Uterine fibroid vascularization: from morphological evidence to clinical implications.

Uterine fibroids are the most common cause of solid pelvic tumours, occurring in 20-30% of fertile women and presenting clinical complications that seriously affect women's health. They commonly cause severe symptoms, such as heavy, prolonged menstrual bleeding and anaemia. The study of microscopic and macroscopic vascular aspects of uterine fibroids is important for understanding the clinical manifestations of uterine fibroids, for predicting the effectiveness of alternative treatments to surgery, i.e. uterine artery embolization, for improving surgery outcomes and for carrying out a differential diagnosis with other benign conditions, e.g. adenomyosis, or malignancy, e.g. leiomyosarcoma, and to develop new therapeutic approaches. In this review, current knowledge of how the vascular network and angiogenesis are implied in the formation of uterine fibroids and in the pathogenesis of related symptoms is explored, and evidence on the role of ultrasound in evaluating fibroid vascularization is summarized. This review combines anatomical, morphological and biomolecular information related to angiogenic mechanisms with diagnostic and clinical information, highlighting the various interconnections. Uterine and fibroid vascularization need further investigation to gain a deeper understanding of the pathogenetic elements that lead to the formation of uterine fibroids and their clinical manifestations.

HPV-Negative Adenocarcinomas of the Uterine Cervix: From Molecular Characterization to Clinical Implications.

Cervical cancer is the fourth most common cancer in women. It is the leading cause of female deaths in developing countries. Most of these cervical neoplasms are represented by squamous lesions. Cervical adenocarcinoma causes about a quarter of cervical cancers. In contrast to squamous lesions, cervical glandular disease is HPV-negative in about 15-20% of cases. HPV-negative cervical adenocarcinomas typically present in advanced stages at clinical evaluation, resulting in a poorer prognosis. The overall and disease-free survival of glandular lesions is lower than that of squamous lesions. Treatment options require definitive treatments, as fertility-sparing is not recommended. Moreover, the impact of HPV vaccination and primary HPV screening is likely to affect these lesions less; hence, the interest in this challenging topic for clinical practice. An updated review focusing on clinical and molecular characterization, prognostic factors, and therapeutic options may be helpful for properly managing such cervical lesions.

Ultrasound Appearance of Intravascular Uterine Smooth Muscle Tumor of Uncertain Malignant Potential (STUMP): A Case Report.

A 43-year-old patient with a history of uterine fibromatosis was referred to our hospital for menometrorrhagia and pelvic pain. At the pelvic ultrasound, a highly-vascularized myometrial lesion in volumetric increase was described. An elongated, solid, hypoechoic, painless, and highly vascularized left parauterine mass was identified. On histological examination, a uterine smooth muscle tumor of uncertain malignant potential (STUMP) with intravascular invasion of the left uterine vein was diagnosed. The adnexa and peritoneum were free of disease. On a retrospective evaluation of the ultrasound images, we noticed that the intravascular lesion showed sonographic features comparable to the original mass. Moreover, the Color Doppler (CD) analysis revealed an interrupted blood flow within the left uterine vein. In this case, the ultrasound proved to be an accurate diagnostic tool. When inhomogeneous uterine masses are suspected, and a parauterine/paraadnexal mass surrounded by irregular vessels are identified, the sonographer should take into account a risk of intravascular invasion. The patency of uterine and ovarian vessels should be accurately evaluated, to guide a tailored patient surgical approach.

Atypical Endometrial Hyperplasia and Concurrent Cancer: A Comprehensive Overview on a Challenging Clinical Condition.

The present review regarding atypical endometrial hyperplasia (AEH) focused on the main debated factors regarding this challenging clinical condition: (i) predictive variables of occult endometrial cancer (EC); (ii) the rate of EC underestimation according to different endometrial sampling methods; and (iii) the appropriateness of lymph node status assessment. When cancer is detected, approximately 90% of cases include low-risk EC, although intermediate/high-risk cases have been found in 10-13% of women with cancer. Older age, diabetes, high BMI, and increased endometrial thickness are the most recurrent factors in women with EC. However, the predictive power of these independent variables measured on internal validation sets showed disappointing results. Relative to endometrial sampling methods, hysteroscopic endometrial resection (Hys-res) provided the lowest EC underestimation, ranging between 6 and 11%. Further studies, including larger sample sizes of women undergoing Hys-res, are needed to confirm these findings. These data are urgently needed, especially for female candidates for conservative treatment. Finally, the evaluation of lymph node status measured on 660 of over 20,000 women showed a lymph node positivity of 2.3%. Although there has been an increase in the use of this procedure in AEH in recent years, the present data cannot recommend this option in AEH based on a cost/risk/benefit ratio.

Long-Term Follow-Up Outcomes in Women with In Situ/Microinvasive Adenocarcinoma of the Uterine Cervix Undergoing Conservative Treatment-Cervical Adenocarcinoma Study Group Italian Society of Colposcopy and Cervico-Vaginal Pathology.

OBJECTIVE: The present study aimed to assess long-term follow-up outcomes in women with in situ/microinvasive adenocarcinoma (AC) of the uterine cervix treated conservatively. METHODS: Retrospective multi-institutional study including women with early glandular lesions and 5-year follow-up undergoing fertility-sparing treatment. Independent variables associated with recurrence were evaluated. Logistic regression analysis and Kaplan-Meier survival analysis with Logrank test were performed. RESULTS: Of 269 women diagnosed with in situ/microinvasive AC, 127 participants underwent conservative treatment. During follow-up, recurrences were found in nine women (7.1%). The only factor associated with recurrence during follow-up was positive high-risk Human Papillomavirus (hr-HPV) testing (odds ratio 6.21, confidence interval 1.47-26.08, p = 0.012). HPV positivity in follow-up showed a recurrence rate of 21.7% against 3.8% in patients who were HPV-negative (p = 0.002, Logrank test). Among women with negative high-risk HPV tests in follow-up, recurrences occurred in 20.0% of non-usual-type histology vs. 2.1% of usual-type cases (p = 0.005). CONCLUSION: HPV testing in follow-up is of pivotal importance in women with early glandular lesions undergoing conservative treatment, given its recurrence predictive value. However, women who are high-risk HPV-negative in follow-up with non-usual-type histopathology may represent a sub-population at increased risk of recurrences. Further studies should confirm these findings.

Microbiome Changes in Pregnancy Disorders.

The human microbiota comprises all microorganisms, such as bacteria, fungi, and viruses, found within a specific environment that live on our bodies and inside us. The last few years have witnessed an explosion of information related to the role of microbiota changes in health and disease. Even though the gut microbiota is considered the most important in maintaining our health, other regions of the human body, such as the oral cavity, lungs, vagina, and skin, possess their own microbiota. Recent work suggests a correlation between the microbiota present during pregnancy and pregnancy complications. The aim of our literature review was to provide a broad overview of this growing and important topic. We focused on the most significant changes in the microbiota in the four more common obstetric diseases affecting women's health. Thus, our attention will be focused on hypertensive disorders, gestational diabetes mellitus, preterm birth, and recurrent miscarriage. Pregnancy is a unique period in a woman's life since the body undergoes different adaptations to provide an optimal environment for fetal growth. Such changes also involve all the microorganisms, which vary in composition and quantity during the three trimesters of gestation. In addition, special attention will be devoted to the potential and fundamental advances in developing clinical applications to prevent and treat those disorders by modulating the microbiota to develop personalized therapies for disease prevention and tailored treatments.

Concurrent Endometrial Cancer in Women with Atypical Endometrial Hyperplasia: What Is the Predictive Value of Patient Characteristics?

BACKGROUND: The rate of concurrent endometrial cancer (EC) in atypical endometrial hyperplasia (AEH) can be as high as 40%. Some patient characteristics showed associations with this occurrence. However, their real predictive power with related validation has yet to be discovered. The present study aimed to assess the performance of various models based on patient characteristics in predicting EC in women with AEH. METHODS: This is a retrospective multi-institutional study including women with AEH undergoing definitive surgery. The women were divided according to the final histology (EC vs. no-EC). The available cases were divided into a training and validation set. Using k-fold cross-validation, we built many predictive models, including regressions and artificial neural networks (ANN). RESULTS: A total of 193/629 women (30.7%) showed EC at hysterectomy. A total of 26/193 (13.4%) women showed high-risk EC. Regression and ANN models showed a prediction performance with a mean area under the curve of 0.65 and 0.75 on the validation set, respectively. Among the best prediction models, the most recurrent patient characteristics were age, body mass index, Lynch syndrome, diabetes, and previous breast cancer. None of these independent variables showed associations with high-risk diseases in women with EC. CONCLUSIONS: Patient characteristics did not show satisfactory performance in predicting EC in AEH. Risk stratification in AEH based mainly on patient characteristics may be clinically unsuitable.

Recurrence of Uterine Smooth Muscle Tumor of Uncertain Malignant Potential: A Systematic Review of the Literature.

Background: This study aimed to systematically review the existing literature on uterine smooth muscle tumor of uncertain malignant potential (STUMP) to provide information about characteristics and outcomes of patients and the risk factors for recurrence over a period of 60 years (1960−2021). Methods: According to PRISMA guidelines, we searched for "uterine smooth muscle tumor of uncertain malignant potential" in PubMed (all fields) and Scopus (Title/Abstract/Keywords) databases (accessed on 1 January 2022). Relevant articles were obtained in full-text format and screened for additional references. The only filter used was the English language. Studies including full case description of patients with histopathological diagnosis of STUMP in accordance with Stanford criteria were included. Results: Thirty-four studies, including 189 cases, were included. The median age was 43 years, and in 21.5% of cases there was a recurrence of the disease. Bivariate analysis showed a significant association between use of morcellation without bag and risk of recurrence (p = 0.001). Unprotected morcellation during demolitive or conservative surgery was independently associated with a higher risk of disease recurrence with a relative risk of 2.94 (p < 0.001). A significant progressive decrease in the recurrence rate was observed over time (r = −0.671, p = 0.008). The percentage of patients who underwent surgery followed by in-bag protected morcellation significantly increased after the publication of the U.S. Food and Drug Administration alert about the risk linked to this procedure (p = 0.01). Conclusions: Unprotected morcellation of the lesion is associated with the relapse of the disease. However, this clinical condition showed a drastic decrease over time. This could likely be due to the increased awareness by surgeons of the importance of customizing surgical treatment.

Malignant Transformation of Postmenopausal Endometriosis: A Systematic Review of the Literature.

Objective: This study aimed to systematically review the existing literature on malignant transformation of postmenopausal endometriosis to provide information about patient characteristics, hormonal replacement therapy (HRT) use, and outcomes over a period of 52 years (1969-2021). Methods: According to PRISMA guidelines, we searched for (endometriosis OR endometriotic) AND (cancer OR malignancy OR malignant transformation) AND (menopause OR menopausal OR postmenopause OR postmenopausal) in Pubmed (all fields) (accessed on 12 February 2021) and Scopus (Title/Abstract/Keywords) (accessed on 12 February 2021) databases. The only filter used was the English language. Relevant articles were obtained in full-text format and screened for additional references. Eligibility/inclusion criteria: studies including full case description of malignant transformation of endometriosis-related lesions in postmenopause. Results: 75 studies, including 90 cases, were retrieved. The mean age was 55.8 ± 8.5 years. Overall, about 65% of women had a positive personal history of endometriosis/adenomyosis, and 64% of women underwent previous hysterectomy ± bilateral salpingo-oophorectomy. Forty-nine of 74 women used HRT (66.2%). Among the women who used HRT, estrogen-only treatment was taken by approximately 75%. Duration of HRT was longer than five years in 63.3% of cases. About 70% of subjects had histology of endometrioid adenocarcinoma or clear cell carcinoma. Follow-up outcome, available for 61 women, showed a survival rate of 78.7%, recurrence of 9.8%, death of 11.5%. The duration of follow-up had a median of 12 months (interquartile range, 6.75-25 months). Interestingly, over the years of case publication there was a significant inverse correlation with previous history of endometriosis (r = -0.28, p = 0.007), HRT use (r = -0.31, p = 0.006), and previous definitive surgery (r = -0.42, p < 0.001). Conclusions: In the malignant transformation of postmenopausal endometriosis, there are some recurrent clinical conditions: previous endometriosis, major definitive surgery before menopause, and estrogen-only HRT for a relatively long time. However, these clinical conditions have shown a drastic decrease over time. This could likely be the consequence of different attitudes and management of gynecologists linked to up-to-date scientific evidence about the use of major surgery in gynecological pathologies. Malignant transformation of postmenopausal endometriosis is a clinical challenge to be explored further.

Comparison of uterine fibroids' growth pattern during pregnancy according to fetal sex: an observational study.

BACKGROUND: To investigate the effect of fetal sex on fibroids' growth during pregnancy according to the hCG serum levels METHODS: Observational study conducted from January 2007 to December 2016 on women with ultrasound identification of uterine fibroids who had a pregnancy within 1 year from diagnosis. The fibroids diameter was determined during the pre-pregnancy ultrasound, early first trimester (5-7 weeks), late first trimester (11-13 weeks), second trimester (19-21 weeks), and third trimester (31-33 weeks). The diameter growth was calculated in each interval between two ultrasounds. The hCG serum levels were determined both in early and late first trimester. The correlation between hCG levels and fibroid diameter was evaluated. Obstetric outcomes collected were gestational weeks at birth and the rate of cesarean section. Neonatal outcomes were birthweight and Apgar score at 1 min. RESULTS: Eighty-seven of the included women had a male fetus, and 70 had a female fetus. A progressive increase of fibroid diameter was observed from pre-pregnancy to second trimester for both fetal sexes. In third trimester, the mean ± SD fibroid diameter of female fetuses showed a slowdown, while the mean ± SD fibroid diameter of male fetuses continued to grow. Women carrying a female fetus presented a higher fibroid diameter in early first trimester (33.5 ± 13.3 mm vs 27.4 ± 11.0 mm, p < 0.01), late first trimester (40.2 ± 13.9 mm vs 34.6 ± 11.7 mm, p < 0.01), and second trimester (40.5 ± 14.9 mm vs 34.7 ± 10.3 mm, p < 0.01). The hCG serum levels resulted higher in women with a female fetus: 61406 (50554-71760) mU/ml vs 46016 (37160-56744) mU/ml (p < 0.01). A positive correlation between hCG levels and fibroid diameter was found both for male and female fetuses (male r = 0.77, 95% CI 0.71-0.82, p < 0.01 and female r = 0.82, 95% CI 0.76-0.86, p < 0.01). CONCLUSION: Women with female fetus seem to have a higher growth of fibroids up to second trimester of pregnancy. This process may be mediated by the higher serum hCG levels found in women expecting a female fetus.

The association between childbirth, breastfeeding, and uterine fibroids: an observational study.

The aim of this study was to investigate the effect of childbirth and breastfeeding on uterine fibroids and to identify the factors associated with size variations. This was a monocenter observational study carried on women with a sonographic diagnosis of uterine fibroids from January 2007 to December 2016, with no indication for immediate treatment, and who became pregnant within one year from diagnosis. All patients were re-evaluated six months after delivery. Fibroid diameters were compared between pre-pregnancy period, first, second, third trimester and post-delivery. The rate of "regressed" (growth of diameter <-40%), "unchanged" (growth of diameter between -40% and +40%) or "increased" (growth of diameter >+40%) fibroids at the post-delivery evaluation with respect to the pre-pregnancy state was calculated. One-hundred fifty-seven women were included in the final analysis. At the post-delivery ultrasound, a significant reduction of the fibroid diameter with respect to all previous examinations was observed, and there was no evidence of 67 (37.2%) fibroids. Ongoing breastfeeding was positively associated with an "unchanged" or "regressed" fibroid diameter (adOR 3.23, 95%CI: 1.35-7.70, p < 0.01). Smaller pre-gravidic fibroids were more likely to return to pre-pregnancy dimensions or to regress, with a cut-off of 32 mm for lactating women and of 26 mm for non-lactating women. In conclusion, fibroids seem to return to pre-pregnancy dimensions or to regress in the post-partum period. This process may be sustained by uterine involution and hormonal variations, with an additional role of breastfeeding.