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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.
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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.
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Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Feminino , Humanos , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/tratamento farmacológico , Países Baixos/epidemiologia , Estadiamento de Neoplasias , Carcinoma Epitelial do Ovário/patologia , Cistadenocarcinoma Seroso/cirurgia , Estudos RetrospectivosRESUMO
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.
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Carcinoma in Situ , Carcinoma de Células Escamosas , Infecções por Papillomavirus , Lesões Intraepiteliais Escamosas Cervicais , Lesões Intraepiteliais Escamosas , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Compostos Orgânicos Voláteis , Humanos , Feminino , Neoplasias do Colo do Útero/patologia , Detecção Precoce de Câncer/métodos , Projetos Piloto , Carcinoma de Células Escamosas/patologia , Algoritmos , Displasia do Colo do Útero/patologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/epidemiologia , Papillomaviridae , Lesões Intraepiteliais Escamosas Cervicais/diagnósticoRESUMO
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.
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Secções Congeladas , Neoplasias Ovarianas/patologia , Feminino , Humanos , Invasividade NeoplásicaRESUMO
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.
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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.
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Adenocarcinoma Mucinoso/patologia , Omento/patologia , Neoplasias Ovarianas/patologia , Peritônio/patologia , Adenocarcinoma Mucinoso/diagnóstico , Biópsia , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/diagnóstico , Estudos RetrospectivosRESUMO
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.
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Aminoquinolinas/uso terapêutico , Antineoplásicos/uso terapêutico , Atitude do Pessoal de Saúde , Médicos , Competência Profissional , Displasia do Colo do Útero/tratamento farmacológico , Neoplasias Vaginais/tratamento farmacológico , Feminino , Humanos , Imiquimode , Países Baixos , Inquéritos e QuestionáriosRESUMO
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.
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Hemangiossarcoma/terapia , Neoplasias Vaginais/terapia , Evolução Fatal , Feminino , Hemangiossarcoma/diagnóstico , Humanos , Pessoa de Meia-Idade , Prognóstico , Neoplasias Vaginais/diagnósticoRESUMO
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.
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Biomarcadores Tumorais/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Rearranjo Gênico , Proteínas de Fusão Oncogênica/genética , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Feminino , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Literatura de Revisão como Assunto , Sarcoma do Estroma Endometrial/tratamento farmacológicoRESUMO
OBJECTIVE: Cervical intraepithelial neoplasia grades 2-3 (CIN2-3) are usually treated by cone excision, although only 30% progress to cancer and 6-50% regress spontaneously. Biomarkers predicting CIN2-3 regression would be of great clinical value and could reduce unnecessary cone excision and associated complications. The aim of this study was to investigate whether punch-biopsy derived immunohistochemical biomarkers, local immune response, CIN lesion size and condom use are independently correlated to regression of CIN2-3. METHODS: A prospective population-based cohort study of 162 women aged 25-40, with first-time onset diagnosis of CIN2-3 in colposcopy-directed biopsies was carried out. The median biopsy-cone interval was 16 weeks. Regression was defined as CIN1 or less in the cone biopsy. RESULTS: The regression rate was 21% (34/162). pRb>30% in the lower epithelial half was the strongest predictor for regression (30% regression, p<0.0001). If additionally a CIN-lesion was smaller than 2.5mm and CD4+ lymphoid cells in the subepithelial stroma ≤ 195 per 1.04 mm basal membrane, the regression rate was 53%. In CIN-lesions>2.5mm and CD4+-stroma ≤195, consistent condom use increased the regression rate from 13% to 67% (p=0.003). If pRb was ≤30%, the regression rate was low (6%). CONCLUSION: Biomarkers and CIN lesion length can predict CIN2-3 regression, and might be helpful to identify patients who can increase the regression rate of CIN lesions by consistent condom use.
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Preservativos , Displasia do Colo do Útero/patologia , Neoplasias do Colo do Útero/patologia , Adulto , Biomarcadores , Contagem de Linfócito CD4 , Estudos de Coortes , Feminino , Humanos , Papillomaviridae/isolamento & purificação , Estudos Prospectivos , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/virologia , Displasia do Colo do Útero/imunologia , Displasia do Colo do Útero/virologiaRESUMO
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.
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Colo do Útero/cirurgia , Recidiva Local de Neoplasia/cirurgia , Neoplasia Residual/cirurgia , Reoperação , Displasia do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/cirurgia , Adulto , Idoso , Colo do Útero/patologia , Feminino , Seguimentos , Humanos , Histerectomia/estatística & dados numéricos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasia Residual/patologia , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias do Colo do Útero/patologia , Displasia do Colo do Útero/patologiaRESUMO
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.
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Displasia do Colo do Útero , Neoplasias do Colo do Útero , Feminino , Humanos , Imiquimode , Masculino , Resultado do Tratamento , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/tratamento farmacológico , Displasia do Colo do Útero/diagnóstico , Displasia do Colo do Útero/tratamento farmacológico , Displasia do Colo do Útero/patologiaRESUMO
The prognostic value of molecular biomarkers, microsatellite instability, DNA ploidy and morphometric mean shortest nuclear axis in endometrial cancer is conflicting, possibly due to the fact that different studies have used mixtures of histotypes, FIGO stages and different non-standardized non-automated methods. We have evaluated the prognostic value of classical prognostic factors, molecular biomarkers, microsatellite instability, DNA ploidy and morphometric mean shortest nuclear axis in a population-based cohort of FIGO stage I endometrial endometrioid adenocarcinomas. Curettings of 224 FIGO stage I endometrial endometrioid adenocarcinoma patients were reviewed. Clinical information, including follow-up, was obtained from the patients' charts. Microsatellite instability and morphometric mean shortest nuclear axis were obtained in whole tissue sections and molecular biomarkers using tissue microarrays. DNA ploidy was analyzed by image cytometry. Univariate (Kaplan-Meier method) and multivariate (Cox model) survival analysis was performed. With median follow-up of 66 months (1-209), 14 (6%) patients developed metastases. Age, microsatellite instability, molecular biomarkers (p16, p21, p27, p53 and survivin) and morphometric mean shortest nuclear axis had prognostic value. With multivariate analysis, combined survivin, p21 and microsatellite instability overshadowed all other variables. Patients in which any of these features had favorable values had an excellent prognosis, in contrast to those with either high survivin or low p21 (97 vs 78% survival, P<0.0001, hazard ratio=7.8). Combined high survivin and low p21 values and microsatellite instability high identified a small subgroup with an especially poor prognosis (survival rate 57%, P=0.01, hazard ratio=5.6). We conclude that low p21 and high survivin expression are poor prognosis indicators in FIGO stage I endometrial endometrioid adenocarcinoma, especially when high microsatellite instability occurs.
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Biomarcadores Tumorais/análise , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/metabolismo , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Instabilidade de Microssatélites , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Endometrioide/patologia , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Inibidor de Quinase Dependente de Ciclina p21/genética , Dilatação e Curetagem , Neoplasias do Endométrio/patologia , Feminino , Humanos , Proteínas Inibidoras de Apoptose/biossíntese , Proteínas Inibidoras de Apoptose/genética , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Survivina , Análise Serial de TecidosRESUMO
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.
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Secções Congeladas/normas , Neoplasias Ovarianas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Fifteen to thirty percent of cases with histologically confirmed CIN2-3 in cervical biopsies regress spontaneously (ie, show CIN1 or less in the follow-up cervical cone). The balance between immune-reactive cells from the host and high-risk human papillomavirus (hrHPV) genotypes may provide a biological explanation for this phenomenon. We retrospectively studied 55 cases of CIN2-3 in a cervical biopsy with subsequent cervical cone to assess whether hrHPV genotypes (by AMPLICOR and Linear Array tests) CD4, CD8, CD25, CD138 and Foxp3 cells (by quantitative immunohistochemistry) in the cervical biopsies can predict regression (defined as CIN1 or less in the follow-up cone biopsy). Eighteen percent of the CIN2-3 cases regressed (median biopsy-cervical cone time interval: 12.0 weeks, range: 5.0-34.1 weeks). HPV-16 correlated with low CD8+ and high CD25+. None of the regressing CIN2-3 lesions contained HPV-16. The regressing CIN2-3 lesions had lower numbers of stromal CD138+ and higher numbers of stromal CD8+cells; higher stromal and intra-epithelial ratios of CD4+/CD25+ cells; higher ratios of CD8+/CD25+ cells and lower ratios of CD8+/CD4+, CD138+/Foxp3+ and CD25+/Foxp3+ cells in the stroma. With multivariate survival analysis, stromal CD8+ cell numbers, CD4+/CD25+ cell ratios and CD138+ cell numbers are found to be independent regression predictors. In conclusion, in non-HPV-16 CIN2-3 lesions, assessing stromal immune cells can be a useful prognostic indicator of regression or persistence.
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Regressão Neoplásica Espontânea/imunologia , Infecções por Papillomavirus/genética , Displasia do Colo do Útero/imunologia , Neoplasias do Colo do Útero/imunologia , Adulto , Feminino , Genótipo , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Linfócitos do Interstício Tumoral , Pessoa de Meia-Idade , Regressão Neoplásica Espontânea/patologia , Papillomaviridae/genética , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/imunologia , Reação em Cadeia da Polimerase , Prognóstico , Estudos Retrospectivos , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Adulto Jovem , Displasia do Colo do Útero/genética , Displasia do Colo do Útero/virologiaRESUMO
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.
RESUMO
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.
RESUMO
Clinically, it is important to distinguish cervical intraepithelial neoplasia grade 3 (CIN3) lesions with and without coexisting adenocarcinoma in situ (AIS), but endocervical curetting can be false negative. The frequency of high-risk human papillomavirus genotypes in CIN3 patients with and without AIS differs. CIN3 epithelial cell cycle regulator expression may reflect these differences and thereby indicate coexistent AIS. G1 pathway epithelial cell cycle regulators (pRb, p53, cyclin D, p16) and Ki-67 were analyzed by quantitative immunohistochemistry in CIN3s with and without AIS. Compared with the normal cervical squamous epithelium, the CIN3 epithelium in small punch biopsies showed strong diffuse p16 and Ki-67 expression. CIN3s with coexistent AIS had a significantly lower percentage of pRb (P = .03)- and p53 (P = .03)-positive nuclei in the lower half of the epithelium than CIN3s without coexistent AIS. None of the 10 cases with values of either pRb-positive nuclei 30% or greater or p53-positive nuclei 15% or greater in the lower half of the epithelium had coexistent AIS, contrasting 8 (24%) of the 33 cases with both low values of p53- and pRb-positive nuclei. Combined low p53 and pRb expression in the lower half of the epithelium in punch biopsies is associated with coexistent AIS in the cone. Despite the fact that the results of the current study are interesting and potentially clinically relevant, it should be emphasized that they must be confirmed according to Good Laboratory Practice in independent patient groups, preferably also in a prospective study.
Assuntos
Biomarcadores Tumorais/análise , Infecções por Papillomavirus/complicações , Proteína do Retinoblastoma/análise , Proteína Supressora de Tumor p53/análise , Displasia do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteína do Retinoblastoma/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Displasia do Colo do Útero/patologia , Displasia do Colo do Útero/virologiaRESUMO
Simplex vulvar intraepithelial neoplasia (VIN) is an important precursor of vulvar invasive squamous cell carcinoma and characteristically occurs in postmenopausal women. In this report, the absence of high-risk human papillomavirus (HPV) combined with specific p53 and p16INK4a expression patterns points to the HPV-independent pathway as the causative agent for vulvar squamous cell carcinoma in a 28-year-old woman. Its precursor simplex VIN was initially interpreted as eczema. Although simplex VIN has a predilection for postmenopausal women, it can occur in young patients. The development of invasive vulvar squamous cell carcinoma underlines the importance of including simplex VIN in the differential diagnosis of vulvar lesions, even at a young age. Furthermore, knowledge about the HPV status in the tumor and thus the underlying causative pathway can alert the gynecologist for the presence or absence of multicentric lower genital tract disease, as this is frequent in the HPV-dependent and not in the HPV-independent pathway.
Assuntos
Carcinoma de Células Escamosas/patologia , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Proteína Supressora de Tumor p53/biossíntese , Neoplasias Vulvares/patologia , Adulto , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/virologia , DNA Viral/análise , Feminino , Humanos , Imuno-Histoquímica , Papillomaviridae/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Neoplasias Vulvares/metabolismo , Neoplasias Vulvares/cirurgia , Neoplasias Vulvares/virologiaRESUMO
Up to 30% of cervical intraepithelial grades 2-3 (CIN2-3) lesions regress, but some believe that "regression" is due to "curative" punch biopsies. If this is true, CIN2-3 in the resection margins of the biopsies would be associated with more frequent "persistent" CIN2-3. If, however, immunology-related regression exists, regression would increase with increasing biopsy-cone interval. In 61 punch biopsies diagnosed as CIN3 at careful review by two independent gynaecological pathologists, CIN3 in the resection margins and duration of the biopsy-cone interval was evaluated in relation to CIN2-3-or-not in the cones (again after independent review by expert pathologists). 10 of 61 (16%) patients with CIN3 showed CIN1 or less in the follow-up cones. CIN3-or-not in the resection margins, size of the lesion in the punch biopsy, and presence or absence of CIN2-3 in the cones were not correlated with regression-or-not. However, the number of cones without CIN2-3 increased with longer biopsy-cone interval, 5% in patients with a punch-cone biopsy interval under 9 weeks and 38%> or =9 weeks (p<0.001). These results favour the hypothesis that CIN3 can regress, and do not support the "curative punch biopsy" theory.