Accuracy of MRI-ultrasound fusion-guided and systematic biopsy of the prostate.

OBJECTIVES: Prostate multiparametric MRI (mpMRI) with subsequent targeted biopsy of suspicious lesions has a critical role in the diagnostic workup of prostate cancer. The objective was to evaluate the diagnostic accuracy of systematic biopsies, targeted biopsies, and the combination of both in prostate cancer detection. METHODS: From January 1, 2013 to June 1, 2022, biopsy-naïve and prior biopsy-negative patients who underwent both systematic and targeted biopsies were included. MRIs were evaluated according to PI-RADS with biopsy threshold set at PI-RADS ≥3. Systematic biopsies consisted of 8-12 cores, based on prostate volume. Overall prostate cancer and clinically significant cancer (Gleason Score ≥3 + 4) detection rates were stratified based on PI-RADS and location within the prostate, and compared between biopsy types using McNemar test. RESULTS: Among 867 patients, 615 had prostate cancer, with 434 clinically significant cases. Overall detection rates were: PI-RADS 3 48%, PI-RADS 4 72%, and PI-RADS 5 90%. Detection rates for clinically significant cancer were 21%, 53%, and 72%, respectively. The combination of biopsy methods was most accurate in detecting clinically significant prostate cancer (P < .001). Targeted biopsies alone detected more clinically significant prostate cancer than systematic biopsies alone (43.1% vs 40.3%, P = .046). For posterior PI-RADS 5 lesions, no statistically significant difference was found between all biopsy methods. CONCLUSIONS: In the detection of clinically significant prostate cancer, the combination of systematic and targeted biopsies proves most effective. Targeted biopsies rarely missed significant cancer for posterior PI-RADS 5 lesions, suggesting systematic biopsies could be reserved for instances where targeted biopsy results are negative. ADVANCES IN KNOWLEDGE: This study emphasizes on the efficacy of mpMRI and targeted biopsies in suspected prostate cancer in real-world clinical context. For PI-RADS 5 lesions, systematic biopsies provide limited clinical benefit and may only be necessary when targeted biopsy results are negative.

Functional estrogen receptor signal transduction pathway activity and antihormonal therapy response in low-grade ovarian carcinoma.

BACKGROUND: Advanced low-grade ovarian carcinoma (LGOC) is difficult to treat. In several studies, high estrogen receptor (ER) protein expression was observed in patients with LGOC, which suggests that antihormonal therapy (AHT) is a treatment option. However, only a subgroup of patients respond to AHT, and this response cannot be adequately predicted by currently used immunohistochemistry (IHC). A possible explanation is that IHC only takes the ligand, but not the activity, of the whole signal transduction pathway (STP) into account. Therefore, in this study, the authors assessed whether functional STP activity can be an alternative tool to predict response to AHT in LGOC. METHODS: Tumor tissue samples were obtained from patients with primary or recurrent LGOC who subsequently received AHT. Histoscores of ER and progesterone receptor (PR) were determined. In addition, STP activity of the ER STP and of six other STPs known to play a role in ovarian cancer was assessed and compared with the STP activity of healthy postmenopausal fallopian tube epithelium. RESULTS: Patients who had normal ER STP activity had a progression-free survival (PFS) of 16.1 months. This was significantly shorter in patients who had low and very high ER STP activity, with a median PFS of 6.0 and 2.1 months, respectively (p < .001). Unlike ER histoscores, PR histoscores were strongly correlated to the ER STP activity and thus to PFS. CONCLUSIONS: Aberrant low and very high functional ER STP activity and low PR histoscores in patients with LGOC indicate decreased response to AHT. ER IHC is not representative of functional ER STP activity and is not related to PFS.

The effects of Saline Infusion Sonography on the histological quality of endometrial sampling in women with postmenopausal bleeding.

BACKGROUND: The aim of this study is to analyze the histopathological features of endometrial samples obtained by aspiration when performed before or after the saline contrast sonohysterography in women with postmenopausal bleeding and a thickened endometrium. Hypothetically, the saline infusion could disrupt the tissue and therefore affect the quality of the sample. Furthermore, we want to determine which histological features have impact on the quality of the endometrial sample. METHODS: We performed a randomized controlled trial (ESPRESSO trial) in which we analyzed the aspiration samples in two groups. Women were allocated either to saline contrast sonohysterography and subsequent endometrial sampling (SCSH-Sampling group) or to the opposite order (Sampling-SCSH group). Dedicated gyneco-pathologists retrospectively assessed the specimens and recorded the type (blood, mucus, epithelium, intact glands, stroma and tissue context) and quantity (on a scale of 0-3) of material that was found in the specimens. RESULTS: This analysis consisted of 197 samples, with 101 women in the SCSH-Sampling group and 96 women in the Sampling-SCSH group. No significant differences were found in the histological features between the two groups. All significant histological features differed significantly in the sufficient samples compared to the insufficient samples: higher amounts of blood, more endometrial epithelium, presence of intact endometrial glands, better stroma and tissue context. Oppositely, a significantly higher amount of mucus was found in the insufficient samples. CONCLUSION: This study shows that the histological features of the endometrial sample were not affected by the saline contrast sonohysterography, when performed prior to the tissue sampling. Trial registration ESPRESSO TRIAL, NTR5690, registered 16 February 2016, https://trialsearch.who.int/Trial2.aspx?TrialID=NTR5690 .

Biomarker concordance between primary colorectal cancer and ovarian metastases: a Dutch cohort study.

PURPOSE: The genetic characteristics and mismatch repair (MMR) status of the primary tumor and corresponding metastases in colorectal cancer (CRC) are generally considered to be highly concordant. This implies that either the primary or metastatic tumor can be used for testing gene mutation and MMR status. However, whether this is also true for CRC and their ovarian metastases is currently unknown. Ovarian metastases generally show a poorer response to systemic therapy compared to other metastatic sites. Differences in biomarker status between primary CRC and ovarian metastases could possibly explain this difference in therapy response. METHODS: The study cohort was selected from CRC patients treated in two Dutch hospitals. Eligible patients with CRC and ovarian metastasis who were surgically treated between 2011 and 2018 were included. CRC and corresponding ovarian metastatic tissues were paired. Gene mutation status was established using next-generation sequencing, while the MMR status was established using either immunohistochemistry or microsatellite instability analysis. RESULTS: Matched samples of CRC and ovarian metastasis from 26 patients were available for analysis. A biomarker concordance of 100% was detected. CONCLUSION: Complete biomarker concordance was found between MMR proficient CRC and their matching ovarian metastasis. Biomarker testing of MMR proficient CRC tissue appears to be sufficient, and additional testing of metastatic ovarian tissue is not necessary. Differences in therapy response between ovarian metastases and other metastases from CRC are thus unlikely to be caused by differences in the genetic status.

Establishment of the Dutch Nationwide, Interdisciplinary Infrastructure and Biobank for Fundamental and Translational Ovarian Cancer Research: Archipelago of Ovarian Cancer Research.

OBJECTIVES: Ovarian cancer has the worst overall survival rate of all gynecologic malignancies. For the majority of patients, the 5-year overall survival rate of less than 50% has hardly improved over the last decades. To improve the outcome of patients with all subtypes of ovarian cancer, large-scale fundamental and translational research is needed. To accommodate these types of ovarian cancer research, we have established a Dutch nationwide, interdisciplinary infrastructure and biobank: the Archipelago of Ovarian Cancer Research (AOCR). The AOCR will facilitate fundamental and translational ovarian cancer research and enhance interdisciplinary, national, and international collaboration. DESIGN: The AOCR biobank is a prospective ovarian cancer biobank in which biomaterials are collected, processed, and stored in a uniform matter for future (genetic) scientific research. All 19 Dutch hospitals in which ovarian cancer surgery is performed participate and collaborate in the AOCR biobank. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients of 16 years and older with suspected or diagnosed ovarian, fallopian tube, or primary peritoneal cancer are recruited for participation. Patients who agree to participate give written informed consent for collection, storage, and issue of their biomaterials for future studies. After inclusion, different blood samples are taken at various predefined time points both before and during treatment. In case of a diagnostic paracentesis or biopsy, the residual biomaterials of these procedures are stored in the biobank. During surgery, primary tumor tissue and, if applicable, tissue from metastatic sites are collected and stored. From each patient, a representative histological hematoxylin and eosin stained slide is digitalized for research purposes, including reassessment by a panel of gynecologic pathologists. Clinical and pathological data are obtained on a per-study basis from Dutch registries. Research proposals for the issue of biomaterials and data are evaluated by both the Archipelago Scientific Committee and the Steering Committee. Researchers using the biomaterials from the AOCR biobank are encouraged to enrich the biobank with data and materials resulting from their analyses and experiments. LIMITATIONS: The implementation and first 4 years of collection are financed by an infrastructural grant from the Dutch Cancer Society. Therefore, the main limitation is that the costs for sustaining the biobank after the funding period will have to be covered. This coverage will come from incorporation of budget for biobanking in future grant applications and from fees from external researchers and commercial parties using the biomaterials stored in the AOCR biobank. Moreover, we will apply for grants aimed at sustaining and improving research infrastructures and biobanks. CONCLUSIONS: With the establishment of the Dutch nationwide, interdisciplinary Archipelago of Ovarian Cancer Research infrastructure and biobank, fundamental and translational research on ovarian cancer can be greatly improved. The ultimate aim of this infrastructure is that it will lead to improved diagnostics, treatment, and survival of patients with ovarian cancer.

Signal transduction pathway activity in high-grade serous carcinoma, its precursors and Fallopian tube epithelium.

OBJECTIVE: To determine the activity of key signal transduction pathways in serous tubal intraepithelial carcinoma (STIC) and concurrent high-grade serous carcinoma (HGSC) and compare this to pathway activity in normal Fallopian tube epithelium (FTE). METHODS: We assessed mRNA expression levels of pathway-specific target genes with RT-qPCR in STIC and concurrent HGSC (n = 8) and normal FTE (n = 8). Subsequently, signal transduction pathway assays were used to assess functional activity of the androgen (AR) and estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor beta (TGF-ß) and canonical wingless-type MMTV integration site (Wnt) pathways. RESULTS: There were no statistically significant differences in pathway activity between STIC and HGSC, but STIC and HGSC demonstrated significantly lower ER and higher PI3K and HH pathway activity in comparison to normal FTE, suggesting these pathways as putative early drivers. In addition, we determined FOXO3a protein expression by immunohistochemistry and found loss of FOXO3a protein expression in STIC and HGSC compared to normal FTE. This observation confirmed that activation of PI3K signaling by loss of FOXO is an early hallmark of serous carcinogenesis. Furthermore, HGSC demonstrated significant loss of AR and Wnt pathway activity in relation to FTE, suggesting these pathways contribute to disease progression. CONCLUSION: Our observations, together with the previously described associations between p53 signaling and both PI3K and HH pathway activity, provide evidence that increased PI3K and HH pathway activity and loss of ER pathway activity may be underlying events contributing to neoplastic transformation of FTE into STIC.

Cyclic activity of signal transduction pathways in fimbrial epithelium of the human fallopian tube.

INTRODUCTION: The local environment of the fallopian tube represents the optimal conditions for reproductive processes. To maintain tissue homeostasis, signal transduction pathways are thought to play a pivotal role. Enhancing our understanding of functional signal transduction pathway activity is important to be able to clarify the role of aberrant signal transduction pathway activity leading to female subfertility and other tubal diseases. Therefore, in this study we investigate the influence of the hormonal cycle on the activity of key signal transduction pathways in the fimbrial epithelium of morphologically normal fallopian tubes. MATERIAL AND METHODS: We included healthy pre- (n = 17) and postmenopausal (n = 8) patients who had surgical interventions for benign gynecologic conditions. Histologic sections of the fallopian tubes were reviewed by two pathologists and, for the premenopausal patients, hormone serum levels and sections of the endometrium were examined to determine the hormonal phase (early follicular [n = 4], late follicular [n = 3], early luteal [n = 5], late luteal [n = 5]). After laser capture microdissection, total mRNA was extracted from the fimbrial epithelium and real-time quantitative reverse transcription-PCR was performed to determine functional signal transduction pathway activity of the androgen receptor (AR), estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor-beta (TGF-ß) and canonical wingless-type MMTV integration site (Wnt) pathways. RESULTS: The early luteal phase demonstrated high AR and ER pathway activity in comparison with the late luteal phase (p = 0.016 and p = 0.032, respectively) and low PI3K activity compared with the late follicular phase (p = 0.036), whereas the late luteal phase showed low activity of HH and Wnt compared with the early follicular phase (both p = 0.016). Signal transduction pathway activity in fimbrial epithelium from postmenopausal patients was most similar to the early follicular and/or late luteal phase with regard to the AR, ER and PI3K pathways. Wnt pathway activity in postmenopausal patients was comparable to the late follicular and early luteal phase. We observed no differences in HH and TGF-ß pathway activity between pre- and postmenopausal samples. The cyclic changes in signal transduction pathway activity suggest a stage-specific function which may affect the morphology and physiology of the human fallopian tube. CONCLUSIONS: We demonstrated cyclic changes in activity of the AR, ER, PI3K, HH and Wnt pathways throughout the hormonal cycle.

Functional estrogen receptor signaling pathway activity in high-grade serous ovarian carcinoma as compared to estrogen receptor protein expression by immunohistochemistry.

PURPOSE: Anti-estrogen therapy may be used as a palliative treatment option in high-grade serous ovarian carcinomas (HGSC). However, clinical implementation is limited as the use of estrogen receptor (ER) protein expression by immunohistochemistry remains insufficient in predicting therapy response. To determine the accuracy of ER protein expression as a marker for ER signaling pathway activity, we aimed to correlate ER protein expression to functional ER signaling pathway activity in HGSC. METHODS: Immunohistochemical ER protein expression was visually scored using total percentages of stained tumor cells and histoscores. Subsequently, mRNA was extracted, and RT-qPCR analysis was performed. Functional ER pathway activity was assessed by a computational Bayesian model inferring ER signaling pathway activity from mRNA levels of ER-specific target genes. RESULTS: Our analysis of 29 HGSCs shows that neither total percentage of ER protein expression, nor ER histoscores are significantly correlated to ER signaling pathway activity (respectively, p = 0.473 and p = 0.606). Classification of HGSC into three groups based on ER histoscores 0-100 (n = 6), 101-200 (n = 15) and 201-300 (n = 8) resulted in comparable mean ER signaling pathway activity among the groups (p = 0.356). Several samples in the higher ER histoscore groups had low ER signaling pathway activity, indicating that nuclear ER protein expression is not sufficient to describe transcriptional ER activation. CONCLUSION: Positive immunohistochemical ER staining is not always indicative of an active ER signaling pathway and is, therefore, a poor predictor of anti-estrogen response. Further research is needed to prove the predictive value of ER signaling pathway activity regarding anti-estrogen sensitivity in HGSC patients.

Type of preoperative therapy and stage-specific survival after surgery for rectal cancer: a nationwide population-based cohort study.

Preoperative chemoradiation therapy (CRT) may induce downstaging in rectal cancer (RC). Short-course radiation therapy (SC-RT) with immediate surgery does not cause substantial downstaging. However, the TNM classification adds the "y" prefix in both groups to indicate possible treatment effects. We aim to compare stage-specific survival in these patients. RC patients treated with surgery only, preoperative SC-RT followed by surgery within 10 days, or preoperative CRT, and diagnosed between 2008 and 2014 were included in this population-based study. Clinicopathological and outcome characteristics were analyzed. The study included 11,925 patients. Large discrepancies existed between clinical and pathological stages after surgery only. Surgery-only patients were older with more comorbidities compared with SC-RT and CRT and had worse 5-year survival (64%, 76%, and 74%, respectively; p < 0.001). Five-year survival for stage I was similar after CRT and SC-RT (85% vs. 85%; p = 0.167) and comparable between CRT-treated patients with stage I and those reaching a pathological complete response (pCR; 85% vs. 89%; p = 0.113). CRT was independently associated with worse overall survival compared with SC-RT for stage II (HR 1.57 [95%CI 1.27-1.95]; p < 0.001) and stage III (HR 1.43 [95%CI 1.23-1.70]; p < 0.001). Stage I disease after CRT has an excellent prognosis, comparable with pCR and with same-stage SC-RT-treated patients without regression. Stage II or III after CRT has worse prognosis than after SC-RT with immediate surgery. TNM should take the impact of preoperative therapy type on stage-specific survival into account. In addition, clinical stage was a poor predictor of pathological stage.

Measuring the depth of invasion in vulvar squamous cell carcinoma: interobserver agreement and pitfalls.

AIMS: The depth of invasion is an important prognostic factor for patients with vulvar squamous cell carcinoma (SCC). The threshold of 1 mm distinguishes between FIGO stages IA and ≥IB disease and guides the need for groin surgery. Therefore, high interobserver agreement is crucial. The conventional and the alternative method are described to measure the depth of invasion. The aims of this study were to assess interobserver agreement for classifying the depth of invasion using both methods and to identify pitfalls. METHODS AND RESULTS: Fifty slides of vulvar SCC with a depth of invasion approximately 1 mm were selected, digitally scanned and independently assessed by 10 pathologists working in a referral or oncology centre and four pathologists in training. The depth of invasion was measured using both the conventional and alternative method in each slide and categorised into ≤1 and >1 mm. The percentage of agreement and Light's kappa for multi-rater agreement were calculated, and 95% confidence intervals were calculated by bootstrapping (1000 runs). The agreement using the conventional method was moderate (κ = 0.57, 95% confidence interval = 0.45-0.68). The percentage of agreement among the participating pathologists using the conventional method was 85.0% versus 89.4% using the alternative method. Six pitfalls were identified: disagreement concerning which invasive nest is deepest, recognition of invasive growth and where it starts, curved surface, carcinoma situated on the edge of the tissue block, ulceration and different measurement methods. CONCLUSIONS: Pathologists reached only moderate agreement in determining the depth of invasion in vulvar SCC, without a notable difference between the two measurement methods.

Acute toxicity and surgical complications after preoperative (chemo)radiation therapy for rectal cancer in patients with inflammatory bowel disease.

PURPOSE: Preoperative therapy reduces local recurrences and may facilitate surgery in rectal cancer patients. However, in patients with inflammatory bowel disease (IBD) this treatment is often withheld due to the perceived risk of excessive side-effects, even though evidence is limited. The purpose of this study is to investigate the effects of preoperative therapy on acute toxicity and post-operative complications in IBD patients with rectal cancer. METHODS: The Dutch pathology registry (PALGA) was searched for patients with IBD and rectal cancer treated between January 1991 and May 2010. Histopathology and clinical charts were reviewed to confirm IBD diagnosis and evaluate clinical and pathological characteristics. RESULTS: Out of 161 patients, 66 received preoperative therapy (41%), including short-course radiation therapy (SC-RT), long course radiation therapy (LC-RT), and chemoradiation therapy (CRT) in 32, 13, and 21 patients respectively. Grade≥3 acute toxicity occurred in 0 patients (0.0%), 1 patient (7.7%), and 6 patients (28.6%) respectively (p=0.004). Systemic corticosteroids were used by 10.5% of patients at time of treatment. Grade≥3 post-operative 30-day complication rate (28.1% overall) was not associated with type of preoperative therapy. CONCLUSION: Results did not show excessive rates of toxicity or post-operative complications and support the use of standard preoperative therapies for rectal cancer (especially SC-RT) in IBD patients with relatively indolent disease. Caution is warranted in patients with active IBD, since the exact impact of active bowel inflammation could not be determined retrospectively. Prospective studies should investigate the influence of active IBD on acute and late toxicity in patients receiving pelvic irradiation.

Clinicopathological characteristics predict lymph node metastases in ypT0-2 rectal cancer after chemoradiotherapy.

AIMS: Changes in rectal cancer treatment include increasing emphasis on organ preservation. Local excision after chemoradiotherapy (CRT) for rectal cancer with excellent clinical response reduces morbidity and mortality compared to total mesorectal excision, although residual lymph node metastases (LNM) may cause local recurrence. Our aim is to identify clinicopathological factors predicting the presence of residual LNM in rectal cancer patients with ypT0-2 tumours after neoadjuvant CRT. These risk factors may help to select patients who can be spared radical surgery without compromising oncological outcomes. METHODS AND RESULTS: Rectal cancer patients with ypT0-2 tumours after CRT and radical resection from five centres treated between June 1999 and February 2012 were included. Histopathology was reviewed extensively. Clinicopathological characteristics and their association with residual LNM were investigated. Of 657 consecutive CRT-treated rectal cancer patients 210 with ypT0-2 disease were included. Residual nodal disease was found in 44 cases (21.0%). Independent predictors of LNM were clinical nodal involvement (cN+ ) [odds ratio (OR): 2.79, 95% confidence interval (CI): 1.04-7.48, P = 0.042], high-grade histopathology assessed in the post-CRT resection specimen (OR: 6.46, 95% CI: 1.23-34.02, P = 0.028) and residual tumour diameter (RTD) ≥10 mm (OR: 2.54, 95% CI: 1.06-6.09, P = 0.036). An algorithm combining these factors stratified patients adequately according to LNM risk, independently of ypT category. CONCLUSIONS: Clinical nodal involvement, high-grade histopathology and RTD ≥10 mm are strong and independent predictors of residual nodal disease in rectal cancer patients with ypT0-2 tumours after CRT. Risk stratification based on these factors may help to identify patients suitable for organ preserving therapy and should be validated in appropriately selected populations.

Modern Treatment of Rectal Cancer Closes the Gap Between Common Adenocarcinoma and Mucinous Carcinoma.

BACKGROUND: Mucinous carcinoma (MC) is a distinct form of rectal cancer (RC) comprising 10 % of all cases and has been associated with an impaired prognosis compared with non-mucinous adenocarcinoma (AC). The benefit of today's modern treatment for MC patients is unknown but a prospective randomized trial to answer this does not seem feasible. This study provides an analysis of the modern treatment of rectal MC and efficacy of preoperative therapies for MC patients. METHODS: Data from three large (trial) cohorts were used. Data from the Netherlands Cancer Registry (NCR) were used to analyze the prognosis of RC patients over time (N = 38,035). To study the benefit of preoperative short-term radiotherapy, patients from the total mesorectal excision (TME) trial (N = 1,530) were selected, and the benefit from preoperative chemoradiotherapy was analyzed with data on 540 locally advanced RC (LARC) patients from two hospitals. RESULTS: Data from the NCR confirmed that 5-year overall survival for MC was significantly worse from 1989 to 1998, but no longer different from AC from 1999 onwards. MC patients had a higher rate of positive circumferential resection margin than AC patients (TME trial 27.2 vs. 16.5 %, p = 0.006; LARC cohort 34.5 vs. 9.8 %, p < 0.0001), but there was no difference in outcome between MC and AC patients after preoperative short-term radiotherapy or chemoradiotherapy. CONCLUSIONS: Modern treatment of RC has benefited MC patients, leading to equal survival for MC and AC patients. Enhancements in the fields of imaging and quality of surgery have improved outcome and preoperative therapies should be recommended for both histological subtypes.

Tumour regression grading after chemoradiotherapy for locally advanced rectal cancer: a near pathologic complete response does not translate into good clinical outcome.

BACKGROUND: After preoperative chemoradiotherapy (CRT) for rectal cancer, clinically undetectable residual tumour deposits or pathologic lymph nodes may remain in the mesorectum. AIM: The aim of this study was to report histopathological effects of CRT and factors affecting outcome in a uniformly treated series of locally advanced rectal cancer (LARC) patients. METHODS: Between 2004 and 2008, 107 patients with cT3 (threatening the mesorectal fascia or <5 cm from the anal verge), cT4 or cN2 rectal cancer were treated with preoperative CRT (25 × 2 Gy with capecitabine) and TME 6-8 weeks later. Central histopathological review followed. Tumour regression grade (TRG) was scored in pCR, near-pCR, response and no response. Cox regression was performed to identify prognosticators. RESULTS: The 3-year distant metastasis-free interval, disease-free rate and overall survival rate were 82%, 73% and 87% (median 44 months follow-up). TRG consisted of 20% pCR, 11% near-pCR, 55% response and 14% no response. 6/21 pCR patients harboured nodal metastases. 5/12 near-pCR had ypT3 disease, while 6 harboured node metastases. 5/12 near-PCR patients developed distant metastases. ypN and TRG were powerful outcome discriminators. CONCLUSION: The high number of near-pCR with ypT3 or ypN1/2 and their poor outcome demonstrates that "watch-and-wait" in LARC patients should be applied with care.

Predicting lymph node metastasis in pT1 colorectal cancer: a systematic review of risk factors providing rationale for therapy decisions.

BACKGROUND AND STUDY AIM: Population screening for colorectal cancer (CRC) is expected to increase the number of pT1 CRCs. Local excision is an attractive treatment option, but is only oncologically safe in the absence of lymph node metastasis (LNM). A systematic review of the predictive value of pathological risk factors for LNM in pT1 CRC was conducted to provide data for an evidence-based decision regarding follow-up or radical surgery after local excision. METHODS: PubMed was searched for reports on predictors of LNM in pT1 CRC. Published papers written in English and containing at least 50 patients were included. Meta-analyses were performed using Review Manager 5.1. RESULTS: A total of 17 studies were included involving a total of 3621 patients with available nodal status. The strongest independent predictors of LNM were lymphatic invasion (relative risk [RR] 5.2, 95 % confidence interval [CI] 4.0 - 6.8), submucosal invasion ≥ 1 mm (RR 5.2, 95 %CI 1.8 - 15.4), budding (RR 5.1, 95 %CI 3.6 - 7.3), and poor histological differentiation (RR 4.8, 95 %CI 3.3 - 6.9). Limitations of the study were: results could not be stratified according to location in the colon or rectum; very early tumors removed by polypectomy without surgical resection were not included in the meta-analysis; and included studies were primarily from Asian countries and results therefore need to be verified in Western populations. CONCLUSION: The absence of lymphatic invasion, budding, submucosal invasion ≥ 1 mm, and poor histological differentiation were each associated with low risk of LNM. Risk stratification models integrating these factors need to be investigated further.

Interobserver variability and the effect of education in the histopathological diagnosis of differentiated vulvar intraepithelial neoplasia.

No published data concerning intraobserver and interobserver variability in the histopathological diagnosis of differentiated vulvar intraepithelial neoplasia (DVIN) are available, although it is widely accepted to be a subtle and difficult histopathological diagnosis. In this study, the reproducibility of the histopathological diagnosis of DVIN is evaluated. Furthermore, we investigated the possible improvement of the reproducibility after providing guidelines with histological characteristics and tried to identify histological characteristics that are most important in the recognition of DVIN. A total number of 34 hematoxylin and eosin-stained slides were included in this study and were analyzed by six pathologists each with a different level of education. Slides were reviewed before and after studying a guideline with histological characteristics of DVIN. Kappa statistics were used to compare the interobserver variability. Pathologists with a substantial agreement were asked to rank items by usefulness in the recognition of DVIN. The interobserver agreement during the first session varied between 0.08 and 0.54, which slightly increased during the second session toward an agreement between -0.01 and 0.75. Pathologists specialized in gynecopathology reached a substantial agreement (kappa 0.75). The top five of criteria indicated to be the most useful in the diagnosis of DVIN included: atypical mitosis in the basal layer, basal cellular atypia, dyskeratosis, prominent nucleoli and elongation and anastomosis of rete ridges. In conclusion, the histopathological diagnosis of DVIN is difficult, which is expressed by low interobserver agreement. Only in experienced pathologists with training in gynecopathology, kappa values reached a substantial agreement after providing strict guidelines. Therefore, it should be considered that specimens with an unclear diagnosis and/or clinical suspicion for DVIN should be revised by a pathologist specialized in gynecopathology. When adhering to suggested criteria the diagnosis of DVIN can be made easier.

The Importance of the Pathologist's Role in Assessment of the Quality of the Mesorectum.

Total mesorectal excision (TME) is considered standard of care for rectal cancer treatment. Failure to remove the mesorectal fat envelope entirely may explain part of observed local and distant recurrences. Several studies suggest quality of the mesorectum after TME surgery as determined by pathological evaluation may influence prognosis. We aimed to determine the prognostic value of the plane of surgery as well as factors influencing the likelihood of a high-quality specimen by reviewing the literature. A pooled meta-analysis of relevant outcome data was performed where appropriate. A muscularis propria resection plane was found to increase the risk of local recurrence (RR 2.72 [95 % CI 1.36 to 5.44]) and overall recurrence (RR 2.00 [95 % CI 1.17 to 3.42]) compared to an (intra)mesorectal plane. Plane of surgery is an important factor in rectal cancer treatment and the documentation by pathologists is essential for the improvement of TME quality and patient outcome.