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Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian carcinoma characterized by unique biological features and highly malignant characteristics including low chemosensitivity. Therefore, new therapeutic targets are needed. These could include the downstream pathways of receptor tyrosine kinases, especially the human epidermal growth factor receptor 2 (HER2). Our main objective was to characterize the HER2 status using immunohistochemistry (IHC) and FISH on 118 OCCCs, also considering the novel paradigm of HER2-zero and HER2-low status. Other aims included determination of the association between HER2 status and survival, HER2 gene DNA and RNA NGS analysis, HER2 gene expression analysis, and correlation between IHC and gene expression in HER2-zero and HER2-low cases. Cases with HER2 overexpression/amplification accounted for 5.1% (6/118), with additional 3% harbouring HER2 gene mutation. The remaining 112 (94.9%) cases were HER2-negative. Of these, 75% were classified as HER2-zero and 25% as HER2-low. This percentage of HER2 aberrations is significant concerning their possible therapeutic influence. Cases from the HER2-zero group showed significantly better survival. Although this relationship lost statistical significance in multivariate analysis, the results have potential therapeutic significance. HER2 gene expression analysis showed a significant correlation with HER2 IHC status in the entire cohort (HER2-positive vs. HER2-negative), while in the cohort of only HER2-negative cases, the results did not reach statistical significance, suggesting that gene expression analysis would not be suitable to confirm the subdivision into HER2-low and HER2-zero. Our results also emphasize the need for standardized HER2 testing in OCCC to determine the best predictor of clinical response. [ABSTRACT FROM AUTHOR]

To individualise breast cancer (BC) prevention, markers to follow a person's changing environment and health extending beyond static genetic risk scores are required. Here, we analysed cervical and breast DNA methylation (n = 1848) and single nucleotide polymorphisms (n = 1442) and demonstrate that a linear combination of methylation levels at 104 BC-associated methylation quantitative trait loci (mQTL) CpGs, termed the WID™-qtBC index, can identify women with breast cancer in hormone-sensitive tissues (AUC = 0.71 [95% CI: 0.65–0.77] in cervical samples). Women in the highest combined risk group (high polygenic risk score and WID™-qtBC) had a 9.6-fold increased risk for BC [95% CI: 4.7–21] compared to the low-risk group and tended to present at more advanced stages. Importantly, the WID™-qtBC is influenced by non-genetic BC risk factors, including age and body mass index, and can be modified by a preventive pharmacological intervention, indicating an interaction between genome and environment recorded at the level of the epigenome. Our findings indicate that methylation levels at mQTLs in relevant surrogate tissues could enable integration of heritable and non-heritable factors for improved disease risk stratification. [ABSTRACT FROM AUTHOR]

In 2018, the European Society of Gynecological Oncology (ESGO) jointly with the European Society for Radiotherapy and Oncology (ESTRO) and the European Society of Pathology (ESP) published evidence-based guidelines for the management of patients with cervical cancer. Given the large body of new evidence addressing the management of cervical cancer, the three sister societies jointly decided to update these evidence-based guidelines. The update includes new topics to provide comprehensive guidelines on all relevant issues of diagnosis and treatment in cervical cancer. To serve on the expert panel (27 experts across Europe) ESGO/ESTRO/ESP nominated practicing clinicians who are involved in managing patients with cervical cancer and have demonstrated leadership through their expertise in clinical care and research, national and international engagement, profile, and dedication to the topics addressed. To ensure the statements were evidence based, new data identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the international development group. Before publication, the guidelines were reviewed by 155 independent international practitioners in cancer care delivery and patient representatives. These updated guidelines are comprehensive and cover staging, management, follow-up, long-term survivorship, quality of life and palliative care. Management includes fertility sparing treatment, early and locally advanced cervical cancer, invasive cervical cancer diagnosed on a simple hysterectomy specimen, cervical cancer in pregnancy, rare tumors, recurrent and metastatic diseases. The management algorithms and the principles of radiotherapy and pathological evaluation are also defined. [ABSTRACT FROM AUTHOR]

Genetic and non-genetic factors contribute to breast cancer development. An epigenome-based signature capturing these components in easily accessible samples could identify women at risk. Here, we analyse the DNA methylome in 2,818 cervical, 357 and 227 matched buccal and blood samples respectively, and 42 breast tissue samples from women with and without breast cancer. Utilising cervical liquid-based cytology samples, we develop the DNA methylation-based Women's risk IDentification for Breast Cancer index (WID-BC-index) that identifies women with breast cancer with an AUROC (Area Under the Receiver Operator Characteristic) of 0.84 (95% CI: 0.80–0.88) and 0.81 (95% CI: 0.76–0.86) in internal and external validation sets, respectively. CpGs at progesterone receptor binding sites hypomethylated in normal breast tissue of women with breast cancer or in BRCA mutation carriers are also hypomethylated in cervical samples of women with poor prognostic breast cancer. Our data indicate that a systemic epigenetic programming defect is highly prevalent in women who develop breast cancer. Further studies validating the WID-BC-index may enable clinical implementation for monitoring breast cancer risk. Breast cancer is most commonly diagnosed via a needle biopsy. In this study, the authors show that cervical samples from women with breast cancer have a methylation signature different to that of healthy controls. [ABSTRACT FROM AUTHOR]

The vast majority of epithelial ovarian cancer arises from tissues that are embryologically derived from the Müllerian Duct. Here, we demonstrate that a DNA methylation signature in easy-to-access Müllerian Duct-derived cervical cells from women with and without ovarian cancer (i.e. referred to as the Women's risk IDentification for Ovarian Cancer index or WID-OC-index) is capable of identifying women with an ovarian cancer in the absence of tumour DNA with an AUC of 0.76 and women with an endometrial cancer with an AUC of 0.81. This and the observation that the cervical cell WID-OC-index mimics the epigenetic program of those cells at risk of becoming cancerous in BRCA1/2 germline mutation carriers (i.e. mammary epithelium, fallopian tube fimbriae, prostate) further suggest that the epigenetic misprogramming of cervical cells is an indicator for cancer predisposition. This concept has the potential to advance the field of risk-stratified cancer screening and prevention. Most ovarian cancers originate from cells originally derived from Müllerian Duct cells. Here, the authors show that the methylation profile of Müllerian Duct cells isolated from cervical samples can predict whether a woman has cervical cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide. ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined. [ABSTRACT FROM AUTHOR]

Hepatocyte nuclear factor-1-beta (HNF1B) is a transcription factor crucial for the development of several tissues, and a promising biomarker of certain solid tumours. Thus far, two HNF1B alternative splicing variants (ASVs) have been described, however, the complete spectrum, prevalence and role of HNF1B ASVs in tumorigenesis are unclear. Considering the equivocal data about HNF1B ASVs and expression presented in literature, our aim was to characterize the spectrum of HNF1B mRNA splicing variants across different tissues. Here, we characterize HNF1B ASVs with high sensitivity in carcinomas of the uterine corpus, large intestine, kidney, pancreas, and prostate, with selected paired healthy tissues, using the previously described multiplex PCR and NGS approach. We identified 45 ASVs, of which 43 were novel. The spectrum and relative quantity of expressed ASVs mRNA differed among the analysed tissue types. Two known (3p, Δ7_8) and two novel (Δ7, Δ8) ASVs with unknown biological functions were detected in all the analysed tissues in a higher proportion. Our study reveals the wide spectrum of HNF1B ASVs in selected tissues. Characterization of the HNF1B ASVs is an important prerequisite for further expression studies to delineate the HNF1B splicing pattern, potential ASVs functional impact, and eventual refinement of HNF1B's biomarker role. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate morbidity and oncological outcome in a multicentre series of women with gynaecological malignancies infiltrating pelvic side wall (PSW) that received laterally extended pelvic resection (LEPR).Methods: Patients operated between 2007 and 2017 at three institutions were included. LEPR was defined as an en bloc lateral resection of a pelvic tumour involving sidewall muscle, and/or bone, and/or major nerve, and/or major vascular structure. Postsurgical complications and survivals were evaluated.Results: Sixty-three women with gynaecological tumours involving PSW were treated with LEPR. Five women underwent primary LEPR, whereas 58 (92%) patients needed LEPR because of recurrence. Twenty-four women (38%) received previous radiation therapy before the surgery. R0 resection was achieved in 54 patients (85.7%), whereas the pathologic margins were microscopically and macroscopically positive in 8 (12.7%) patients and 1 (1.6%) patient, respectively. There was one perioperative death, whereas major postoperative complications occurred in 17 patients (27.7%). Thirty (47.5%) women experienced recurrences: 24/54 (44.4%) were in the R0 group, and 6/9 (66.6%) were in the R1 group, with a median PFS of 15 months and 7 months, respectively (p = 0.024). In total, 11 of 54 (20.3%) patients died of disease in the R0 group and 5 of 9 (55.5%) in the R1 group; a median OS was not reached and was 32 months for R0 and R1 groups, respectively (p = 0.033).Conclusions: Involvement of the PSW should not prevent obtaining R0 resection. Although the LEPR is associated with considerable morbidity (≈ 30%), a long-term survival seems to be achieved in those women with complete resection. [ABSTRACT FROM AUTHOR]

Background: Despite significant advances in the screening, detection, and treatment of preinvasive cervical lesions, invasive cervical cancer is the fifth most common cancer in European women. There are large disparities in Europe and worldwide in the incidence, management, and mortality of cervical cancer.Objective: The European Society of Gynecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly develop clinically relevant and evidence-based guidelines in order to improve the quality of care for women with cervical cancer across Europe and worldwide.Methods: The ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of cervical cancer (23 experts across Europe). To ensure that the guidelines are evidence based, the current literature identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 159 international reviewers, selected through ESGO/ESTRO/ESP and including patient representatives.Results: The guidelines cover comprehensively staging, management, and follow-up for patients with cervical cancer. Management includes fertility sparing treatment; stage T1a, T1b1/T2a1, clinically occult cervical cancer diagnosed after simple hysterectomy; early and locally advanced cervical cancer; primary distant metastatic disease; cervical cancer in pregnancy; and recurrent disease. Principles of radiotherapy and pathological evaluation are defined. [ABSTRACT FROM AUTHOR]

Background: One of the most important principles in modern cervical cancer surgery is the concept of tailoring surgical radicality. In practice, this means abandoning the 'one-fits-all' concept in favor of tailored operations. The term 'radical hysterectomy' is used to describe many different procedures, each with a different degree of radicality. Anatomic structures are subjected to artificial dissection artifacts, as well as different interpretations and nomenclatures. This study aimed to refine and standardize the principles and descriptions of the different classes of radical hysterectomy as defined in the Querleu-Morrow classification and to propose its universal applicability. Methods: All three authors independently examined the current literature and undertook a critical assessment of the original classification. Images and pathologic slides demonstrating different types of radical hysterectomy were examined to document a consensual vision of the anatomy. The Cibula 3-D concept also was included in this update. Results: The Querleu-Morrow classification is based on the lateral extent of resection. Four types of radical hysterectomy are described, including a limited number of subtypes when necessary. Two major objectives remain constant: excision of central tumor with clear margins and removal of any potential sites of nodal metastasis. Conclusion: Studies evaluating radicality in the surgical management of cervical cancer should be based on precise, universally accepted descriptions. The authors' updated classification presents standardized, universally applicable descriptions of different types of hysterectomies performed worldwide, categorized according to degree of radicality, independently of theoretical considerations. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to determine oncological outcomes and incidence of lymph node (LN) metastases in women who underwent systematic pelvic and paraaortic lymphadenectomy for surgical staging of apparent stage I low-grade epithelial ovarian cancer (LGEOC). Materials and Methods: A retrospective study was performed at nine institutions across Europe and the US, and patients who underwent surgical staging for presumed stage I LGEOC between 2000 and 2016 were included. To ensure surgical quality, a minimum number of ≥10 pelvic and ≥10 paraaortic LNs was required. Patients with preoperative radiologic or clinical evidence of extraovarian or LN disease, and those with nonepithelial histology, were excluded. Results: The overall incidence of LN metastases was 4.3% in the 163 evaluated patients, and the incidence of LN involvement in serous, endometrioid, and mucinous subtypes was 10.7, 1.5, and 0%, respectively. However, Upstaging due to LN involvement alone occurred in only 2.4% of the patients. Eighty-nine (54.6%) patients received adjuvant chemotherapy due to International Federation of Gynecology and Obstetrics stage IC or higher disease. The 5-year progression-free survival (PFS) and overall survival (OS) were 93.2% (95% confidence interval [CI] 89.4-97.1%) and 94.5% (95% CI 90.9-98.0%), respectively. There was no significant difference in PFS or OS between LN-negative and LN-positive patients. However, fewer patients received adjuvant chemotherapy in the LN-negative group. Multivariate analysis did not identify any independent prognostic factor of survival. Conclusion: The risk of LN involvement in nonserous apparent stage I LGEOC appears low, with a rate of <1% in this retrospective analysis, raising questions about the value of lymphadenectomy in those patients. Larger-scale prospective studies are warranted to evaluate the oncologic safety of omitting systematic LN staging in apparent stage I nonserous LGEOC. [ABSTRACT FROM AUTHOR]

Background: This study aimed to review the oncologic outcomes of nerve-sparing radical hysterectomy (NSRH) in cervical cancer and to compare them with those of standard conventional radical hysterectomy (CRH). Methods: A search of the MEDLINE (Ovid), EMBASE (Ovid), and Cochrane Central Register of Controlled Trials (CENTRAL) databases for studies published to March 3, 2014 was performed using the search term 'nerve sparing or radical hysterectomy and cervical cancer.' The main outcome measure was the recurrence rate after NSRH. The hazard ratio for recurrence was used to compare NSRH and CRH. Results: A total of 21 studies reported data on oncologic outcomes of NSRH. The recurrence rate after NSRH was reported to be 0 to 19.6 %. Of the 21 studies, 10 comparing outcomes between NSRH and CRH were assessed for their eligibility to be included in a meta-analysis. However, the scarcity and heterogeneity of effect estimates in these comparison trials precluded performance of a meta-analysis. Conclusions: The results showed that the evidence addressing the oncologic safety of NSRH over that of CRH in cervical cancer is neither adequate nor statistically relevant. A properly designed, prospective randomized noninferiority trial is needed to assess the oncologic outcomes of NSRH before this surgical approach is adopted as the standard of care for patients with tumors that have unfavorable prognostic features. Until then, NSRH should be considered primarily for patients with small tumors due to the very low risk of parametrial and lymph node involvement, with maximum benefit conferred to the patient from autonomic nerve preservation without any requirement for adjuvant treatment. [ABSTRACT FROM AUTHOR]

Ultrasound is the primary imaging modality in gynecological oncology. Over the last decade, there has been a massive technology development which led to a dramatic improvement in the quality ultrasound imaging. If performed by an experienced sonographer, ultrasound has an invaluable role in the primary diagnosis of gynecological cancer, in the assessment of tumor extent in the pelvis and abdominal cavity, in the evaluation of the treatment response, and in follow-up. Ultrasound is also a valuable procedure for monitoring patients treated with fertility-sparing surgery. Furthermore, it is an ideal technique to guide tru-cut biopsy for the collection of material for histology. Taking into consideration that besides its accuracy, the ultrasound is a commonly available, non-invasive, and inexpensive imaging method that can be carried out without any risk or discomfort to the patient; it is time to reconsider its role in gynecologic oncology and to allocate resources for a specialized education of future experts in ultrasound imaging in gynecology. [ABSTRACT FROM AUTHOR]

The accurate harvesting of a sentinel node in gynaecological cancer (i.e. vaginal, vulvar, cervical, endometrial or ovarian cancer) includes a sequence of procedures with components from different medical specialities (nuclear medicine, radiology, surgical oncology and pathology). These guidelines are divided into sectione entitled: Purpose, Background information and definitions, Clinical indications and contraindications for SLN detection, Procedures (in the nuclear medicine department, in the surgical suite, and for radiation dosimetry), and Issues requiring further clarification. The guidelines were prepared for nuclear medicine physicians. The intention is to offer assistance in optimizing the diagnostic information that can currently be obtained from sentinel lymph node procedures. If specific recommendations given cannot be based on evidence from original scientific studies, referral is made to 'general consensus' and similar expressions. The recommendations are designed to assist in the practice of referral to, and the performance, interpretation and reporting of all steps of the sentinel node procedure in the hope of setting state-of-the-art standards for high-quality evaluation of possible metastatic spread to the lymphatic system in gynaecological cancer. The final result has been discussed by a group of distinguished experts from the EANM Oncology Committee and the European Society of Gynaecological Oncology (ESGO). The document has been endorsed by the SNMMI Board. [ABSTRACT FROM AUTHOR]

Background: The value of surgery for recurrent epithelial ovarian cancer (OC) is controversial. The aim of the present study was to evaluate the outcome of EOC-patients who underwent tertiary cytoreductive surgery (TCS) and to identify prognostic markers for complete tumor resection and survival. Methods: Retrospective multicenter evaluation of TCS patients treated between 1997 and 2011 in 14 centers across Europe, the United States, and Asia. Results: We evaluated 406 patients (median age, 55 years; range, 16-80 years). Median time from first to second recurrence was 18 months (2-204 months). Median follow-up from TCS was 14 months (0-182 months), and median OS was 26 months (95 % CI, 19.62-32.38 months). Median OS for patients without versus any tumor residuals was 49 months (95 % CI, 42.5-56.4 months) versus 12 months (95 % CI 9.3-14.7 months) ( p < 0.001). The majority of the patients had an advanced initial FIGO stage III/IV (69 %), peritoneal carcinomatosis (51.7 %), and absence of ascites (72.2 %). A total of 224 patients (54.1 %) underwent complete tumor resection. The most frequent tumor dissemination site was the pelvis (73 %). Rates of major operative morbidity and 30-day mortality were 25.9 % and 3.2 %, respectively. Multivariate analysis identified platinum resistance, tumor residuals at secondary surgery, and peritoneal carcinomatosis to be of predictive significance for complete tumor resection, while tumor residuals at secondary and tertiary surgery, decreasing interval to second relapse, ascites, upper abdominal tumor involvement, and nonplatinum third-line chemotherapy significantly affected OS. Conclusions: In this largest known database for TCS, residual tumor retains its high impact on survival even in the tertiary setting of OC. In specialized centers high rates of complete tumor resection can be obtained. Prospective analyses are warranted to define the value of TCS in EOC. [ABSTRACT FROM AUTHOR]

Introduction: Ductal carcinoma in situ (DCIS) is considered to be related to the development of invasive breast cancer. The aim of molecular biological research of preinvasive breast lesion characteristics and comparison with normal tissues and tissue of invasive tumours is to identify patients at high risk of developing invasive tumour on the basis of already established preinvasive lesions, and thus influence clinical decision-making. The aim of our study was to analyse several key molecules involved in different cellular pathways important for cancer development and progression in different types of breast tissue and to describe similarities and differences between premalignant and malignant lesions. Material and methods: Genetic material isolated from both the tumour and healthy tissue was examined by loss of heterozygosity (LOH) analysis and real-time PCR using collagen 2A as a house-keeping gene. Results: We analysed 65 samples of healthy mammary gland, 25 DCIS and 42 invasive ductal breast cancer samples. We analysed the LOH in three genes: BRCA1, BRCA2 and p53; and the gene expression of the VEGF gene and Bcl-2 gene. LOH in the BRCA1 gene was present in 44.74% of invasive samples and in 8.69% of DCIS ( p=0.026); LOH in the BRCA2 gene in 45.0% of invasive samples and in 9.52% of DCIS ( p=0.036); LOH in the p53 gene in 32.5% of invasive samples and in 31.82% of DCIS ( p=0.97). No LOH was observed in normal tissue samples. VEGF was overexpressed in 14.3% of invasive cancers and in 12.0% of DCIS. Overexpression of Bcl-2 was observed in 11.9% of invasive cancers and in 8.0% of DCIS. Conclusion: We have confirmed that some of the molecular characteristics of DCIS are identical to those of invasive carcinoma. This approach could lead to the identification of molecular markers as indicators for the potential development of DCIS into invasive carcinoma or identification of DCIS subgroups with latent invasion. [ABSTRACT FROM AUTHOR]

Two corrections were made to the above publication following its original online publication on 4th May 2018. [ABSTRACT FROM AUTHOR]

Regrettably, the author metadata used for the previous correction (doi: https://doi.org/10.1007/s00428-018-2380-7 ) contained an error in the tagging of W. Glenn McCluggage's name; this has been corrected. No further adjustments have been made to the Correction, or the original Guideline paper (doi: https://doi.org/10.1007/s00428-018-2362-9 ). [ABSTRACT FROM AUTHOR]