Extending treatment criteria for Barrett's neoplasia: results of a nationwide cohort of 138 endoscopic submucosal dissection procedures.

BACKGROUND: The use of endoscopic submucosal dissection (ESD) is gradually expanding for treatment of neoplasia in Barrett's esophagus (BE). We aimed to report outcomes of all ESDs for BE neoplasia performed in the Netherlands. METHODS: Retrospective assessment of outcomes, using treatment and follow-up data from a joint database. RESULTS: 130/138 patients had complete ESDs, with 126/130 (97 %) en bloc resections. Median (interquartile range (IQR)) procedure time was 121 minutes (90-180). Pathology findings were high grade dysplasia (HGD) (5 %) or esophageal adenocarcinoma (EAC) T1a (43 %) or T1b (52 %; 19 % sm1, 33 % ≥ sm2). Among resections of HGD or T1a EAC lesions, 87 % (95 %CI 75 %-92 %) were both en bloc and R0; the corresponding value for T1b EAC lesions was 49 % (36 %-60 %). Among R1 resections, 10/34 (29 %) showed residual cancer, all detected at first endoscopic follow-up. The remaining 24 patients (71 %) showed no residual neoplasia. Six of these patients underwent surgery with no residual tumor; the remaining 18 underwent endoscopic follow-up during median 31 months with 1 local recurrence (annual recurrence rate 2 %). Among R0 resections, annual local recurrence rate during median 27 months was 0.5 %. CONCLUSION: In expert hands, ESD allows safe removal of bulky intraluminal neoplasia and submucosal cancer. ESD of the latter showed R1 resection margins in 50 %, yet only one third had persisting neoplasia at follow-up. To better stratify R1 patients with an indication for additional surgery, repeat endoscopy after healing of the ESD might be a helpful possible prognostic factor for residual cancer.

Tissue Systems Pathology Test Objectively Risk Stratifies Barrett's Esophagus Patients With Low-Grade Dysplasia.

INTRODUCTION: Low-grade dysplasia (LGD) is the best predictor of neoplastic progression in Barrett's esophagus (BE). Most LGD cases are downstaged to nondysplastic (ND) BE on expert pathologist review, which is prone to interobserver variation and not widely available. Recent studies indicate that a risk prediction assay (TissueCypher) risk stratifies patients with NDBE for neoplastic progression. We aimed to investigate whether this risk prediction assay predicts neoplastic progression in BE patients with LGD. METHODS: A blinded, retrospective cohort study was derived from the screening cohort of a randomized controlled trial of SURveillance vs RadioFrequency ablation for BE patients with LGD. Hematoxylin and eosin and p53 immunohistochemistry slides from the first endoscopy with LGD were independently reviewed by 3 expert pathologists and tested by the risk prediction assay. Revision diagnoses of NDBE were considered low risk, although indefinite for dysplasia, and LGD were considered high risk for progression. RESULTS: A total of 155 BE patients (123 men), mean age 61 ± 10 years, were analyzed. Thirty-four patients (22%) progressed to high-grade dysplasia/esophageal adenocarcinoma (median time 2.4 years) and 121 did not progress (median high-grade dysplasia/esophageal adenocarcinoma-free surveillance 7.9 years). The risk prediction assay sensitivity was 68% vs 76% for the 3 pathologists, and specificity was 79% vs 64%-77.0% for the pathologists. The assay detected 50%-56% of progressors that were downstaged to NDBE by the pathologists. DISCUSSION: The risk prediction assay provided significant risk stratification in BE patients with LGD and identified progressors that the experts downstaged to NDBE. This objective assay provides an effective solution to the lack of standardization of expert pathology review of LGD.

A novel cryoballoon ablation system for eradication of dysplastic Barrett's esophagus: a first-in-human feasibility study.

BACKGROUND: Endoscopic cryoablation for Barrett's esophagus (BE) might offer advantages over heat-based ablation. Focal cryoballoon ablation has been promising for short-segment BE, whereas the novel 90°-swipe cryoballoon ablation system (CbSAS90) ablates larger areas in a single step (90° over 3 cm). The system allows for dose adjustment. CbSAS90 has been feasible and safe in animal and pre-esophagectomy studies. This is the first clinical study to assess feasibility, safety, and efficacy of CbSAS90 for eradication of dysplastic BE. METHODS: In this prospective study in dysplastic BE patients, dose finding started with semi-circumferential treatment at 0.8 mm/s (dose 1). The dose was escalated by reducing speed by 0.1 mm/s in six patients until BE surface regression was ≥ 80 % without complications ("effective dose"). The effective dose was subsequently confirmed with circumferential treatment in 12 new patients. Post-procedural pain (0 - 10) and dysphagia (0 - 4) were evaluated. Outcomes were feasibility, safety, and BE surface regression. RESULTS: 25 patients were included, with technically successful treatment in 92 % (95 %CI 73 % - 99 %). Median (95 %CI) BE surface regression was 78 % (50 % - 85 %) for dose 1 and 85 % (55 % - 95 %) for dose 2 (0.7 mm/s), which was defined as the effective dose. Circumferential treatment resulted in 93 % (88 % - 96 %) regression. Two of 12 patients with circumferential treatment developed strictures that required dilation. Median pain and dysphagia scores were low (0 - 3 and 0, respectively). CONCLUSIONS: CbSAS90 was feasible and effective for ablating larger BE areas. The optimal dose for circumferential treatment that balances safety and efficacy requires further evaluation.

Optimizing histopathologic evaluation of EMR specimens of Barrett's esophagus-related neoplasia: a randomized study of 3 specimen handling methods.

BACKGROUND AND AIMS: Endoscopic resection is the cornerstone of treatment of Barrett's esophagus (BE)-related neoplasia. However, accurate histopathologic evaluation of endoscopic resection specimens can be challenging, and the preferred specimen handling method remains unknown. Therefore, the aim of our study was to compare 3 different specimen handling methods for assessment of all clinically relevant histopathologic parameters and time required for specimen handling. METHODS: In this multicenter, randomized study EMR specimens of BE-related neoplasia with no suspicion of submucosal invasion during endoscopy were randomized to 3 specimen handling methods: pinning on paraffin using needles, direct fixation in formalin without prior tissue handling, and the cassette technique (small box for enclosing specimens). The histopathologic evaluation scores were assessed by 2 dedicated GI pathologists blinded to the handling method. RESULTS: Of the 126 randomized EMR specimens, 45 were assigned to pinning on paraffin, 41 to direct fixation in formalin, and 40 to the cassette technique. The percentages of specimens with overall optimal histopathologic evaluation scores were similar for the pinning method (98%; 95% confidence interval [CI], 88.0-99.9) and for no handling (90%; 95% CI, 76.9-97.3) but were significantly lower (64%; 95% CI, 47.2-78.8) for the cassette technique (P < .001). Time required for specimen handling was shortest when no handling method was used (P < .001 vs pinning and cassette). CONCLUSIONS: Both pinning on paraffin and direct fixation in formalin resulted in optimal histopathologic evaluation scores in a high proportion of specimens, whereas the cassette technique performs significantly worse, and its use in clinical daily practice should be discouraged. Given the significantly shorter handling time, direct fixation in formalin appears to be the preferred method over pinning on paraffin. However, the latter needs to be confirmed in larger studies with inclusion of all EMR specimens. (Clinical trial registration number: ISRCTN50525266.).

Efficacy of the CryoBalloon Focal Ablation System for the eradication of dysplastic Barrett's esophagus islands.

Background and study aim Cryoablation can be used for the treatment of Barrett's esophagus (BE). A recent dosimetry study, using the CryoBalloon Focal Ablation System (CryoBalloon), demonstrated that 10-second ablations result in complete eradication of BE. However, the efficacy of 10-second ablation in a larger cohort of patients has not been investigated, nor has the potential of precise targeting of specific areas. The aim of the study was to assess the efficacy and performance (i. e. targeting of BE islands) of a 10-second cryoablation using the CryoBalloon. Results A total of 30 patients were enrolled (worst pathology: low grade dysplasia in 14 [47 %], high grade dysplasia in 7 [23 %], early adenocarcinoma in 9 [30 %]). Of the 47 BE islands, 44 (94 %) were adequately targeted. Complete eradication of intestinal metaplasia and dysplasia was observed in 100 % of the completely ablated areas. No stenoses were observed. Conclusion Cryoablation of BE islands using the CryoBalloon is effective. BE islands were effectively targeted.

Diffusion-weighted MRI for Early Prediction of Treatment Response on Preoperative Chemoradiotherapy for Patients With Locally Advanced Rectal Cancer: A Feasibility Study.

OBJECTIVE: This study investigates the predictive value of diffusion-weighted magnetic resonance imaging (DW-MRI) for good pathological response at different time points during and after preoperative chemoradiotherapy (CRT) in locally advanced rectal cancer. BACKGROUND: Preoperative CRT followed by total mesorectal excision (TME) is the standard of care for locally advanced rectal cancer. The use of standard radical surgery in good treatment responders after CRT is being questioned. METHODS: Patients with locally advanced rectal adenocarcinoma were treated with preoperative CRT followed by surgery. DW-MRI scans were performed before CRT, during the third week of CRT, 4 weeks post-CRT and presurgery. Tumor apparent diffusion coefficient (ADC) values were acquired from the DW-MRI scans. After surgery the pathological tumor regression grade was assessed according to the classification by Mandard et al [Cancer. 1994;73:2680-2686]. Patients with pathological complete or near-complete response (tumor regression grade 1-2) were classified as good responders (GRs). RESULTS: Twenty-two patients participated of which 9 were GRs (41%). Pre-CRT ADC values were lower in good versus moderate/poor responders (P = 0.04). ADC values during CRT and four weeks post-CRT were higher in GR. ADC values presurgery did not differ between response groups. For all time points the relative ADC increase (ΔADC) compared to the ADC pre-CRT was higher in GR (P < 0.001). The ΔADC during CRT and four weeks post-CRT were the best predictive parameters for pathological good response. CONCLUSIONS: This study shows that DW-MRI is feasible to select good treatment responders during preoperative CRT for locally advanced rectal cancer.

Paediatric nodal marginal zone B-cell lymphadenopathy of the neck: a Haemophilus influenzae-driven immune disorder?

Many hyperplasias and lymphomas of marginal zone B-cells are associated with infection. We identified six children and one adolescent with cervical lymphadenopathy showing prominent polyclonal nodal marginal zone hyperplasia (pNMZH) and four adolescents with monoclonal paediatric nodal marginal zone lymphoma (pNMZL). The clonality status was assessed using BIOMED-2-IG PCR analysis. Haemophilus influenzae was identified in all six cases of pNMZH that could be tested by direct culture (N = 3) or a very sensitive PCR for the H. influenzae gyrase gene in frozen materials (N = 5). H. influenzae was not detected in three pNMZLs and 28 non-specific reactive cervical lymph nodes of age-matched controls, except for a single control node that was obtained during oropharyngeal surgery for a cleft palate showing very low copy numbers of H. influenzae. pNMZH patients were younger than pNMZL patients (median age 12 versus 21 years). pNMZH showed a prominent nodular appearance with variable fibrosis without acute inflammation. Within the nodules, the expanded germinal centres and variably sized marginal zones were colonized by activated B-cells with weak expression of IgD and lack of CD10 and/or BCL6 expression. Some areas showed skewed light chain expression in plasma cells (4/5 cases lambda). In four cases tested, this was confirmed by flow cytometry for surface Ig (3/4 cases lambda). In contrast, pNMZL showed more extensive expansion of marginal zones by centrocytoid cells and often expression of BCL2 protein. Several H. influenzae strains are known to interact with the constant part of IgD on human B-cells, leading to their polyclonal proliferation and activation. We speculate that in vivo stimulation of IgD+ marginal zone B-cells by this bacterium may be implicated in this particular lymphadenopathy that should be distinguished from monoclonal pNMZL.

Management of patients with T1b esophageal adenocarcinoma: a retrospective cohort study on patient management and risk of metastatic disease.

BACKGROUND: Esophagectomy for submucosal (T1b) esophageal adenocarcinoma (EAC) is performed in order to optimize patient outcomes given the risk of concurrent lymph node metastases (LNM). However, not seldom, comorbidity precludes these patients from surgery. Therefore, the aim of our study was to assess the course of follow-up after treatment in submucosal EAC patients undergoing surgery versus conservative therapy and to evaluate the incidence of metastatic disease. METHODS: Between 2001 and 2012, all patients undergoing diagnostic endoscopic resection for EAC in two centers were reviewed. Only patients with histopathologically proven submucosal tumor invasion were included. Submucosal EACs were divided into tumors that were removed radically (R0) and irradically (R1). Subsequently, in the R0 group, EACs were classified as either low risk (LR; submucosal invasion <500 nm, G1-G2, no LVI) or high risk (HR; deep submucosal invasion >500 nm, G3-G4 and/or LVI). Metastatic disease was defined as LNM in surgical resection specimen and/or evidence of malignant disease during follow-up (FU). RESULTS: Sixty-nine patients with a submucosal EAC were included [23 R1-resections and 46 R0-resection (14 R0-LR and 32 R0-HR)]. Twenty-six patients underwent surgical treatment (1 R0-LR, 12 R0-HR and 13 R1). None of the 14 R0-LR patients developed metastatic disease after a median FU of 60 months. In the R0-HR group and R1 group, metastatic disease was diagnosed in 16 and 30 % of patients, respectively. Surgical patients tended to have a better overall survival than non-surgical patients (p = 0.09). Tumor-related deaths, however, were 12 % in both groups. CONCLUSIONS: In LR submucosal EAC, the risk of metastatic disease appears to be very low. In deep submucosal EAC (either R0- or R1-resection), the rate of metastatic disease is lower than reported in earlier surgical series. Given the reasonable disease-free survival and high background mortality, conservative management of these patients seems to be a valid alternative for surgery in selected cases.

The estimation of tumor cell percentage for molecular testing by pathologists is not accurate.

Molecular pathology is becoming more and more important in present day pathology. A major challenge for any molecular test is its ability to reliably detect mutations in samples consisting of mixtures of tumor cells and normal cells, especially when the tumor content is low. The minimum percentage of tumor cells required to detect genetic abnormalities is a major variable. Information on tumor cell percentage is essential for a correct interpretation of the result. In daily practice, the percentage of tumor cells is estimated by pathologists on hematoxylin and eosin (H&E)-stained slides, the reliability of which has been questioned. This study aimed to determine the reliability of estimated tumor cell percentages in tissue samples by pathologists. On 47 H&E-stained slides of lung tumors a tumor area was marked. The percentage of tumor cells within this area was estimated independently by nine pathologists, using categories of 0-5%, 6-10%, 11-20%, 21-30%, and so on, until 91-100%. As gold standard, the percentage of tumor cells was counted manually. On average, the range between the lowest and the highest estimate per sample was 6.3 categories. In 33% of estimates, the deviation from the gold standard was at least three categories. The mean absolute deviation was 2.0 categories (range between observers 1.5-3.1 categories). There was a significant difference between the observers (P<0.001). If 20% of tumor cells were considered the lower limit to detect a mutation, samples with an insufficient tumor cell percentage (<20%) would have been estimated to contain enough tumor cells in 27/72 (38%) observations, possibly causing false negative results. In conclusion, estimates of tumor cell percentages on H&E-stained slides are not accurate, which could result in misinterpretation of test results. Reliability could possibly be improved by using a training set with feedback.

Circumferential balloon-based radiofrequency ablation of Barrett's esophagus with dysplasia can be simplified, yet efficacy maintained, by omitting the cleaning phase.

BACKGROUND & AIMS: The current procedure for circumferential balloon-based radiofrequency ablation (c-RFA) for the removal of dysplastic Barrett's esophagus (BE) is labor intensive, comprising 2 ablation passes with a cleaning step to remove debris from the ablation zone and electrode. We compared the safety and efficacy of 3 different c-RFA ablation regimens. METHODS: We performed a prospective trial of consecutive patients with flat-type BE with high-grade dysplasia. Fifty-seven patients (45 men; age, 64 ± 15 y; 28 with prior endoscopic resection) were assigned randomly to groups that underwent c-RFA with a double application of RFA (12 J/cm(2)). The standard group received c-RFA, with device removal and cleaning, followed by c-RFA; the simple-with-cleaning group underwent c-RFA, with device cleaning without removal, followed by c-RFA; and the simple-no-cleaning group received 2 applications of c-RFA, and the device was not removed or cleaned. The primary outcome was surface regression of BE 3 months later, graded by 2 blinded expert endoscopists. Calculated sample size was 57 patients, based on a noninferiority design. RESULTS: Median BE surface regression at 3 months was 83% in the standard group, 78% in the simple-with-cleaning group, and 88% in the simple-no-cleaning group (P = .14). RF ablation time was 20 minutes (interquartile range [IQR], 18-25 min) for the standard group, 13 minutes (IQR, 11-15 min) for the simple-with-cleaning group, and 5 minutes (IQR, 5-9 min) for the simple-no-cleaning group (P < .01). The median number of introductions (RFA devices/endoscope) for the standard group was 7, vs 4 for the simple groups (P < .01). CONCLUSIONS: This randomized, prospective study suggests that c-RFA is easier and faster, but equally safe and effective, when the cleaning phase between ablations is omitted or simplified. Trialregister.nl, NTR 2495.

Composition of carotid atherosclerotic plaque is associated with cardiovascular outcome: a prognostic study.

BACKGROUND: Identification of patients at risk for primary and secondary manifestations of atherosclerotic disease progression is based mainly on established risk factors. The atherosclerotic plaque composition is thought to be an important determinant of acute cardiovascular events, but no prospective studies have been performed. The objective of the present study was to investigate whether atherosclerotic plaque composition is associated with the occurrence of future vascular events. METHODS AND RESULTS: Atherosclerotic carotid lesions were collected from patients who underwent carotid endarterectomy and were subjected to histological examination. Patients underwent clinical follow-up yearly, up to 3 years after carotid endarterectomy. The primary outcome was defined as the composite of a vascular event (vascular death, nonfatal stroke, nonfatal myocardial infarction) and vascular intervention. The cumulative event rate at 1-, 2-, and 3-year follow-up was expressed by Kaplan-Meier estimates, and Cox proportional hazards regression analyses were performed to assess the independence of histological characteristics from general cardiovascular risk factors. During a mean follow-up of 2.3 years, 196 of 818 patients (24%) reached the primary outcome. Patients whose excised carotid plaque revealed plaque hemorrhage or marked intraplaque vessel formation demonstrated an increased risk of primary outcome (risk difference=30.6% versus 17.2%; hazard ratio [HR] with [95% confidence interval]=1.7 [1.2 to 2.5]; and risk difference=30.0% versus 23.8%; HR=1.4 [1.1 to 1.9], respectively). Macrophage infiltration (HR=1.1 [0.8 to 1.5]), large lipid core (HR=1.1 [0.7 to 1.6]), calcifications (HR=1.1 [0.8 to 1.5]), collagen (HR=0.9 [0.7 to 1.3]), and smooth muscle cell infiltration (HR=1.3 [0.9 to 1.8]) were not associated with clinical outcome. Local plaque hemorrhage and increased intraplaque vessel formation were independently related to clinical outcome and were independent of clinical risk factors and medication use. CONCLUSIONS: The local atherosclerotic plaque composition in patients undergoing carotid endarterectomy is an independent predictor of future cardiovascular events.

No non-sentinel node involvement in melanoma patients with limited Breslow thickness and low sentinel node tumour load.

AIMS: Most melanoma patients with a positive sentinel node (SN) undergo completion lymph node dissection and frequently experience associated morbidity. However, only 10-30% of SN-positive patients have further lymph node metastases. The aim of the present study was to predict the absence of non-SN metastases in a multicentre study of patients with a positive SN based on primary melanoma features and SN tumour load. METHODS AND RESULTS: Of 70 SN positive patients, 18 had non-SN metastases. Penetrative depth of metastatic cells into the SN and SN tumour load was assessed by morphometry. None of the 14 patients (20%) with a Breslow thickness <2.0 mm and an SN tumour load <0.2 mm2 had non-SN metastases. Similarly, none of the 15 patients (21%) with a Breslow thickness <2.0 mm and SN penetrative depth <600 µm had non-SN metastases. Lastly, none of the 14 patients (20%) with a Breslow thickness <2.0 mm and a diameter of the largest SN deposit <500 µm had non-SN metastases. CONCLUSIONS: A combination of limited Breslow thickness and low SN tumour load predicts absence of non-SN metastases in melanoma patients with a positive SN with high accuracy. We propose that this subgroup may be spared completion lymph node dissection.

Presence of Propionibacterium acnes in granulomas associates with a chronic disease course in Dutch sarcoidosis patients.

Several studies demonstrated that Propionibacterium acnes may be involved in sarcoidosis pathogenesis. Presence of P. acnes was found in granulomas of the majority of Japanese sarcoidosis patients. However, presence of P. acnes in tissue has never been related to sarcoidosis phenotypes and clinical outcome. Therefore, the aims of our study were to demonstrate whether P. acnes can be detected in granulomas of Dutch sarcoidosis patients and to investigate whether its presence is related to a clinical phenotype and/or course of disease. Sections of formalin-fixed paraffin-embedded tissue blocks of 76 sarcoidosis patients were examined by immunostaining with a P. acnes-specific monoclonal antibody (PAB antibody) using a Ventana BenchMark ULTRA. Clinical outcome status (COS) was determined and classified into two phenotype groups: A: resolved, minimal or persistent disease without treatment (COS 1-6) and B: persistent disease with need for treatment (COS 7-9). P. acnes was detected in samples of 31 patients (41%) and located within granulomas in samples of 13 patients (17%). The frequency of P. acnes detected in granulomas at diagnosis was significantly higher in patients with phenotype B compared to patients with phenotype A (29% versus 0%, p=0.021). Presence of P. acnes in granulomas can be confirmed in Dutch sarcoidosis patients. It is intriguing that presence of P. acnes in granulomas is more frequently found in patients with chronic disease requiring treatment. This adds to the rationale that a subgroup of sarcoidosis patients might benefit from antibiotic therapy.

Detection of Cutibacterium acnes in granulomas of patients with either hypersensitivity pneumonitis or vasculitis reveals that its presence is not unique for sarcoidosis.

Presence of C. acnes in granulomas is not unique to sarcoidosis but can also be found in patients with HP or EGPA. C. acnes may be involved in the pathogenesis of those granulomatous diseases in a mitogenic way. https://bit.ly/3pU0PeC.

Activation of Downstream mTORC1 Target Ribosomal Protein S6 Kinase (S6K) Can Be Found in a Subgroup of Dutch Patients with Granulomatous Pulmonary Disease.

Mechanistic target of rapamycin complex 1 (mTORC1) has been linked to different diseases. The mTORC1 signaling pathway is suggested to play a role in the granuloma formation of sarcoidosis. Recent studies demonstrated conflicting data on mTORC1 activation in patients with sarcoidosis by measuring activation of its downstream target S6 kinase (S6K) with either 33% or 100% of patients. Therefore, the aim of our study was to reevaluate the percentage of S6K activation in sarcoidosis patients in a Dutch cohort. To investigate whether this activation is specific for sarcoid granulomas, we also included Dutch patients with other granulomatous diseases of the lung. The activation of the S6K signaling pathway was evaluated by immunohistochemical staining of its downstream effector phospho-S6 in tissue sections. Active S6K signaling was detected in 32 (43%) of the sarcoidosis patients. Twelve (31%) of the patients with another granulomatous disorder also showed activated S6K signaling, demonstrating that the mTORC1 pathway may be activated in a range for different granulomatous diseases (p = 0.628). Activation of S6K can only be found in a subgroup of patients with sarcoidosis, as well as in patients with other granulomatous pulmonary diseases, such as hypersensitivity pneumonitis or vasculitis. No association between different clinical phenotypes and S6K activation can be found in sarcoidosis.

Performance of gastrointestinal pathologists within a national digital review panel for Barrett's oesophagus in the Netherlands: results of 80 prospective biopsy reviews.

AIMS: The histopathological diagnosis of low-grade dysplasia (LGD) in Barrett's oesophagus (BO) is associated with poor interobserver agreement and guidelines dictate expert review. To facilitate nationwide expert review in the Netherlands, a web-based digital review panel has been set up, which currently consists of eight 'core' pathologists. The aim of this study was to evaluate if other pathologists from the Dutch BO expert centres qualify for the expert panel by assessing their performance in 80 consecutive LGD reviews submitted to the panel. METHODS: Pathologists independently assessed digital slides in two phases. Both phases consisted of 40 cases, with a group discussion after phase I. For all cases, a previous consensus diagnosis made by five core pathologists was available, which was used as reference. The following criteria were used: (1) percentage of 'indefinite for dysplasia' diagnoses, (2) percentage agreement with consensus diagnosis and (3) proportion of cases with a consensus diagnosis of dysplasia underdiagnosed as non-dysplastic. Benchmarks were based on scores of the core pathologists. RESULTS: After phase I, 1/7 pathologists met the benchmark score for all quality criteria, yet three pathologists only marginally failed the agreement with consensus diagnosis (score 68.3%, benchmark 69%). After a group discussion and phase II, 5/6 remaining aspirant panel members qualified with all scores within the benchmark range. CONCLUSIONS: The Dutch BO review panel now consists of 14 pathologists, who-after structured assessments and group discussions-can be considered homogeneous in their review of biopsies with LGD.

Interobserver, intraobserver, and interlaboratory variability in reporting pT4a colon cancer.

Clinical significance of the pT4 category in colon cancer is increasing with several therapeutic implications. The aim of this study was to evaluate variability in diagnosing pT4a colon cancer. Twelve pathologists classified 66 preselected scanned Hematoxylin/Eosin-stained slides with tumor cells at a distance of 25-1500 µm (n = 22), 0-25 µm (n = 22), or on (n = 22) the peritoneal surface. Inter- and intraobserver variability were calculated using Kappa statistics. For interlaboratory variability, pathology reports of pT3 and pT4a colon cancer were extracted from the Dutch Pathology Registry between 2012 and 2015. The proportion of pT4a (pT4a/(pT3+pT4a)) was compared between 33 laboratories. Potential risk of understaging was assessed by determining the average number of blocks taken from pT3 and pT4a N0-2M0 tumors with metachronous peritoneal metastasis. Interobserver variability among 12 pathologists was 0.50 (95%CI 0.41-0.60; moderate agreement). Intraobserver variability (8 pathologists) was 0.71 (substantial agreement). A total of 7745 reports with pT3 or pT4aN0-2M0 colon cancer from 33 laboratories were included for interlaboratory analysis. Median percentage of pT4a was 15.5% (range 3.2-24.6%). After adjustment for case mix, 8 labs diagnosed pT4a significantly less or more frequently than the median lab. Metachronous peritoneal metastases were histologically verified in 170 of 6629 pT3 and in 129 of 1116 pT4a tumors, with a mean number of blocks of 4.03(SD 1.51) and 4.78 (SD 1.76) taken from the primary tumors, respectively (p < 0.001). A substantial variability in diagnosing pT4a colon cancer exists, both at pathologist and laboratory level. Diagnosis of pT4a stage appears to be challenging and there is a need for standardizing assessment of this pathological entity.

Sarcoidosis in a patient clinically diagnosed with silicosis; is silica associated sarcoidosis a new phenotype?

A diagnosis of silicosis is made on the basis of exposure and typical radiological findings, according to the ILO's International Classification of Radiographs of Pneumoconiosis. Radiological patterns of silicosis can, however, resemble sarcoidosis. Sarcoidosis is a multi-systemic disorder of unknown etiology, although a role for initiating inorganic triggers such as metals or silica has been suggested. In this case report, we illustrate a patient previously diagnosed with silicosis based on exposure and radiological features, progressive under immunosuppressive treatment. In view of these findings, an open lung biopsy was performed and revealed sarcoidosis. The patient was effectively treated with infliximab. Further analysis showed the presence of silica in the granulomas. Sensitization to silica was also demonstrated, suggesting an association between silica exposure and sarcoidosis in this patient.

Atherosclerotic plaque composition and occurrence of restenosis after carotid endarterectomy.

CONTEXT: Previous studies have assessed the predictive value of clinical and angiographic parameters for development of restenosis after vascular interventions. The composition of the atherosclerotic plaque at the intervention site has had limited evaluated as a marker for restenosis [corrected]. OBJECTIVE: To investigate the relationship between atherosclerotic plaque histology and the occurrence of restenosis after carotid endarterectomy. DESIGN, SETTING, AND PATIENTS: The Athero-Express study is a longitudinal vascular biobank study that includes the collection of atherosclerotic plaques of patients undergoing primary carotid endarterectomy. Five hundred patients were prospectively followed up between April 1, 2002, and March 14, 2006, to assess carotid artery restenosis measured by duplex ultrasound 1 year after the intervention. MAIN OUTCOME MEASURES: Risk of carotid restenosis in relation to predefined histological characteristics (macrophage and smooth muscle cell infiltration, collagen, calcifications, intraplaque bleeding, luminal thrombus, and lipid core size), adjusted for clinical characteristics (multivariate logistic regression analysis). RESULTS: At 1 year, 85 patients (17%) developed 50% or greater restenosis, including 40 patients (8%) who developed 70% or greater restenosis of the target vessel. Patients whose histological examination of the plaque revealed marked macrophage infiltration (n = 286) had a lower risk than those with none or minor macrophage infiltration (n = 214) of developing 50% or greater restenosis (risk difference, 11.5% vs 24.3%; adjusted odds ratio [OR], 0.43; 95% confidence interval [CI], 0.26-0.72) and a lower risk of developing 70% or greater restenosis (risk difference, 4.5% vs 12.6%; adjusted OR, 0.36; 95% CI, 0.17-0.74). Patients (n = 177) with a plaque having a large lipid core size (>40%) had a lower risk than those (n = 94) with a plaque having a lipid core size of less than 10% of developing 50% or greater restenosis (risk difference, 11.3% vs 25.5%; adjusted OR, 0.40; 95% CI, 0.19-0.81) and a lower risk of developing 70% or greater restenosis (risk difference, 5.6% vs 14.9%; adjusted OR, 0.42; 95% CI, 0.17-1.04), independent of clinical characteristics. CONCLUSIONS: Plaque composition is an independent predictor of restenosis after carotid endarterectomy. The dissection of a lipid-rich, inflammatory plaque is associated with reduced risk of restenosis.

Added Value of 50-Gene Panel Sequencing to Distinguish Multiple Primary Lung Cancers from Pulmonary Metastases: A Systematic Investigation.

Differentiation between multiple primary lung cancers and pulmonary metastases (PM) has important implications in staging, prognosis, and treatment strategies. Clinical and immunohistopathologic criteria have been standardized; however, a substantial number of cases remain difficult to classify. Using next-generation sequencing, it is now possible to improve the classification of multiple lung cancer lesions. This study systematically investigated the value of routine morphologic and IHC characteristics, p53 protein expression, TP53 mutation analysis, and 50-gene panel sequencing (GPS) in 111 lesions from 50 patients with multiple lung lesions. Based on immunohistopathologic criteria, 32 paired lesions were classified as multiple primary lung cancer (MPLC) and 21 as PM. TP53 mutation analysis indicated MPLC in 23 and PM in 6 pairs, but in the majority of cases (n = 28, 49%) no mutation was observed and no conclusion could be drawn. In contrast, only 2 pairs were not conclusive using GPS. In a significant number of matching tumor samples (n = 19, 39%), sequencing results were contradictory to the initial immunohistopathology diagnosis. No separation in overall survival for classifications based on immunohistopathology was observed, while a clear but nonsignificant trend was observed concerning survival in MPLC patients (hazard ratio = 3.98) using 50-gene GPS. In about one-third of the patients, GPS provided additional information to improve the differentiation between MPLC and PM.