J.M.A. Pijnenborg

Diagnostic workup for postmenopausal bleeding: a randomised controlled trial

To evaluate the effectiveness of hysteroscopy for the detection and treatment of endometrial polyps versus expectant management in women with postmenopausal bleeding (PMB), a thickened endometrium and benign endometrial sampling.

Molecular profiles of benign and (pre)malignant endometrial lesions

Endometrial carcinomas are histologically classified as endometrioid, assumed to originate from hyperplastic endometrium, or non-endometrioid carcinomas, assumed to originate from atrophic endometrium. However, both on a histological and a molecular level there are indications that there are more carcinoma types and carcinogenetic pathways. This study aims to analyze endometrial carcinogenesis on a molecular level. The presence of known KRAS, PIK3CA, AKT1, CTNNB1, BRAF, EGFR and NRAS mutations was studied in proliferative, atrophic and hyperplastic endometrium, endometrioid and serous carcinomas, and the endometrium next to these carcinomas, using single molecule Molecular Inversion Probes. Mutations were found in 9 (15%) of the 62 non atypical, and in 6 (18%) of the 34 atypical hyperplasia cases. In comparison, mutations were found in 1 (3%) of the simple, and 8 (30%) of the 27 complex hyperplasia cases. In 12/22 (55%) endometrioid carcinomas, a mutation was found. The KRAS gene was most often mutated in carcinomas next to hyperplastic endometrium, whereas PIK3CA and CTNNB1 mutations were found in endometrioid carcinomas with adjacent atrophic endometrium. Complex hyperplasia rather than atypical hyperplasia appears to be the most important lesion in the carcinogenesis of endometrioid carcinomas, and KRAS, PIK3CA and CTNNB1 mutations appear to play an important role in this process. Carcinogenesis of endometrioid carcinomas next to hyperplasia seems to be different to that of those next to atrophia. The value of these findings in managing endometrial hyperplasia and carcinoma should be studied.

Survivorship care plans have a negative impact on long-term quality of life and anxiety through more threatening illness perceptions in gynecological cancer patients: the ROGY care trial

PurposePrior results from the registration system oncological gynecology (ROGY) care trial showed that survivorship care plans (SCPs) increased threatening illness perceptions in gynecological cancer survivors, but it remained unclear whether this would result in poorer physical and psychosocial outcomes. The aim of the current study is to assess the direct and indirect effects of SCPs on health-related quality of life (HRQoL) and anxiety and depression, through illness perceptions.MethodsTwelve hospitals in the South of the Netherlands were randomized to providing ‘SCP care’ or ‘usual care.’ Newly diagnosed endometrial and ovarian cancer patients completed questionnaires after initial treatment (endometrial, 221 [75%]; ovarian, 174 [71%]) and after 6, 12, and 24xa0months. SCPs were automatically generated after initial treatment by the oncology providers through the web-based ROGY. Illness perceptions were measured after initial treatment and HRQoL and anxiety and depression after 6, 12, and 24xa0months.ResultsStructural equation models showed that endometrial cancer patients who experienced more symptoms or concern due to the SCP reported worse social functioning (βu2009=u2009−u20090.82; pu2009=u20090.01) and more fatigue, insomnia, pain, and anxiety (βu2009=u20090.58–0.86, pu2009<u20090.05) within 12xa0months after treatment. Ovarian cancer patients who had lower trust that the treatment would cure their disease due to the SCP reported worse emotional functioning 6 months after treatment (βu2009=u20090.27, pu2009=u20090.02).ConclusionsCurrent results show that SCPs may have negative effects on HRQoL and anxiety in patients who experience more threatening illness perceptions due to the SCP. We should be aware of the potential negative consequences of SCPs.Trial Registration clinicaltrials.gov Identifier: NCT01185626.

Compliance with adjuvant treatment guidelines in endometrial cancer : Room for improvement in high risk patients

OBJECTIVESnCompliance of physicians with guidelines has emerged as an important indicator for quality of care. We evaluated compliance of physicians with adjuvant therapy guidelines for endometrial cancer patients in the Netherlands in a population-based cohort over a period of 10years.nnnMETHODSnData from all patients diagnosed with endometrial cancer between 2005 and 2014, without residual tumor after surgical treatment, were extracted from the Netherlands Cancer Registry (N=14,564). FIGO stage, grade, tumor type and age were used to stratify patients into risk groups. Possible changes in compliance over time and impact of compliance on survival were assessed.nnnRESULTSnPatients were stratified into low/low-intermediate (52%), high-intermediate (21%) and high (20%) risk groups. Overall compliance with adjuvant therapy guidelines was 85%. Compliance was highest in patients with low/low-intermediate risk (98%, no adjuvant therapy indicated). The lowest compliance was determined in patients with high risk (61%, external beam radiotherapy with/without chemotherapy indicated). Within this group compliance decreased from 64% in 2005-2009 to 57% in 2010-2014. In high risk patients with FIGO stage III serous disease compliance was 55% (chemotherapy with/without radiotherapy indicated) and increased from 41% in 2005-2009 to 66% in 2010-2014.nnnCONCLUSIONnWhile compliance of physicians with adjuvant therapy guidelines is excellent in patients with low and low-intermediate risk, there is room for improvement in high risk endometrial cancer patients. Eagerly awaited results of ongoing randomized clinical trials may provide more definitive guidance regarding adjuvant therapy for high risk endometrial cancer patients.

Less-favourable prognosis for low-risk endometrial cancer patients with a discordant pre- versus post-operative risk stratification

BACKGROUNDnPre-operative risk stratification based on endometrial sampling determines the extent of surgery for endometrial cancer (EC). We investigated the concordance of pre- and post-operative risk stratifications and the impact of discordance on survival.nnnMETHODSnPatients diagnosed with EC within the first 6 months of the years 2005-2014 were selected from the Netherlands Cancer Registry (Nxa0=xa07875). Pre- and post-operative risk stratifications were determined based on grade and/or histological subtype for 3784 eligible patients.nnnRESULTSnA discordant risk stratification was found in 10% of patients: 4% (Nxa0=xa0155) had high pre- and low post-operative risk and 6% (Nxa0=xa0215) had low pre- and high post-operative risk. Overall survival of patients with high pre- and low post-operative risk was less favourable compared to those with a concordant low risk (80% versus 89%, pxa0=xa00.002). This difference remained significant when correcting for age, stage, surgical staging and adjuvant therapy (hazard ratio 1.80, 95% confidence interval 1.28-2.53, pxa0=xa00.001). Survival of patients with low pre- and high post-operative risk did not differ from those with a concordant high risk (64% versus 62%, pxa0=xa00.295).nnnCONCLUSIONnPatients with high pre- and low post-operative risk have a less favourable prognosis compared to patients with a concordant low risk. Pre-operative risk stratifications contain independent prognostic information and should be incorporated into clinical decision-making.

Vulvar mucinous adenocarcinoma with neuroendocrine differentiation: A case report and review of the literature

BACKGROUNDnThere are limited cases in literature of patients with mucinous adenocarcinoma of the vulva with neuroendocrine differentiation have. With this new case, we aim to provide an overview of the existing literature and present a tool with relevant markers for the pathologist in the differential diagnosis.nnnCASE DESCRIPTIONnA 92-year-old multiparous, Caucasian woman presented with a 8 cm spherical tumor of the left major labium. Since the initial punch biopsy was not conclusive, a local resection was performed. Histopathological examination showed mucus production, large pools of mucin with trabeculae and cribriform glandular structures with strongly atypical columnar epithelium. Additional immunohistochemical analysis demonstrated expression of: CEA, CK7, EMA, and the neuroendocrine markers synaptophysin and chromogranin supporting the diagnosis.nnnCONCLUSIONnIn this report, we present a new case of a mucinous adenocarcinoma of the vulva with neuroendocrine differentiation based immunohistochemical analysis. Due to the indolent tumor behavior, partial vulvectomy is the therapy of choice.

The impact of the survivorship care plan on health care use: 2-year follow-up results of the ROGY care trial

PurposeThe purpose of this paper was to assess the impact of survivorship care plan (SCP) provision and moderating factors on health care use following endometrial cancer treatment.MethodsWomen newly diagnosed with endometrial cancer were included in a pragmatic cluster randomized trial at 12 hospitals in the Netherlands and were randomly assigned to SCP or usual care (nxa0=xa0221; 75% response). The SCP was generated using the web-based Registrationsystem Oncological GYnecology (ROGY) and provided tailored information regarding disease, treatment, and possible late-effects. Cancer-related use of general practitioner, specialist, and additional health care was collected through questionnaires after diagnosis and at 6-, 12-, and 24-month follow-up and compared using linear multilevel regression analyses.ResultsWomen who received an SCP had more cancer-related primary care visits compared to the usual care arm during the first year after diagnosis (βxa0=xa00.7, pxa0<xa00.01). At 6-month follow-up, women in the SCP group used more additional health care compared to women receiving usual care (24 vs. 11%, pxa0=xa00.04). Women with anxious symptoms (pxa0=xa00.03) and women who received radiotherapy (pxa0=xa00.01) had a higher primary care use within the first year after treatment, when receiving an SCP.ConclusionsThe SCP increases primary health care consumption the first year after treatment, particularly in women treated with radiotherapy and women with anxious symptoms.Implications for cancer survivorsThese findings imply that the SCP enables women in need of supportive care to seek relevant care at an early stage after treatment. Whether this results in improved patient-reported outcomes in the long-term needs to be further studied.

Course of chemotherapy-induced peripheral neuropathy and its impact on health-related quality of life among ovarian cancer patients: A longitudinal study

OBJECTIVEnChemotherapy-induced peripheral neuropathy (CIPN) presents itself as sensory peripheral neuropathy (SPN) or motor peripheral neuropathy (MPN). Our aim was to examine the course of SPN and MPN, and their impact on health-related quality of life (HRQoL) among ovarian cancer patients.nnnMETHODSnAll newly diagnosed ovarian cancer patients from twelve hospitals in the South of the Netherlands were eligible for participation. Patients (N=174) completed questions on CIPN (EORTC QLQ-OV28) and HRQoL (EORTC QLQ-C30) after initial treatment and at 6, 12, and 24months (response rates were 70%, 71%, 58%, and 43% respectively).nnnRESULTSnGeneralized linear mixed models showed that among chemotherapy-treated patients (N=98), SPN levels were stable over time. For MPN, symptoms significantly improved at 12months. At 2years, 13% still reported high SPN. Also, 11% still reported high MPN. Regarding HRQoL, patients with high SPN reported a worse physical, role, emotional, social, and cognitive functioning compared to those with low SPN. Moreover, those who changed from low to high SPN over time worsened on physical functioning. For MPN, a worse global quality of life and a worse functioning was reported among patients with high MPN. Also, those who changed from low to high MPN over time worsened on global quality of life and on physical, role, social, and cognitive functioning.nnnCONCLUSIONSnAmong chemotherapy-treated ovarian cancer patients, SPN levels were stable over time. In contrast, MPN symptoms significantly improved at 12months. These symptoms seriously impacted HRQoL. Future studies should examine the impact of different treatment decisions and alterations on CIPN, so recommendations can be made to reduce CIPN (prevalence).

A Structured Assessment to Decrease the Amount of Inconclusive Endometrial Biopsies in Women with Postmenopausal Bleeding.

Objective. To determine whether structured assessment of outpatient endometrial biopsies decreases the number of inconclusive samples. Design. Retrospective cohort study. Setting. Single hospital pathology laboratory. Population. Endometrial biopsy samples of 66 women with postmenopausal bleeding, collected during the usual diagnostic work-up and assessed as insufficient for a reliable histological diagnosis. Methods. Endometrial biopsy samples were requested from the pathology laboratories. The retrieved samples were systematically reassessed by a single pathologist specialized in gynecology. Main Outcome Measure. Disagreement between initial assessment and conclusion after structured reassessment. Results. We retrieved 36 of 66 endometrial biopsy samples from six different pathology laboratories. Structured reassessment of the retrieved samples by a single pathologist specialized in gynecology did not change the conclusion in 35 of the 36 samples. The remaining sample contained a large amount of endometrial tissue and the diagnosis at reassessment was endometrial hyperplasia without atypia. All other samples contained insufficient material for a reliable diagnosis. Conclusion. A structured reassessment of endometrial biopsies samples, which were classified as inconclusive due to insufficient material, did not change the conclusion. Although it might be helpful for pathologists to have diagnostic criteria for adequacy and/or inadequacy of an endometrial biopsy sample, the gain in efficiency is likely to be small.

Tissue microarray is suitable for scientific biomarkers studies in endometrial cancer

The aim of this study was to define the concordance between tissue microarrays (TMAs) of different sizes and whole slide for 15 different antibodies in endometrial cancer and study the use of TMAs in preoperative endometrial samples. Cores of preoperative and hysterectomy specimens of 14 endometrial cancer and three atypical hyperplasia cases were collected in TMA blocks. Two 0.6-mm and two 2.0-mm cores were used from each sample. Different antibodies were tested in TMAs and compared with results of whole slides of hysterectomy. Tested antibodies were as follows: ER, PR, p53, Ki-67, MLH1, PMS2, MSH2, MSH6, ARID1A, stathmin, IMP3, L1CAM, PTEN, β-catenin, and p16. Seventeen cases with four cores per paraffin block (both 0.6 and 2.0xa0mm in duplicate) and 15 different antibodies resulted in a total of 1020 cores for both preoperative and hysterectomy specimen. Overall, 2.0-mm cores were more assessable for evaluation than 0.6-mm cores (96.0 versus 79.5%, pu2009<u20090.01). For most antibodies, a substantial to good agreement between hysterectomy TMA and whole slide was present, with lowest agreement for p16 and stathmin and perfect agreement for mismatch repair proteins. Preoperative TMAs showed for most antibodies moderate to perfect agreement with hysterectomy TMAs. In conclusion, 2.0-mm cores are the preferred size for immunohistochemical studies in endometrial cancer. For all tested antibodies, TMAs are a good alternative for whole slide analysis in scientific studies with large patient cohorts, even in preoperative endometrial samples. However, caution is required for interpretation of TMA results of p16 and stathmin.