Surgical margins in squamous cell carcinoma, different for the vulva?

INTRODUCTION: The recommended pathological resection margin (8 mm) for vulvar squamous cell carcinoma (SCC) is broader than for SCC located elsewhere, and does not depend on tumor grade or lesion size. Our aim is to evaluate the resection margin in vulvar SCC in relation to local recurrence, and to determine the impact of other prognostic factors. MATERIALS AND METHODS: Data of all surgically treated patients at the Gynecological Oncology Center South with vulvar SCC, FIGO IB-IIIC, between 2005 and 2015 were analysed retrospectively. The relation between the pathological resection margin and other clinicopathological factors with the risk of local recurrence was analysed. RESULTS: In this cohort of 167 patients, the tumor was radically removed in 87% of the patients. Yet, in 57% the pathological resection margin was <8 mm. Including re-excisions, the median closest margin was 7.0 mm. There was no significant difference in the risk of local recurrence for a resection margin <8 mm or ≥8 mm (25.0% (n = 20) and 22.2% (n = 16)), nor in the median resection margin of patients with or without local recurrence (6.5 mm and 7.0 mm). Lichen sclerosus was the only significant risk factor for local recurrence. CONCLUSION: A pathological resection margin <8 mm was not related to an increased risk of local recurrence. The most important predictor of local recurrence was the presence of lichen sclerosus. A resection margin <8 mm in vulvar SCC can therefore be accepted, especially in tumors located close to clitoris, urethra or anus.

MMP-14 and CD44 in Epithelial-to-Mesenchymal Transition (EMT) in ovarian cancer.

BACKGROUND: To investigate the expression of MMP-14 and CD44 as well as epithelial-to-mesenchymal transition(EMT)-like changes in ovarian cancer and to determine correlations with clinical outcome. METHODS: In 97 patients with ovarian cancer, MMP-14 and CD44 expression as determined by immunohistochemistry was investigated in relation to EMT-like changes. To determine this, immunohistochemical staining of E-cadherin and vimentin was performed. RESULTS: Patients with expression of both MMP-14 and CD44 in their tumors had a poor prognosis despite complete debulking. Serous histology in advanced-stage tumors (FIGO IIB-IV) correlated with CD44 (rho .286, p < 0.01). Also, CD44 correlated with percentage vimentin expression (rho .217, p < 0.05). In logistic regression analysis with complete debulking as the outcome parameter, CD44 expression was found to be significant (OR 3,571 (95 % Confidence Interval 1,112-11,468) p = 0.032), though this was not the case for MMP-14 and EMT parameters. CONCLUSION: The subgroup of patients with double expression of MMP-14 and CD44 had a poor prognosis despite complete debulking. Serous subtype in advanced-stage patients and CD44 expression were found to be correlated with vimentin expression, and CD44 expression was found to be significantly correlated with complete debulking. However, a significant correlation between EMT and clinical parameters was not found.

PIpelle Prospective ENDOmetrial carcinoma (PIPENDO) study, pre-operative recognition of high risk endometrial carcinoma: a multicentre prospective cohort study.

BACKGROUND: Endometrial carcinoma is the most common gynaecologic malignancy in industrialised countries and the incidence is still rising. Primary treatment is based on preoperative risk classification and consists in most cases of hysterectomy with bilateral salpingo-oophorectomy. In patients with serous and clear cell histology a complete surgical staging is mandatory. However, in routine clinical practice final histology regularly does not correspond with the preoperative histological diagnosis. This results in both over and under treatment. METHODS/DESIGN: The aim of this multicentre, prospective cohort study is to select a panel of prognostic biomarkers to improve preoperative diagnosis of endometrial carcinoma in order to identify those patients that need extended surgery and/or additional treatment. Additionally, we will determine whether incorporation of cervical cytology and comorbidity could improve this preoperative risk classification. All patients treated for endometrial carcinoma in the participating hospitals from September 2011 till December 2013 are included. Patient characteristics, as well as comorbidity are registered. Patients without preoperative histology, history of hysterectomy and/or endometrial carcinoma or no surgical treatment including hysterectomy are excluded. The preoperative histology and final pathology will be reviewed and compared by expert pathologists. Additional immunohistochemical analysis of IMP3, p53, ER, PR, MLH1, PTEN, beta-catenin, p16, Ki-67, stathmin, ARID1A and L1CAM will be performed. Preoperative histology will be compared with the final pathology results. Follow-up will be at least 24 months to determine risk factors for recurrence and outcome. DISCUSSION: This study is designed to improve surgical treatment of endometrial carcinoma patients. A total of 432 endometrial carcinoma patients were enrolled between 2011 and 2013. Follow-up will be completed in 2015. Preoperative histology will be evaluated systematically and background endometrium will be classified. This is the first study incorporating immunohistochemistry, cervical cytology and comorbidity to define the optimal panel of prognostic biomarkers that contribute in clinical decision making in the management of endometrial carcinoma. TRIAL REGISTRATION: Netherlands Trial Register number NTR3503.

Spontaneous regression and recurrence of stage III Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a malignant neuroendocrine carcinoma originating in the skin. It is typically aggressive with a tendency to recur locally and metastasise. There have been several case reports about spontaneous regression of MCC over the past years, but to the best of our knowledge this is the first case of a regional lymph node metastasised MCC with complete spontaneous regression and recurrence. In addition, the primary tumour has an unusual localisation on the foot.

Liquid-based cervical cytology using ThinPrep technology: weighing the pros and cons in a cost-effectiveness analysis.

PURPOSE: Cervical cancer screening with liquid-based cytology (LBC) has been developed as an alternative to the conventional Papanicolaou (CP) smear. Cost-effectiveness is one of the issues when evaluating LBC. Based on the results of a Dutch randomised controlled trial, we conducted cost-effectiveness threshold analyses to investigate under what circumstances manually screened ThinPrep LBC is cost-effective for screening. METHODS: The MISCAN-Cervix microsimulation model and data from the Dutch NETHCON trial (including 89,784 women) were used to estimate the costs and (quality-adjusted) life years ((QA)LYs) gained for EU screening schedules, varying cost-effectiveness threshold values. Screening strategies were primary cytological screening with LBC or CP, and triage with human papillomavirus (HPV) testing. RESULTS: Threshold analyses showed that screening with LBC as a primary test can be cost-effective if LBC is less than 3.2 more costly per test than CP, if the sensitivity of LBC is at least 3-5 % points higher than CP, if the quality of life for women in triage follow-up is only 0.39, or if the rate of inadequate CP smears is at least 16.2 %. CONCLUSIONS: Regarding test characteristics and costs of LBC and CP, only under certain conditions will a change from CP to manually screened ThinPrep LBC be cost-effective. If none of these conditions are met, implementation of manually screened ThinPrep LBC seems warranted only if there are advantages other than cost-effectiveness. Further research is needed to establish whether other LBC systems will be more favorable with regard to cost-effectiveness.

[13-Year old boy with abdominal pain]. / Een jongen met pijn rechts in de onderbuik.

A 13-year old boy presents with pain in the lower right abdomen, showing clinical signs of appendicitis. During McBurney' incision an appendix sana was seen. Histologic examination showed penetrating enterobiasis. This was treated with mebendazol.

Causes and relevance of unsatisfactory and satisfactory but limited smears of liquid-based compared with conventional cervical cytology.

CONTEXT: Recent randomized controlled trials have shown a significant decrease in unsatisfactory rates for liquid-based cytology (LBC) compared with conventional Papanicolaou test (CP). The underlying causes and relevance of unsatisfactory results for LBC and CP have never been compared within the setting of a randomized controlled trial. OBJECTIVE: To examine differences in causes and relevance of unsatisfactory and satisfactory but limited by (SBLB) results for LBC and CP. DESIGN: Data from the Netherlands ThinPrep Versus Conventional Cytology (NETHCON) trial were used, involving 89 784 women. Causes and relevance of unsatisfactory and SBLB results were analyzed. RESULTS: The primary cause for unsatisfactory results for CP and LBC was scant cellularity. Other causes for unsatisfactory CPs were virtually eliminated with LBC. The same was true for SBLB subcategories, with the exception of SBLB absence of transformation zone component and SBLB scant cellularity. The SBLB absence of transformation zone component showed a statistically significant 22% and SBLB scant cellularity a 12% nonsignificant increase with LBC. The detection rates of abnormalities found during 18 months of follow-up of unsatisfactory test results did not differ significantly between the 2 study arms, nor did they differ from the initial test positivity rates from the NETHCON trial. CONCLUSIONS: Liquid-based cytology shows an almost complete elimination of most causes for unsatisfactory CP, with scant cellularity remaining as the sole cause for unsatisfactory LBC. On the other hand, with LBC a significant increase of smears without a transformation zone component was noted. Women with an unsatisfactory test result are not at increased risk for cervical abnormalities either with LBC or with CP. TRIAL REGISTRATION: Nederlands Trial Register, NTR1032, www.trialregister.nl .

Comparison of liquid-based cytology with conventional cytology for detection of cervical cancer precursors: a randomized controlled trial.

CONTEXT: Liquid-based cytology has been developed as an alternative for conventional cervical cytology. Despite numerous studies and systematic reviews, controversy remains about its diagnostic accuracy. OBJECTIVE: To assess the performance of liquid-based cytology compared with conventional cytology in terms of detection of histologically confirmed cervical intraepithelial neoplasia (CIN). DESIGN, SETTING, AND PARTICIPANTS: Cluster randomized controlled trial involving 89,784 women aged 30 to 60 years participating in the Dutch cervical screening program at 246 family practices. One hundred twenty-two practices were assigned to use liquid-based cytology and screened 49,222 patients and 124 practices were assigned to use the conventional Papanicolaou (Pap) test and screened 40,562 patients between April 2004 and July 1, 2006. Patients were followed up for 18 months through January 31, 2008. INTERVENTION: Screening for CIN using liquid-based cytology or conventional papanicolaou (Pap) test and the blinded review of all follow-up of screen-positive women (blinded to the type of cytology and the initial result). MAIN OUTCOME MEASURES: Intention-to-treat and per-protocol analysis of the detection rates of and positive predictive values for histologically verified CIN in both cytology systems. Outcomes are presented as crude and adjusted rate ratios (adjustment for age, urbanization, study site, and period). RESULTS: The adjusted detection rate ratios for CIN grade 1+ was 1.01 (95% confidence interval [CI], 0.85-1.19); for CIN grade 2+, 1.00 (95% CI, 0.84-1.20); for CIN grade 3+, 1.05 (95% CI, 0.86-1.29); and for carcinoma, 1.69 (95% CI, 0.96-2.99). The adjusted positive predictive value (PPV) ratios, considered at several cytological cutoffs and for various outcomes of CIN did not differ significantly from unity. CONCLUSION: This study indicates that liquid-based cytology does not perform better than conventional Pap tests in terms of relative sensitivity and PPV for detection of cervical cancer precursors. TRIAL REGISTRATION: trialregister.nl Identifier: NTR1032.

Cytologic detection of cervical abnormalities using liquid-based compared with conventional cytology: a randomized controlled trial.

OBJECTIVE: To compare test positivity rates of liquid-based and conventional cytology. METHODS: This study was a cluster randomized controlled trial with family practice as the unit of randomization, performed within the Dutch national cervical screening program. Women aged 30-60 years (n=89,784) recruited from 246 family practices were included. One-hundred twenty-two practices (49,222 individuals) were randomly assigned to the experimental arm, and 124 practices (40,562 participants), to the conventional arm. Inclusion was performed during a 3-year period between April 2003 and July 2006. Cytologic test positivity rates of liquid-based compared with conventional cytology was compared in terms of crude and adjusted odds ratios, applying a per-protocol analysis. RESULTS: Crude ratios of the odds of test positivity rates of liquid-based compared with conventional cytology for atypical squamous cells of undetermined significance or more severe, low-grade squamous intraepithelial lesion or more severe, and high-grade squamous intraepithelial lesion or more severe were 0.95 (95% confidence interval [CI] 0.82-1.10), 1.00 (95% CI 0.83-1.20), and 0.97 (95% CI 0.77-1.22), respectively. Liquid-based cytology resulted in fewer unsatisfactory tests (odds ratio 0.30, 95% CI 0.23-0.38). The results did not change when the odds ratios were adjusted for age, study site, study period, and urbanization level. Of 128 women screened with liquid-based cytology, one unsatisfactory preparation is avoided. CONCLUSION: This study found no statistically significant difference in cytologic test positivity rates between liquid-based and conventional cytology. However, liquid-based cytology resulted in significantly fewer unsatisfactory tests. CLINICAL TRIAL REGISTRATION: Nederlands Trial Register, www.trialregister.nl, NTR1032 LEVEL OF EVIDENCE: I.

Liquid compared with conventional cervical cytology: a systematic review and meta-analysis.

OBJECTIVE: To compare test performance characteristics of conventional Pap tests and liquid-based cervical cytology samples. DATA SOURCES: Eligible studies, published between 1991 and 2007, were retrieved through PubMed/EmBase searching and completed by consultation of other sources. METHODS OF STUDY SELECTION: Studies were selected if a conventional and a liquid-based sample were prepared from the same woman or when one or the other type of sample was taken from a separate but similar cohort. The current systematic review and meta-analysis is restricted to studies where all subjects were submitted to gold standard verification, based on colposcopy and histology of colposcopy-targeted biopsies, allowing computation of absolute and relative test validity for cervical intraepithelial neoplasia grade 2 or worse. Randomized trials were selected as well if all test-positive cases were verified with the same gold standard, allowing computation of the relative sensitivity. Impact of study characteristics on accuracy was assessed by subgroup meta-analyses, meta-regression, and summary receiver operating characteristic curve regression. TABULATION, INTEGRATION, AND RESULTS: The relative sensitivity, pooled from eight studies, with complete gold standard verification and from one randomized clinical trial, did not differ significantly from unity. Also, the specificity, considering high-grade and low-grade squamous intraepithelial lesions as cutoff, was similar in conventional and liquid cytology. However, a lower pooled specificity was found for liquid-based cytology when presence of atypical squamous cells of undetermined significance was the cutoff (ratio 0.91, 95% confidence interval 0.84-0.98). Differences in study characteristics did not explain interstudy heterogeneity. CONCLUSION: Liquid-based cervical cytology is neither more sensitive nor more specific for detection of high-grade cervical intraepithelial neoplasia compared with the conventional Pap test.

Liquid-based cervical cytology.

BACKGROUND: The objective of the current study was to evaluate the applicability of liquid-based cytology in the Netherlands population screening program for cervical cancer. METHODS: A special committee performed an evaluation of all the available literature. Two methods were investigated: the AutoCytePrep system (currently known as ShurePath-system; TriPath Imaging, Burlington, NC) and the ThinPrep system (Cytyc, Boxborough, MA) for the detection of squamous epithelial abnormalities. All literature up to May 2000 was evaluated. RESULTS: For the AutoCytePrep system, there were indications that the detection rate for atypical squamous cells of undetermined significance (ASCUS) or higher had lower sensitivity compared with conventional screening. No definitive statement could be made concerning the value of the AutoCytePrep system for the detection rate of low-grade squamous intraepithelial lesions (LSIL) or higher and high-grade squamous intraepithelial lesions (HSIL) or higher because of conflicting results. For the ThinPrep system, there were indications that the detection rate of ASCUS or higher had a higher detection rate compared with conventional screening, with slightly lower specificity. It is likely that the detection rate of LSIL or higher with the ThinPrep system had greater sensitivity compared with conventional screening with almost unchanged specificity. In addition, it is likely that the detection rate of HSIL or higher with the ThinPrep system had a higher detection rate and greater absolute sensitivity compared with conventional screening with almost unchanged relative and absolute specificity. CONCLUSIONS: Further research that complies with the standards stated in the current study will be necessary to evaluate the applicability of the AutoCytePrep method. Further evaluation of the costs and benefits of the ThinPrep method should be undertaken to decide definitively whether to implement this method in the Netherlands population screening program.