Tumor infiltrating lymphocytes and change in tumor load on MRI to assess response and prognosis after neoadjuvant chemotherapy in breast cancer.

PURPOSE: In this study, we aimed to explore if the combination of tumor infiltrating lymphocytes (TILs) and change in tumor load on dynamic contrast-enhanced magnetic resonance imaging leads to better assessment of response to neoadjuvant chemotherapy (NAC) in patients with breast cancer, compared to either alone. METHODS: In 190 NAC treated patients, MRI scans were performed before and at the end of treatment. The percentage of stromal TILs (%TILs) was assessed in pre-NAC biopsies according to established criteria. Prediction models were developed with linear regression by least absolute shrinkage and selection operator and cross validation (CV), with residual cancer burden as the dependent variable. Discrimination for pathological complete response (pCR) was evaluated using area under the receiver operating characteristic curves (AUC). We used Cox regression analysis for exploring the association between %TILs and recurrence-free survival (RFS). RESULTS: Fifty-one patients reached pCR. In all patients, the %TILs model and change in MRI tumor load model had an estimated CV AUC of 0.69 (95% confidence interval (CI) 0.53-0.78) and 0.69 (95% CI 0.61-0.79), respectively, whereas a model combining the variables resulted in an estimated CV AUC of 0.75 (95% CI 0.66-0.83). In the group with tumors that were ER positive and HER2 negative (ER+/HER2-) and in the group with tumors that were either triple negative or HER2 positive (TN&HER2+) separately, the combined model reached an estimated CV AUC of 0.72 (95% CI 0.60-0.88) and 0.70(95% CI 0.59-0.82), respectively. A significant association was observed between pre-treatment %TILS and RFS (hazard ratio (HR) 0.72 (95% CI 0.53-0.98), for every standard deviation increase in %TILS, p = 0.038). CONCLUSION: The combination of TILs and MRI is informative of response to NAC in patients with both ER+/HER2- and TN&HER2+ tumors.

Tumor-infiltrating lymphocytes and immune-related adverse events in advanced melanoma.

Background: The predictive value of tumor-infiltrating lymphocytes (TILs) in immune-related adverse event (irAE) development remains unknown, although an association between tumor immunogenicity and irAEs has been suggested. We investigated the association between TIL abundance in pretreatment primary and metastasis specimens and the subsequent development of severe irAEs. Patients and methods: We retrospectively identified patients with advanced cutaneous melanoma who received first-line anti-programmed cell death protein 1 (PD-1) with or without anti-cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4) from 10 hospitals in the Netherlands. TILs were scored on representative hematoxylin and eosin (H&E) stains of the primary melanoma and pretreatment melanoma metastasis as 'absent', 'nonbrisk', or 'brisk'. A univariable logistic regression analysis was carried out to assess the association between the TIL scores and the development of severe irAEs. Fine and Gray subdistribution hazard models were used to estimate the cumulative incidence of severe irAEs. Results: Of the 1346 eligible patients, 536 patients had primary melanoma specimens available, and 613 patients had metastasis specimens available. Severe irAEs occurred in 15% of anti-PD-1-treated patients and 49% of anti-PD-1 + anti-CTLA-4-treated patients. The presence of TILs was not associated with the occurrence of grade ≥3 irAEs in primary melanoma specimens (P = 0.70) nor pretreatment metastasis specimens (P = 0.91). In the univariable analysis, patients with brisk TILs did not have a higher chance of developing severe irAEs compared with patients with absent TILs, for both primary specimen (odds ratio 1.15, 95% confidence interval 0.60-2.18) and metastasis specimen (odds ratio 0.77, 95% confidence interval 0.37-1.59). There was also no significant difference in the lifetime risk or timing of the development of severe irAEs in patients with TILs present compared with patients with TILs absent. Conclusion: There was no association between the TIL scores on H&E-stained slides from the primary melanoma or pretreatment metastasis and the development of grade 3 or higher irAEs. Additionally, no correlation was found between the presence of TILs and the timing of irAEs.

Clinical implementation of artificial-intelligence-assisted detection of breast cancer metastases in sentinel lymph nodes: the CONFIDENT-B single-center, non-randomized clinical trial.

Pathologists' assessment of sentinel lymph nodes (SNs) for breast cancer (BC) metastases is a treatment-guiding yet labor-intensive and costly task because of the performance of immunohistochemistry (IHC) in morphologically negative cases. This non-randomized, single-center clinical trial (International Standard Randomized Controlled Trial Number:14323711) assessed the efficacy of an artificial intelligence (AI)-assisted workflow for detecting BC metastases in SNs while maintaining diagnostic safety standards. From September 2022 to May 2023, 190 SN specimens were consecutively enrolled and allocated biweekly to the intervention arm (n = 100) or control arm (n = 90). In both arms, digital whole-slide images of hematoxylin-eosin sections of SN specimens were assessed by an expert pathologist, who was assisted by the 'Metastasis Detection' app (Visiopharm) in the intervention arm. Our primary endpoint showed a significantly reduced adjusted relative risk of IHC use (0.680, 95% confidence interval: 0.347-0.878) for AI-assisted pathologists, with subsequent cost savings of ~3,000 €. Secondary endpoints showed significant time reductions and up to 30% improved sensitivity for AI-assisted pathologists. This trial demonstrates the safety and potential for cost and time savings of AI assistance.

Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer.

BACKGROUND: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. MATERIALS AND METHODS: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. RESULTS: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. CONCLUSIONS: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.

Predicting response to neoadjuvant chemotherapy with liquid biopsies and multiparametric MRI in patients with breast cancer.

Accurate prediction of response to neoadjuvant chemotherapy (NAC) can help tailor treatment to individual patients' needs. Little is known about the combination of liquid biopsies and computer extracted features from multiparametric magnetic resonance imaging (MRI) for the prediction of NAC response in breast cancer. Here, we report on a prospective study with the aim to explore the predictive potential of this combination in adjunct to standard clinical and pathological information before, during and after NAC. The study was performed in four Dutch hospitals. Patients without metastases treated with NAC underwent 3 T multiparametric MRI scans before, during and after NAC. Liquid biopsies were obtained before every chemotherapy cycle and before surgery. Prediction models were developed using penalized linear regression to forecast residual cancer burden after NAC and evaluated for pathologic complete response (pCR) using leave-one-out-cross-validation (LOOCV). Sixty-one patients were included. Twenty-three patients (38%) achieved pCR. Most prediction models yielded the highest estimated LOOCV area under the curve (AUC) at the post-treatment timepoint. A clinical-only model including tumor grade, nodal status and receptor subtype yielded an estimated LOOCV AUC for pCR of 0.76, which increased to 0.82 by incorporating post-treatment radiological MRI assessment (i.e., the "clinical-radiological" model). The estimated LOOCV AUC was 0.84 after incorporation of computer-extracted MRI features, and 0.85 when liquid biopsy information was added instead of the radiological MRI assessment. Adding liquid biopsy information to the clinical-radiological resulted in an estimated LOOCV AUC of 0.86. In conclusion, inclusion of liquid biopsy-derived markers in clinical-radiological prediction models may have potential to improve prediction of pCR after NAC in breast cancer.

Biomedical students' satisfaction with and engagement in laboratory e-learning support are related to their self-regulation.

Laboratory e-learning support tools can assist students' learning while preparing for laboratory classes. To successfully work in such virtual experimental environments (VEEs) outside class, students require self-regulated learning (SRL) skills. A deeper understanding of the continuous reciprocal interactions between SRL, satisfaction, and online engagement is needed to develop more effective online learning experiences. This study therefore aimed to explore the interconnection between students' satisfaction with, effort/importance and engagement in an exemplary VEE, and to relate this to their perceived SRL and learning outcomes. Based on surveys in 79 university students, SRL was related to VEE engagement, effort/importance, and satisfaction. VEE engagement and satisfaction were not related to learning outcomes, while SRL and effort were. Students with different SRL also tended to interact differently with the VEE and experienced differing degrees of procedural and feedback support by the e-environment. We conclude that, for optimal learning experience and outcomes, students' effort regulation and SRL need to be supported while interacting with the VEE, preferably by interventions that integrate personalized and adaptive features. This study has implications for designing and optimizing VEEs and indicates that future research should focus on VEEs taking students' SRL and effort regulation into account to support individual learners effectively.

MRI to assess response after neoadjuvant chemotherapy in breast cancer subtypes: a systematic review and meta-analysis.

This meta-analysis aimed to estimate and compare sensitivity, specificity, positive- (PPV) and negative predictive value (NPV) of magnetic resonance imaging (MRI) for predicting pathological complete remission (pCR) after neoadjuvant chemotherapy (NAC) in patients with early-stage breast cancer. We stratified for molecular subtype by immunohistochemistry (IHC) and explored the impact of other factors. Two researchers systematically searched PUBMED and EMBASE to select relevant studies and extract data. For meta-analysis of sensitivity and specificity, we used bivariate random-effects models. Twenty-six included studies contained 4497 patients. There was a significant impact of IHC subtype on post-NAC MRI accuracy (p = 0.0082) for pCR. The pooled sensitivity was 0.67 [95% CI 0.58-0.74] for the HR-/HER2-, 0.65 [95% CI 0.56-0.73] for the HR-/HER2+, 0.55 [95% CI 0.45-0.64] for the HR+/HER2- and 0.60 [95% CI 0.50-0.70] for the HR+/HER2+ subtype. The pooled specificity was 0.85 [95% CI 0.81-0.88] for the HR-/HER2-, 0.81 [95% CI 0.74-0.86] for the HR-/HER2+, 0.88[95% CI 0.84-0.91] for the HR+/HER2- and 0.74 [95% CI 0.63-0.83] for the HR+/HER2+ subtype. The PPV was highest in the HR-/HER2- subtype and lowest in the HR+/HER2- subtype. MRI field strength of 3.0 T was associated with a higher sensitivity compared to 1.5 T (p = 0.00063). The accuracy of MRI for predicting pCR depends on molecular subtype, which should be taken into account in clinical practice. Higher MRI field strength positively impacts accuracy. When intervention trials based on MRI response evaluation are designed, the impact of IHC subtype and field strength on MR accuracy should be considered.

Feasibility of Narrow-Band Imaging, Intraductal Biopsy, and Laser Ablation During Mammary Ductoscopy: Protocol for an Interventional Study.

Introduction: Ductoscopy is a minimally invasive micro-endoscopic approach for direct visualization of intraductal lesions of the breast. Challenges of ductoscopy are low sensitivity for detecting malignancy, the lack of a proper intraductal biopsy device, and adequate treatment of intraductal lesions. This study will analyze three new approaches to enhance the effectiveness of interventional ductoscopy in patients with (premalignant) intraductal lesions: narrow-band imaging (NBI), new intraductal biopsy tools, and intraductal laser ablation. The main aims of the present study are to improve diagnostic accuracy and therapeutic efficacy of interventional ductoscopy in patients with pathological nipple discharge (PND) and to explore the feasibility of the new approaches in diagnosing and removing intraductal precursor lesions. Methods and analysis: This prospective, single-center, diagnostic feasibility study will include two patient groups. Group A: women with PND with no radiological suspicion for malignancy. Group B: women undergoing mastectomy (preventive or therapeutic). The primary endpoints for both groups are the technical feasibility of NBI ductoscopy, intraductal biopsy, and laser ablation, and as secondary endpoint the number of diagnosed and successfully treated intraductal lesions. Discussion: Enhanced ductoscopy with NBI, intraductal biopsy, and laser ablation could prevent unnecessary surgery in patients with PND. Ethics and dissemination: This study was approved by the Medical Research Ethics Committee UMC Utrecht in The Netherlands (METC protocol number 21-688/H-D). The results of this study will be published in peer-reviewed journals and presented at national and international conferences. Highlights: - Pathological nipple discharge (PND) is a common breast-related complaint in women.- Ductoscopy, a minimally invasive technique, is used in the treatment of PND.- This study will analyze three new approaches to enhance interventional ductoscopy of the breast: narrow-band imaging, new intraductal biopsy tools, and intraductal laser ablation in patients with (premalignant) intraductal lesions.

Genomic copy number alterations as biomarkers for triple negative pregnancy-associated breast cancer.

BACKGROUND: PABC, commonly defined as breast cancer diagnosed during or ≤ 1 year after pregnancy, accounts for 7% of all breast cancers in women ≤ 45 years. Compared to age-matched non-PABC patients, PABC is characterized by a particularly aggressive histopathologic profile with poorly differentiated and estrogen- and progesterone receptor negative tumors and associated high mortality rates. This study assessed the genomic background of triple-negative PABC tumors by detection of copy number alterations (CNAs). METHODS: MLPA was used to compare CNAs in breast cancer-associated chromosomal loci between triple-negative PABC- and subtype-matched non-PABC patients. Both CNA patterns were evaluated by cluster analysis; associations between individual gene CNAs, pathological characteristics and survival were explored. RESULTS: Triple-negative PABC tumors exhibited unique CNAs compared to non-PABC tumors, including enrichment for TOP2A copy number loss, an independent predictor of worse overall survival (HR 8.96, p = 0.020). Cluster analysis based on CNA profiles identified a triple-negative PABC-subgroup with a particularly poor prognosis, characterized by chromosome 8p copy number loss. Individual gene CNAs analysis revealed that FGFR1 copy number loss on chromosome 8p11.23 was an independent predictor of poor outcome in multivariate analysis (HR 3.59, p = 0.053) and predicted the development of distant metastases (p = 0.048). CONCLUSION: This study provides novel insights into the biology of triple-negative PABC tumors suggesting that CNAs, particularly 8p loss and TOP2A loss, are involved in the development of breast cancer during pregnancy. FGFR1 loss and TOP2A loss seem to be promising new biomarkers that independently identify subgroups of PABC patients with poor prognosis. These genomic biomarkers may provide clues for personalized therapy.

Limiting systemic endocrine overtreatment in postmenopausal breast cancer patients with an ultralow classification of the 70-gene signature.

PURPOSE: Guidelines recommend endocrine treatment for estrogen receptor-positive (ER+) breast cancers for up to 10 years. Earlier data suggest that the 70-gene signature (MammaPrint) has potential to select patients that have an excellent survival without chemotherapy and limited or no tamoxifen treatment. The aim was to validate the 70-gene signature ultralow-risk classification for endocrine therapy decision making. METHODS: In the IKA trial, postmenopausal patients with non-metastatic breast cancer had been randomized between no or limited adjuvant tamoxifen treatment without receiving chemotherapy. For this secondary analysis, FFPE tumor material was obtained of ER+HER2- patients with 0-3 positive lymph nodes and tested for the 70-gene signature. Distant recurrence-free interval (DRFI) long-term follow-up data were collected. Kaplan-Meier curves were used to estimate DRFI, stratified by lymph node status, for the three predefined 70-gene signature risk groups. RESULTS: A reliable 70-gene signature could be obtained for 135 patients. Of the node-negative and node-positive patients, respectively, 20% and 13% had an ultralow-risk classification. No DRFI events were observed for node-negative patients with an ultralow-risk score in the first 10 years. The 10-year DRFI was 90% and 66% in the low-risk (but not ultralow) and high-risk classified node-negative patients, respectively. CONCLUSION: These survival analyses indicate that the postmenopausal node-negative ER+HER2- patients with an ultralow-risk 70-gene signature score have an excellent 10-year DRFI after surgery with a median of 1 year of endocrine treatment. This is in line with published results of the STO-3-randomized clinical trial and supports the concept that it is possible to reduce the duration of endocrine treatment in selected patients.

Value of routine cytokeratin immunohistochemistry in detecting low volume disease in cervical cancer.

OBJECTIVE: In cervical cancer, sentinel lymph nodes (SLNs) are processed according to the pathological ultrastaging protocol. According to current guidelines, immunohistochemistry with pancytokeratin antibodies is performed in addition to step sectioning with hematoxylin and eosin (H&E), aiding the detection of low volume disease (micrometastasis and isolated tumor cells (ITC)). We studied the added clinical value, and costs, of routine immunohistochemistry (IHC). METHODS: We retrospectively included all FIGO stage IA-IIA1 cervical cancer patients who had undergone SLN procedures at UMC Utrecht from 2008 to 2020. Pathological data were derived from the Dutch Pathology Registry (PALGA) including SLN tumor status and number of slides stained with IHC. RESULTS: In total 234 cervical cancer patients were included. In the 516 surgically resected SLN specimens, 630 SLNs were discovered by the pathologist. Hereof, 579 SLNs from 211 patients were routinely processed with IHC. IHC identified three patients with micrometastasis and five patients with ITC undetected with H&E staining. Thereby, IHC significantly increased the number of patients with low volume disease from 11 (5.3%) to 19 patients (9.1%) (p = 0.04). To achieve this, 3791 slides were stained with IHC at an estimated additional cost of €94,775. In 1.4% (95% CI 0.3%-4.3%) of patients routine use of IHC adjusted the adjuvant treatment. CONCLUSIONS: Routine use of IHC increases detection of low volume disease in cervical cancer SLNs compared to step sectioning with H&E alone by nearly 4%, with an impact on therapeutic strategy-decisions in about 1% of patients. In view of the high associated costs, cost-effectiveness of routine IHC is questionable.

Prognosis of pregnancy-associated breast cancer: inferior outcome in patients diagnosed during second and third gestational trimesters and lactation.

PURPOSE: Pregnancy-associated breast cancer, although most commonly defined as breast cancer diagnosed during pregnancy or ≤1 year following delivery, knows a variety of definitions, likely related to the diversity of reported clinicopathological features and prognosis. More insight into the different breast cancer subgroups during pregnancy, time after delivery and the postpartum period is therefore warranted. METHODS: Patients with breast cancer diagnosed during pregnancy or ≤6 months postdelivery were included, and subdivided according to gestational trimester, and postpartum patients according to lactational status. Subgroups were compared to matched non-PABC patients, to investigate the influence of pregnancy and lactation on clinical course and outcome. RESULTS: Overall, 662 PABC patients were included (median age 34 years, median follow-up 6.5 years). PABC patients showed an advanced stage at diagnosis and an inferior 5-years-OS (75.4% vs. 83.2%, p = 0.000) compared to 1392 matched non-PABC patients. In subgroup analysis, first trimester PABC patients showed a significantly lower tumor size and stage as compared to other trimesters. Patients diagnosed during the first trimester and postpartum non-lactating patients had a relatively good OS (81.3% and 77.9%, respectively) versus patients diagnosed during the second and third trimesters and during lactation (OS 60.0%, 64.9% and 65.6%, respectively, p = 0.003). CONCLUSION: In this large (uniquely specified) PABC cohort, an inferior outcome was found for patients diagnosed within the second and third gestational trimesters and during lactation. These findings indicate that PABC is clinically a heterogeneous group of breast cancer patients that should be redefined based on trimester of diagnosis and lactational status.

Grading of invasive breast carcinoma: the way forward.

Histologic grading has been a simple and inexpensive method to assess tumor behavior and prognosis of invasive breast cancer grading, thereby identifying patients at risk for adverse outcomes, who may be eligible for (neo)adjuvant therapies. Histologic grading needs to be performed accurately, on properly fixed specimens, and by adequately trained dedicated pathologists that take the time to diligently follow the protocol methodology. In this paper, we review the history of histologic grading, describe the basics of grading, review prognostic value and reproducibility issues, compare performance of grading to gene expression profiles, and discuss how to move forward to improve reproducibility of grading by training, feedback and artificial intelligence algorithms, and special stains to better recognize mitoses. We conclude that histologic grading, when adequately carried out, remains to be of important prognostic value in breast cancer patients.

Idiopathic granulomatous mastitis after ductoscopy: A case report.

INTRODUCTION AND IMPORTANCE: Idiopathic granulomatous mastitis (IGM) is an uncommon, benign, chronic inflammatory breast disease of unknown etiology, unpredictable duration, and unclear therapy. PRESENTATION OF CASE: A 41-year-old woman presented with pathological nipple discharge for which ductoscopy was performed. Post-ductoscopy, the patient developed abscesses in her breast with histopathological confirmation of granulomatous mastitis (GM). CLINICAL DISCUSSION AND CONCLUSION: IGM has an unknown etiology and atypical presentation. This is the only case described in which IGM occurred after ductoscopy. This can be related to trauma-induced GM or underlying IGM aggravated by ductoscopy.

Predicting recurrence in patients with sentinel node-negative melanoma: validation of the EORTC nomogram using population-based data.

BACKGROUND: Identifying patients with sentinel node (SN)-negative melanoma who are at greatest risk of recurrence is important. The European Organization for Research and Treatment of Cancer (EORTC) Melanoma Group proposed a prognostic model that has not been validated in population-based data. The EORTC nomogram includes Breslow thickness, ulceration status and anatomical location as parameters. The aim of this study was to validate the EORTC model externally using a large national data set. METHODS: Adults with histologically proven, invasive cutaneous melanoma with a negative SN biopsy in the Netherlands between 2000 and 2014 were identified from the Dutch Pathology Registry, and relevant data were extracted. The EORTC nomogram was used to predict recurrence-free survival. The predictive performance of the nomogram was assessed by discrimination (C-statistic) and calibration. RESULTS: A total of 8795 patients met the eligibility criteria, of whom 14·7 per cent subsequently developed metastatic disease. Of these recurrences, 20·9 per cent occurred after the first 5 years of follow-up. Validation of the EORTC nomogram showed a C-statistic of 0·70 (95 per cent c.i. 0·68 to 0·71) for recurrence-free survival, with excellent calibration (R2 = 0·99; P = 0·999, Hosmer-Lemeshow test). CONCLUSION: This population-based validation confirmed the value of the EORTC nomogram in predicting recurrence-free survival in patients with SN-negative melanoma. The EORTC nomogram could be used in clinical practice for personalizing follow-up and selecting high-risk patients for trials of adjuvant systemic therapy.

Predicting sentinel node positivity in patients with melanoma: external validation of a risk-prediction calculator (the Melanoma Institute Australia nomogram) using a large European population-based patient cohort.

BACKGROUND: A nomogram to predict sentinel node (SN) positivity [the Melanoma Institute Australia (MIA) nomogram] was recently developed and externally validated using two large single-institution databases. However, there remains a need to further validate the nomogram's performance using population-based data. OBJECTIVES: To perform further validation of the nomogram using a European national patient cohort. METHODS: Patients with cutaneous melanoma who underwent SN biopsy in the Netherlands between 2000 and 2014 were included. Their data were obtained from the Dutch Pathology Registry. The predictive performance of the nomogram was assessed by discrimination (C-statistic) and calibration. Negative predictive values (NPVs) were calculated at various predicted probability cutoffs. RESULTS: Of the 3049 patients who met the eligibility criteria, 23% (691) were SN positive. Validation of the MIA nomogram (including the parameters Breslow thickness, ulceration, age, melanoma subtype and lymphovascular invasion) showed a good C-statistic of 0·69 (95% confidence interval 0·66-0·71) with excellent calibration (R2 = 0·985, P = 0·40). The NPV of 90·1%, found at a 10% predicted probability cutoff for having a positive SN biopsy, implied that by using the nomogram, a 16·3% reduction in the rate of performing an SN biopsy could be achieved with an error rate of 1·6%. Validation of the MIA nomogram considering mitotic rate as present or absent showed a C-statistic of 0·70 (95% confidence interval 0·68-0·74). CONCLUSIONS: This population-based validation study in European patients with melanoma confirmed the value of the MIA nomogram in predicting SN positivity. Its use will spare low-risk patients the inconvenience, cost and potential risks of SN biopsy while ensuring that high-risk patients are still identified.

[Histopathologic grading of breast cancer; large variation with major consequences?] / Histopathologische gradering van het mammacarcinoom.

The pathologist's assessment of tumor tissue plays a critical role in therapeutic decision-making in early-stage invasive breast cancer. In daily practice, however, there appears to be considerable variation in grading between the different Dutch pathology laboratories and between individual pathologists within the same laboratory. This underlines the need to standardize grading by pathologists as much as possible in order to minimize the risk of a worse outcome for patients due to under-treatment and of unnecessary toxicity from over-treatment. Therefore, two initiatives were launched, i.e. laboratory-specific feedback reports and an e-learning module in which pathologists were trained in grading of invasive breast cancer. While these initiatives have yielded encouraging results, the overall variation in grading remains significant. Awareness of this variation, and of the inherent difficulties of subjective grading, among the various clinicians involved in breast cancer management, is therefore of utmost importance to improve clinical decision-making for patients.

Pregnancy-associated breast cancer: nationwide Dutch study confirms a discriminatory aggressive histopathologic profile.

PURPOSE: Breast cancer is the most common type of malignancy in pregnant women, occurring approximately once in every 3000 pregnancies. Pregnancy-associated breast cancer (PABC) is commonly defined as breast cancer diagnosed during or within one year after pregnancy, and it accounts for up to 6.9% of all breast cancers in women younger than 45 years old. Whether these cancers arise before or during pregnancy, and whether they are stimulated by the high hormonal environment of pregnancy, is currently unknown. This study assesses the histopathological profile of PABC in a large Dutch population-based cohort. METHODS: We identified 744 patients with PABC (in this cohort defined as breast cancer diagnosed during or within 6 months after pregnancy) diagnosed between 1988 and 2019, in the nationwide Dutch Pathology Registry (PALGA). An age-matched PALGA cohort of unselected breast cancer patients (≤ 45 years), diagnosed between 2013 and 2016, was used as a control. Histopathologic features of both cohorts were compared. RESULTS: The median age of PABC patients was 34.3 years old (range 19-45 years) and most breast cancers were diagnosed during pregnancy (74.2%). As compared to age-matched controls, PABC patients had tumors of higher Bloom-Richardson grade (grade I: 1.5% vs. 12.4%, grade II: 16.9% vs. 31.3%, grade III: 80.3% vs. 39.5%, p < 0.0001). Furthermore, estrogen (ER)- and progesterone (PR)-receptor expression was less frequently reported positive (ER: 38.9% vs. 68.2% and PR: 33.9% vs. 59.0%, p < 0.0001), while a higher percentage of PABC tumors overexpressed HER2 (20.0% vs. 10.0%, p < 0.0001). The most observed intrinsic subtype in PABC was triple-negative breast cancer (38.3% vs. 22.0%, p < 0.0001), whereas hormone-driven cancers were significantly less diagnosed (37.9% vs. 67.3%, p < 0.0001). CONCLUSION: This study, based on a large population-based cohort of 744 PABC Dutch patients, underlines the more aggressive histopathologic profile compared to age-matched breast cancer patients ≤ 45 years. Further in-depth genetic analysis will be performed to unravel the origin of this discriminating phenotype. It definitely calls for timely detection and optimal treatment of this small but delicate subgroup of breast cancer patients.