Jacopo Di Giuseppe

Uterine Fibroids: Pathogenesis and Interactions with Endometrium and Endomyometrial Junction

Uterine leiomyomas (fibroids or myomas) are benign tumors of uterus and clinically apparent in a large part of reproductive aged women. Clinically, they present with a variety of symptoms: excessive menstrual bleeding, dysmenorrhoea and intermenstrual bleeding, chronic pelvic pain, and pressure symptoms such as a sensation of bloatedness, increased urinary frequency, and bowel disturbance. In addition, they may compromise reproductive functions, possibly contributing to subfertility, early pregnancy loss, and later pregnancy complications. Despite the prevalence of this condition, myoma research is underfunded compared to other nonmalignant diseases. To date, several pathogenetic factors such as genetics, microRNA, steroids, growth factors, cytokines, chemokines, and extracellular matrix components have been implicated in the development and growth of leiomyoma. This paper summarizes the available literature regarding the ultimate relative knowledge on pathogenesis of uterine fibroids and their interactions with endometrium and subendometrial myometrium.

Number and size of uterine fibroids and obstetric outcomes

Abstract Objective: Estimating the impact of sonographically identified multiple or large (≥5 cm in diameter) fibroids on obstetric outcomes. Methods: Retrospective cohort study of 219 women with uterine fibroids (identified on a routine second-trimester ultrasound survey over a 3-year period, 2010–2012) and their age-matched controls. Inclusion criteria were singleton pregnancy, delivery at >24 weeks of gestation and no pathological conditions (chronic hypertension, gestational diabetes or pre-existing diabetes mellitus, uterine anomalies or fetal malformations). Results: Compared to women with no fibroids, women with multiple fibroids (n = 34) had a significantly higher rate of preterm birth (29.4% versus 5%, p < 0.001), cesarean section (73.5% versus 37%, p < 0.001) and breech presentation (11.8% versus 2.7%, p = 0.04). Women with large fibroids (n = 48) had a higher rate of preterm birth (16.7% versus 5%, p = 0.01) and pPROM (10.4% versus 0.5%, p < 0.001). By multivariate analysis, only multiple fibroids and previous preterm birth showed an independent significant association with preterm birth (OR = 7.37, 95% CI 2.50–21.68 and OR = 13.01, 95% CI 3.56–47.52, respectively). Conclusions: Women with uterine fibroids are at an increased risk of obstetric complications. In particular, multiple rather than large fibroids are associated with a significantly increased risk of preterm birth and cesarean delivery while large fibroids are associated with a higher risk of pPROM. No correlation with IUGR, placenta previa or placental abruption was found.

Loop electrosurgical excision procedure and risk of miscarriage

OBJECTIVE To evaluate the risk of miscarriage in the subsequent pregnancy after a loop electrosurgical excision procedure (LEEP), also considering time elapsed from LEEP to pregnancy. DESIGN Multicenter, retrospective cohort study. SETTING Tertiary care university hospitals. PATIENT(S) Women who had undergone LEEP from January 2000 to December 2011. Women with histologic assessment of low-grade cervical dysplasia, not requiring subsequent surgical treatment, constituted the control group. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) The first pregnancy after the procedure was evaluated, and only women with singleton spontaneous pregnancies were considered. Women with time intervals of <12 months and women with intervals of ≥12 months or more from LEEP to pregnancy were then compared, to identify adjusted odds ratios for miscarriage. RESULT(S) In women previously treated with LEEP, a total of 116 cases of miscarriage (18.1%) was reported. The mean time interval from LEEP to pregnancy for women with miscarriage compared with women without miscarriage was significantly shorter (25.1 ± 11.7 months vs. 30.1 ± 13.3 months). A higher rate of miscarriage in women with a LEEP-to-pregnancy interval of <12 months compared with controls emerged (28.2% vs. 13.4%; adjusted odds ratio 2.60, 95% confidence interval 1.57-4.3). No significant difference in the rate of miscarriage in women with a LEEP-to-pregnancy interval of ≥12 months compared with controls emerged. CONCLUSION(S) Women with a time interval from LEEP to pregnancy of <12 months are at increased risk for miscarriage.

Surgical Treatment of Paget Disease of the Vulva: Prognostic Significance of Stromal Invasion and Surgical Margin Status.

ObjectiveThe aim of the study was to evaluate the risk of recurrence according to the surgical margin status and the presence of invasion or of superficially invasive carcinoma in patients with extramammary Paget disease (EMPD) of the vulva, who underwent elective surgical treatment. Materials and MethodsWe performed a retrospective analysis of 27 patients with first diagnosis of extramammary Paget disease of the vulva, who underwent primary and elective surgical treatment from January 1989 to December 2014. A p value of less than .05 was considered statistically significant. Multivariable logistic regression was performed to adjust for confounding factors. ResultsWe observed invasive disease in 11 cases, with microinvasion in 8 of them. A positive surgical margin was found in 10 patients. During a median follow-up period of 79.5 months, 8 patients (29.6%) showed a first recurrence after a median (range) time of 4.9 (2.3–7.1) years. No significant differences were observed between patients with recurrence and patients without recurrence with respect to age, number of vulvar sectors involved, bilaterality and multifocality, presence of invasion or microinvasion, and surgical margin status. However, during the follow-up period, the presence of invasion was higher (67% vs 41%) in patients with recurrence compared with patients without recurrence. ConclusionsThe rate of recurrence of the disease after therapy is high. Patients should be subjected to a close and long-term follow-up to identify those who must undergo further treatment, especially if they presented with an invasive or even microinvasive disease. A free margin of no greater than 1 to 2 cm might be the most appropriate surgical choice.

Topical Imiquimod 5% cream therapy for external anogenital warts in pregnant women: Report of four cases and review of the literature

Objectives: Imiquimod 5% cream (Aldara, Meda Farm, Milan, Italy) is largely used for the treatment of anogenital warts. However, its use during pregnancy is not consolidated with only a small number of patients worldwide that have been treated. The aim of this study is to assess the first line therapeutic efficacy and safety of Imiquimod 5% cream in pregnant women with external anogenital warts, including extensive condylomata. Study design: Four pregnant women’s with external anogenital warts were treated with Imiquimod 5% cream, three times a week for four weeks. Results: Mean number of warts treated per patient was 4.5 (5 SD) and mean area treated was 3.2 cm2 (1.7 SD). A complete response was observed in two women, while two women had a partial response with a rate of clearing of 70% and 84% respectively. No cases of severe adverse local effects were observed in the sites of Imiquimod application. No adverse fetal outcomes or fetal and neonatal abnormalities were observed. No complications were observed in the postpartum and follow-up period. Conclusions: Anogenital warts treatment with Imiquimod in pregnancy seems to be promising and not compromise a good pregnancy outcome, in extensive condylomata too. These preliminary data need to be confirmed by larger studies. Similarly, no definitive conclusion may be obtained form a systematic review of the English literature.

Laser Excisional Treatment for Vaginal Intraepithelial Neoplasia to Exclude Invasion: What Is the Risk of Complications?

Objective We undertook a retrospective analysis of the incidence of complications of carbon dioxide (CO2) laser excision for high-grade vaginal intraepithelial neoplasia (HG-VaIN). Materials and Methods Retrospective large case series on 128 CO2 laser excisions for HG-VaIN in 106 women treated at the Department of Gynecologic Oncology, Oncologic Referral Center, Aviano, Italy. These procedures were performed under local anesthesia with a 20-W continuous laser beam focused to a 0.2-mm spot size. Complications were defined as “minor” when limited to vagina, and “major” when surrounding organs were injured or the vaginal vault was opened. To identify possible factors associated with surgical complications, we performed a univariate analysis with the t test for continuous variables and &khgr;2 or Fisher exact test for qualitative variables as appropriate. Results The overall rate of complication was 7.8% (10/128); nine of them were vaginal bleeding, and only one (0.8%) was a major complication with vaginal vault perforation. A greater number of previous destructive treatments and of two or more previous laser vaginal excisional treatments was present in patients with complications compared with ones without complications (10% vs 3.9 %, p = .92, and 30% vs 15.2%, p = .44, respectively), although these differences were not statistically significant. A total of 10.5% (6/57) of occult vaginal cancer was detected in women with initial diagnosis of VaIN3 (HG-VaIN) on biopsy. Conclusions Carbon dioxide laser excision for HG-VaIN seems to be a safe approach with low rate of complications, probably because of the better accuracy achieved by CO2 laser resections, and permits diagnosis of occult invasive disease.

Cervical intraepithelial neoplasia in pregnancy: Interference of pregnancy status with p16 and Ki-67 protein expression

To date, there are evidence-based guidelines available for cervical dysplasia diagnosed in pregnancy. Certain functional biomarkers have proven useful in the prediction of regressing and non-regressing cervical intraepithelial neoplasia (CIN) lesions in non-pregnant women. In the present study, Ki-67 and p16 immunostaining were evaluated in different grades of CIN lesions diagnosed in pregnant or non-pregnant women with the aim to identify any differences in order to better understand the behavior of CIN in pregnancy. The current retrospective case-control study included 17 pregnant patients that conceived naturally with first-time onset of CIN occurring at no later than 16 gestational weeks. The control group included 17 non-pregnant patients matched for age, parity and number of previous sexual partners. Exclusion criteria included previous cervical treatment, immunocompromised status, chronic hepatitis B and/or C and cigarette smoking. p16 and Ki-67 protein expression were respectively detected using the CINtec Histology kit and monoclonal antibodies against Ki-67. p16 and Ki-67 staining were analyzed using a classification system based on the distribution of positivity on a semi-quantitative three point-scale. p16 and Ki-67 immune reactivity correlated positively with the grade of epithelial dysplasia in the total cohort of pregnant and non-pregnant patients; expression increased linearly from CIN1 to CIN3. Furthermore, the association between p16 immunostaining and CIN grade was significant in non-pregnant patients but not in pregnant patients. In pregnant patients, positivity for Ki-67 was less intense than in non-pregnant patients. These results appear to suggest that pregnancy status interferes with the expression of cellular proteins involved in cell-cycle regulation and the carcinogenic process induced by high-risk human papilloma virus, exhibiting increased variability in their staining.

Triple synchronous invasive malignancies of the female genital tract in a patient with a history of leukemia: A case report and review of the literature.

BACKGROUND Three primary synchronous cancers in the female genital tract are extremely rare. In the literature, only four studies have described three different invasive gynecologic cancers of epithelial origin identified simultaneously in the same patient. CASE PRESENTATION This is the first case in the literature that reports on triple primary ovarian, endometrial and endocervical cancers in a 38-year-old woman with a history of previously treated malignant disease (acute lymphatic leukemia). With a preoperative diagnosis of endocervical adenocarcinoma stage Ib1 (according to International Federation of Gynecology and Obstetrics-FIGO), as well as an adnexal mass, she underwent radical hysterectomy with bilateral adnexectomy. Pathologic examination of the surgical specimen revealed a mucinous adenocarcinoma of the cervix, an endometrioid adenocarcinoma of the uterine corpus, and a mucinous adenocarcinoma of the left ovary. Eighteen months after appropriate treatment, the patient is free of disease. CONCLUSION The incidental diagnosis of more than one tumor is often a post-operative finding, usually with the detection of low-stage neoplasms. Multiple synchronous gynecologic cancers have a better prognosis than metastatic or advanced primitive disease. In a patient with multiple neoplasms, the prognosis is determined by the tumor with the worst prognosis.

Conservative treatment of coexisting microinvasive squamous and adenocarcinoma of the cervix: report of two cases and literature review

Coexistence of microinvasive squamous cell carcinoma (MISCC) and microinvasive adenocarcinoma (MIAC) of the cervix is a rare phenomenon with very few clinically significant cases described in the literature. While a conservative approach has been studied, and may be effective in MISCC, a lower number of studies that recommend conservative treatment are available for MIAC. We report two cases of synchronous cervix lesions in two separate foci, MISCC and MIAC, who underwent fertility-sparing treatment with long-term follow-up. We describe clinical, histological, and immunohistochemical features of the two cases. The first case is a 41-year-old female with a diagnosis of MIAC of endocervical type, grade 1 differentiation, with a stromal invasion, associated with a separate area of squamous cell carcinoma (International Federation of Gynecology and Obstetrics/TNM stage: pT1a1G1). The second case is a 45-year-old female with a diagnosis of plurifocal MISCC, associated with an MIAC of endocervical type with a stromal invasion (International Federation of Gynecology and Obstetrics/TNM stage: pT1a1G1). After multidisciplinary counseling, both patients accepted conization as definitive treatment. Eleven years after the conization, all tests (Papanicolaou smear, colposcopy, cervical curettage, and hybrid capture 2-human papillomavirus test) planned quarterly in the first year and every 6 months in the subsequent years were negative in both patients. In women affected by stage IA1 squamous cervical cancer coexisting with stage IA1 adenocarcinoma endocervical type, with clear margins, and without lymphovascular space invasion, cervical conization may be considered a fertility-preserving, safe, and definitive therapeutic option.

Vaginal Intraepithelial Neoplasia: Histopathological Upgrading of Lesions and Evidence of Occult Vaginal Cancer.

Objective The aim of this study was to analyze women treated with excisional procedures for vaginal high-grade squamous intraepithelial lesions (HSILs). The histopathological upgrading of the lesions previously detected on vaginal biopsy and the presence of occult invasive vaginal cancer in the specimens excised were investigated, to identify a higher risk subset of women. Materials and Methods A retrospective analysis of the medical records of 86 women with a biopsy histopathologic diagnosis of vaginal HSIL (vaginal intraepithelial neoplasias [VaINs]: VaIN2 and VaIN3) and subsequent excisional therapy, consecutively referred to the Aviano National Cancer Institute (Aviano, Italy) from January 1991 to April 2014, was performed. Results Of the 86 patients, 4 cases (4.6%) of occult vaginal cancer were detected, all of them in women previously diagnosed with VaIN3 on biopsy (4/39 cases, 10.3%). Women with diagnosis of VaIN2 on biopsy showed an upgrading of lesions, with diagnosis of VaIN3 on the final specimen in 5 (10.6%) of 47 cases, with no cases of VAIN2 upgraded to invasive cancer. In 33.3% of the women initially diagnosed with VaIN2 and with previous hysterectomy for human papillomavirus–related disease, a final histopathological upgrading of lesions emerged. Furthermore, tobacco use was significantly related to the histopathological upgrading of lesions previously detected on vaginal biopsy. Conclusions Women diagnosed with VaIN3 should be treated with excisional procedures as first-line surgical approach, given the risk of occult invasive disease in 10% of the cases. Women diagnosed with VaIN2 and with previous hysterectomy for human papillomavirus–related cervical diseases should always be carefully evaluated and possibly excised, given the higher risk of histopathological upgrading of lesions and thus the potential risk of occult vaginal cancer. Tobacco users should be considered as high-risk group.