Coelomic metaplasia theory of endometriosis: evidence from in vivo studies and an in vitro experimental model

Ultrastructure studies of pelvic peritoneal tissue from women undergoing laparotomy suggest that before endometriosis has become established in the peritoneum, there might be a metaplastic change by peritoneal mesothelial cells into endometrial glandular cells. A new in vitro experimental model of endometriosis using human ovarian surface epithelium cells has shown evidence that endometriotic lesions can arise by a process of metaplasia from the ovarian surface epithelium. In this model, when both ovarian surface epithelium and ovarian stromal cells were cocultured with 17beta estradiol in a three-dimensional collagen gel lattice, the ovarian surface epithelium cells formed a lumen structure, surrounded by endometrial stromal cells with an epithelial mesenchymal structure. Immunoreactivity for epithelial membrane antigen and cytokeratin was shown in the glandular cells and cilia, as well as in the microvilli. Electron microscopy showed evidence of tight junctions on cell surfaces. These findings suggest that endometriosis may manifest as a serial change from the adjacent mesothelial cells.     

Expression of CD44s, vascular endothelial growth factor, matrix metalloproteinase-2 and Ki-67 in peritoneal, rectovaginal and ovarian endometriosis

OBJECTIVE: To understand the pathogenetic mechanisms of endometriosis by examining the expression of adhesion molecules (CD44s), angiogenic factor (VEGF) and matrix protease and to perform Ki-67 labeling for evaluation of proliferative activity. STUDY DESIGN: Twenty-nine peritoneal endometriosis lesions (9 red, 12 black and 8 white), 11 rectovaginal and 22 ovarian were obtained. Immunohistochemical staining was performed with antibodies for CD44, VEGF, MMP-2 and Ki-67. RESULTS: CD44s were expressed mainly in stroma and showed higher expression in glandular epithelium of peritoneal endometriosis than in rectovaginal and ovarian endometriosis. The stroma in red and white lesions showed higher MMP-2 expression than in black lesions. The stromal cells in rectovaginal endometriosis showed significantly lower expression of Ki-67 (p = 0.002) than in peritoneal and ovarian endometriosis. When endometriosis was analyzed according to the revised American Fertility Society classification, Ki-67 expression was high in glandular epithelium in stages I and II (p = 0.025), whereas MMP-2 expression in stromal cells was significantly high (p < 0.001) in stages III and IV. CONCLUSION: CD44, VEGF and MMP-2 were consistently expressed in endometriotic epithelial and stromal cells. White lesions of peritoneal endometriosis should not be regarded as an inactive state, and MMP-2 in stromal cells may be responsible for the progression of endometriosis. The macroscopic appearance of endometriotic lesions should not be used as a criterion to define the degree of activity.     

Clinicopathological characteristics of ovarian carcinomas associated with endometriosis

Introduction  

Substantial histopathology data provide evidence that endometriosis might be viewed as a precursor lesion of endometrioid and clear cell carcinoma of the ovary, via intermediary atypical borderline lesions. Also, genes involved in both endometriosis and epithelial ovarian cancer have been shown to play a role in the pathogenesis of endometriosis-associated ovarian carcinoma.     

Ovarian mucinous and mixed epithelial carcinomas of mullerian (endocervical-like) type: a clinicopathologic analysis of four cases of an uncommon variant associated with endometriosis.

The epithelial cells of ovarian mucinous carcinomas may sometimes appear similar to those of gastrointestinal or endocervical mucinous carcinomas, but most are composed of cells that do not suggest any particular derivation. We report four cases of mucinous ovarian carcinoma in which the cells were entirely or almost entirely endocervical-like. The patients' ages were 34, 43, 44, and 50 years. Two patients had bilateral tumors confined to the ovaries at initial staging; both also had synchronous endometrial carcinomas of the mucinous type. The two other patients had unilateral tumors, both with invasive metastases in the pelvis and abdomen at initial staging. In one of the latter cases a mullerian (endocervical-like) mucinous borderline tumor (MMBT) of the opposite ovary had been removed 5 years earlier, and in this case and two other cases the ovarian carcinomas had foci resembling MMBT, suggesting that they may be an invasive counterpart to these tumors. The six tumors ranged from 4 to 19 cm; five were grossly cystic with papillary or solid areas, and one was entirely solid. They were composed of closely packed glands, cysts, and cysts containing complex papillae. There was abundant intraglandular and intracystic mucin. The epithelial cells were well differentiated with infrequent mitoses and most were tall with mucinous cytoplasm resembling normal endocervical glandular cells. In three tumors there also were round to polygonal cells with eosinophilic cytoplasm; endometrioid foci were present in three tumors and a squamous focus was present in one. One tumor had a focally infiltrative growth pattern with a desmoplastic stromal reaction; the remaining five tumors had an exclusively confluent (expansile) pattern of invasion. Endometriosis was present in residual ovarian tissue adjacent to four tumors in three patients and had marked epithelial proliferation in three. All patients were treated postoperatively with chemotherapy and were without clinical recurrence with follow-up intervals of 8 months, 1.2 years, 2.9 years, and 3.8 years. By immunohistochemical analysis the neoplastic epithelium was positive for estrogen and progesterone receptor proteins, vimentin, and cytokeratin 7, and negative or only focally positive for carcinoembryonic antigen and cytokeratin 20, a profile that differs from that of the usual mucinous ovarian carcinoma and is supportive of a mullerian derivation. As with MMBTs, there was a strong association with endometriosis, and these tumors likely arise from endometriosis, possibly through an MMBT precursor in some cases. To better understand their clinicopathologic features and pathogenesis, this uncommon variant should be separated from the usual type in future studies of mucinous carcinomas of the ovary.     

Ovarian clear cell carcinoma associated with endometriosis: a case report with immunohistochemical study

Endometriosis is a frequent benign gynecological disease; nonetheless, it can demonstrate some aspects that resemble malignant disease. Malignant transformation of endometriosis occurs mainly in the ovary. A rare case of transition between typical endometriosis and clear cell carcinoma with immunohistochemical study is presented. The patient, a 30-year-old Caucasian woman (para 0), was diagnosed with endometriosis ten years before. Six months later she developed a left cystic ovarian tumor (58 cm3) that persisted after two ultrasounds in a four-month period. Tumor markers were normal (CA125, CA 15.3, CA 19.9, alpha-fetoprotein, carcinoembrionary antigen A1). There was no ascites. The left ovarian mass was removed by laparotomy and endometriosis in continuity with carcinoma positive for cytokeratin 7 and estrogen receptor was revealed. CD10 was positive in the stromal cells of the endometriosis. Clear cell carcinoma grade 3 was diagnosed. In conclusion, although a rare event, the association of typical endometriosis and clear cell carcinoma of the ovary should be kept in mind, mainly in patients with a persistent ovarian cyst.     

卵巢子宫内膜异位症与卵巢恶性肿瘤的相关性分析

目的卵巢子宫内膜异位症（EM）是常见的妇科良性疾病,具有潜在的恶变可能。本研究通过对卵巢EM恶变、合并EM及未合并EM的卵巢恶性肿瘤病例的分析,了解卵巢EM恶变与卵巢恶性肿瘤的关系。方法 回顾性分析新疆医科大学第一附属医院2003年1月至2010年12月经病理确诊的原发性卵巢恶性肿瘤患者共362例,根据卵巢EM恶变诊断标准及病理结果,将EM恶变的17例患者分为A组,其他仅合并卵巢EM的卵巢恶性肿瘤16例患者分为B组,未合并卵巢EM的卵巢恶性肿瘤329例为C组,从卵巢恶性肿瘤的临床病理资料对三组进行对照分析。同期在本院经手术确诊的卵巢EM患者共1 946例。结果A、B组临床症状多以腹痛为主,其次为盆腔包块;从临床分期来看,A、B组以Ⅱ期居多,分别占70.6%、56.5%,C组以Ⅲ期为多,占47.7%;从组织类型来看,A、B组多为透明细胞癌（分别为70.6%、56.2%）,而C组则以浆液性腺癌（50.2%）为主。三组在一般特征、临床分期及病理组织分类的分布差异均有统计学意义。结论卵巢EM恶变的临床症状以腹痛为多,其次为盆腔包块,肿块直径超过9 cm,且CA125水平多在200 U/ml以上;卵巢EM恶变及卵巢恶性肿瘤合并EM病例中早期患者比例较高,具有年轻化（尤其是卵巢内异症恶变患者）的特点,且多为卵巢透明细胞癌和子宫内膜样癌;卵巢EM恶变的诊断与组织病灶程度、临床分期可能有关,卵巢EM病灶恶变可能来源于透明细胞癌和子宫内膜样癌,因此卵巢EM可被认为是卵巢恶性肿瘤的危险因素。     

Angiogenesis in endometriosis and angiogenic factors

Among angiogenic factors, VEGF secreted from activated macrophages under the influence of ovarian steroids, IL-8 expressed in endometrial stromal cells, and basic FGF expressed in endometriotic tissue and PD-ECGF expressed in lining epithelial cells independently of the sex steroidal milieu might contribute to the characteristic advancement of angiogenic lesions in endometriosis in individual manners. Copyrightz1999S.KargerAG,Basel     

Borderline clear cell adenofibroma of the ovary associated with ovarian endometriosis: a case report

Clear cell tumours of the ovary are relatively uncommon. Most of them are clear cell carcinomas. Benign and borderline clear cell tumours are extremely rare and almost always fibromatous. We report a case of a 34-year-old woman. Ultrasound and computed tomography showed a right ovarian mass 8 cm in diameter. The patient underwent right salpingo-oophorectomy. Microscopic examination revealed glands and cysts different in size and shape within an abundant stromal component without evidence of stromal invasion. Many cysts and glands were lined by a single layer of flattened, cuboidal or hobnail cells with mild to moderate cytologic atypia and prominent nucleoli. Psammomatous calcifications were occasionally indentified. Features of endometriosis were also present adjacent to the tumour. Lesional cells were positive for Ker 7 and CA125. Staining for p53 was focally positive. Based on the above characteristic morphologic and immunohistochemical findings a diagnosis of borderline clear cell adenofibroma was made. The patient was free of recurrence four years after surgery.     

A rare case of the coexistence of ovarian clear cell carcinoma, mucinous cystadenoma, and endometriosis in the same ovary

Clear cell carcinomas and endometrioid carcinomas are associated with endometriosis. The association of clear cell carcinomas with mucinous lesions has only been reported infrequently, and with mucinous cystadenoma has been rarely reported. This is the second reported case of the coexistence of ovarian clear cell carcinoma, mucinous cystadenoma, and endometriosis in the same ovary. A 57-year-old woman presented with lower abdominal pain for three weeks. Ultrasonography revealed a 16 x 14 x 10 cm mass in the left ovary with solid and cystic components. Hysterectomy and bilateral salpingo-oophorectomy were performed. Histopathological examination of the left ovary revealed the presence of clear cell carcinoma, mucinous cystadenoma, and endometriosis. Continuity between the areas of mucinous epithelium and clear cell carcinoma were noted; this may suggest that clear cell carcinoma may arise from endometriosis or mucinous cystic tumors.     

Novel therapeutic strategies for endometriosis: a pathophysiological perspective

It has previously been considered that the therapeutic effects of gonadotropin-releasing hormone (GnRH) analogues on endometriosis could be explained by the suppression of estrogen levels due to pituitary downregulation; however, recent research on the pathogenesis of endometriosis suggests that these effects may be exerted by multiple mechanisms. These include the inhibition of ovulation, which results in a reduction in the exposure of endometriotic lesions to midkine, a growth factor present in ovarian follicular fluid that is thought to be involved in the proliferation of endometriotic cells and development of endometriosis. Also the inhibition of bleeding induced by GnRH analogue therapy can reduce the exposure of endometriotic lesions to thrombin, which is produced in the process of coagulation. Thrombin and its specific receptor, protease-activated receptor 1 (PAR1), are important factors in inflammation and cell proliferation and may be involved in the pathophysiology of endometriosis. Abnormal uterine contractions have been observed in women with endometriosis, and it is thought that the resulting mechanical stretch might stimulate the production of pro-inflammatory mediators, such as interleukin-8 (IL-8), as has been observed in studies with endometrial stromal cell cultures. The inhibition of uterine contractions by GnRH analogue therapy, in particular during menstruation, would block the mechanical stress on the endometrium and ultimately inhibit the development of endometriosis. Alongside the recent revolutionary progress in T-cell immunology, it has been argued that the development of endometriosis is associated with an abnormal T-cell function, and the existence of a 'T-cell immune network' is hypothesized to explain the etiology of the disease.     

Pelvic endometriosis and ureteral obstruction.

Pelvic endometriosis may completely obstruct the ureters and destroy the kidneys with little or no gynecologic symptoms. Five cases are discussed, all causing ureteral obstruction. Two patients suffered the complete loss of a kidney and in each case the remaining kidney was in jeopardy because of partial obstruction due to endometriosis. All these patients were treated by complete removal of all ovarian tissue, dissection of the ureter, and dissection of the scar tissue. In severe cases, retroperitoneal clamping of the infundibular pelvic ligament with clear exposure of the ureter is mandatory to avoid leaving small remnants of ovary in the infundibular ligament clamp. With complete removal of all ovarian tissue, postoperative estrogen therapy will not cause recurrence of the disease.     

Postmenopausal endometriosis

The frequency of postmenopausal endometriosis (ovarian endometriosis and adenomyosis) was 2.2%. The mean of the menopausal ages in 11 patients with ovarian endometriosis was 50.3 yr and the average time elapsed since menopause, 7.3 yr. The corresponding values in 8 patients with adenomyosis were 52.1 and 8.8 yr. Carcinoma was a common associated finding in patients with ovarian endometriosis. Increased estrogen activity was observed more frequently in patients with adenomyosis than in those with ovarian endometriosis. Only one of the patients had received estrogen therapy. Hormone-producing tumors in the ovaries or adrenal glands were not confirmed. 70% of the patients were obese and the signs of increased estrogen activity could be explained by extraglandular estrogen formation.     

Immunoscintigraphy of ovarian endometriosis. A preliminary study

CA-125 is a membrane antigen detected in the serum of some women with gynaecological disease including endometriosis. We attempted to use a radioiodinated anti-CA-125 monoclonal antibody, OC-125, to image ovarian endometriosis using immunoscintigraphy. Two women with significant endometriosis and normal serum CA-125 levels had positive immunoscintigraphy. In one woman, all areas of endometriosis were imaged; in the other, endometriosis in one affected ovary was seen, but uptake in the other ovary was less than the extent of the disease.     

Immunoscintigraphy of ovarian endometriosis. A preliminary study

Summary. CA-125 is a membrane antigen detected in the serum of some women with gynaecological disease including endometriosis. We attempted to use a radioiodinated anti-CA-125 monoclonal antibody, OC-125, to image ovarian endometriosis using immunoscintigraphy. Two women with significant endometriosis and normal serum CA-125 levels had positive immunoscintigraphy. In one woman, all areas of endometriosis were imaged; in the other, endometriosis in one affected ovary was seen, but uptake in the other ovary was less than the extent of the disease.     

The role of p53 mutation in the carcinomas arising from endometriosis.

To probe the mechanism of the development of ovarian cancer from endometriosis, which is a multistep process that involves the activation of oncogenes and inactivation of tumor suppressor genes, we evaluated p53 mutations in solitary endometriosis and endometriosis coexisting with ovarian clear cell carcinoma (OCCA) and ovarian endometrioid carcinoma (OEC). We examined 7 cases of solitary ovarian endometriosis, 13 cases of OCCA, and 9 cases of OEC. Cancer tissue specimens that also contained endometriosis without atypia were chosen. Using a laser microdissection system, epithelial cells from the areas of endometriosis were isolated, and DNA was extracted. We amplified exons 5, 6, 7, and 8 of the p53 gene, and direct sequencing was performed. p53 mutation was observed in 4 (30.8%) of 13 specimens of endometriosis coexisting with OCCA, whereas no mutations were detected in solitary endometriosis or endometriosis coexisting with OEC. We thought that some genetic alterations, which induce p53 mutations in endometriosis, may affect malignant transformation of endometriosis into OCCA.     

Immunocytochemistry of the estrogen receptor in spontaneous endometriosis in rhesus macaques

Immunocytochemical, biochemical, and histologic analysis of endometriotic lesions and endometria from rhesus macaques with endometriosis revealed several distinctions between ectopic and eutopic endometrium. In lesions, unlike endometrium, neither the mean percentages of estrogen receptor positive (ER+) cells nor the total ER content changed significantly during the menstrual cycle. In eutopic endometria, ER staining in both stromal and epithelial cells increased and decreased synchronously during the cycle, but in endometriotic lesions, such synchrony was lacking. Moreover, in lesions, unlike endometria, the percentage of ER+ cells was low in the stroma and highly variable in epithelium throughout the cycle. These data, taken together, indicate a defect in the hormonal regulation of ER in endometriotic lesions of monkeys.