metastasis).
In this group of cases, 6 cases underwent CT and MRI examination and 5 cases were misdiagnosed, indicating CT and MRI examination insensitivity to its diagnosis. Soleen Ghafoor reported a case of PEM in the posterior vaginal dome, which was misdiagnosed as cervical cancer by CT, but MRI could use the effect of diffusion weighted imaging to locate the tumor, whether the tumor was of tumor origin, and whether there were signs of proliferation around it to distinguish PEM from malignant tumors[20]. Yasushi summarized the characteristics of MRI examinations in 6 cases of misdiagnosis of ovarian PEM reported between 2003 and 2008: ovarian PEM showed low signal intensity margins on T2WI, and solid nodules showed rounded edges with smooth edges. However, in EMS-induced ovarian cancer, no such low signal intensity edge was observed on T2WI, and the nodular edge was irregular, which may help to distinguish PEM from EMS-related malignancy [28].
3.2 Clinicopathological features
The diagnosis of PEM depends on pathology. Based on the summary of the cases in this group and the literature reports, the general manifestations were all single or multi-focal cysts or exogenous masses of different sizes, which were connected to the surrounding tissues with pedles or broad bases of different thickness, and severe pelvic adhesion could be observed intraoperically. The PEM of the ovary was cystic and solid. The cystic portion of the tumor contained chocolate or brown serous fluid, while the solid portion of the tumor had a polypoid or malignant tumor or gray-yellow necrotic tissue appearance. The PEM of the vagina or cervix showed like cauliflower pattern or florid, and the deep part showed red polyps. The PEM section of the serosal surface of the uterus was grayish white or grayish red. Cleo Tsai also reported a case of PEM behind pelvic uterus with the appearance of taupe florid polypoid soft tissue [18].
The term PEM (or "endometrial polyposis") was first coined by Mostoufizadeh and Scully for endometriosis[1]. Microscopy showed that the pathological morphology of the lesion was similar to that of endometrial polyps occurring in the uterine cavity. The pathological tissues were all composed of endometrioid glands and stromal components, which had the pathological characteristics of common EM, but were more diverse than that of common EM. The surface is erosive or covered with a single layer of columnar, cubic, or dwarf cubic epithelium. It may be accompanied by a small amount of active epithelial hyperplasia, cystic dilatation of the gland, intensive hyperplasia of the focal glands, abundant interstitial cells in some parts, moderate atypia, nuclear mitosis, or borderline changes, metaplasia of the fallopian tube, and atypical hyperplasia, which also bring great confusion for pathological examination [22-24]. At present, the immunohistochemical studies on PEM mostly suggest ER(+), PR(+), and Vinmentin(++), as previously mentioned [26,29]. Two immunohistochemical examinations of 7 cases in this group showed P16(+). Colin JR, compares the 15 cases of PEM and 20 cases of PEM EMs (NPE) immune histology CD10 and p16 staining, and estimates the p16 positive proportion of stromal cells and epithelial cells, the results suggest: pathological morphology and immunohistochemical features of EMs is similar and NPE are similar, morphology and endometrial polyps similar 5 cases, the stromal cells and epithelial cells p16 expression [23]. Nicolae A also proposed that the metaplasia changes in the endometrium might be related to the increased expression of p16 [30].
In conclusion, PEM, a rare type of EMs, clinical easily misdiagnosed as malignant tumor, often with endometrial polyps, uterine adenomyosis, abnormal uterine bleeding, infertility and so on, auxiliary examination suggests higher abnormal CA125, MRI is helpful to identify whether for EMs related to malignant tumor, pathological examination as the gold standard, immunohistochemical prompt ER (+), PR (+) and P16 (+). The clinician should combine the medical history, physical examination, tumor markers and other examination results to make comprehensive judgment.