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1.  Secretory IgA from submucosal glands does not compensate for its airway surface deficiency in chronic obstructive pulmonary disease 
Secretory immunoglobulin A (SIgA) reaches the airway lumen by local transcytosis across airway epithelial cells or with tracheobronchial submucosal gland secretions. In chronic obstructive pulmonary disease (COPD), deficiency of SIgA on the airway surface has been reported, however, reduction of SIgA levels in sputum and bronchoalveolar lavage (BAL) has not been consistently observed. To explain this discrepancy, we analyzed BAL fluid and lung tissue from patients with COPD and control subjects. Immunohistochemical analysis of large and small airways of COPD patients showed MUC5AC was the predominant mucin expressed by airway epithelial cells, whereas MUC5B was expressed in submucosal glands of large airways. In addition to showing a reduction of IgA on the airway surface, dual immunostaining with anti-IgA and anti-MUC5B antibodies showed an accumulation of IgA within MUC5B-positive luminal mucus plugs, suggesting that luminal SIgA originates from submucosal glands in COPD patients. Although the concentration of SIgA in BAL inversely correlated with FEV1 in COPD, the ratio of SIgA/MUC5B was a better predictor of FEV1, particularly in patients with moderate COPD. Together, these findings suggest that SIgA production by submucosal glands, which are expanded in COPD, is insufficient to compensate for reduced SIgA transcytosis by airway epithelial cells. Localized SIgA deficiency on the surface of small airways is associated with COPD progression and represents a potential new therapeutic target in COPD.
PMCID: PMC5081073  PMID: 26432569
chronic obstructive pulmonary disease; secretory IgA; submucosal glands; MUC5B; MUC5AC
2.  The many faces of small B cell lymphomas with plasmacytic differentiation and the contribution of MYD88 testing 
Plasmacytic differentiation may occur in almost all small B cell lymphomas (SBLs), although it varies from being uniformly present (as in lymphoplasmacytic lymphoma (LPL)) to very uncommon (as in mantle cell lymphomas (MCLs)). The discovery of MYD88 L265P mutations in the vast majority of LPLs has had a major impact on the study of these lymphomas. Review of the cases contributed to the 2014 European Association for Haematopathology/Society for Hematopathology slide workshop illustrated how mutational testing has helped refine the diagnostic criteria for LPL, emphasizing the importance of identifying a clonal monotonous lymphoplasmacytic population and highlighting how LPL can still be diagnosed with extensive nodal architectural effacement, very subtle plasmacytic differentiation, follicular colonization, or uncommon phenotypes such as CD5 or CD10 expression. MYD88 L265P mutations were found in 11/11 LPL cases versus only 2 of 28 other SBLs included in its differential diagnosis. Mutational testing also helped to exclude other cases that would have been considered LPL in the past. The workshop also highlighted how plasmacytic differentiation can occur in chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, SOX11 negative MCL, and particularly in marginal zone lymphomas, all of which can cause diagnostic confusion with LPL. The cases also highlighted the difficulty in distinguishing lymphomas with marked plasmacytic differentiation from plasma cell neoplasms. Some SBLs with plasmacytic differentiation can be associated with amyloid, other immunoglobulin deposition, or crystal-storing histiocytosis, which may obscure the underlying neoplasm. Finally, although generally indolent, LPL may transform, with the workshop cases suggesting a role for TP53 abnormalities.
PMCID: PMC5002945  PMID: 26454445
Lymphoplasmacytic lymphoma; MYD88; Marginal zone lymphoma; Mantle cell lymphoma; Chronic lymphocytic leukemia; Follicular lymphoma; Plasmacytic differentiation
3.  Testing for ROS1 in non-small cell lung cancer: a review with recommendations 
Virchows Archiv  2016;469(5):489-503.
Rearrangements of the ROS1 gene occur in 1–2 % of non-small cell lung cancers (NSCLCs). Crizotinib, a highly effective inhibitor of ROS1 kinase activity, is now FDA-approved for the treatment of patients with advanced ROS1-positive NSCLC. Consequently, focus on ROS1 testing is growing. Most laboratories currently rely on fluorescence in situ hybridisation (FISH) assays using a dual-colour break-apart probe to detect ROS1 rearrangements. Given the rarity of these rearrangements in NSCLC, detection of elevated ROS1 protein levels by immunohistochemistry may provide cost-effective screening prior to confirmatory FISH testing. Non-in situ testing approaches also hold potential as stand-alone methods or complementary tests, including multiplex real-time PCR assays and next-generation sequencing (NGS) platforms which include commercial test kits covering a range of fusion genes. In order to ensure high-quality biomarker testing, appropriate tissue handling, adequate control materials and participation in external quality assessment programmes are essential, irrespective of the testing technique employed. ROS1 testing is often only considered after negative tests for EGFR mutation and ALK gene rearrangement, based on the assumption that these oncogenic driver events tend to be exclusive. However, as the use of ROS1 inhibitors becomes routine, accurate and timely detection of ROS1 gene rearrangements will be critical for the optimal treatment of patients with NSCLC. As NGS techniques are introduced into routine diagnostic practice, ROS1 fusion gene testing will be provided as part of the initial testing package.
PMCID: PMC5082594  PMID: 27535289
Fluorescence in situ hybridisation; Immunohistochemistry; Non-small cell lung cancer; Predictive marker; ROS1; RT-PCR
4.  Molecularly determined total tumour load in lymph nodes of stage I–II colon cancer patients correlates with high-risk factors. A multicentre prospective study 
Virchows Archiv  2016;469(4):385-394.
Stage I–II (pN0) colorectal cancer patients are surgically treated although up to 25 % will eventually die from disease recurrence. Lymph node (LN) status is an independent prognostic factor in colorectal cancer (CRC), and molecular tumour detection in LN of early-stage CRC patients is associated with an increased risk of disease recurrence and poor survival. This prospective multicentre study aimed to determine the relationship between LN molecular tumour burden and conventional high-risk factors in stage I–II colon cancer patients. A total of 1940 LN from 149 pathologically assessed pN0 colon cancer patients were analysed for the amount of tumour cytokeratin 19 (CK19) messenger RNA (mRNA) with the quantitative reverse transcription loop-mediated isothermal amplification molecular assay One-Step Nucleic Acid Amplification. Patient’s total tumour load (TTL) resulted from the sum of all CK19 mRNA tumour copies/μL of each positive LN from the colectomy specimen. A median of 15 LN were procured per case (IQR 12;20). Molecular positivity correlated with high-grade (p < 0.01), mucinous/signet ring type (p = 0.017), male gender (p = 0.02), number of collected LN (p = 0.012) and total LN weight per case (p < 0.01). The TTL was related to pT stage (p = 0.01) and tumour size (p < 0.01) in low-grade tumours. Multivariate logistic regression showed independent correlation of molecular positivity with gender, tumour grade and number of fresh LN [AUC = 0.71 (95 % CI = 0.62–0.79)]. Our results show that lymph node CK19 mRNA detection correlates with classical high-risk factors in stage I–II colon cancer patients. Total tumour load is a quantitative and objective measure that may help to better stage early colon cancer patients.
Electronic supplementary material
The online version of this article (doi:10.1007/s00428-016-1990-1) contains supplementary material, which is available to authorized users.
PMCID: PMC5033997  PMID: 27447172
Colorectal neoplasms; Neoplasm staging; Molecular pathology; Lymph nodes; Cytokeratin 19
5.  Tumor evolution and progression in multifocal and paired non-invasive/invasive urothelial carcinoma 
Although multifocal tumors and non-invasive/invasive components are commonly encountered in surgical pathology, their genetic relationship is often poorly characterized. We used next generation sequencing (NGS) to characterize somatic alterations in a patient with five spatially distinct, high grade papillary urothelial carcinomas (UC), with one tumor harboring an underlying invasive component. NGS of 409 cancer related genes was performed on DNA isolated from formalin fixed paraffin embedded (FFPE) blocks representing each papillary tumor (n=5), the invasive component of one tumor, and matched normal tissue. We identified 9 unique non-synonymous somatic mutations across the six UC samples, including five present in each carcinoma sample, consistent with clonal origin and limited intertumoral heterogeneity. Copy number and loss of heterogeneity (LOH) profiles were similar in all six carcinomas; however, the invasive carcinoma component uniquely showed focal CDKN2A loss and chromosome 9 LOH, and did not harbor gains of chromosomes 5p or X that were present in the other tumor samples. Phylogenetic analysis supported the invasive component arising from a shared progenitor prior to the outgrowth of cells in the non-invasive tumors. Results were extended to three additional cases of upper tract UC with paired non-invasive/ invasive components, which identified driving alterations exclusive to both non-invasive and invasive components. Lastly, we performed targeted RNAseq using a custom bladder cancer panel, which confirmed gene expression signature differences between paired non-invasive/invasive components. The results and approaches presented here may be useful in understanding the clonal relationships in multifocal cancers or paired non-invasive/invasive components from routine FFPE specimens.
PMCID: PMC4936404  PMID: 25502898
next generation sequencing; clonal evolution; bladder cancer; FFPE tissue
6.  Molecular pathological classification of colorectal cancer 
Virchows Archiv  2016;469:125-134.
Colorectal cancer (CRC) shows variable underlying molecular changes with two major mechanisms of genetic instability: chromosomal instability and microsatellite instability. This review aims to delineate the different pathways of colorectal carcinogenesis and provide an overview of the most recent advances in molecular pathological classification systems for colorectal cancer. Two molecular pathological classification systems for CRC have recently been proposed. Integrated molecular analysis by The Cancer Genome Atlas project is based on a wide-ranging genomic and transcriptomic characterisation study of CRC using array-based and sequencing technologies. This approach classified CRC into two major groups consistent with previous classification systems: (1) ∼16 % hypermutated cancers with either microsatellite instability (MSI) due to defective mismatch repair (∼13 %) or ultramutated cancers with DNA polymerase epsilon proofreading mutations (∼3 %); and (2) ∼84 % non-hypermutated, microsatellite stable (MSS) cancers with a high frequency of DNA somatic copy number alterations, which showed common mutations in APC, TP53, KRAS, SMAD4, and PIK3CA. The recent Consensus Molecular Subtypes (CMS) Consortium analysing CRC expression profiling data from multiple studies described four CMS groups: almost all hypermutated MSI cancers fell into the first category CMS1 (MSI-immune, 14 %) with the remaining MSS cancers subcategorised into three groups of CMS2 (canonical, 37 %), CMS3 (metabolic, 13 %) and CMS4 (mesenchymal, 23 %), with a residual unclassified group (mixed features, 13 %). Although further research is required to validate these two systems, they may be useful for clinical trial designs and future post-surgical adjuvant treatment decisions, particularly for tumours with aggressive features or predicted responsiveness to immune checkpoint blockade.
PMCID: PMC4978761  PMID: 27325016
Colorectal; Cancer; Polymerase epsilon; Ultramutant; Hypermutant; Defective mismatch repair; Microsatellite instability; Chromosomal instability; Mutation; Somatic copy number alterations; Consensus molecular subtypes; The Cancer Genome Atlas; Serrated pathway
7.  MUC1, MUC2, MUC5AC, and MUC6 in colorectal cancer: expression profiles and clinical significance 
Virchows Archiv  2016;469(3):255-265.
Mucin glycoprotein expression can be altered during the carcinogenic process. The impact on the prognosis of patients with colorectal cancer (CRC) is controversial. We analyzed tumors from 381 patients for MUC1, MUC2, MUC5AC, and MUC6 expression by immunohistochemical staining, using tissue microarrays. Progression-free and cancer-specific survival were determined using the Kaplan-Meier method. Expression of intestinal mucin MUC2 was lost in 85 (23 %) CRCs, and patients with MUC6-negative tumors showed shorter progression-free survival (PFS, p = 0.043). Gastric mucins MUC5AC and MUC6 showed high (>50 %) aberrant expression in 28 (8 %) and 9 (2 %) cases, respectively. High expression of MUC5AC was associated with longer PFS (p = 0.055). High expression of MUC6 was associated with 100 % PFS (p = 0.024) and longer cancer-specific survival (CSS, p = 0.043). MUC1 was expressed in 238 (64 %) tumors and had no impact on outcome. When analysis was restricted to stages II and III, loss of MUC2 was associated with adverse outcome. Overexpression of both MUC5AC and MUC6 significantly predicted favorable PFS and CSS. In conclusion, loss of MUC2 expression proved to be a predictor of adverse outcome, while the gain of aberrant expression of MUC5AC and particularly of MUC6 was associated with favorable outcome in CRC, notably in intermediate stages II and III.
PMCID: PMC5007278  PMID: 27298226
Mucin; Prognosis; Stage II; Immunohistochemistry; Large intestine; Prognostic factor
8.  Prognostic factors in the myoepithelial-like spindle cell type of metaplastic breast cancer 
Virchows Archiv  2016;469:191-201.
Metaplastic breast carcinoma (MBC) comprises a heterogeneous group of tumors with difficult to predict biological behavior. A subset of MBC, characterized by spindle-shaped tumor cells with a myoepithelial-like immunophenotype, was entered into a retrospective study (n = 42, median follow-up time 43 months). Molecular parameters (DNA sequences of mutation hot spots in AKT1, ALK, APC, BRAF, CDH1, CTNNB1, EGFR, ERBB2, FBXW7, FGFR2, FOXL2, GNAQ, GNAS, KIT, KRAS, MAP2K1, MET, MSH6, NRAS, PDGFRA, PIK3CA, PTEN, SF3B1, SMAD4, SRC, SRSF2, STK11, TP53, and U2AF1; copy numbers for EGFR, c-myc, FGFR, PLAG, c-met) were assessed. None of the patients had axillary lymph node involvement. In 13 cases, local recurrence developed after surgery (30.9 %). Distant metastasis occurred in seven patients (17 %; four after local recurrence). The most frequent genetic alteration was PIK3CA mutation (50 % of cases). None of the pathological parameters (size, grade, stage, Ki-67 labeling index) was significantly associated with disease-free survival (DFS) or overall survival (OS). PIK3CA mutation, especially the H1047R type, tended to adversely affect OS. Type of resection (mastectomy vs. breast-conserving therapy, width of margins) or adjuvant radiotherapy had no influence on DFS or OS, whereas in the group treated with radio-/chemotherapy, no local recurrence or metastasis and no death occurred. We conclude that the spindle cell type of MBC with myoepithelial features exhibits a higher frequency of PIK3CA mutation than other types of metaplastic or basal-like breast cancer and may benefit from combined radio-/chemotherapy. Classical pathological parameters are not helpful in identifying the high-risk tumors among this subgroup of MBC.
PMCID: PMC4978764  PMID: 27220763
Breast cancer; Metaplastic; Myoepithelial; Prognosis; PIK3CA
9.  Necrotizing Sialometaplasia-Like Change of the Esophageal Submucosal Glands is Associated with Barrett’s Esophagus 
The esophageal submucosal glands (SMG) protect the squamous epithelium from insults such as gastroesophageal reflux disease by secreting mucins and bicarbonate. We have observed metaplastic changes within the SMG acini that we have termed oncocytic glandular metaplasia (OGM), and necrotizing sialometaplasia-like change (NSMLC). The aim of this study is to evaluate the associated clinicopathological parameters of, and to phenotypically characterize the SMG metaplasias. Esophagectomy specimens were retrospectively assessed on hematoxylin and eosin sections and assigned to either a Barrett’s esophagus (BE) or non-BE control group. Clinicopathologic data was collected, and univariate analysis and multivariate logistic regression models were performed to assess the adjusted associations with NSMLC and OGM. Selected cases of SMG metaplasia were characterized. SMG were present in 82 esophagi that met inclusion criteria. On univariate analysis, NSMLC was associated with BE (p=0.002). There was no relationship between NSMLC and patient age, sex, tumor size, or treatment history. OGM was associated with BE (p=0.031). No relationship was found between OGM and patient age, sex, or tumor size. On multivariate analysis, BE was independently associated with NSMLC (odds ratio [OR] 4.95, p =0.003). Treatment history was also independently associated with OGM (p =0.029), but not NSMLC. Both NSMLC and OGM were non-mucinous ductal type epithelia retaining a p63-smooth muscle actin co-positive myoepithelial cell layer. NSMLC and OGM were present in endoscopic mucosal resection specimens. Our study suggests that SMG metaplasia is primarily a reflux-induced pathology. NSMLC may pose diagnostic dilemmas in resection specimens or when only partially represented in mucosal biopsies or endoscopic resection specimens.
PMCID: PMC4868088  PMID: 24863247
Gastroesophageal reflux disease; Barrett’s esophagus; esophageal submucosal glands; necrotizing sialometaplasia; oncocytic metaplasia
10.  Lymph vessels: the forgotten second circulation in health and disease 
Virchows Archiv  2016;469:3-17.
The lymphatic circulation is still a somewhat forgotten part of the circulatory system. Despite this, novel insights in lymph angiogenesis in health and disease, application of immune markers for lymphatic growth and differentiation and also the introduction of new imaging techniques to visualize the lymphatic circulation have improved our understanding of lymphatic function in both health and disease, especially in the last decade. These achievements yield better understanding of the various manifestations of lymph oedemas and malformations, and also the patterns of lymphovascular spread of cancers. Immune markers that recognize lymphatic endothelium antigens, such as podoplanin, LYVE-1 and Prox-1, can be successfully applied in diagnostic pathology and have revealed (at least partial) lymphatic differentiation in many types of vascular lesions.
Electronic supplementary material
The online version of this article (doi:10.1007/s00428-016-1945-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4923112  PMID: 27173782
Lymph vessels; Vascular pathology; Metastasis; Atherosclerosis; Angiogenesis; Vascular malformation; Immunohistochemistry; Genetics; Circulation; Lymphedema
11.  Gene expression profiling for the investigation of soft tissue sarcoma pathogenesis and the identification of diagnostic, prognostic, and predictive biomarkers 
Soft tissue sarcomas are malignant neoplasms derived from mesenchymal tissues. Their pathogenesis is poorly understood and there are few effective treatment options for advanced disease. In the past decade, gene expression profiling has been applied to sarcomas to facilitate understanding of sarcoma pathogenesis and to identify diagnostic, prognostic, and predictive markers. In this paper, we review this body of work and discuss how gene expression profiling has led to advancements in the understanding of sarcoma pathobiology, the identification of clinically useful biomarkers, and the refinement of sarcoma classification schemes. Lastly, we conclude with a discussion of strategies to further optimize the translation of gene expression data into a greater understanding of sarcoma pathogenesis and improved clinical outcomes for sarcoma patients.
PMCID: PMC4847139  PMID: 19412622
Gene expression profiling; Microarrays; Genomics; Bioinformatics; Tumor biology; Soft tissue tumors; Sarcomas; Biomarkers; Molecular pathology; Surgical pathology
12.  The effects of implementing synoptic pathology reporting in cancer diagnosis: a systematic review 
Virchows Archiv  2016;468:639-649.
Pathology reporting is evolving from a traditional narrative report to a more structured synoptic report. Narrative reporting can cause misinterpretation due to lack of information and structure. In this systematic review, we evaluate the impact of synoptic reporting on completeness of pathology reports and quality of pathology evaluation for solid tumours. Pubmed, Embase and Cochrane databases were systematically searched to identify studies describing the effect of synoptic reporting implementation on completeness of reporting and quality of pathology evaluation of solid malignant tumours. Thirty-three studies met the inclusion criteria. All studies, except one, reported an increased overall completeness of pathology reports after introduction of synoptic reporting (SR). Most frequently studied cancers were breast (n = 9) and colorectal cancer (n = 16). For breast cancer, narrative reports adequately described ‘tumour type’ and ‘nodal status’. Synoptic reporting resulted in improved description of ‘resection margins’, ‘DCIS size’, ‘location’ and ‘presence of calcifications’. For colorectal cancer, narrative reports adequately reported ‘tumour type’, ‘invasion depth’, ‘lymph node counts’ and ‘nodal status’. Synoptic reporting resulted in increased reporting of ‘circumferential margin’, ‘resection margin’, ‘perineural invasion’ and ‘lymphovascular invasion’. In addition, increased numbers of reported lymph nodes were found in synoptic reports. Narrative reports of other cancer types described the traditional parameters adequately, whereas for ‘resection margins’ and ‘(lympho)vascular/perineural invasion’, implementation of synoptic reporting was necessary. Synoptic reporting results in improved reporting of clinical relevant data. Demonstration of clinical impact of this improved method of pathology reporting is required for successful introduction and implementation in daily pathology practice.
Electronic supplementary material
The online version of this article (doi:10.1007/s00428-016-1935-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4887530  PMID: 27097810
Pathology; Synoptic reporting; Narrative reporting; Checklist; Template; Proforma; Guideline; Completeness; Quality; Colorectal carcinoma; Breast cancer
13.  Postmortem CT is more accurate than clinical diagnosis for identifying the immediate cause of death in hospitalized patients: a prospective autopsy-based study 
Virchows Archiv  2016;469:101-109.
Despite 75 to 90 % physician accuracy in determining the underlying cause of death, precision of determination of the immediate cause of death is approximately 40 %. In contrast, two thirds of immediate causes of death in hospitalized patients are correctly diagnosed by postmortem computed tomography (CT). Postmortem CT might provide an alternative approach to verifying the immediate cause of death. To evaluate the effectiveness of postmortem CT as an alternative method to determine the immediate cause of death in hospitalized patients, an autopsy-based prospective study was performed. Of 563 deaths from September 2011 to August 2013, 50 consecutive cadavers undergoing hospital autopsies with consent for additional postmortem CT at the University of Fukui were enrolled. The accuracy of determination of the immediate cause of death by postmortem CT was evaluated in these patients. Diagnostic discrepancy was also compared between radiologists and attending physicians. The immediate cause of death was correctly diagnosed in 37 of 50 subjects using postmortem CT (74 %), concerning 29 cases of respiratory failure, 4 of hemorrhage, 3 of liver failure and 1 of septic shock. Six cases of organ failure involving 13 patients were not identified as the cause of death by postmortem CT. Regarding the immediate cause of death, accuracy of clinical diagnosis was significantly lower than that of postmortem CT (46 vs 74 %, P < 0.01). Postmortem CT may be more useful than clinical diagnosis for identifying the immediate cause of death in hospitalized patients not undergoing autopsy.
Electronic supplementary material
The online version of this article (doi:10.1007/s00428-016-1937-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4923108  PMID: 27085336
Autopsy; Diagnostic accuracy; Hospitalized patient; Immediate cause of death; Postmortem CT
14.  Amyloid in biopsies of the gastrointestinal tract—a retrospective observational study on 542 patients 
Virchows Archiv  2016;468:569-577.
In this retrospective observational study, we investigated the histopathological and demographic characteristics of amyloid in gastrointestinal biopsies. From the Amyloid Registry Kiel, we retrieved all cases with amyloid in biopsies of the stomach, duodenum, small intestine, large intestine, and rectum submitted for tertiary referral between January 2003 and April 2013. Amyloid was identified by Congo red staining in combination with polarization microscopy and classified by immunohistochemistry. The TTR-genotype was assessed in 56 patients. Amyloid type was correlated with demographic patient characteristics. Six hundred sixty-three biopsies from 542 patients were retrieved. Amyloid was found in each biopsy as vascular and/or interstitial amyloid deposits. Biopsies were obtained from the colon [254 biopsies (38.3 %)], stomach, [153 (23.1 %)], rectum [112 (16.9 %)], duodenum [105 (15.8 %)], and jejunum/ileum [39 (5.9 %)]. ALλ amyloid was found in 286 (52.8 %), ATTR in 88 (16.2 %), ALκ in 74 (13.7 %), AA in 58 (10.7 %), and ApoAI amyloid in 4 (0.7 %) patients. The remaining 21 cases were ALys amyloid in 4 (0.7 %), AL n.o.s. in 14 (2.6 %), and mixed type amyloidosis in 3 (0.6 %). The amyloid of 11 (2.0 %) cases remained unclassified. The median age of the patients was 68 years. Men [332 (61.7 %)] were significantly more prevalent than women [206 (38.3 %); p < 0.001]. TTR mutations were found in 24 % of the patients with ATTR amyloidosis. The median age, the histoanatomical distribution (proximal to distal; mucosal to submucosal), and the deposition pattern (vascular/interstitial) varied between different amyloid types. Amyloid in gastrointestinal biopsies mainly affects male elderly patients and shows amyloid-type-specific demographic patient characteristics.
Electronic supplementary material
The online version of this article (doi:10.1007/s00428-016-1916-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4856726  PMID: 26915034
Amyloid; Gastrointestinal tract; Biopsy
15.  [No title available] 
PMCID: PMC4830890  PMID: 26868144
16.  Quality assurance in postgraduate pathology training the Dutch way: regular assessment, monitoring of training programs but no end of training examination 
Virchows Archiv  2016;468:109-113.
It might seem self-evident that in the transition from a supervised trainee to an independent professional who is no longer supervised, formal assessment of whether the trainee knows his/her trade well enough to function independently is necessary. This would then constitute an end of training examination. Such examinations are practiced in several countries but a rather heterogeneous situation exists in the EU countries. In the Netherlands, the training program is not concluded by a summative examination and reasons behind this situation are discussed. Quality assurance of postgraduate medical training in the Netherlands has been developed along two tracks: (1) not a single testing moment but continuous evaluation of the performance of the trainee in ‘real time’ situations and (2) monitoring of the quality of the offered training program through regular site-visits. Regular (monthly and/or yearly) evaluations should be part of every self-respecting training program. In the Netherlands, these evaluations are formative only: their intention is to provide the trainee a tool by which he or she can see whether they are on track with their training schedule. In the system in the Netherlands, regular site-visits to training programs constitute a crucial element of quality assurance of postgraduate training. During the site-visit, the position and perceptions of the trainee are key elements. The perception by the trainee of the training program, the institution (or department) offering the training program, and the professionals involved in the training program is explicitly solicited and systematically assessed. With this two-tiered approach high-quality postgraduate training is assured without the need for an end of training examination.
PMCID: PMC4751191  PMID: 26818830
Pathology; Postgraduate education; Quality assurance; examination
17.  [No title available] 
PMCID: PMC4830882  PMID: 26573425
19.  Dimethylarginine dimethylaminohydrolase 2 promotes tumor angiogenesis in lung adenocarcinoma 
Virchows Archiv  2015;468:179-190.
Although embryonal proteins have been used as tumor marker, most are not useful for detection of early malignancy. In the present study, we developed mouse monoclonal antibodies against fetal lung of miniature swine, and screened them to find an embryonal protein that is produced at the early stage of malignancy, focusing on lung adenocarcinoma. We found an antibody clone that specifically stained stroma of lung adenocarcinoma. LC-MS/MS identified the protein recognized by this clone as dimethylarginine dimethylaminohydrolase 2 (DDAH2), an enzyme known for antiatherosclerotic activity. DDAH2 was found to be expressed in fibroblasts of stroma of malignancies, with higher expression in minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma than in adenocarcinoma in situ (AIS). Moreover, tumors with high stromal expression of DDAH2 had a poorer prognosis than those without. In vitro analysis showed that DDAH2 increases expression of endothelial nitric oxide synthase (eNOS), inducing proliferation and capillary-like tube formation of vascular endothelial cells. In resected human tissues, eNOS also showed higher expression in invasive adenocarcinoma than in AIS and normal lung, similarly to DDAH2. Our data indicate that expression of DDAH2 is associated with invasiveness of lung adenocarcinoma via tumor angiogenesis. DDAH2 expression might be a prognostic factor in lung adenocarcinoma.
Electronic supplementary material
The online version of this article (doi:10.1007/s00428-015-1863-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4778151  PMID: 26515557
DDAH2; Angiogenesis; Adenocarcinoma; Malignant stroma; Prognosis
20.  Old dilemma: asthma with irreversible airway obstruction or COPD 
Virchows Archiv  2015;467(5):583-593.
Older asthmatic patients may develop fixed airway obstruction and clinical signs of chronic obstructive pulmonary disease (COPD). We investigated the added value of pathological evaluation of bronchial biopsies to help differentiate asthma from COPD, taking into account smoking, age, and inhaled corticosteroid (ICS) use. Asthma and COPD patients (24 of each category) were matched for ICS use, age, FEV1, and smoking habits. Five pulmonary and five general pathologists examined bronchial biopsies using an interactive website, without knowing patient information. They were asked to diagnose asthma or COPD on biopsy findings in both a pairwise and randomly mixed order of cases during four different phases, with intervals of 4–6 weeks, covering a maximal period of 36 weeks. Clinically concordant diagnoses of asthma or COPD varied between 63 %-73 %, without important differences between pairwise vs randomly mixed examination or between general vs pulmonary pathologists. The highest percentage of concordant diagnoses was in young asthmatic patients without ICS use and in COPD patients with ICS use. In non ICS users with fixed airway obstruction, a COPD diagnosis was favored if abnormal presence of glands, squamous metaplasia, and submucosal infiltrate was present and an asthma diagnosis in case of abnormal presence of goblet cells. In ICS users with fixed airway obstruction, abnormal presence of submucosal infiltrates, basement membrane thickening, eosinophils, and glands was associated with asthma. Histological characteristics in bronchial biopsies are reproducibly recognized by pathologists, yet the differentiation by histopathology between asthma and COPD is difficult without information about ICS use.
Electronic supplementary material
The online version of this article (doi:10.1007/s00428-015-1824-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4656713  PMID: 26369547
Asthma; COPD; Asthma COPD Overlap Syndrome; Pathology
21.  Mesenchymal tumours of the mediastinum—part I 
Virchows Archiv  2015;467:487-500.
The mediastinum is an anatomically defined space in which organs and major blood vessels reside with surrounding soft tissue elements. The thymus is an important organ in the mediastinum, and many of the masses encountered in the mediastinum are related to this organ. Most neoplasms diagnosed in the mediastinum are epithelial tumours (thymomas and thymic carcinomas), lymphomas or germ cell tumours. In contrast, soft tissue tumours of the mediastinum are rare. In 1963, Pachter and Lattes systematically reviewed soft tissue pathology of the mediastinum, covering the hitherto described [2, 226, 227] In this review, based on the 2013 WHO classification of soft tissue tumours and the 2015 WHO classification of tumours of the lung, pleura, thymus and heart, we provide an updated overview of mesenchymal tumours that may be encountered in the mediastinum.
PMCID: PMC4656709  PMID: 26358059
Mediastinum; Mesenchymal tumours; Soft tissue tumours
22.  Mesenchymal tumours of the mediastinum—part II 
Virchows Archiv  2015;467:501-517.
This is the second part of a two-part review on soft tissue tumours which may be encountered in the mediastinum. This review is based on the 2013 WHO classification of soft tissue tumours and the 2015 WHO classification of tumours of the lung, pleura, thymus and heart and provides an updated overview of mesenchymal tumours that have been reported in the mediastinum.
PMCID: PMC4656710  PMID: 26358060
Mediastinum; Mesenchymal tumours; Soft tissue tumours
23.  The medical autopsy as quality assurance tool in clinical medicine: dreams and realities 
Virchows Archiv  2015;468:75-81.
The purpose of medical autopsy has changed to issues of quality assurance today. In addition, autopsies are considered valuable in medical education, e.g., delivering cases for problem-based learning for students. Many studies underscore the need for autopsies also in the era of technical progress emphasizing the continuing discrepancies between antemortem and post mortem diagnoses. Despite these important tasks, we face a decline of autopsy for several reasons with complex interactions. The role of all persons involved in this decline is evaluated and suggestions for changes are proposed. Last but not least, the future of the autopsy is in the hands of pathology itself.
PMCID: PMC4751188  PMID: 26316183
Autopsy; Quality tool; History; Future
24.  Proficiency testing in immunohistochemistry—experiences from Nordic Immunohistochemical Quality Control (NordiQC) 
Virchows Archiv  2015;468:19-29.
Despite extensive use of immunohistochemistry (IHC) for decades, lack of standardization remains a major problem, even aggravated in the era of targeted therapy. Nordic Immunohistochemical Quality Control (NordiQC) is an international academic proficiency testing (PT) program established in 2003 primarily aimed at assessing the analytical phases of the laboratory IHC quality. About 700 laboratories from 80 countries are currently participating. More than 30,000 IHC slides have been evaluated during 2003–2015. Overall, about 20 % of the staining results in the breast cancer IHC module and about 30 % in the general module have been assessed as insufficient for diagnostic use. The most common causes for insufficient results are less successful antibodies (poor and less robust antibodies, poorly calibrated ready-to-use (RTU) products, and stainer platform-dependent antibodies; 17 %), insufficiently calibrated antibody dilutions (20 %), insufficient or erroneous epitope retrieval (27 %), less sensitive visualization systems (19 %), and other (heat- and proteolysis-induced impaired morphology, endogenous biotin reaction, drying out phenomena, stainer platform-dependant protocol issues; 17 %). Approximately, 90 % of the insufficient results are characterized by either a too weak or false negative staining, whereas in the remaining 10 %, a poor signal-to-noise ratio or false positive staining is seen. Individually tailored recommendations for protocol optimization and identification of best tissue controls to ensure appropriate calibration of the IHC assay have for many markers improved IHC staining as well as inter-laboratory consistency of the IHC results. RTUs will not always provide an optimal result and data sheets frequently misguide the laboratories hampering the improvement in IHC quality. The overall data generated by NordiQC during 12 years indicates that continuous PT is valuable and necessary. Detailed description of the results of the NordiQC programme is available on and summarized in this paper.
PMCID: PMC4751198  PMID: 26306713
Immunohistochemistry; NordiQC; External quality assurance
25.  Mitochondrial D310 mutation as clonal marker for solid tumors 
Virchows Archiv  2015;467(5):595-602.
Patients with multiple tumors, either synchronous or metachronous, can have metastatic disease or suffer from multiple independent primary tumors. While proper diagnosis of these patients is important for prognosis and treatment, this can be challenging using only clinical and histological criteria. The aim of the present study was to evaluate the value of mitochondrial D310 mutation analysis in diagnostic questions regarding tumor clonality for a wide range of tumor types. Sanger sequencing of D310 was performed on a diagnostic cohort of 382 patients with 857 tumors that were previously analyzed using routine molecular analysis on genomic DNA. The D310 mononucleotide repeat was frequently somatically mutated (56/321, 17 %) in several tumor types, including breast, head and neck, gynecological, lung, colorectal, and skin tumors. For 84/327 (26 %) patients, a D310 mutation was detected in at least one of their tumors; for these patients, D310 can be used to determine the clonal relationship between their multiple tumors. Clonality assessments based on mitochondrial DNA (mtDNA) and routine genomic DNA analysis were concordant in 52/73 (71 %) patients. We conclude that D310 mutation status might aid in determining clonality of clinically challenging synchronous or metachronous tumors. To this end, next generation sequencing targeted genomic DNA assays should be complemented with mtDNA markers, such as the D310 repeat.
Electronic supplementary material
The online version of this article (doi:10.1007/s00428-015-1817-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4656708  PMID: 26276353
Mitochondrial DNA; Tumor clonality; Synchronous tumors; Metachronous tumors

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