Clinical significance of atypical glandular cells on cytology: 10 years' experience of a colposcopic referral center.

INTRODUCTION: 'Atypical glandular cells' (AGC) is an uncommon cytological result of cervical Pap smears which includes a wide of histopathological diagnoses, from benign to premalignant and malignant cervical disorders, endometrial cancer and, occasionally, other genital malignancies. This study aims to provide a comprehensive overview of AGC, assessing risk factors and clinical and histological features in affected patients. MATERIALS AND METHODS: A retrospective analysis was conducted on a cohort of 239 women diagnosed with AGC between 2012 and 2022 at the 'Regional Referral Center for Prevention, Diagnosis and Treatment of HPV-related Genital Disorders', Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Following AGC detection, patients underwent colposcopy with endocervical sampling and endometrial assessment via pelvic ultrasound. Selective cases also received endometrial biopsies. RESULTS: Among a total of 190 women who underwent both colposcopy and endometrial assessment, 116 (61%) had negative clinical and histopathological findings. The remainder displayed various abnormalities: 36 women (18.9%) were found to have endometrial or cervical polyps, 23 (12.1%) were diagnosed with preinvasive cervical neoplasia, and 21 (10.9%) with invasive cervical or endometrial disease. Menopause, multiparity, and older age were all significantly associated with endometrial cancer, but none of the abovementioned variables were significantly associated with cervical neoplasia. CONCLUSION: Our data confirm that AGC may reveal the presence of a wide range of histopathological conditions. Patients diagnosed with AGC should undergo a careful evaluation including both colposcopy with endocervical sampling and an endometrial assessment.

Potential anatomical determinants of retrograde menstruation: a comprehensive narrative review.

A century ago, Sampson identified three uterine anatomical structures that may determine the amount of retrograde menstruation and the likelihood of the development of endometriosis: the cervix, the intramural portion of the fallopian tubes, and the myometrium. Critical appraisal was undertaken of data published over the last 40 years on the potential effect of the characteristics of these three anatomical variables on the risk of endometriosis. There is some evidence to support the pathogenic role of the diameter of the cervical canal, stenosis of internal or external orifices, and stiffness of cervical tissue. One study showed a significant association between the morphology of the intramural tubal tract and the frequency of endometriosis. A large body of evidence points to abnormalities of the myometrial structure as the anatomical aberration most consistently associated with endometriosis. These abnormalities have largely been interpreted as signs of early-onset adenomyosis, which may precede endometriosis and even lead to its development by increasing the amount of retrograde menstruation. Future research should aim to verify whether a positive relationship exists between the substantially increased number of ovulatory menses occurring in the decade following menarche, the development of anatomical myometrial abnormalities, changes in the amount of retrograde menstruation over time, and the risk of endometriosis.

Artificial Intelligence in the Management of Women with Endometriosis and Adenomyosis: Can Machines Ever Be Worse Than Humans?

Artificial intelligence (AI) is experiencing advances and integration in all medical specializations, and this creates excitement but also concerns. This narrative review aims to critically assess the state of the art of AI in the field of endometriosis and adenomyosis. By enabling automation, AI may speed up some routine tasks, decreasing gynecologists' risk of burnout, as well as enabling them to spend more time interacting with their patients, increasing their efficiency and patients' perception of being taken care of. Surgery may also benefit from AI, especially through its integration with robotic surgery systems. This may improve the detection of anatomical structures and enhance surgical outcomes by combining intra-operative findings with pre-operative imaging. Not only that, but AI promises to improve the quality of care by facilitating clinical research. Through the introduction of decision-support tools, it can enhance diagnostic assessment; it can also predict treatment effectiveness and side effects, as well as reproductive prognosis and cancer risk. However, concerns exist regarding the fact that good quality data used in tool development and compliance with data sharing guidelines are crucial. Also, professionals are worried AI may render certain specialists obsolete. This said, AI is more likely to become a well-liked team member rather than a usurper.

Questionnaires for the Assessment of Central Sensitization in Endometriosis: What Is the Available Evidence? A Systematic Review with a Narrative Synthesis.

It has been suggested that central sensitization (CS) may be involved in the failure of standard medical and surgical treatment to relieve endometriosis-related pain. However, there is no gold standard for the diagnosis of CS, and self-reported questionnaires are used as diagnostic surrogates. The main objective of this review was to identify all CS questionnaires used in clinical endometriosis studies. The secondary objective was to qualitatively analyze strengths and weaknesses of each questionnaire. A PubMed and EMBASE systematic literature search conducted in April 2023 using the terms "endometriosis; central pain; central sensitization; questionnaire; patient-reported outcome measure; screening tool" identified 122 publications: six articles were included in the review. The Central Sensitization Inventory (CSI) is the most frequently used questionnaire for the detection of CS in patients with endometriosis. It has been validated in patients with endometriosis, in whom it appears to have good psychometric proprieties. The Fibromyalgia Survey Questionnaire (FSQ) has also been used, although it has not been specifically validated in endometriosis patients. The debate regarding these questionnaires' construct validity is still open and will be so until a gold standard diagnostic tool for CS is found. In fact, some authors argue these questionnaires are measuring psychological vulnerability and a hypervigilant state that is associated with pain, rather than CS itself. However, their use should not be discouraged as they are able to identify chronic pain patients which warrant further attention and who may benefit from broader treatment strategies.

Proposal for targeted, neo-evolutionary-oriented secondary prevention of early-onset endometriosis and adenomyosis. Part II: medical interventions.

According to consistent epidemiological data, the slope of the incidence curve of endometriosis rises rapidly and sharply around the age of 25 years. The delay in diagnosis is generally reported to be between 5 and 8 years in adult women, but it appears to be over 10 years in adolescents. If this is true, the actual onset of endometriosis in many young women would be chronologically placed in the early postmenarchal years. Ovulation and menstruation are inflammatory events that, when occurring repeatedly for years, may theoretically favour the early development of endometriosis and adenomyosis. Moreover, repeated acute dysmenorrhoea episodes after menarche may not only be an indicator of ensuing endometriosis or adenomyosis, but may also promote the transition from acute to chronic pelvic pain through central sensitization mechanisms, as well as the onset of chronic overlapping pain conditions. Therefore, secondary prevention aimed at reducing suffering, limiting lesion progression, and preserving future reproductive potential should be focused on the age group that could benefit most from the intervention, i.e. severely symptomatic adolescents. Early-onset endometriosis and adenomyosis should be promptly suspected even when physical and ultrasound findings are negative, and long-term ovulatory suppression may be established until conception seeking. As nowadays this could mean using hormonal therapies for several years, drug safety evaluation is crucial. In adolescents without recognized major contraindications to oestrogens, the use of very low-dose combined oral contraceptives is associated with a marginal increase in the individual absolute risk of thromboembolic events. Oral contraceptives containing oestradiol instead of ethinyl oestradiol may further limit such risk. Oral, subcutaneous, and intramuscular progestogens do not increase the thromboembolic risk, but may interfere with attainment of peak bone mass in young women. Levonorgestrel-releasing intra-uterine devices may be a safe alternative for adolescents, as amenorrhoea is frequently induced without suppression of the ovarian activity. With regard to oncological risk, the net effect of long-term oestrogen-progestogen combinations use is a small reduction in overall cancer risk. Whether surgery should be considered the first-line approach in young women with chronic pelvic pain symptoms seems questionable. Especially when large endometriomas or infiltrating lesions are not detected at pelvic imaging, laparoscopy should be reserved to adolescents who refuse hormonal treatments or in whom first-line medications are not effective, not tolerated, or contraindicated. Diagnostic and therapeutic algorithms, including self-reported outcome measures, for young individuals with a clinical suspicion of early-onset endometriosis or adenomyosis are proposed.

Correlation Between Colposcopic Patterns and Histological Grade of Vaginal Intraepithelial Neoplasia: A Retrospective Cohort Study.

BACKGROUND/AIM: Vaginal intraepithelial neoplasia (VaIN) is a rare human papillomavirus (HPV)- related premalignant condition. VaIN lesions are diagnosed histologically through colposcopy-guided biopsies of suspicious areas, conduced by gynecologists with expertise in lower genital tract diseases. The present study aimed to evaluate the accuracy of colposcopy in the diagnosis of VaIN of any grade. PATIENTS AND METHODS: We conducted a retrospective analysis on a cohort of 149 women diagnosed with low grade (LG)-VaIN (VaIN1) and high grade (HG)-VaIN (VaIN2-3) between 2010 and 2022 at the "Regional Referral Center for Prevention, Diagnosis and Treatment of HPV-related Genital Disorders", Ospedale Maggiore Policlinico, Milan, Italy. All women had been referred to our center for an abnormal Pap smear or as part of routine follow-up of other HPV-related diseases and had undergone a vaginal biopsy under colposcopic guidance. RESULTS: The distribution of the histological grades of VaIN lesions was the following: 62 women (41.6%) were diagnosed with VaIN1, 51 (34.2%) with VaIN2, and 36 (24.2%) with VaIN3. Grade II (major) abnormal colposcopic patterns were recorded in 71 cases (47.7%) and were more commonly observed in women with VaIN3 (80.6%). However, we found a poor and not statistically significant association between colposcopic and histological grade of VaIN. The sensitivity, specificity, positive predictive value, and negative predictive value of colposcopy for histologically confirmed VaIN were 56.3%, 64.5%, 69% and 51.2%, respectively. The overall diagnostic accuracy of colposcopy was 59.7%. CONCLUSION: Colposcopy-guided biopsy plays an important role in the diagnosis of VaIN and in the distinction between low and high-grade lesions. Our data show that major colposcopic abnormalities moderately correlate with HG-VaIN and that grade I colposcopic findings do not exclude HG-VaIN, especially VaIN2. Targeted biopsies of suspicious vaginal areas must be performed in all women with an abnormal Pap smear.

Fat Grafting in Vulvar Lichen Sclerosus: Long Term Follow-Up.

OBJECTIVE: The rationale for the use of autologous fat grafting in the treatment of vulvar lichen sclerosus (VLS) consists in reduction of inflammation, regeneration of tissues, volume increase, and pain fiber control. The main outcome of this study was the evaluation of patients' satisfaction after treatment. Secondary outcomes included modifications in symptoms, psychosexual wellbeing, vulvar hydration, and histology after surgery. METHODS: Eligible for this study were women aged 18-85 years with a histological diagnosis of VLS who underwent at least one autologous vulvar fat grafting at the authors' center, between 2010 and 2019. In 2021, all women underwent a clinical reevaluation, comprehensive of vulvoscopy, vulvar biopsy, and handing out of validated questionnaires. RESULTS: Overall, 88.7% of patients declared themselves very satisfied/satisfied with the procedure. All symptoms were improved postsurgery; in particular, the difference was statistically significant for pruritus, burning, and dyspareunia ( p < .05). Sexual function was also improved at time of reevaluation, as were depressive and anxiety symptoms ( p < .05). No cases of vulvar intraepithelial neoplasia or cancer occurred during follow-up and vulvar architecture remained stable, although patients reported a significantly reduced need for topical steroids ( p < .0001). Lastly, in postoperative biopsies, inflammatory infiltrate was stable or reduced, and the distribution of elastic fibers was comparable or restored in most patients. CONCLUSIONS: Patient satisfaction with fat grafting is detectable up to 11 years after surgery, and as such, it may represent a valid therapeutic option in selected cases of VLS.

Non-response to first-line hormonal treatment for symptomatic endometriosis: overcoming tunnel vision. A narrative review.

One-fourth to one-third of women with endometriosis receiving first-line hormonal treatment lacks an adequate response in terms of resolution of painful symptoms. This phenomenon has been ascribed to "progesterone resistance", an entity that was theorized to explain the gap between the ubiquity of retrograde menstruation and the 10% prevalence of endometriosis among women of reproductive age.Nevertheless, the hypothesis of progesterone resistance is not free of controversies. As our understanding of endometriosis is increasing, authors are starting to set aside the traditionally accepted tunnel vision of endometriosis as a strictly pelvic disease, opening to a more comprehensive perspective of the condition. The question is: are patients not responding to first-line treatment because they have an altered signaling pathway for such treatment, or have we been overlooking a series of other pain contributors which may not be resolved by hormonal therapy?Finding an answer to this question is evermore impelling, for two reasons mainly. Firstly, because not recognizing the presence of further pain contributors adds a delay in treatment to the already existing delay in diagnosis of endometriosis. This may lead to chronicity of the untreated pain contributors as well as causing adverse consequences on quality of life and psychological health. Secondly, misinterpreting the consequences of untreated pain contributors as a non-response to standard first-line treatment may imply the adoption of second-line medical therapies or of surgery, which may entail non-negligible side effects and may not be free of physical, psychological and socioeconomic repercussions.The current narrative review aims at providing an overview of all the possible pain contributors in endometriosis, ranging from those strictly organic to those with a greater neuro-psychological component. Including these aspects in a broader psychobiological approach may provide useful suggestions for treating those patients who report persistent pain symptoms despite receiving first-line hormonal medical treatment.

High-grade vaginal intraepithelial neoplasia and recurrence risk: analysis of an Italian regional referral center series.

PURPOSE: The main aim of this study was to investigate the long-term risk of disease recurrence in women treated for high-grade vaginal intraepithelial neoplasia (HG-VaIN). METHODS: We conducted a retrospective analysis on a cohort of 82 women diagnosed with HG-VaIN between 2010 and 2021 at the "Regional Referral Center for Prevention, Diagnosis and Treatment of HPV-related Genital Disorders", Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. All women underwent either ablative treatment (CO2 laser ablation or electrocoagulation) or cold-knife excision. RESULTS: In our series, the recurrence rate following treatment was 17%. The 5-year cumulative probability of recurrence was 30.4% and the median time to recurrence was 15.5 months. None of the patients progressed to invasive vaginal cancer during follow-up. A concomitant cervical or vulvar intraepithelial lesion was significatively associated with an increased risk of recurrence (p = 0.006). CONCLUSIONS: The results of our study suggest that women with HG-VaIN are at high risk of developing disease recurrence after treatment, especially patients with a concomitant cervical or vulvar intraepithelial lesion. In these women strict monitoring is mandatory to obtain an early identification of recurrence.

Novel pharmacological therapies for the treatment of endometriosis.

INTRODUCTION: Endometriosis is a chronic, estrogen-dependent, inflammatory disease associated with pelvic pain, infertility, impaired sexual function, and psychological suffering. Therefore, tailored patient management appears of primary importance to address specific issues and identify the appropriate treatment for each woman. Over the years, abundant research has been carried out with the objective to find new therapeutic approaches for this multifaceted disease. AREAS COVERED: This narrative review aims to present the latest advances in the pharmacological management of endometriosis. In particular, the potential role of GnRH antagonists, selective progesterone receptor modulators (SPRMs), and selective estrogen receptors modulators (SERMs) will be discussed. We performed a literature search in PubMed and Embase, and selected the best quality evidence, giving preference to the most recent and definitive original articles and reviews. EXPERT OPINION: Medical therapy represents the cornerstone of endometriosis management, although few advances have been made in the last decade. Most studies have focused on the evaluation of the efficacy and safety of GnRH antagonists (plus add-back therapy in cases of prolonged treatment), which should be used as second-line treatment options in selected cases (i.e. non-responders to first-line treatments). Further studies are needed to identify the ideal treatment for women with endometriosis.