Patient satisfaction with ultrasound, whole-body CT and whole-body diffusion-weighted MRI for pre-operative ovarian cancer staging: a multicenter prospective cross-sectional survey.

BACKGROUND: In addition to the diagnostic accuracy of imaging methods, patient-reported satisfaction with imaging methods is important. OBJECTIVE: To report a secondary outcome of the prospective international multicenter Imaging Study in Advanced ovArian Cancer (ISAAC Study), detailing patients' experience with abdomino-pelvic ultrasound, whole-body contrast-enhanced computed tomography (CT), and whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) for pre-operative ovarian cancer work-up. METHODS: In total, 144 patients with suspected ovarian cancer at four institutions in two countries (Italy, Czech Republic) underwent ultrasound, CT, and WB-DWI/MRI for pre-operative work-up between January 2020 and November 2022. After having undergone all three examinations, the patients filled in a questionnaire evaluating their overall experience and experience in five domains: preparation before the examination, duration of examination, noise during the procedure, radiation load of CT, and surrounding space. Pain perception, examination-related patient-perceived unexpected, unpleasant, or dangerous events ('adverse events'), and preferred method were also noted. RESULTS: Ultrasound was the preferred method by 49% (70/144) of responders, followed by CT (38%, 55/144), and WB-DWI/MRI (13%, 19/144) (p<0.001). The poorest experience in all domains was reported for WB-DWI/MRI, which was also associated with the largest number of patients who reported adverse events (eg, dyspnea). Patients reported higher levels of pain during the ultrasound examination than during CT and WB-DWI/MRI (p<0.001): 78% (112/144) reported no pain or mild pain, 19% (27/144) moderate pain, and 3% (5/144) reported severe pain (pain score >7 of 10) during the ultrasound examination. We did not identify any factors related to patients' preferred method. CONCLUSION: Ultrasound was the imaging method preferred by most patients despite being associated with more pain during the examination in comparison with CT and WB-DWI/MRI. TRIAL REGISTRATION NUMBER: NCT03808792.

Direct mailing of HPV self-sampling kits to women aged 50-65 non-participating in cervical screening in the Czech Republic.

BACKGROUND: A population-based cervical cancer screening programme is implemented in the Czech Republic. However, participation is insufficient among women over 50 years. This study aimed to estimate the potential improvement in participation through directly mailed HPV self-sampling kits (HPVssk) compared with standard invitation letters in women aged 50-65 non-participating in screening. METHODS: The study recruited 1564 eligible women (no cervical cancer screening in the last 3 years or more, no previous treatment associated with cervical lesions or cervical cancer). Eight hundred women were mailed with an HPVssk (HPVssk group), and 764 women were sent a standard invitation letter (control group) inviting them to a routine screening (Pap test). The primary outcome was a comparison of the overall participation rate between study groups using a binominal regression model. RESULTS: The participation rate in the HPVssk group was 13.4% [95% confidence interval (CI) 11.2-15.9%; 7.4% of women returned the HPVssk and 6.0% attended gynaecological examination] and 5.0% (95% CI 3.6-6.8%) in the control group. Using the binominal regression model, the difference between the groups was estimated as 7.6% (95% CI 5.0-10.2%; P < 0.001). In the HPVssk group, 22% of women who returned HPVssk had a positive result and 70% of them underwent a follow-up examination. CONCLUSIONS: Compared with traditional invitation letters, the direct mailing of the HPVssk achieved a significantly higher participation rate, along with a notable HPV positivity rate among HPVssk responders. This approach offers a potentially viable method for engaging women who have not yet attended a cervical screening programme.

Is phased implementation of HPV testing and triage with dual staining the way to transform organized cytology screening?

OBJECTIVE: The substantial material and legislative investments in establishing and maintaining cytological screening in the Czech Republic represent barriers to a direct transition to primary HPV screening. Therefore, the LIBUSE project was implemented to test the efficacy of phasing in HPV DNA testing as a co-test to cytology in routine screening of women >30 years of age. METHODS: Women aged 30 to 60 years who underwent regular annual Pap smears were co-tested for HPV DNA with selective 16/18 genotyping at 3-year intervals. All HPV 16/18-positive cases and/or cases with a severe abnormality in cytology were sent for colposcopy; HPV non-16/18-positive cases and LSILs were graded using p16/Ki67 dual-stain cytology, and positive cases were sent for colposcopy. RESULTS: Overall, 2409 patients were included. After the first combined screening (year 'zero') visit, 7.4% of women were HPV-positive and 2.0% were HPV16/18-positive; only 8 women had severe Pap smear abnormalities. Triage by dual staining was positive in 21.9% of cases (28/128). Biopsy confirmed 34 high-grade precancer lesions. At the second combined visit (year 'three'), the frequency of HPV infection (5.3% vs. 7.4%) frequency of HPV16/18 (1.1% vs. 2.0%), referrals for colposcopy (35 vs. 83), and biopsy verified high-grade lesions (5 vs. 34) were significantly lower (all P  ≤ 0.001). CONCLUSION: The addition of HPV DNA testing with selective genotyping of HPV16/18 to existing cytology screening significantly increased the safety of the program. The gradual introduction of HPV testing was well received by healthcare professionals and patients, and can facilitate transformation of the cytology-based screening. ClinicalTrials.gov Identifier: NCT05578833.

HPV testing as an effective triage strategy in the follow-up after fertility-sparing treatment for glandular lesions of the uterine cervix.

OBJECTIVE: The management and surveillance of glandular pre-cancerous lesions of the uterine cervix present distinct challenges compared with squamous lesions, primarily attributed to the lower effectiveness of diagnostic methods such as cytology or colposcopy. This study aimed to investigate the long-term safety of fertility-sparing treatment for adenocarcinoma in situ and microinvasive adenocarcinoma of the cervix, while identifying factors associated with recurrence, with a particular emphasis on the role of human papillomavirus (HPV) testing. METHODS: We retrospectively reviewed data from all patients with histopathologically confirmed adenocarcinoma in situ or microinvasive cervical adenocarcinoma who received treatment at a single center between 2002 and 2023. The study involved the examination of consecutive surgical specimens and the follow-up details. Factors associated with recurrence were assessed in a subgroup of patients with available long-term follow-up data (at least 6 months). RESULTS: In total, 143 patients (112 with adenocarcinoma in situ and 31 with adenocarcinoma) were included in the analysis. Among the 86 patients who underwent fertility-sparing treatment, the recurrence rate was 9% (12% for adenocarcinoma in situ and 4% for adenocarcinoma) during a median follow-up period of 56.6 months (range 7-179). No patients who were HPV negative experienced recurrence during the follow-up period. In contrast, among patients who were HPV positive, the recurrence rate was 38%. Additionally, HPV 16/18 positivity displayed a notable association with a higher risk of recurrence compared with the other high-risk genotypes, although this difference did not reach statistical significance (83% vs 10%; p=0.083, log-rank). CONCLUSION: Our retrospective study demonstrated a significant association between the risk of recurrence and HPV status during the follow-up period. Consequently, long-term follow-up utilizing HPV testing and genotyping appears to be a secure alternative to a hysterectomy.

Risk Factors for the Anal and Oral Human Papillomavirus (HPV) Infections among Women with Severe Cervical Lesions: A Prospective Case-Control Study.

The carcinogenicity of HPV infection in the anogenital and oropharyngeal regions is broadly accepted. The aim of the study was to define risk factors for anal and oral HPV infections in high-risk patients with biopsy-proven severe cervical lesions (CIN2+). Altogether immunocompetent 473 females with CIN2+ were categorized into the study group and another 245 women into the control group. The strongest risk factor for anal HPV infection was the presence of cervical HPV infection (p < 0.001). Furthermore, ten or more lifetime sexual partners (p = 0.013), a sexual non-coital contact with the anal area (p < 0.001), and actively practicing anal-penetrative intercourse (p < 0.001) were significantly associated with anal HPV. A history of genital warts in the woman (p = 0.010) and the presence of genital warts in the male partner (p = 0.029) were found statistically significant for the risk of oral HPV infection. Our data suggest that the presence of HPV infection, especially high-risk genotypes, in one anatomical site poses the greatest risk for HPV infection in another anatomical site. The cervix is the main reservoir of infection, but the risk factors for anal and oral HPV infections are dissimilar according to different anatomical distances and more complex routes of transmission.

Germline multigene panel testing of patients with endometrial cancer.

Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. The present study aimed to determine the frequency of germline pathogenic variants (PV) in patients with EC. In this multicenter retrospective cohort study, germline genetic testing (GGT) was performed in 527 patients with EC using a next generation sequencing panel targeting 226 genes, including 5 Lynch syndrome (LS) and 14 hereditary breast and ovarian cancer (HBOC) predisposition genes, and 207 candidate predisposition genes. Gene-level risks were calculated using 1,662 population-matched controls (PMCs). Patients were sub-categorized to fulfill GGT criteria for LS, HBOC, both or none. A total of 60 patients (11.4%) carried PV in LS (5.1%) and HBOC (6.6%) predisposition genes, including two carriers of double PV. PV in LS genes conferred a significantly higher EC risk [odds ratio (OR), 22.4; 95% CI, 7.8-64.3; P=1.8×10-17] than the most frequently altered HBOC genes BRCA1 (OR, 3.9; 95% CI, 1.6-9.5; P=0.001), BRCA2 (OR, 7.4; 95% CI, 1.9-28.9; P=0.002) and CHEK2 (OR, 3.2; 95% CI, 1.0-9.9; P=0.04). Furthermore, >6% of patients with EC not fulfilling LS or HBOC GGT indication criteria carried a PV in a clinically relevant gene. Carriers of PV in LS genes had a significantly lower age of EC onset than non-carriers (P=0.01). Another 11.0% of patients carried PV in a candidate gene (the most frequent were FANCA and MUTYH); however, their individual frequencies did not differ from PMCs (except for aggregated frequency of loss-of-function variants in POLE/POLD1; OR, 10.44; 95% CI, 1.1-100.5; P=0.012). The present study demonstrated the importance of GGT in patients with EC. The increased risk of EC of PV carriers in HBOC genes suggests that the diagnosis of EC should be included in the HBOC GGT criteria.

Uterine smooth muscle tumors with uncertain malignant potential: analysis following fertility-saving procedures.

OBJECTIVE: The aim of this study was to analyze the clinical and reproductive outcomes of patients treated with myomectomy who were histologically diagnosed with uterine smooth muscle tumor of uncertain malignant potential (STUMP). METHODS: Patients who were diagnosed with STUMP and underwent a myomectomy at our institution between October 2003 and October 2019 were identified. Variables of interest obtained from the institution's database included patient age, relevant medical history, pre-operative appearance of the tumor on ultrasound, parameters of the surgical procedure, histopathological analysis of the tumor, post-operative clinical course, and course of follow-up, including reinterventions and fertility outcomes. RESULTS: There were a total of 46 patients that fulfilled the criteria of STUMP. The median patient age was 36 years (range, 18-48 years) and the mean follow-up was 47.6 months (range, 7-149 months). Thirty-four patients underwent primary laparoscopic procedures. Power morcellation was used for specimen extraction in 19 cases (55.9% of laparoscopic procedures). Endobag retrieval was used in nine patients and six procedures were converted to an open approach due to the suspicious peri-operative appearance of the tumor. Five patients underwent elective laparotomy due to the size and/or number of tumors; three patients had vaginal myomectomy; two patients had the tumor removed during planned cesarean section; and two underwent hysteroscopic resection.There were 13 reinterventions (five myomectomies and eight hysterectomies) with benign histology in 11 cases and STUMP histology in two cases (4.3% of all patients). We did not observe any recurrence as leiomyosarcoma or other uterine malignancy. We did not observe any deaths related to the diagnosis. Twenty-two pregnancies were recorded among 17 women, which resulted in 18 uncomplicated deliveries (17 by cesarean section and one vaginal), two missed abortions, and two pregnancy terminations. CONCLUSIONS: Our study found that uterus-saving procedures and fertility-preservation strategies in women with STUMP are feasible, safe, and seem to be associated with a low risk of malignant recurrence, even while maintaining the mini-invasive laparoscopic approach.

Analysis of risk factors for recurrence in cervical cancer patients after fertility-sparing treatment: The FERTIlity Sparing Surgery retrospective multicenter study.

BACKGROUND: Fertility-sparing treatment in patients with cervical cancer should, in principle, follow identical algorithms to that in patients without future reproductive plans. In recent years, a trend toward nonradical procedures, such as conization or simple trachelectomy, has become apparent in medical literature, because of their associations with better pregnancy outcomes. However, the published reports included small numbers of patients and heterogenous treatment strategies to ascertain the safety of such approaches. OBJECTIVE: This study aimed to collect multi-institutional data regarding the oncological outcomes after fertility-sparing treatment in patients with cervical cancer and to identify prognostic risk factors, including the influence of the radicality of individual cervical procedures. STUDY DESIGN: Patients aged 18 to 40 years with International Federation of Gynecology and Obstetrics 2018 stage IA1 with positive lymphovascular space invasion or ≥IA2 cervical cancer who underwent any type of fertility-sparing procedure were eligible for this retrospective observational study, regardless of their histotype, tumor grade, and history of neoadjuvant chemotherapy. Associations between disease- and treatment-related characteristics with the risk of recurrence were analyzed. RESULTS: A total of 733 patients from 44 institutions across 13 countries were included in this study. Almost half of the patients had stage IB1 cervical cancer (49%), and two-thirds of patients were nulliparous (66%). After a median follow-up of 72 months, 51 patients (7%) experienced recurrence, of whom 19 (2.6%) died because of the disease. The most common sites of recurrence were the cervix (53%) and pelvic nodes (22%). The risk of recurrence was 3 times higher in patients with tumors >2 cm in size than in patients with smaller tumors, irrespective of the treatment radicality (19.4% vs 5.7%; hazard ratio, 2.982; 95% confidence interval, 1.383-6.431; P=.005). The recurrence risk in patients with tumors ≤2 cm in size did not differ between patients who underwent radical trachelectomy and patients who underwent nonradical (conization and simple trachelectomy) cervical procedures (P=.957), regardless of tumor size subcategory (<1 or 1-2 cm) or lymphovascular space invasion. CONCLUSION: Nonradical fertility-sparing cervical procedures were not associated with an increased risk of recurrence compared with radical procedures in patients with tumors ≤2 cm in size in this large, multicenter retrospective study. The risk of recurrence after any type of fertility-sparing procedure was significantly greater in patients with tumors >2 cm in size.

Current knowledge on fertility-sparing treatment of cervical cancer patients.

INTRODUCTION: Cervical cancer directly affects the reproductive function of women of childbearing age. Up to one-third of the disease is dia-gnosed in women younger than 45 years of age, who may still have open reproductive plans. Therefore, in recent years, there has been increasing interest in performing fertility-sparing treatment (FST), which aims to preserve fertility while achieving the same oncologic safety as radical surgical treatment. OBJECTIVE: To summarize the current knowledge on FST in women with early stages of cervical cancer. METHODS: Review of published literature on the topic using medical databases. RESULTS: FST is reserved for patients with HPV-associated cervical cancer up to stage IB with negative nodes. Conservative procedures (conization and simple vaginal trachelectomy) and radical trachelectomy are available. Conservative procedures for tumors 2cm have comparable oncological outcomes as radical treatment with a significantly lower rate of perinatological complications. On average, 55% of patients become pregnant after treatment and of these, on average 70% give birth to a live newborn. Approximately 38% of deliveries are preterm, most often after radical trachelectomy. The most common postoperative complication with direct impact on fertility is cervical stenosis. CONCLUSION: In a selected group of patients with tumors up to 2cm, FST is a safe procedure with good perinatological outcomes. However, it remains unclear whether it is safe to offer this treatment to patients with larger tumors. The use of neoadjuvant chemotherapy followed by conservative surgery is a promising approach but requires further validation in clinical trials.

CERVANTES: an international randomized trial of radical surgery followed by adjuvant (chemo) radiation versus no further treatment in patients with early-stage, intermediate-risk cervical cancer (CEEGOG-CX-05; ENGOT-CX16).

BACKGROUND: The role of adjuvant treatment in the intermediate-risk group of patients with early-stage cervical cancer is controversial and is supported by a single randomized Gynecologic Oncology Group (GOG) 92 study performed more than 20 years ago. Recent retrospective studies have shown excellent local control in this group of patients after radical surgery with no additional adjuvant treatment. PRIMARY OBJECTIVE: To evaluate if adjuvant (chemo)radiation is associated with a survival benefit after radical surgery in patients with intermediate-risk cervical cancer. STUDY HYPOTHESIS: Radical surgery alone is non-inferior to the combined treatment of radical surgery followed by adjuvant (chemo)radiation in disease-free survival in patients with intermediate-risk cervical cancer. TRIAL DESIGN: This is a phase III, international, multicenter, randomized, non-inferiority trial in which patients with intermediate-risk cervical cancer will be randomized 1:1 into arm A, with no additional treatment after radical surgery, and arm B, receiving adjuvant external beam radiotherapy±brachytherapy ± concomitant chemotherapy. Patient data will be collected over 3 years post-randomization of the last enrolled patient for primary endpoint analysis or for 6 years for the overall survival analysis. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients with intermediate-risk early-stage cervical cancer (IB1-IIA), defined as lymph node-negative patients with a combination of negative prognostic factors (tumor size >4 cm; tumor size >2 cm and lymphovascular space invasion; deep stromal invasion >2/3; or tumor-free distance <3 mm) with squamous cell carcinoma or human papillomavirus (HPV)-related adenocarcinoma, are eligible for the trial. PRIMARY ENDPOINT: Disease-free survival defined as time from randomization to recurrence diagnosis. SAMPLE SIZE: 514 patients from up to 90 sites will be randomized. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: It is estimated that the accrual will be completed by 2027 (with 3 additional years of follow-up) and primary endpoint results will be published by 2031. Estimated trial completion is by 2034. TRIAL REGISTRATION: NCT04989647.

Current data on the efficacy of prophylactic HPV vaccination in the primary prevention of cervical lesions.

OBJECTIVE: A review of current knowledge on the efficacy of HPV (human papillomavirus) HPV vaccination against pre-cancers and cervical cancer. METHODS AND RESULTS: HPV infection is probably the most common sexually transmitted disease and the cause of approximately 5% of all human cancers. Currently, three prophylactic vaccines against HPV infection are on the market: bivalent Cervarix, quadrivalent Gardasil (formerly Silgard) and nonavalent Gardasil9. The Czech Republic is one of the countries with a national vaccination program where HPV vaccination is covered by health insurance for girls and boys aged 13-14 years. Extensive scientific data on the efficacy of the vaccines clearly demonstrate significant efficacy against the development of cervical pre-cancers for all three vaccines. According to a high-certainty evidence of the Cochrane database, the efficacy of HPV vaccines against cervical intraepithelial neoplasia grade 2 or 3 associated with HPV 16, 18 compared with placebo in girls and women aged 15-26 is 99%. There is also moderate-certainty evidence that HPV vaccines reduce the risk of adenocarcinoma in situ for approximately 90% for the same population. Initial data also demonstrate a direct impact on reducing the incidence of invasive cervical cancer in vaccinated individuals. In addition, quadrivalent and nonavalent vaccines are highly effective in preventing genital warts. CONCLUSION: All three available prophylactic vaccines show high efficacy in preventing the development of cervical lesions. Efficacy is highest against lesions caused by vaccine genotypes and the highest efficacy is achieved in the HPV naive population.

Fertility-sparing surgery after neo-adjuvant chemotherapy in women with cervical cancer larger than 4 cm: a systematic review.

OBJECTIVE: The objective of this systematic review was to assess the oncologic and fertility outcomes of patients with cervix-confined cancer >4 cm who underwent neo-adjuvant chemotherapy followed by fertility-sparing surgery. METHODS: This study was registered in PROSPERO (registration number CRD42021254816). PubMed/MEDLINE, ClinicalTrials, EMBASE, Cochrane Central Register of Controlled Trials, SCOPUS, and OVID databases were searched from inception to July 2021. The included patients were those with cancer confined to the cervix and tumor diameter >4 cm (International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IB3) with squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma who underwent intra-venous neo-adjuvant chemotherapy followed by successful fertility-sparing surgery. RESULTS: The initial search identified 2990 articles. A total of 40 patients from 11 studies had attempted fertility preservation surgery (conization, simple or radical trachelectomy) and in 26 patients (65%) it was successful. All patients received platinum-based chemotherapy. A complete pathological response occurred in 56% of patients and two patients (7.7%) had a recurrence. The 4.5-year disease-free survival was 92.3% and the 4.5-year overall survival rate was 100%. Of six patients who tried to conceive, four (67%) achieved at least one pregnancy and three of the five pregnancies (60%) were pre-term deliveries (all after radical trachelectomy). All patients with recurrence received cisplatin and ifosfamide instead of cisplatin and paclitaxel, underwent non-radical surgery, and had residual disease in the final specimen. CONCLUSIONS: Evidence for fertility-sparing surgery after neo-adjuvant chemotherapy in patients with cervical cancer and tumors >4 cm is limited, and this approach should be considered as an experimental intervention. As the use of non-radical surgery could be a risk factor, if neo-adjuvant chemotherapy is used, patients should undergo fertility-sparing radical surgery.

The annual recurrence risk model for tailored surveillance strategy in patients with cervical cancer.

PURPOSE: Current guidelines for surveillance strategy in cervical cancer are rigid, recommending the same strategy for all survivors. The aim of this study was to develop a robust model allowing for individualised surveillance based on a patient's risk profile. METHODS: Data of 4343 early-stage patients with cervical cancer treated between 2007 and 2016 were obtained from the international SCCAN (Surveillance in Cervical Cancer) consortium. The Cox proportional hazards model predicting disease-free survival (DFS) was developed and internally validated. The risk score, derived from regression coefficients of the model, stratified the cohort into significantly distinctive risk groups. On its basis, the annual recurrence risk model (ARRM) was calculated. RESULTS: Five variables were included in the prognostic model: maximal pathologic tumour diameter; tumour histotype; grade; number of positive pelvic lymph nodes; and lymphovascular space invasion. Five risk groups significantly differing in prognosis were identified with a five-year DFS of 97.5%, 94.7%, 85.2% and 63.3% in increasing risk groups, whereas a two-year DFS in the highest risk group equalled 15.4%. Based on the ARRM, the annual recurrence risk in the lowest risk group was below 1% since the beginning of follow-up and declined below 1% at years three, four and >5 in the medium-risk groups. In the whole cohort, 26% of recurrences appeared at the first year of the follow-up, 48% by year two and 78% by year five. CONCLUSION: The ARRM represents a potent tool for tailoring the surveillance strategy in early-stage patients with cervical cancer based on the patient's risk status and respective annual recurrence risk. It can easily be used in routine clinical settings internationally.

Tumour-free distance: a novel prognostic marker in patients with early-stage cervical cancer treated by primary surgery.

BACKGROUND: Models predicting recurrence risk (RR) of cervical cancer are used to tailor adjuvant treatment after radical surgery. The goal of our study was to compare available prognostic factors and to develop a prognostic model that would be easy to standardise and use in routine clinical practice. METHODS: All consecutive patients with early-stage cervical cancer treated by primary surgery in a single referral centre (01/2007-12/2016) were eligible if assessed by standardised protocols for pre-operative imaging and pathology. Fifteen prognostic markers were evaluated in 379 patients, out of which 320 lymph node (LN)-negative. RESULTS: The best predictive model for the whole cohort entailed a combination of tumour-free distance (TFD) ≤ 3.5 mm and LN positivity, which separated two subgroups with a substantially distinct RR 36% and 6.5%, respectively. In LN-negative patients, a combination of TFD ≤ 3.5 mm and adenosquamous tumour type separated a group of nine patients with RR 33% from the rest of the group with 6% RR. CONCLUSIONS: A newly identified prognostic marker, TFD, surpassed all traditional tumour-related markers in the RR assessment. Predictive models combining TFD, which can be easily accessed on pre-operative imaging, with LN status or tumour type can be used in daily practice and can help to identify patients with the highest RR.

Sentinel lymph node mapping and intraoperative assessment in a prospective, international, multicentre, observational trial of patients with cervical cancer: The SENTIX trial.

BACKGROUND: SENTIX (ENGOT-CX2/CEEGOG-CX1) is an international, multicentre, prospective observational trial evaluating sentinel lymph node (SLN) biopsy without pelvic lymph node dissection in patients with early-stage cervical cancer. We report the final preplanned analysis of the secondary end-points: SLN mapping and outcomes of intraoperative SLN pathology. METHODS: Forty-seven sites (18 countries) with experience of SLN biopsy participated in SENTIX. We preregistered patients with stage IA1/lymphovascular space invasion-positive to IB2 (4 cm or smaller or 2 cm or smaller for fertility-sparing treatment) cervical cancer without suspicious lymph nodes on imaging before surgery. SLN frozen section assessment and pathological ultrastaging were mandatory. Patients were registered postoperatively if SLN were bilaterally detected in the pelvis, and frozen sections were negative. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02494063). RESULTS: We analysed data for 395 preregistered patients. Bilateral detection was achieved in 91% (355/395), and it was unaffected by tumour size, tumour stage or body mass index, but it was lower in older patients, in patients who underwent open surgery, and in sites with fewer cases. No SLN were found outside the seven anatomical pelvic regions. Most SLN and positive SLN were localised below the common iliac artery bifurcation. Single positive SLN above the iliac bifurcation were found in 2% of cases. Frozen sections failed to detect 54% of positive lymph nodes (pN1), including 28% of cases with macrometastases and 90% with micrometastases. INTERPRETATION: SLN biopsy can achieve high bilateral SLN detection in patients with tumours of 4 cm or smaller. At experienced centres, all SLN were found in the pelvis, and most were located below the iliac vessel bifurcation. SLN frozen section assessment is an unreliable tool for intraoperative triage because it only detects about half of N1 cases.

Micrometastases in Sentinel Lymph Nodes Represent a Significant Negative Prognostic Factor in Early-Stage Cervical Cancer: A Single-Institutional Retrospective Cohort Study.

The data on the prognostic significance of low volume metastases in lymph nodes (LN) are inconsistent. The aim of this study was to retrospectively analyze the outcome of a large group of patients treated with sentinel lymph node (SLN) biopsy at a single referral center. Patients with cervical cancer, stage T1a-T2b, common tumor types, negative LN on preoperative staging, treated by primary surgery between 01/2007 and 12/2016, with at least unilateral SLN detection were included. Patients with abandoned radical surgery due to intraoperative SLN positivity detected by frozen section were excluded. All SLNs were postoperatively processed by an intensive protocol for pathological ultrastaging. Altogether, 226 patients were analyzed. Positive LN were detected in 38 (17%) cases; macrometastases (MAC), micrometastases (MIC), isolated tumor cells (ITC) in 14, 16, and 8 patients. With the median follow-up of 65 months, 22 recurrences occurred. Disease-free survival (DFS) reached 90% in the whole group, 93% in LN-negative cases, 89% in cases with MAC, 69% with MIC, and 87% with ITC. The presence of MIC in SLN was associated with significantly decreased DFS and OS. Patients with MIC and MAC should be managed similarly, and SLN ultrastaging should become an integral part of the management of patients with early-stage cervical cancer.

Management of pregnancy after fertility-sparing surgery for cervical cancer.

Cervical cancer is increasingly diagnosed in women who have not yet completed their reproductive plans. For women with early-stage disease (FIGO stage IA1-IB1), fertility-sparing procedures, such as conization, trachelectomy or radical trachelectomy, represent the treatments of choice. However, women who undergo repeated conization or trachelectomy represent a challenge for obstetricians because they are at increased risk of infertility, mid-trimester miscarriage, preterm premature rupture of membranes and preterm delivery. So far, the evidence-based guidance on the management of these pregnancies is limited. This article reviews the literature discussing pregnancy management in women after fertility-sparing surgery for early cervical cancer. Although the evidence is limited, certain measures are desirable, including screening and treatment of asymptomatic bacteriuria, screening for cervical incompetence and progressive cervical shortening by transvaginal ultrasonography, and fetal fibronectin testing. Vaginal progesterone supplementation should be primary prevention for all women after trachelectomy. Women with a history of preterm delivery or late miscarriage may benefit from cervical cerclage. Elective delivery by cesarean section in the early-term period is desirable.

The role of a pathologist in surgical staging for carcinoma of the cervix uteri.

The incidence of cervical cancer is high in the Czech Republic. Altogether 822 new cases were found in this country during 2016 which means the incidence 15,3 new diseases / 100,000 women. FIGO (Fédération Internationale de Gynécologie et d´Obstétrique) staging of carcinoma for the cervix was changed as follows. Lateral extension measurement is removed in the stage IA, the only criterion is the measured deepest invasion.

Impact of sentinel lymph node frozen section evaluation to avoid combined treatment in early-stage cervical cancer.

BACKGROUND: The need for radical surgery followed by adjuvant chemoradiation may be reduced by abandoning radical surgery in patients in whom lymph node involvement is detected intra-operatively. OBJECTIVES: To analyze, in a retrospective cohort study, the efficacy of the algorithm using intra-operative pathological assessment of sentinel lymph nodes. METHODS: A retrospective single-institution study was carried out, which analyzed data from all consecutive patients with cervical cancer who were referred for primary surgical treatment between May 2005 and December 2015. Inclusion criteria were as follows: (1) TNM stage T1a1 with lymphovascular space invasion, T1a2, T1b, T2a, and selected T2b with incipient parametrial invasion; (2) adenocarcinoma, squamous cell carcinoma, or adenosquamous carcinoma; (3) no evidence of enlarged suspicious nodes or distant metastases on pre-operative imaging; (4) primary surgery with curative intent; (5) successful detection of sentinel lymph node, at least, unilaterally. All patients had at least one sentinel lymph node detected and submitted for frozen section evaluation. When sentinel lymph node involvement was detected intra-operatively, the cervical procedure was abandoned and the patient was referred for definitive chemoradiation. Radical surgery was completed in patients with intra-operative negative sentinel lymph nodes. The reliability of intra-operative sentinel lymph node assessment was evaluated by calculating the sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio. RESULTS: The study included a total of 309 patients. Sentinel lymph nodes were detected bilaterally in 86% of the patients. Lymph node positivity was detected intra-operatively in 18 (6%) patients in whom the cervical procedure was abandoned. Adjuvant radiotherapy after completed radical surgery was given to 29 (9%) patients, including 20 patients with macrometastases (8) or micrometastases (12) reported from the final histology, eight patients with positive parametria (all ≤3 mm), and one patient with a positive vaginal resection margin. The sensitivity, specificity, positive predictive value, and negative predictive value for the intra-operative detection of lymph node positivity (macrometastases or micrometastases) was 47% (95% CI 31% to 64%), 100%, 100%, and 93% (95% CI 90% to 96%), respectively. A total of 18 (6%) patients were spared combined treatment owing to the intra-operative sentinel lymph node triage; 29 patients (9%) received combined treatment with both radical surgery and adjuvant radiotherapy CONCLUSIONS: Of 47 patients with high-risk prognostic risk factors (lymph node, parametria, or surgical margin involvement), combined treatment was successfully avoided in 18 (38%). Despite an effort to triage the patients intra-operatively, 9% received a combination of cervical procedure and adjuvant chemoradiation, mostly owing to the low sensitivity of the frozen section in the detection of micrometastases and macrometastases.

The association among cervical, anal, and oral HPV infections in high-risk and low-risk women.

OBJECTIVE: The human papillomavirus (HPV) can cause premalignant and malignant tumors in the anogenital and oropharyngeal regions. The aim of this study was to describe the association in the prevalence of cervical, anal, and oral HPV infections in high-risk patients with biopsy-confirmed high-grade cervical lesion compared to low-risk women. STUDY DESIGN: A total of 718 immunocompetent women were enrolled in the study. The high-risk (HR) group consisted of 473 patients with biopsy-confirmed high-grade cervical lesion while the low-risk (LR) group consisted of other 245 women. All participants completed an anonymous self-administered questionnaire and were subjected to cervical, anal, and oral HPV genotyping using the Linear array HPV test. RESULTS: A total of 81.4% women were infected in the cervix, 43.3% in the anus, and 2.7% in the oral cavity in the HR group in comparison with only 26.9%, 24.5%, and 1.4% in the low-risk LR group, respectively. The cervical and anal HPV infections were much more frequent in the HR patients (p < 0.001); the difference in the oral HPV prevalence was not significant (p = 0.511) between groups. Concurrent cervical-anal infection was observed in 39.3% of HR women and in 8.3% of the LR patients (p < 0.001) and it significantly increased with the grade of cervical lesion (ptrend<0.001). The higher prevalence of concurrent cervical-oral, anal-oral, and cervical-anal-oral infections in HR women was statistically not significant according to the generally small oral HPV prevalence. CONCLUSIONS: All HPV infections occurred more often in HR than in LR women but not all results were statistically significant. The genotype HPV 16 was found in approximately half of all infections at all sites.