Background: Interest is growing in the dynamic role of gut microbiome disturbances in human health and disease. No direct evidence is yet available to link gut microbiome dysbiosis to endometrial cancer. This review aims to understand any association between microbiome dysbiosis and important risk factors of endometrial cancer, high estrogen levels, postmenopause and obesity. Methods: A systematic search was performed with PubMed as primary database. Three separate searches were performed to identify all relevant studies. Results: Fifteen studies were identified as highly relevant and included in the review. Eight articles focused on the relationship with obesity and eight studies focused on the menopausal change or estrogen levels. Due to the heterogeneity in patient populations and outcome measures, no meta-analysis could be performed. Both the menopausal change and obesity were noted to enhance dysbiosis by reducing microbiome diversity and increasing the Firmicutes to Bacteroidetes ratio. Both also incurred estrobolome changes, leading to increased systemic estrogen levels, especially after menopause. Furthermore, microbiome dysbiosis was reported to be related to systemic inflammation through toll-like receptor signaling deficiencies and overexpression of pro-inflammatory cytokines. Conclusions: This review highlights that the female gut microbiome is intrinsically linked to estrogen levels, menopausal state and systemic inflammation, which indicates gut microbiome dysbiosis as a potential hallmark for risk stratification for endometrial cancer. Studies are needed to further define the role the gut microbiome plays in women at risk for endometrial cancer.

Persistent high-risk Human Papillomavirus infection is the primary factor in cervical carcinogenesis. However, other host-related features are believed to play a role as well. Recent research suggests that the vaginal microbiome and the immune microenvironment play a significant role in the acquisition and persistence of Human Papillomavirus infection, as well as in the regression or progression of cervical intraepithelial lesions. Studies in this emerging field describe factors associated with this interaction, though the precise nature remains incompletely understood. In this narrative review, we aim to summarize the current literature on the topic and propose hypotheses and recommendations for future research and treatment strategies.

Topical imiquimod could be an alternative, noninvasive, treatment modality for high-grade cervical intraepithelial neoplasia (CIN). However, evidence is limited, and there are no studies that compared treatment effectiveness and side effects of topical imiquimod cream to standard large loop excision of the transformation zone (LLETZ) treatment. A multi-center, nonrandomized controlled trial was performed among women with a histologic diagnosis of CIN 2/3. Women were treated with either vaginal imiquimod (6.25 mg 3 times weekly for 8 to 16 wk) or LLETZ according to their own preference. Successful treatment was defined as the absence of high-grade dysplasia at the first follow-up interval after treatment (at 20 wk for the imiquimod group and at 26 wk for the LLETZ group). Secondary outcome measures were high-risk human papillomavirus (hrHPV) clearance, side effects, and predictive factors for successful imiquimod treatment. Imiquimod treatment was successful in 60% of women who completed imiquimod treatment and 95% of women treated with LLETZ. hrHPV clearance occurred in 69% and 67% in the imiquimod group and LLETZ group, respectively. This study provides further evidence on topical imiquimod cream as a feasible and safe treatment modality for high-grade CIN. Although the effectiveness is considerably lower than LLETZ treatment, imiquimod treatment could prevent initial surgical treatment in over 40% of women and should be offered to a selected population of women who wish to avoid (repeated) surgical treatment of high-grade CIN.

Cervical high-grade squamous intraepithelial lesions (cHSILs) develop as a result of a persistent high-risk human papilloma virus (hrHPV) infection. The natural course of cHSIL is hard to predict, depending on a multitude of viral, clinical, and immunological factors. Local immunity is pivotal in the pathogenesis, spontaneous regression, and progression of cervical dysplasia; however, the underlying mechanisms are unknown. The aim of this review is to outline the changes in the immune microenvironment in spontaneous regression, persistence, and responses to (immuno)therapy. In lesion persistence and progression, the immune microenvironment of cHSIL is characterized by a lack of intraepithelial CD3+, CD4+, and CD8+ T cell infiltrates and Langerhans cells compared to the normal epithelium and by an increased number of CD25+FoxP3+ regulatory T cells (Tregs) and CD163+ M2 macrophages. Spontaneous regression is characterized by low numbers of Tregs, more intraepithelial CD8+ T cells, and a high CD4+/CD25+ T cell ratio. A ‘hot’ immune microenvironment appears to be essential for spontaneous regression of cHSIL. Moreover, immunotherapy, such as imiquimod and therapeutic HPV vaccination, may enhance a preexisting pro-inflammatory immune environment contributing to lesion regression. The preexisting immune composition may reflect the potential for lesion regression, leading to a possible immune biomarker for immunotherapy in cHSILs.

Objective: Vulvar cancer surgery is associated with high postoperative wound complication rates. Reconstructive surgery (RS) in vulvar cancer is generally reserved for surgery of extensive tumors or local recurrences. The primary aim of the study is to determine the incidence and risk factors for wound complications after vulvar cancer surgery. As a secondary aim, we compare the effects of primary closure (PC) versus reconstructive surgery on wound complications. Methods: In a retrospective cohort study in four gynecologic oncology centers in the Netherlands, patients undergoing surgical treatment (2018–2022) for vulvar cancer were included. Wound complications after PC and RS and risk factors associated with complications were analyzed by using logistic regression adjusting for confounds. Results: We included 394 women, 318 with PC and 76 with RS. The incidence of wound complications was 46.7%, with 42.4% of wound breakdowns comprising the majority of complications. The use of RS was associated with an increased risk of wound complications. Larger tumor size, proximity to the urethra, resection of the urethra during surgery, and perineal tumor location were additional risk factors for wound complications. However, after multivariate analyses, RS remained the only significant risk factor (OR 1.2; 95% CI 1.1–1.2). Conclusions: Risk factors for wound complications after vulvar cancer surgery include larger tumor size, proximity to the urethra, resection of the urethra during surgery, and perineal tumor location. RS is also associated with an increased risk of wound complications, probably related to case selection.

(1) Background: The worldwide endometrial cancer (EC) incidence is rising, amongst others linked to obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome, possibly due to low-grade adipose tissue inflammation. We studied immune cell infiltration in the endometrium in relation to diagnosis and obesity. (2) Methods: A cohort was created (n = 44) from postmenopausal women, lean (n = 15) and obese (n = 29), with bleeding complaints due to EC (n = 18) or benign pathology (n = 26). Endometrial biopsies were used to study the immune microenvironment and stained for macrophages (CD68 and CD163), T-cells (CD3 and CD8), and NK-cells (CD56). (3) Results: Malignant samples showed reduced intraepithelial CD3+ and CD8+ T-cells and increased stromal CD3+ T-cells. In obese patients, increased intraepithelial CD3+ and CD8+ T-cells were detected, especially in obese patients with T2DM. Epithelial CD56+ NK-cells were depleted in EC; however, no effect of obesity on NK-cell infiltration was observed. Stromal CD68+ cells were reduced in EC patients, whereas the CD163+ cells were increased. (4) Conclusions: Obesity and malignancy are associated with differences in immune cell presence. The alterations in immune cell infiltration seen in obese EC patients with and without diabetes suggest a complex interaction where obesity-related low-grade inflammation plays a central role.