Using the novel pelvic organ prolapse histologic quantification system to identify phenotypes in uterosacral ligaments in women with pelvic organ prolapse.

BACKGROUND: Pelvic organ prolapse is common, but the underlying etiologies are poorly understood, which limits our current prevention and treatment options. OBJECTIVE: Our primary objective was to compare the uterosacral ligament histologic features in women with and without prolapse using the novel pelvic organ prolapse histologic quantification system. Our secondary aim was to determine whether composite histologic findings in uterosacral ligaments are associated with prolapse risk factors. STUDY DESIGN: This was a prospective cohort study in which paracervical uterosacral ligament biopsies were performed at the time of hysterectomy for primary prolapse or other benign gynecologic indications and processed for histologic evaluation. The pelvic organ prolapse quantification system was used to determine the prolapse stage. In this study, 9 prominent histologic features were semiquantitatively scored using the pelvic organ prolapse histologic quantification system in a blinded fashion and compared between prolapse and control groups. Unbiased principal component analysis of these scores was independently performed to identify potential relationships between histologic measures and prolapse risk factors. RESULTS: The histologic scores of 81 prolapse and 33 control ligaments were analyzed. Compared with the control group, women in the prolapse group were significantly older and more likely to be in the menopausal phase. There was no difference in the number of vaginal deliveries, body mass index, hormone use, or smoking status between the groups. To control for baseline differences, patients were also stratified by age over 40 years and menopausal status. Compared with the control group, the prolapse ligaments in the premenopausal group had significantly more loss of smooth muscle fibers within the fascicles (P<.001), increased inflammatory infiltrates of neutrophils within the tissue and perineural inflammatory cells (P<.01 and P=.04, respectively), and reduced neointimal hyperplasia (P=.02). Prolapse ligaments in the postmenopausal group exhibited elevated adipose content compared with that of the control group (P=.05). Amount of fibrillar collagen, total nonvascular smooth muscle, and muscle fiber vesicles of prolapse ligaments did not differ in either the premenopausal or postmenopausal group compared with that of the control group. Unbiased principal component analysis of the histologic scores separated the prolapse ligaments into 3 phenotypes: (1) increased adipose accumulation, (2) increased inflammation, and (3) abnormal vasculature, with variable overlap with controls. Posthoc analysis of these subgroups demonstrated a positive correlation between increasing number of vaginal deliveries and body mass index with increasing adipose content in the adipocyte accumulation and inflammatory phenotype and increasing neointimal hyperplasia in the vascular phenotype. However, only the relationship between vaginal delivery and adipocytes was significant in the adipose phenotype (R2=0.13; P=.04). CONCLUSION: Histologic phenotypes exist in pelvic support ligaments that can be distinguished using the pelvic organ prolapse histologic quantification system and principle component analysis. Vaginal delivery is associated with aberrant adipose accumulation in uterosacral ligaments. Our findings support a multifactorial etiology for pelvic organ prolapse contributing to altered smooth muscle, vasculature, and connective tissue content in crucial pelvic support structures. To confirm these associations and evaluate the biomechanical properties of histologic phenotypes of prolapse, larger studies are warranted. Closing this gap in knowledge will help optimize personalized medicine and help identify targets for prevention and treatment of this complex condition.

Inflammatory Cells in Control and Prolapsed Uterosacral Ligament Tissue.

Pelvic organ prolapse (POP), a downward descent of the vagina and/or uterus through the vaginal canal, is a prevalent condition affecting up to 40% of women. Several risk factors of POP have been identified, including childbirth, connective tissue defects, and chronic intra-abdominal pressure; however, the underlying etiologies of POP development are not fully understood, leading to a high burden on patients and the healthcare systems. The uterosacral ligaments are key support structures of the uterus and upper vagina. Our previous work describes observed histopathological changes in uterosacral ligament (USL) tissue and demonstrates the presence of neutrophils in a subgroup of POP individuals. This presence of neutrophils prompted an examination for the presence of a broader spectrum of inflammatory cell types in the USL. Immunohistochemical staining was performed to identify neutrophils, lymphocytes, macrophages, and mast cells outside of the vasculature. All 4 inflammatory cell types were increased in the POP-HQ system-defined POP-Inflammatory (POP-I) phenotype USL tissue relative to the USL tissues of control or other POP-HQ phenotypes. Focal T-lymphocyte and macrophage co-accumulations were observed in the arterial walls from some patients of the POP-vascular (POP-V) phenotype suggesting previous arterial injury. In addition, 1 control and 2 POP-V subjects' USLs contained arterial wall foamy macrophages, evidence of atherosclerosis. These findings further support a complex etiology for POP and indicate that personalized approaches to preventing and treating the condition may be warranted.

Estrogen and Androgen Receptor Status in Uterosacral Ligaments of Women with Pelvic Organ Prolapse Stratified by the Pelvic Organ Prolapse Histology Quantification System.

Menopause is a significant risk factor for pelvic organ prolapse (POP), suggesting that ovarian sex steroids play a major role in the etiology of the condition. POP results from failure of the uterine-cervix-vagina support structures, including the uterosacral ligament (USL). We previously identified consistent degenerative USL phenotypes that occur in POP and used their characteristics to develop a standardized POP Histologic Quantification System (POP-HQ). In this study, POP and matched control USL tissue was first segregated into the unique POP-HQ phenotypes, and specimens were then compared for estrogen receptor (ER) alpha (ERα), ERbeta (ERß), the G-protein estrogen receptor (GPER), and androgen receptor (AR) content via immunohistochemical staining. ER and AR expression levels in the control USL tissues were indistinguishable from those observed in the POP-A phenotype, and partially overlapped with those of the POP-I phenotype. However, control-USL steroid receptor expression was statistically distinct from the POP-V phenotype. This difference was driven mainly by the increased expression of GPER and AR in smooth muscle, connective tissue, and endothelial cells, and increased expression of ERα in connective tissue. These findings support a multifactorial etiology for POP involving steroid signaling that contributes to altered smooth muscle, vasculature, and connective tissue content in the USL. Furthermore, these data support the concept that there are consistent and distinct degenerative processes that lead to POP and suggest that personalized approaches are needed that target specific cell and tissues in the pelvic floor to treat or prevent this complex condition.

Surgical risk score predicts suboptimal debulking or a major perioperative complication in patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer.

BACKGROUND: Patients who present with an advanced ovarian cancer are typically treated with primary debulking surgery (PDS) or neoadjuvant chemotherapy (NAC) followed by interval debulking surgery. The accurate pretreatment identification of patients best suited for PDS versus NAC is challenging. A paradigm for selecting one approach over the other could improve patient outcomes. In this study, we developed a prediction model for "successful surgery" (defined as optimal residual disease and no major perioperative complication) in patients who underwent PDS. PATIENTS: Preoperative clinical characteristics, laboratory values, computed tomography findings, and surgical outcomes of 106 consecutive medically fit patients with advanced ovarian, tubal, or peritoneal cancer were reviewed. Preoperative predictors of suboptimal residual disease and major perioperative complications were determined using regression analysis. A surgical risk score (SRS) that minimized the false-negative rate (ie, likelihood of incorrectly predicting successful surgery) was constructed. RESULTS: Sixty (57%) of the 106 patients were optimally cytoreduced. Fifty-six "radical procedures" were performed, and there were a total of 24 major perioperative complications. Diffuse peritoneal studding (P < 0.0001), para-aortic lymphadenopathy (P < 0.0001), and mesenteric involvement (Mes, P = 0.006) were associated with suboptimal (>1 cm) residual disease. Low albumin (P = 0.04) and splenic disease (spleen, P = 0.02) were the only 2 parameters associated with a higher risk of a major perioperative complication. The median SRSs of patients who had successful and "unsuccessful surgery" were 1 (0-4) and 3 (0-6), respectively. The false-negative rate of the SRS was only 7%. CONCLUSIONS: We developed a model that incorporated complications, in addition to residual disease status, into predicting surgical outcome for medically fit patients with advanced ovarian cancer. The SRS might be useful in determining the initial treatment strategy (ie, PDS vs NAC) for these patients. The accuracy of the SRS needs to be validated in a prospective manner.

Comparison of clients of a mobile health van and a traditional STD clinic.

The objective of this study was to determine if there were any demographic, behavioral, and clinical differences between clients seen aboard a mobile sexually transmitted disease (STD)/HIV clinic compared with those seen in a traditional municipal STD/HIV health clinic for receipt of STD/HIV services. Clients seen in the two different settings were interviewed about demographic characteristics, reasons for their visit, STD history, their HIV/STD risk factors, and the risk factors of their sex partners. Clients in both settings were also offered testing for syphilis, gonorrhea, chlamydia, and HIV. Results suggested that clients seen at the mobile clinic were older, more likely to be injecting drug users themselves and/or to have sex partners who were, or had engaged in prostitution for money or drugs. Over half (54.4%) of the mobile clinic clients sought testing for HIV, and they were far less likely to be seeking care for symptoms of an STD. In contrast, only 7.1% of municipal clinic clients indicated HIV testing as the reason for their visit, whereas nearly two thirds (64.5%) reported symptoms of disease. Two percent of municipal clinic clients and 5.4% of mobile clinic clients had a positive HIV test ( p<.001), and 17.8% of STD clinic clients and 5.6% of mobile van clients had a positive gonorrhea and/or test ( p<.001). These data suggest that a mobile STD/HIV clinic may be an effective strategy to reach individuals at high risk for HIV who are not being served by traditional municipal STD/HIV health clinics.