Topical imiquimod treatment of residual or recurrent cervical intraepithelial neoplasia lesions (TOPIC-2): A randomised controlled trial.

OBJECTIVE: To investigate the efficacy of imiquimod in women with residual or recurrent cervical intraepithelial neoplasia (rrCIN), compared with large loop excision of the transformation zone (LLETZ). DESIGN: Randomised controlled non-inferiority trial. SETTING: One academic and one regional hospital in the Netherlands. POPULATION: Thirty-five women with rrCIN were included in the study between May 2016 and May 2021. METHODS: Women were randomised to receive treatment with 5% imiquimod cream (12.5 mg) intravaginally (three times a week for a duration of 16 weeks) or a LLETZ procedure (standard treatment). MAIN OUTCOME MEASURES: The primary outcome was reduction to normal cytology at 6 months after starting treatment. Secondary outcomes were clearance of high-risk human papilloma virus (hr-HPV) in both groups and reduction to ≤CIN1 in the imiquimod group. Side effects were monitored. RESULTS: Treatment success was 33% (6/18) in the imiquimod group versus 100% (16/16) in the LLETZ group (P < 0.001), whereas HPV clearance was 22% (4/18) in the imiquimod group versus 88% (14/16) in the LLETZ group (P < 0.001). After the randomisation of 35 women, the futility of treatment with imiquimod was proven and the trial was prematurely finished. In the follow-up period, three patients remained without additional treatment, whereas all other patients underwent LLETZ, conisation or hysterectomy. In the LLETZ group none of the patients received additional treatment during 2 years of follow-up. CONCLUSIONS: This is the first randomised controlled trial to show that topical imiquimod has a significantly lower success rate in terms of reduction to normal cytology and hr-HPV clearance, compared with LLETZ, in women with rrCIN. Additionally, imiquimod has numerous side effects and after using imiquimod most women with rrCIN still required additional surgical treatment.

Stage, treatment and survival of low-grade serous ovarian carcinoma in the Netherlands: A nationwide study.

INTRODUCTION: Serous ovarian carcinomas constitute the largest group of epithelial ovarian cancer (60%-75%) and are further classified into high- and low-grade serous carcinoma. Low-grade serous carcinoma (LGSC) is a relatively rare subtype (approximately 5% of serous carcinomas) and epidemiologic studies of large cohorts are scarce. With the present study we aimed to report trends in stage, primary treatment and relative survival of LGSC of the ovary in a large cohort of patients in an effort to identify opportunities to improve clinical practice and outcome of this relatively rare disease. MATERIAL AND METHODS: Patients diagnosed with LGSC between 2000 and 2019 were identified from the Netherlands Cancer Registry (n = 855). Trends in FIGO stages and primary treatment were analyzed with the Cochran-Armitage trend test, and differences in and trends of 5-year relative survival were analyzed using multivariable Poisson regression. RESULTS: Over time, LGSC was increasingly diagnosed as stage III (39.9%-59.0%) and IV disease (5.7%-14.4%) and less often as stage I (34.6%-13.5%; p < 0.001). Primary debulking surgery was the most common strategy (76.2%), although interval debulking surgery was preferred more often over the years (10.6%-31.1%; p < 0.001). Following primary surgery, there was >1 cm residual disease in only 15/252 patients (6%), compared with 17/95 patients (17.9%) after interval surgery. Full cohort 5-year survival was 61% and survival after primary debulking surgery was superior to the outcome following interval debulking surgery (60% vs 34%). Survival following primary debulking surgery without macroscopic residual disease (73%) was better compared with ≤1 cm (47%) and >1 cm residual disease (22%). Survival following interval debulking surgery without macroscopic residual disease (51%) was significantly higher than after >1 cm residual disease (24%). Except FIGO stage II (85%-92%), survival did not change significantly over time. CONCLUSIONS: Over the years, LGSC has been diagnosed as FIGO stage III and stage IV disease more often and interval debulking surgery has been increasingly preferred over primary debulking in these patients. Relative survival did not change over time (except for stage II) and worse survival outcomes after interval debulking surgery were observed. The results support the common recommendation to perform primary debulking surgery in patients eligible for primary surgery.

Development of an Algorithm for Cervical High-Grade Squamous Intraepithelial Lesion Based on Breath Print Analysis.

OBJECTIVES: This study was designed to develop an algorithm for the diagnosis of cervical high-grade squamous intraepithelial lesions (HSIL), based on patterns of volatile organic compounds, evaluated using an e-nose. METHODS: For this pilot study, the study population consisted of a group of 25 patients with histologically confirmed HSIL and a group of 26 controls. Controls consisted of women visiting the outpatient department for gynecological complaints unrelated to cancer. Women had a negative high-risk human papillomavirus and/or normal cytology (negative for intraepithelial lesions of malignancy) of their most recent test performed in the context of participation in routine cervical cancer screening. Breath tests were performed and labeled with the correct diagnosis. Machine-learning techniques were used to develop a model for predicting HSIL. Based on the receiver operating characteristics curve, both sensitivity and specificity were calculated. RESULTS: Individual classifications of all patients with HSIL and controls, as calculated by the model, showed a sensitivity of 0.88 (95% CI = 0.68-0.97) and specificity of 0.92 (95% CI = 0.73-0.99). The positive predictive value and the negative predictive value were 0.92 (95% CI = 0.72-0.99) and 0.89 (95% CI = 0.70-0.97), respectively. The Cohen κ coefficient was 0.80. CONCLUSIONS: E-nose can detect distinctive patterns of volatile organic compounds between cervical HSIL patients and controls. Validation of the algorithm in further studies is necessary before possible implementation into daily practice.

Topical Imiquimod Treatment of High-grade Cervical Intraepithelial Neoplasia (TOPIC-3): A Nonrandomized Multicenter Study.

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.

Efficacy and Long-term Outcomes of Repeated Large Loop Excision of the Transformation Zone of the Cervix.

OBJECTIVE: To evaluate the efficacy and long-term outcome of repeat large loop excision of the transformation zone in women with residual or recurrent cervical intraepithelial neoplasia. METHODS: PALGA (the Dutch Pathology Registry), a database of deidentified cervical cytologic and histologic data, was used to examine women with cervical dysplasia who underwent two or more large loop excision of the transformation zone procedures between January 2005 and June 2015. We obtained cervical cytology and histology results. The main outcome was efficacy of repeated large loop excision of the transformation zone procedure in women with residual or recurrent cervical intraepithelial neoplasia. We also examined subsequent excisional procedures and hysterectomy. RESULTS: We identified 499 women who had undergone two or more large loop excision of the transformation zone procedures. After their second procedure, 60.7% of women had a normal first cervical cytologic sample. The mean duration of follow-up was 68 months (0-163 months). Additional cervical excisional procedures were performed in 33.7% of women. Overall, 1.2% of women developed cervical cancer during follow-up. Moreover, 19.0% of women eventually underwent hysterectomy. CONCLUSION: One third of the women who undergo two large loop excision of the transformation zone procedures require an additional excisional procedure or hysterectomy. Almost one fifth of these women eventually undergo hysterectomy.

Borderline ovarian tumor frozen section diagnoses with features suspicious of invasive cancer: a retrospective study.

BACKGROUND: A frozen section diagnosis of a borderline ovarian tumor with suspicious features of invasive carcinoma ("at least borderline" or synonymous descriptions) presents us with the dilemma of whether or not to perform a full ovarian cancer staging procedure. Quantification of this dilemma may help us with the issue of this clinical decision. The present study assessed and compared both the prevalence of straightforward borderline and "at least borderline" frozen section diagnoses and the proportion of these women with a final histopathological diagnosis of invasive carcinoma, with a special interest in histologic subtypes. METHODS: A retrospective cohort study was performed in three hospitals in The Netherlands. All women that underwent ovarian surgery with perioperative frozen section evaluation in one of these hospitals between January 2007 and July 2018 were identified and included in case of a borderline or "at least borderline" frozen section diagnosis and a borderline ovarian tumor or invasive carcinoma as a final diagnosis. RESULTS: A total of 223 women were included, of which 41 women (18.4%) were diagnosed with "at least borderline" at frozen section. Thirteen of forty-one women (31.7%) following "at least borderline" frozen section diagnosis and 14 of 182 women (7.7%) following a straightforward borderline frozen section diagnosis were diagnosed with invasive carcinoma at paraffin section evaluation (p < 0.001). When compared to straightforward borderline frozen section diagnoses, the proportion of women diagnosed with invasive carcinoma increased from 3.1 to 35.7% for serous tumors (p = 0.001), 10.0 to 21.7% for mucinous tumors (p = 0.129) and 50.0 to 75.0% (p = 0.452) in case of other histologic subtypes following an "at least borderline" frozen section diagnosis. CONCLUSIONS: Overall, when compared to women with a decisive borderline frozen section diagnosis, women diagnosed with "at least borderline" frozen section diagnoses were found to have a higher chance of carcinoma upon final diagnosis (7.7% vs 31.7%). Especially in the serous subtype, full staging during initial surgery might be considered after preoperative consent to prevent a second surgical procedure or chemotherapy in unstaged women. Further studies are needed to evaluate whether additional sampling in case of an "at least borderline" diagnosis may decrease the risk of surgical over-treatment.

Frozen section diagnosis of borderline ovarian tumors with suspicious features of invasive cancer is a devil's dilemma for the surgeon: A systematic review and meta-analysis.

INTRODUCTION: Frozen section diagnoses of borderline ovarian tumors are not always straightforward and a borderline frozen section diagnosis with suspicious features of invasive carcinoma (reported as "at least borderline" or synonymous descriptions) presents us with the dilemma of whether or not to perform a full surgical staging procedure. By performing a systematic review and meta-analysis, the prevalence of straightforward borderline and "at least borderline" frozen section diagnoses, as well as proportion of patients with a final diagnosis of invasive carcinoma in these cases, were assessed and compared, as quantification of this dilemma may help us with the issue of this clinical decision. MATERIAL AND METHODS: PubMed, EMBASE and Cochrane library databases were searched and studies discussing "at least borderline" frozen section diagnoses were included in the review. Numbers of specific frozen section diagnoses and subsequent final histological diagnoses were extracted and pooled analysis was performed to compare the proportion of patients diagnosed with invasive carcinoma following borderline and "at least borderline" frozen section diagnoses, presented as risk ratio and risk difference with 95% confidence intervals (95% CI). RESULTS: Of 4940 screened records, eight studies were considered eligible for quantitative analysis. A total of 921 women was identified and 230 (25.0%) of these women were diagnosed with "at least borderline" ovarian tumor at the time of frozen section. Final histological diagnoses were reported in five studies, including 61 women with an "at least borderline" diagnosis and 290 women with a straightforward borderline frozen section diagnosis. Twenty-five of 61 women (41.0%) of the "at least borderline" group had invasive cancer at final diagnosis, compared with 28 of 290 women (9.7%) of the straightforward borderline frozen section group (risk difference -0.34, 95% CI -0.53 to -0.15; relative risk 0.25, 95% CI 0.13-0.50). CONCLUSIONS: Women diagnosed with "at least borderline" frozen section diagnoses were found to have a higher chance of carcinoma upon final diagnosis when compared with women with a straightforward borderline frozen section diagnosis (41.0% vs 9.7%). Especially in the serous subtype, and after preoperative consent, full staging during initial surgery might be considered in these cases to prevent a second surgical procedure.

Systemic adverse events in imiquimod use for cervical intraepithelial neoplasia - A case series.

Treatment for cervical intraepithelial neoplasia (CIN) often consists of an excisional procedure. However, less invasive treatment methods have been explored, such as topical treatment with imiquimod cream. Imiquimod has been proven to be effective in the regression of vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VAIN). Previous studies have investigated the effect of imiquimod in CIN and showed well tolerated adverse effects. During a current study in the Netherlands, a number of adverse events have occurred. This case series presents a selection of these. Gynaecologists should be aware of the possible adverse effects of topical treatment with imiquimod cream.

Vaginal hysterectomy with or without bilateral salpingo-oophorectomy may be an alternative treatment for endometrial cancer patients with medical co-morbidities precluding standard surgical procedures: a systematic review.

OBJECTIVE: Vaginal hysterectomy with bilateral salpingo-oophorectomy may be an alternative strategy for patients with low-risk endometrial cancer and medical co-morbidities precluding laparoscopic or abdominal procedures. The current study evaluates the prevalence of co-existent ovarian malignancy in patients with endometrial cancer and the influence of bilateral salpingo-oophorectomy on survival outcomes in these patients. METHODS: Medline and EMBASE were searched for studies published between January 1, 2000 and November 20, 2017 that investigated (1) the prevalence of co-existing ovarian malignancy (either metastases or primary synchronous ovarian cancer in women with endometrial cancer, and (2) the influence of bilateral salpingo-oophorectomy on recurrence and/or survival rates. RESULTS: Of the pre-menopausal and post-menopausal patients (n=6059), 373 were identified with metastases and 106 were identified with primary synchronous ovarian cancer. Of the post-menopausal patients (n=6016), 362 were identified with metastases and 44 were identified with primary synchronous ovarian cancer. Survival outcomes did not differ for pre-menopausal patients with endometrial cancer with and without bilateral salpingo-oophorectomy (5-year overall survival rates were 89-94.5% and 86-97.8%, respectively). CONCLUSION: Bilateral salpingo-oophorectomy during vaginal hysterectomy seems to have a limited impact on disease outcome in patients with endometrial cancer. These results support the view that vaginal hysterectomy alone or with bilateral salpingo-oophorectomy may be an option for patients with endometrial cancer who are not ideal surgical candidates.

Borderline tumours of the ovary: Common practice in the Netherlands.

OBJECTIVES: Discordance between frozen section diagnosis and the definite histopathological diagnosis and the fact that the frozen section result is not always unambiguous, may contribute to differences in clinical practice regarding perioperative treatment and follow-up of borderline ovarian tumours (BOTs) patients amongst gynaecologic oncologists, which may lead to over- and undertreatment. The aim of the study was to map the Dutch gynaecologists' preferred treatment and follow-up strategy in case of BOTs. METHODS: A questionnaire was sent to all Dutch gynaecologists involved in ovarian surgery with perioperative frozen section analysis, and the outcomes were assessed using descriptive statistics. RESULTS: Nearly half of the respondents (41.0%) would not perform a staging procedure in case of a BOT. In case of an ambiguous frozen section diagnosis, tending towards invasive carcinoma, a considerable number (sBOT 56.4%; mBOT 30.8%) would perform a lymph node sampling as part of the staging procedure. A relaparotomy/relaparoscopy, to perform a lymph node sampling in case of a serous or mucinous carcinoma after a BOT frozen section diagnosis, would be performed by 97.4% and 48.7% of the respondents, respectively. CONCLUSIONS: A considerable number of gynaecologists would perform a staging procedure that is recommended for ovarian cancer in case of an ambiguous BOT frozen section diagnosis, especially for serous tumours. In addition, nearly all gynaecologists would perform a second procedure including a lymph node sampling in case of a serous invasive carcinoma after a BOT frozen section diagnosis, which applies to half of the gynaecologists in case of a mucinous carcinoma.

Staging procedures in patients with mucinous borderline tumors of the ovary do not reveal peritoneal or omental disease.

OBJECTIVES: Staging in case of a borderline tumor of the ovary (BOT) is a controversial issue. Upstaging is not uncommon, but this occurs especially with presumed stage I serous borderline tumors. There are only a few documented cases of BOTs of non-serous histology that were not confined to the ovary. The aim of this study was to assess the incidence of non-invasive and invasive implants in the omentum and other (extra)pelvic peritoneal surfaces in patients with a mucinous BOT (mBOT). METHODS: A retrospective cohort study was performed in three hospitals in the Netherlands. All patients with a histopathological diagnosis of mBOT diagnosed from January 1st 1990 to December 1st 2015 were identified and included when the inclusion criteria were met. RESULTS: In total, 74 patients were included. Of these 74 patients, 46 (62.2%) underwent a staging procedure. In 12 (26.1%) patients, only omental tissue was obtained, in 32 (69.6%) patients, omental tissue and peritoneal biopsies were obtained and in two (4.3%) patients, only peritoneal biopsies were obtained. No implants were seen upon microscopic examination in any of the patients. Two patients (3%) developed a recurrence. CONCLUSIONS: Because no extra-ovarian disease was found, staging procedures in the case of an mBOT may be omitted. However, the actual perioperative decision for staging or not should be taken in the context of a frozen section diagnosis, which is not always accurate and straightforward. Recurrence with malignant disease is rare after mBOT. The value of post-treatment surveillance seems limited after bilateral salpingo-oophorectomy.

Physicians' Awareness, Attitudes, and Experiences Regarding Imiquimod Treatment of Vaginal and Cervical Intraepithelial Neoplasia.

OBJECTIVE: The aim of the study was to assess awareness, attitudes, and current clinical experiences of gynecologists regarding imiquimod as a potential treatment modality for vaginal intraepithelial neoplasia (VAIN) and cervical intraepithelial neoplasia (CIN). MATERIALS AND METHODS: A 37-item questionnaire consisting of both multiple choice and open questions was sent to all Dutch gynecologists who regularly perform colposcopies in all 87 Dutch hospitals, in December 2014. The outcomes were assessed using descriptive statistics. RESULTS: Gynecologists from 52 hospitals (60%) completed the questionnaire. Of the 77 respondents, 79% and 58% were aware of imiquimod for treating VAIN and CIN, respectively. Twelve and 5 respondents had used imiquimod to treat VAIN and CIN, respectively; most treatments were for intractable VAIN lesions and recurrent lesions and to avoid surgical treatment for CIN in patients with a future pregnancy wish. Most respondents reported successful treatment outcomes but frequent adverse effects. Most (96%) stated that they would consider using imiquimod to treat high-grade CIN in selected patients, but only upon additional evidence and inclusion into treatment guidelines. CONCLUSIONS: The awareness of imiquimod as a potential treatment for VAIN and CIN was limited, possibly because of the paucity of evidence regarding vaginal imiquimod efficacy, the lack of inclusion into guidelines, and the high frequency of adverse effects. Imiquimod was applied off-label in a limited number of selected patients, with good treatment results. The respondents generally had a positive attitude toward treating VAIN and CIN with imiquimod. Additional evidence on treatment efficacy and inclusion in treatment guidelines is necessary before application in clinical practice.

Natural history of high-grade cervical intraepithelial neoplasia: a review of prognostic biomarkers.

The natural history of high-grade cervical intraepithelial neoplasia (CIN) is largely unpredictable and current histopathological examination is unable to differentiate between lesions that will regress and those that will not. Therefore, most high-grade lesions are currently treated by surgical excision, leading to overtreatment and unnecessary complications. Prognostic biomarkers may differentiate between lesions that will regress and those that will not, making individualized treatment of high-grade CIN possible. This review identifies several promising prognostic biomarkers. These biomarkers include viral genotype and viral DNA methylation (viral factors), human leukocyte antigen-subtypes, markers of lymphoproliferative response, telomerase amplification and human papillomavirus-induced epigenetic effects (host factors) and Ki-67, p53 and pRb (cellular factors). All identified biomarkers were evaluated according to their role in the natural history of high-grade CIN and according to established criteria for evaluation of biomarkers (prospective-specimen-collection, retrospective-blinded-evaluation [PROBE] criteria). None of the biomarkers meets the PROBE criteria for clinical applicability and more research on prognostic biomarkers in high-grade CIN is necessary.

Aggressive behavior and poor prognosis of endometrial stromal sarcomas with YWHAE-FAM22 rearrangement indicate the clinical importance to recognize this subset.

OBJECTIVES: Although the World Health Organization (WHO) in 2003 defined endometrial stromal sarcomas (ESSs) in general have a good prognosis, considerable differences in clinical behavior and prognosis may exist between different patients with ESS. The ESSs of the type associated with YWHAE-NUTM2 (previously named YWHAE-FAM22) fusion have a more aggressive clinical behavior and poorer prognosis than conventional ESS. Recently, the WHO 2014 classification recognizes this subset of ESS as a separate entity and classifies these as high-grade ESSs. Recognition of this subset has therefore an important clinical impact. We performed a review of the literature to delineate the clinicopathologic features of ESS patients with an YWHAE-NUTM2 rearrangement, with the goal to recognize this subset of ESS. METHODS: We report a case of a woman with WHO 2014-defined high-grade ESS. Furthermore, published English literature was reviewed for YWHAE-FAM22 ESS and uterus. RESULTS: Twenty patients were identified, with a median age of 50 (range, 28-67) years. There were no clinical features able to recognize YWHAE-NUTM2 ESS. However, they characteristically contain specific histopathological features. Furthermore, YWHAE-NUTM2 ESSs are strongly cyclin D1 positive in contrast to conventional low-grade ESSs. CONCLUSIONS: YWHAE-NUTM2 ESSs represent a subset of ESSs with an aggressive clinical behavior and poor prognosis. Specific histopathological features may indicate the presence of YWHAE-NUTM2 rearrangement, which subsequently can be confirmed by cyclin D1 immunostaining.

A family history questionnaire improves detection of women at risk for hereditary gynecologic cancer: a pilot study.

Pilot study to evaluate whether the use of a standardized questionnaire to document family history of cancer improves identification of women who warrant referral to cancer genetic services (CGS) for increased risk of hereditary cancer, compared to their identification in usual care. Prospective intervention study with historic control group. Gynecology outpatient clinic, Maastricht University Medical Centre, the Netherlands. The prospective intervention group consisted of new outpatients between June 1 and August 1, 2011. The historic control group consisted of new outpatients between May 1, 2009 and April 30, 2010. A standardized questionnaire based on established referral criteria for hereditary breast/ovarian cancer and Lynch syndrome was completed for the intervention group. The referral rate in routine consultation, based on non-standardized family history recording, was determined retrospectively for the control group. The difference in referral rate between intervention and control group, tested by Chi square test. In the control group, 8 of 3,036 women (0.26 %) were referred to CGS. In the intervention group, 209 (42 %) of 500 screening questionnaires were completed. Nineteen women (9, 1 %) met the referral guidelines, of which 5 were newly referred to CGS (2, 4 %). Referral rates differed significantly (p < 0.001) between the two groups. This pilot study shows that the routine use of a screening questionnaire may improve detection and referral rate to CGS of individuals at risk for hereditary cancer. Improving genetic literacy of physicians and use of web-site questionnaires deserve attention in future studies.

The majority of metachronous CIN1 and CIN3 lesions are caused by different human papillomavirus genotypes, indicating that the presence of CIN1 seems not to determine the risk for subsequent detection of CIN3.

Cervical intraepithelial neoplasia (CIN) is historically viewed as a progressive biologic continuum leading to cervical cancer. However, it has been questioned whether CIN1 lesions ever progress. To this end, we evaluated the number of patients with a CIN3 and a previous CIN1 diagnosis. Subsequently, metachronous CIN1 and CIN3 lesions were reviewed and human papillomavirus (HPV) genotyping was performed to evaluate whether CIN1 lesions do progress. The medical records of 1819 patients diagnosed with a CIN3 lesion were retrieved from the archives, and prior Pap smear surveillance was available for 1474 patients. Forty-four CIN3 patients (3.0%) had a previous CIN1 lesion, and review of the biopsies confirmed 43 out of 44 CIN3 lesions and 37 out of 44 CIN1 lesions (78%). Three cases were not available for analysis, and in another three cases the quality of the isolated DNA was insufficient for further analysis. Out of the 30 remaining patients, 19 patients had different HPV genotypes in their CIN1 and CIN3 lesion. The cytological diagnosis leading to the CIN1 biopsy showed high-grade squamous intraepithelial lesion in 11 out of 19 patients with a different HPV genotype in the metachronous CIN1 and CIN3 lesions. High-grade squamous intraepithelial lesion was detected in 7 out of 11 patients with the same HPV genotype. Our results show that CIN3 lesions are rarely preceded by a CIN1 lesion. The majority of metachronous CIN1 and CIN3 lesions are caused by different HPV genotypes, indicating that the presence of CIN1 seems not to determine the risk for subsequent detection of CIN3.

Angiosarcomas of primary gynecologic origin: a clinicopathologic review and quantitative analysis of survival.

OBJECTIVE: Angiosarcomas are aggressive, malignant soft tissue neoplasms of endothelial origin and occur rarely in the female genital tract. There is lack of consensus on risk factors for poor outcome and optimal treatment. To this end, we performed a clinicopathologic review and survival analysis. METHODS: We report a case of a woman with an angiosarcoma of the vagina. Published English literature was reviewed for angiosarcomas of the vulva, vagina, uterus, and ovary. Survival was evaluated by using Kaplan-Meier analysis and the effect of clinical and demographic variables on survival by using Cox regression analysis. RESULTS: A total of 51 patients were identified with a median age of 47 years (range, 17-87 years). Two of the patients had an angiosarcoma of the vulva; 2 had an angiosarcoma of the vagina; 18 had an angiosarcoma of the uterus, and 29 had an angiosarcoma of the ovary. Five-year overall survival was 27% (SE, 8%). Most patients presented with locoregional disease, having surgery as their primary intervention. Overall, adjuvant therapy significantly improved survival (hazards ratio, 0.17; 95% confidence interval, 0.05-0.59; adjusted for age and tumor size). Adjuvant treatment consisted of radiotherapy for angiosarcomas of the vulva, vagina, and uterus and chemotherapy for ovarian angiosarcomas. Subgroup analysis of the female genital tract site was hampered by the small number of cases. CONCLUSIONS: This review supports the use of surgical and adjuvant radiotherapy for angiosarcomas of the vulva, vagina, and uterus. Cytoreductive surgery and adjuvant chemotherapy remain the primary treatment of angiosarcomas of the ovary.

Molecular biomarkers in cervical cancer diagnosis: a critical appraisal.

INTRODUCTION: It is expected that in the near future high-risk human papillomavirus (hr-HPV) testing will be implemented as the primary cervical cancer screening method in some countries. However, only a fraction of hr-HPV positive women will have a clinically relevant lesion. As a result, there is an urgent need for additional biomarkers that can detect these lesions and that can at the same time be applied to cytological specimens. This overview evaluates the most promising cytological biomarkers. AREAS COVERED: Cytological biomarkers that can be used are being discussed in view of their molecular background. The most promising biomarkers are p16(INK4a)/Ki-67 dual immunostaining; methylation of the promoter region of the cell adhesion molecule 1 (CADM1) gene and the T-lymphocyte maturation associated protein (MAL) gene and viral integration. Their sensitivity, specificity and limitations are discussed in detail and their diagnostic accuracy is evaluated. EXPERT OPINION: The most promising cytological biomarkers for cervical cancer screening are p16(INK4a)/Ki-67 dual immunostaining, methylation of CADM1 and MAL and viral integration. Although some of the biomarkers are very promising for this purpose, no studies have evaluated how accurately these biomarkers classify or predict the outcome. Additional clinical trials are needed to determine the true clinical value of these promising cytological biomarkers.

Consistent condom use increases spontaneous regression in high-risk non-HPV16 but not in HPV16 CIN2-3 lesions, a prospective population-based cohort study.

BACKGROUND: The major cause of cervical intraepithelial neoplasia (CIN) is persistent infection with human papillomavirus (HPV). Most CIN grade 2 and 3 lesions are treated with cone excision, although a substantial proportion (6-50%) of CIN2-3 lesions will regresses spontaneously. Predictors for regression of CIN2-3 are desirable in order to reduce this overtreatment. METHODS: In this prospective cohort study, 145 consecutive women with first-time onset CIN2-3 in colposcopy-directed biopsies and standardized biopsy-cone excision interval were included. The genotype of the high-risk human papillomaviruses (=hrHPV) and clinical factors including sexual behaviour, parity, contraception and smoking were assessed. Patients were divided into two groups according to lesions containing HPV16 (hrHPV16+) and high-risk non-HPV16 (hrHPV16-) genotypes. RESULTS: Women whose partners consistently used condoms showed a significantly higher regression rate than women using other types of contraception (53% versus 13%, p<0.0001). However, this effect was only seen in hrHPV16- patients (73% regression rate versus 13%, p<0.0001). HrHPV16+ patients had a significantly higher number of sexual partners and more current smokers compared to hrHPV16- patients. The regression rate was not significantly different in CIN2-3 lesions containing HPV16 (hrHPV16+) versus hrHPV16- genotypes. CONCLUSIONS: Heterogeneity among hrHPV genotypes excists. HPV-genotype analyses can identify women who significantly increase their chance of regression by consistent condom use.