Isthmocele endometriosis: the relationship between cesarean section and endometriosis.

OBJECTIVE: To present a case of endometriosis within an isthmocele membrane and concomitant diffuse peritoneal endometriosis after cesarean sections. In addition, we describe a unique, color-contrasted surgical repair technique and propose a possible correlation between isthmocele formation and endometriosis. DESIGN: Narrated video article featuring the diagnosis, unique surgical management, and pathological findings of a case of isthmocele endometriosis. Informed consent was obtained from the patient, and all identifiers were removed. SETTING: University-affiliated hospital. PATIENT(S): A 44-year-old patient with three prior cesarean sections and a laparoscopic appendectomy, in none of which endometriosis was visualized. She presented with progressive pelvic pain, dysmenorrhea, dyspareunia, and secondary infertility with recurrent embryo transfer failures. The progressively debilitating symptoms started 14 years ago, shortly after her last cesarean section. Magnetic resonance imaging and ultrasound demonstrated a retroverted uterus and a prominent, thin, fluid-filled cesarean scar defect with a residual myometrial thickness of 1.1 mm. INTERVENTION(S): A combined hysteroscopic and laparoscopic approach was performed to allow for complete resection of the defect and reconstruction of the myometrium. The bladder was backfilled with indocyanine green dye to help identify its borders. Methylene blue was added to the hysteroscopy irrigation solution to create contrast and assist with the isthmocele identification. Wide excision of the isthmocele was performed, followed by a three-layer closure and excision of all apparent peritoneal lesions using the Aqua Blue Contrast Technique. MAIN OUTCOME MEASURE(S): Restoration of normal anatomy, resection of isthmocele, and resolution of the symptoms. RESULT(S): In the pathological assessment, multiple foci of endometriosis were identified within the isthmocele membrane, clearly differentiated from intrauterine endometrial tissue. Additionally, all seven excised peritoneal specimens contained peritoneal endometriosis. Two weeks after the procedure, a transvaginal sonographic scan confirmed a thick anterior uterine wall with a myometrial thickness of 9.2 mm, and the patient reported almost complete resolution of her symptoms. CONCLUSION(S): This case demonstrates endometriosis within the isthmocele membrane, with concomitant symptomatic peritoneal endometriosis. We propose a laparoscopic isthmocele excision technique and a three-layer reconstruction, followed by peritoneal endometriosis excision using methylene blue contrast. We suggest a possible link between isthmocele and endometriosis and emphasize the need for wide excision of the isthmocele margins and maintaining clean borders, given the possibility of endometriosis within the isthmocele, which may be a cause or a contributor to the tissue weakness and isthmocele formation.

Mutation and methylation profiles of ectopic and eutopic endometrial tissues.

Adenomyosis and peritoneal endometriosis are common gynecologic lesions; they are characterized by aberrant locations of normal-appearing endometrium in myometrium and peritoneal surface, respectively. Both ectopic lesions are speculated to originate from uterine eutopic endometrium, which is composed of epithelium and stroma, but how these two different tissue types co-evolve in ectopic locations remains unclear. Here, we analyzed exome-wide mutations and global methylation in microdissected epithelium and stroma separately in paired adenomyosis, peritoneal endometriosis, and endometrium to investigate their relationship. Analyses of somatic mutations and their allele frequencies indicate monoclonal development not only in epithelium but also in the stroma of adenomyosis and peritoneal endometriosis. Our preliminary phylogenetic study suggests a plausible clonal derivation in epithelium and stroma of both ectopic and eutopic endometrium from the same founder epithelium-stroma progenitor cells. While a patient-specific methylation landscape is evident, adenomyosis epithelium and stroma can be distinguished from normal-appearing eutopic endometrium epigenetically. In summary, endometrial stroma, like its epithelial counterpart, could be clonal and both ectopic and eutopic endometrium following divergent evolutionary trajectories. Our data also warrant future investigations into the role of endometrial stroma in the pathobiology of endometrium-related disorders. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Epithelial Cells in Endometriosis and Adenomyosis Upregulate STING Expression.

In response to cytosolic DNA, stimulator of interferon gene (STING) initiates and orchestrates host's innate immunity by inducing type I interferon. Since endometriosis is a chronic inflammatory disorder, we sought to determine whether STING pathway is activated in ectopic endometrium in comparison to eutopic endometrium. Immunohistochemistry was employed in evaluating the expression levels of STING in normal endometrium, endometriosis, and adenomyosis. The density of CD45+ intraepithelial lymphocytes was correlated with STING expression levels. A total of 39 cases of endometriosis and/or adenomyosis with normal endometrium were analyzed. Among them, 32 had adenomyosis, 26 had endometriosis, and 19 have both lesions. STING protein expression is mainly evident in the cytoplasm of epithelial cells but much less in stromal cells. Based on H-score, we found that the STING expression levels were significantly higher in the epithelial cells of adenomyosis and endometriosis than in eutopic endometrium (132.7 ± 12.20, 119.6 ± 12.57 vs. 19.74 ± 5.96, p < 0.0001). There was no significant difference in STING expression level between endometriosis and adenomyosis. More intraepithelial lymphocytes were detected in endometriosis and adenomyosis lesions than endometrium (5.60 ± 0.70%, 4.95 ± 0.54% vs. 1.25 ± 0.12%, p < 0.0001). A positive correlation between STING expression and intraepithelial lymphocytic infiltrate was observed (p < 0.0001). In summary, STING was upregulated in the epithelium of ectopic endometrium as compared to eutopic endometrium. Its expression levels correlate with the degree of intraepithelial lymphocyte infiltration, suggesting a role in promoting chronic inflammation of ectopic endometrium.

Analysis of menstrual effluent: diagnostic potential for endometriosis.

BACKGROUND: Endometriosis is a chronic and underdiagnosed disease which affects 5-10% of women of childbearing age and is characterized by growth of endometrial tissue outside of the uterus, most often in the peritoneal cavity. Delay in diagnosis is a major problem for management of this disorder, and treatment is often not initiated until the disease has progressed for many years. Although the exact etiology of endometriosis remains unknown, retrograde menstruation is recognized as a common underlying factor leading to the deposit of menstrual effluent (ME) into the peritoneal cavity. Differences in the cellular biology and genetics of the cells within ME are therefore likely to explain why endometriosis develops in only a subset of women. METHODS: Patients with and without endometriosis were consented to provide ME. ME was analyzed by flow cytometry for CD45- and CD45+ cell populations or used to isolate stromal fibroblast cells. ME-derived stromal fibroblast cells were assessed using decidualization assays following the addition of cAMP and IGFBP-1 concentrations in the culture supernatants were measured by ELISA. In addition, RNA was collected and analyzed by RNA-Seq and qPCR for markers of decidualization and to identify differentially expressed genes in ME-derived stromal fibroblast cells obtained from controls and subjects with endometriosis (±cAMP). RESULTS: Flow cytometry analysis of cell subsets within the CD45+ fraction of ME revealed a significant decrease in the number of uterine NK cells in endometriosis patients compared with controls (p < 0.01). No other significant differences within either the CD45+ or CD45- cell populations were observed. Most strikingly, ME-derived stromal fibroblast cells cultured from endometriosis subjects showed impaired decidualization potential compared with controls. Highly significant differences in decidualization response were detected by measuring IGFBP-1 production at multiple time points after cAMP stimulation (p = 0.0025 at 6 h; p = 0.0045 at 24 h; p = 0.0125 at 48 h). RNA-Seq and qPCR analyses were used to identify genes differentially expressed by ME-derived stromal fibroblast cells obtained from endometriosis and control subjects. CONCLUSIONS: Menstrual effluent can be useful for investigating the pathobiology of endometriosis and for developing a non-invasive diagnostic for endometriosis which may lead to earlier and more effective treatments for this common disorder.

How do adolescent girls and boys perceive symptoms suggestive of endometriosis among their peers? Findings from focus group discussions in New York City.

OBJECTIVE: Symptoms of endometriosis, including pelvic pain, back and nerve pain, and gastrointestinal pain, often begin in adolescence. Yet, research on the experience of these debilitating symptoms among young people is scarce. Of particular concern is the influence of adolescent girls' social context. This study qualitatively examined how, among adolescents, endometriosis and symptoms suggestive of endometriosis is perceived at the family, peer/school and community/society levels. DESIGN: Eight focus groups were conducted; vignettes were used to elicit participants' perceptions of factors that may shape girls' experiences of endometriosis. Data were analysed using constant comparison analysis. PARTICIPANTS: An ethnically diverse sample of girls and boys ages 14-18 (n=54) residing in New York City. RESULTS: Fifteen themes emerged and were distilled to eight cross-cutting factors that influence perceptions of endometriosis at different levels of the ecological model: distrust of community healthcare providers, societal stigma of menstruation, peer stigma of endometriosis symptoms, distrust of school healthcare providers, lack of endometriosis knowledge among peers and school personnel, inequitable gender norms, invisibility of symptoms and the stigma of teen sex among parents. Further, these factors may compound symptoms' impact on individual girl's social, educational and emotional well-being. CONCLUSIONS: Findings underscore the importance of understanding the social environment of girls experiencing symptoms suggestive of endometriosis and educating and engaging their peers, family and school personnel to create a supportive, informed social climate. Efforts should specifically include stigma reduction campaigns targeted towards female and male adolescents.

Cancer-Associated Mutations in Endometriosis without Cancer.

BACKGROUND: Endometriosis, defined as the presence of ectopic endometrial stroma and epithelium, affects approximately 10% of reproductive-age women and can cause pelvic pain and infertility. Endometriotic lesions are considered to be benign inflammatory lesions but have cancerlike features such as local invasion and resistance to apoptosis. METHODS: We analyzed deeply infiltrating endometriotic lesions from 27 patients by means of exomewide sequencing (24 patients) or cancer-driver targeted sequencing (3 patients). Mutations were validated with the use of digital genomic methods in microdissected epithelium and stroma. Epithelial and stromal components of lesions from an additional 12 patients were analyzed by means of a droplet digital polymerase-chain-reaction (PCR) assay for recurrent activating KRAS mutations. RESULTS: Exome sequencing revealed somatic mutations in 19 of 24 patients (79%). Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis. The likelihood of driver genes being affected at this rate in the absence of selection was estimated at P=0.001 (binomial test). Targeted sequencing and a droplet digital PCR assay identified KRAS mutations in 2 of 3 patients and 3 of 12 patients, respectively, with mutations in the epithelium but not the stroma. One patient harbored two different KRAS mutations, c.35G→T and c.35G→C, and another carried identical KRAS c.35G→A mutations in three distinct lesions. CONCLUSIONS: We found that lesions in deep infiltrating endometriosis, which are associated with virtually no risk of malignant transformation, harbor somatic cancer driver mutations. Ten of 39 deep infiltrating lesions (26%) carried driver mutations; all the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions.

Loss of ARID1A expression is an early molecular event in tumor progression from ovarian endometriotic cyst to clear cell and endometrioid carcinoma.

OBJECTIVES: ARID1A is a recently identified tumor suppressor participating in chromatin remodeling. Somatic inactivating mutations of ARID1A and loss of its expression occur frequently in ovarian clear cell and endometrioid carcinomas and in uterine endometrioid carcinomas. Because endometriotic epithelium is thought to be the cell of origin of most ovarian clear cell and endometrioid carcinomas, we undertook an analysis of ARID1A expression of these tumors arising within an endometriotic cyst (endometrioma). MATERIALS AND METHODS: Our immunohistochemical study set consisted of 47 endometriotic cysts containing clear cell carcinoma in 24 cases, well-differentiated ovarian endometrioid carcinoma in 20 cases, and mixed clear cell and endometrioid carcinoma in 3 cases. RESULTS: ARID1A loss was observed in 31 (66%) of 47 carcinomas; and therefore, these cases were informative for determining the temporal sequence of loss of ARID1A expression in tumor progression. In 16 of the 47 cases, ARID1A immunoreactivity was retained in both the endometriotic cyst and the carcinoma; and thus, these cases were not informative. All of the 31 informative cases showed loss of ARID1A immunoreactivity in the carcinoma and in the endometriotic cyst epithelium in direct continuity with the carcinoma but not in the cyst epithelium that was not adjacent to the tumor. CONCLUSIONS: Loss of ARID1A function as shown by loss of expression, presumably due to mutations, is an early molecular event in the development of most ovarian clear cell and endometrioid carcinomas arising in endometriomas.

Rare case of ovarian cystic lymphangioma.

Lymphangiomas are rare, generally benign tumors of the lymphatic system comprised of multiple cystic spaces lined with endothelium. Lymphangiomas may arise in any part of the body. Lymphangioma of the ovary is rare; we have identified only 13 reports in a 50-year literature survey (PubMed 1959-2009). Typically, lymphangiomas are slow-growing tumors that remain asymptomatic for a long time. They are most often found incidentally in abdominal or pelvic imaging studies or at surgery or autopsy. Wide excision of the lesion with microscopically clear margins is the best approach when feasible. A postmenopausal woman had a symptomatic pelvic mass. Imaging studies demonstrated a complex left ovarian cyst. Complete removal of a cystic lymphangioma was successfully performed at laparoscopy. Cystic lymphangiomas should be included in the differential diagnosis of an ovarian cystic mass, and laparoscopic excision may be the method of treatment.