Interobserver variability in upfront dichotomous histopathological assessment of ductal carcinoma in situ of the breast: the DCISion study.

Histopathological assessment of ductal carcinoma in situ, a nonobligate precursor of invasive breast cancer, is characterized by considerable interobserver variability. Previously, post hoc dichotomization of multicategorical variables was used to determine the "ideal" cutoffs for dichotomous assessment. The present international multicenter study evaluated interobserver variability among 39 pathologists who performed upfront dichotomous evaluation of 149 consecutive ductal carcinomas in situ. All pathologists independently assessed nuclear atypia, necrosis, solid ductal carcinoma in situ architecture, calcifications, stromal architecture, and lobular cancerization in one digital slide per lesion. Stromal inflammation was assessed semiquantitatively. Tumor-infiltrating lymphocytes were quantified as percentages and dichotomously assessed with a cutoff at 50%. Krippendorff's alpha (KA), Cohen's kappa and intraclass correlation coefficient were calculated for the appropriate variables. Lobular cancerization (KA = 0.396), nuclear atypia (KA = 0.422), and stromal architecture (KA = 0.450) showed the highest interobserver variability. Stromal inflammation (KA = 0.564), dichotomously assessed tumor-infiltrating lymphocytes (KA = 0.520), and comedonecrosis (KA = 0.539) showed slightly lower interobserver disagreement. Solid ductal carcinoma in situ architecture (KA = 0.602) and calcifications (KA = 0.676) presented with the lowest interobserver variability. Semiquantitative assessment of stromal inflammation resulted in a slightly higher interobserver concordance than upfront dichotomous tumor-infiltrating lymphocytes assessment (KA = 0.564 versus KA = 0.520). High stromal inflammation corresponded best with dichotomously assessed tumor-infiltrating lymphocytes when the cutoff was set at 10% (kappa = 0.881). Nevertheless, a post hoc tumor-infiltrating lymphocytes cutoff set at 20% resulted in the highest interobserver agreement (KA = 0.669). Despite upfront dichotomous evaluation, the interobserver variability remains considerable and is at most acceptable, although it varies among the different histopathological features. Future studies should investigate its impact on ductal carcinoma in situ prognostication. Forthcoming machine learning algorithms may be useful to tackle this substantial diagnostic challenge.

[An unusual case of olmesartan induced enteropathy]. / Un cas inhabituel d'entéropathie secondaire à la prise d'olmesartan.

Olmesartan induced enteropathy was first described in 2012. It is a rare adverse effect of this antihypertensive drug. The clinical presentation commonly includes severe chronic diarrhea leading to weight loss and a variable degree of dehydration. Histological findings are most commonly observed in the duodenum and consist of partial or total villous atrophy, increased intraepithelial lymphocytes and inflammation in the lamina propria. Involvement of gastric and colic mucosa has also been described. We report on the case of a 63-year-old man, treated by olmesartan, who presented with severe chronic diarrhea. Biopsies from different levels of the gastrointestinal tract revealed a pandigestive intraepithelial lymphocytosis.

Dichotomous histopathological assessment of ductal carcinoma in situ of the breast results in substantial interobserver concordance.

AIMS: Robust prognostic markers for ductal carcinoma in situ (DCIS) of the breast require high reproducibility and thus low interobserver variability. The aim of this study was to compare interobserver variability among 13 pathologists, in order to enable the identification of robust histopathological characteristics. METHODS AND RESULTS: One representative haematoxylin and eosin-stained slide was selected for 153 DCIS cases. All pathologists independently assessed nuclear grade, intraductal calcifications, necrosis, solid growth, stromal changes, stromal inflammation, and apocrine differentiation. All characteristics were assessed categorically. Krippendorff's alpha was calculated to assess overall interobserver concordance. Cohen's kappa was calculated for every observer duo to further explore interobserver variability. The highest concordance was observed for necrosis, calcifications, and stromal inflammation. Assessment of solid growth, nuclear grade and stromal changes resulted in lower concordance. Poor concordance was observed for apocrine differentiation. Kappa values for each observer duo identified the 'ideal' cut-off for dichotomisation of multicategory variables. For instance, concordance was higher for 'non-high versus high' nuclear grade than for 'low versus non-low' nuclear grade. 'Absent/mild' versus 'moderate/extensive' stromal inflammation resulted in substantially higher concordance than other dichotomous cut-offs. CONCLUSIONS: Dichotomous assessment of the histopathological features of DCIS resulted in moderate to substantial agreement among pathologists. Future studies on prognostic markers in DCIS should take into account this degree of interobserver variability to define cut-offs for categorically assessed histopathological features, as reproducibility is paramount for robust prognostic markers in daily clinical practice. A new prognostic index for DCIS might be considered, based on two-tier grading of histopathological features. Future research should explore the prognostic potential of such two-tier assessment.

Regorafenib induced severe toxic hepatitis: characterization and discussion.

BACKGROUND: Regorafenib is the first small-molecule multikinase inhibitor which showed survival benefits in pretreated metastatic colorectal cancer (mCRC) patients. Besides classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect. MATERIAL AND METHODS: Patients with refractory mCRC treated with regorafenib in our institution were reviewed. Severe treatment-related liver toxicity was investigated. Clinical history, liver histology and genetic assessment (sequence analysis) of cytochrome P3A4 (CYP3A4) and uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) involved in regorafenib metabolization were here reported for patients with severe hepatotoxicity. RESULTS: Among the 93 reviewed patients, 3 presented severe and icteric toxic hepatitis which was fatal for 1 patient. Histopathological liver lesions were different depending on the onset of hepatotoxicity (acute or subacute): acinar zone 3 necrosis in case of acute symptoms, and portal tract inflammation with porto-central bridging and fibrosis in the delayed presentation. None of the patients had CYP3A4 gene mutations. Similar polymorphisms in UGT1A9 gene promoter region (UGT1A9 variant -118T9>10 [rs3832043]) were found in both patients who presented acute hepatitis. Moreover, it appears retrospectively that both of them already experienced significant toxicity under irinotecan-based chemotherapy. CONCLUSION: This is the first report of severe hepatotoxicity with available liver histology and genetic assessment of enzymes involved in regorafenib metabolization. This report also reminds the importance of close liver tests monitoring during regorafenib treatment.

Predictive markers for pathological complete response (pCR) after neo-adjuvant chemotherapy in HER2-positive breast carcinoma.

OBJECTIVES: Patients with HER2-positive invasive breast cancer that is node-positive and/or larger than 3 cm are generally treated with neoadjuvant chemotherapy (NAC). We aimed to identify predictive markers for pathological complete response (pCR) after NAC in HER2-positive breast carcinoma. METHODS: Hematoxylin/eosin-stained slides of 43 HER2-positive breast carcinoma biopsies were histopathologically reviewed. Immunohistochemistry (IHC) was performed on pre-NAC biopsies, comprising HER2, estrogen receptor (ER), progesterone receptor (PR), Ki-67, epidermal growth factor receptor (EGFR), mucin-4 (MUC4), p53 and p63. Dual-probe HER2 in situ hybridization (ISH) was performed to study the mean HER2 and CEP17 copy numbers. ISH and IHC data were retrospectively collected for a validation cohort, comprising 33 patients. RESULTS: Younger age at diagnosis, 3+ HER2 IHC scores, high mean HER2 copy numbers and high mean HER2/CEP17 ratios were significantly associated with an increased chance of achieving a pCR, and the latter two associations were confirmed in the validation cohort. No other immunohistochemical or histopathological markers were associated with pCR. CONCLUSIONS: This retrospective study of two community-based NAC-treated HER2-positive breast cancer patient cohorts identified high mean HER2 copy numbers as a strong predictor for pCR. Further studies on larger cohorts are required to determine a precise cut-point for this predictive marker.

The Role of c-MET as a Biomarker in Patients with Bladder Cancer Treated with Radical Chemo-Radiotherapy.

BACKGROUND: Bladder cancer is a highly aggressive cancer, and muscle invasive urothelial carcinoma (MIUC) requires aggressive strategy. Concomitant chemo-radiotherapy (CRT) appears as a therapeutic option that allows bladder sparing. No biomarker is currently available to optimally select patients for CRT. METHODS: We retrospectively enrolled patients with MIUC who were treated in a curative setting with CRT. Based on c-MET expression in pre-treatment tumor tissue, patients were stratified into two groups: no expression of c-MET (group A) and expression of c-MET (group B). We evaluated the outcome of these patients based on c-MET expression. RESULTS: After a median follow-up of 40 months, 13 patients were enrolled in this analysis, 8 in group A and 5 in group B. The disease recurrence was 25% in group A and 100% in group B. Compared to group A, patients from group B experienced more frequent and more rapid recurrence in terms of metastases; the 3-year metastatic recurrence rate was 13% and 100%, respectively. The c-MET expression was also associated with a higher rate of cancer-related deaths. CONCLUSIONS: In this retrospective analysis, c-MET expression was associated with worse disease-free survival and survival in patients treated radically with CRT.

Hibernoma-like Changes and TFE3 Expression in Mesothelioma Mimicking TFE3-Translocation Renal Cell Carcinoma: A Diagnostic Pitfall.

The long delay between asbestos exposure and the development of mesothelioma will likely result in an increased incidence of mesothelioma in our industrialized societies. Radiation therapy is another factor known to induce these tumors. We describe a rare case of foamy looking mesothelioma in a 63-year-old patient with a long oncology history of a supposed peritoneal carcinomatosis. The pathologist was faced with a diagnostic pitfall as this peritoneal clear cell tumor expressed transcription factor binding to immunoglobulin heavy constant mu enhancer 3 (TFE3) at the nuclear level. Fortunately, the pathologist performed an extensive panel of immunomarkers, leading to a final diagnosis of epithelioid mesothelioma. Thus, we describe the first case of mesothelioma expressing TFE3. Note that there was no rearrangement of TFE3 in fluorescence in situ hybridization.

Tumor apelin and obesity are associated with reduced neoadjuvant chemotherapy response in a cohort of breast cancer patients.

Obesity is a known factor increasing the risk of developing breast cancer and reducing disease free survival. In addition to these well-documented effects, recent studies have shown that obesity is also affecting response to chemotherapy. Among the multiple dysregulations associated with obesity, increased level of the apelin adipokine has been recently shown to be directly involved in the association between obesity and increased breast cancer progression. In this study, we analyzed in a retrospective cohort of 62 breast cancer patients the impact of obesity and tumoral apelin expression on response to neoadjuvant chemotherapy. In the multivariate logistic regression, obesity and high tumoral apelin expression were associated with a reduced response to NAC in our cohort. However, obesity and high tumoral apelin expression were not correlated, suggesting that those two parameters could be independently associated with reduced NAC response. These findings should be confirmed in independent cohorts.

Is Lugol necessary for endoscopic resection of esophageal squamous cell neoplasia?

Background and study aims Recent evidence suggests that lugol chromoendoscopy (LCE) and narrow-band imaging (NBI) have comparable sensitivity for detection of superficial esophageal squamous cell carcinoma (SCC). However, LCE is time-consuming and associated with side effects. The aim of this study was to compare the effectiveness of NBI and LCE in defining resection margins of esophageal SCC. Patients and methods This was a retrospective observational cohort study of patients with esophageal SCC and dysplasia who underwent en-bloc resection between 1999 and 2017 at the Cliniques universitaires Saint-Luc, Brussels. Two groups were defined: 1) inspection with NBI only; and 2) inspection with LCE (with or without NBI). The primary endpoint was complete lateral resection rate. Multivariate regression was used to adjust for potential confounders. Results A total of 102 patients with 132 lesions were included. Lesions were inspected with LCE in 52 % (n = 68) and with NBI only in 48 % (n = 64). Lesions 0-IIa were more frequent in the NBI group (37 %) and 0-IIb (60 %) in LCE. Lesion location, size, and histology and resection technique (endoscopic submucosal dissection in 122/132 cases, 92 %) were similar between the groups. The rate of complete lateral resection for invasive carcinoma was 90 % in LCE group and 94 % in NBI group ( P  = 0.498) and 65 % and 67 % ( P  = 0.813), respectively, for dysplasia complete lateral resection. These results remained non-significant after adjusting for potential confounders. Conclusions Mucosal inspection and delineation of tumors with lugol chromoendoscopy before endoscopic resection of esophageal squamous cell lesions was not associated with increased complete lateral resection rate when compared to NBI.

Histiocytoid Ductal Carcinoma In Situ of the Breast: Not All Intraductal Foamy Cells Are Macrophages!

With the advent of screening mammography, the incidence of ductal carcinoma in situ (DCIS) has increased. DCIS accounts for around 20% of breast cancers diagnosed at present. The histiocytoid variant of clear cell DCIS is a rare subtype of DCIS, characterized by epithelial cells with a clear and foamy cytoplasm. Histiocytoid DCIS serves as a potential diagnostic pitfall, since it can be easily mistaken for intraductal collections of foamy macrophages. In this article, we report a particular case of biphasic DCIS, characterized by an extensive histiocytoid-type clear cell component and a conventional "non-clear" cell component. Both components presented with HER2 protein overexpression. We discuss the diagnostic challenge and differential diagnosis of clear cell DCIS, as well as the role of HER2 overexpression in DCIS pathogenesis.

Combined excision and ablation of ampullary tumors with biliary or pancreatic intraductal extension is effective even in malignant neoplasms.

Background: The feasibility and outcome of endoscopic resection in ampullary tumors with intraductal growth remains unclear. Objective: To assess the safety, feasibility and outcomes of these patients treated by thermal ablation. Methods: Retrospective observational study. All consecutive patients who underwent an endoscopic snare papillectomy with a 6-month minimum follow-up were included. Ablation was performed with cystotomes and soft/forced coagulation. Successful endoscopic treatment was defined as no adenomatous residual tissue or recurrence observed at follow-up. Results: Of 86 patients presenting with an ampullary tumor, 73 (58 ± 14 years old, 49% men, 34% familial adenomatous polyposis) (median tumor size: 20 mm, range: 8-80) were included. En bloc and curative resection rates were achieved in 46.6% and 83.6%, respectively.Intraductal ingrowth was seen in 18 (24.7%) patients and histologically confirmed in 12 (16.4%). Intraductal ablation achieved a 100% success rate, with a 20-month median follow-up. Most of these patients had malignant forms (n = 8, 66.7%), with a higher adenocarcinoma rate (33.3% versus 3.3%, p = 0.001) compared to extraductal tumors.Overall, there was a 20.5% complication rate with no significant differences between both groups (p = 0.676). Conclusions: Intraductal ablation achieves a high therapeutic success rate in ampullary tumors with ≤20 mm ductal extension, even in malignant forms or biliary and pancreatic involvement. The technique is feasible, cheap and safe and may avoid major surgery.