Christian Gulmann

If it's not CK5/6 positive, TTF-1 negative it's not a squamous cell carcinoma of lung.

Novel targeted treatment of non‐small cell lung cancer (NSCLC) requires accurate classification of NSCLC as squamous cell carcinoma (SCC) and adenocarcinoma (AC). This study details the CK5/6 and TTF‐1 immunoprofile of surgical resections of 45 NSCLCs (24 ACs and 21 SCCs) in tissue microarrays. All SCCs were CK5/6 positive, TTF‐1 negative. 20 of 24 adenocarcinomas had the reverse pattern. In conclusion, all SCCs in this study were CK5/6 positive and TTF‐1 negative, and therefore tumours that do not display this phenotype are unlikely to be SCCs. CK5/6 and TTF‐1 is therefore a practical panel for the distinction between pulmonary SCC from AC in routine histopathology practice.

Immunohistochemical evaluation of novel and traditional markers associated with urothelial differentiation in a spectrum of variants of urothelial carcinoma of the urinary bladder

Data on immunohistochemical expression of novel and traditional urothelial markers in the wide range of urothelial carcinoma variants have so far been very limited. In this study, whole tissue sections from 130 bladder urothelial carcinoma and variants were stained with a panel of novel and traditional immunomarkers supportive of urothelial lineage. The positivity rates were as follows: (a) urothelial carcinomas with or without divergent differentiation: GATA3 (50%), S-100P (86%), uroplakin III (20%), thrombomodulin (40%), cytokeratin 7 (CK7) (80%), CK20 (55%), p63 (87%), and high molecular weight cytokeratin (HMCK) (89%); (b) urothelial carcinoma variants (micropapillary, plasmacytoid, nested, clear cell, and microcystic): GATA3 (88%), S-100P (96%), uroplakin III (33%), thrombomodulin (49%), CK7 (95%), CK20 (61%), p63 (69%), and HMCK (96%); and (c) undifferentiated carcinomas (lymphoepithelioma-like carcinoma, small cell carcinoma, sarcomatoid carcinoma and carcinoma with rhabdoid and giant cells): GATA3 (28%), S-100P (31%), uroplakin III (0%), thrombomodulin (22%), CK7 (50%), CK20 (3%), p63 (50%), and HMCK (49%). In urothelial carcinoma with squamous differentiation, GATA3 expression was lower (20%) in contrast to p63 and S-100P. In urothelial carcinoma with glandular differentiation, GATA3 (50%) and p63 (60%) expression was lower than S-100P (100%). p63 expression was relatively lower in micropapillary (54%) and plasmacytoid (50%) variants compared with the other urothelial carcinoma variants. This study provides comprehensive data for novel and traditionally used markers to support urothelial lineage in urothelial carcinoma variants. Our findings show that GATA3, S-100P, CK7, CK20, HMCK, and p63, in the appropriate differential diagnostic setting, are useful to support urothelial lineage of variant morphologies.

The ERK MAP kinase-PEA3/ETV4-MMP-1 axis is operative in oesophageal adenocarcinoma

BackgroundMany members of the ETS-domain transcription factor family are important drivers of tumourigenesis. In this context, their activation by Ras-ERK pathway signaling is particularly relevant to the tumourigenic properties of many ETS-domain transcription factors. The PEA3 subfamily of ETS-domain transcription factors have been implicated in tumour metastasis in several different cancers.ResultsHere, we have studied the expression of the PEA3 subfamily members PEA3/ETV4 and ER81/ETV1 in oesophageal adenocarcinomas and determined their role in oesophageal adenocarcinoma cell function. PEA3 plays an important role in controlling both the proliferation and invasive properties of OE33 oesophageal adenocarcinoma cells. A key target gene is MMP-1. The ERK MAP kinase pathway activates PEA3 subfamily members and also plays a role in these PEA3 controlled events, establishing the ERK-PEA3-MMP-1 axis as important in OE33 cells. PEA3 subfamily members are upregulated in human adenocarcinomas and expression correlates with MMP-1 expression and late stage metastatic disease. Enhanced ERK signaling is also more prevalent in late stage oesophageal adenocarcinomas.ConclusionsThis study shows that the ERK-PEA3-MMP-1 axis is upregulated in oesophageal adenocarcinoma cells and is a potentially important driver of the metastatic progression of oesophageal adenocarcinomas.

Update for the practicing pathologist: The International Consultation On Urologic Disease-European association of urology consultation on bladder cancer

The International Consultations on Urological Diseases are international consensus meetings, supported by the World Health Organization and the Union Internationale Contre le Cancer, which have occurred since 1981. Each consultation has the goal of convening experts to review data and provide evidence-based recommendations to improve practice. In 2012, the selected subject was bladder cancer, a disease which remains a major public health problem with little improvement in many years. The proceedings of the 2nd International Consultation on Bladder Cancer, which included a ‘Pathology of Bladder Cancer Work Group,’ have recently been published; herein, we provide a summary of developments and consensus relevant to the practicing pathologist. Although the published proceedings have tackled a comprehensive set of issues regarding the pathology of bladder cancer, this update summarizes the recommendations regarding selected issues for the practicing pathologist. These include guidelines for classification and grading of urothelial neoplasia, with particular emphasis on the approach to inverted lesions, the handling of incipient papillary lesions frequently seen during surveillance of bladder cancer patients, descriptions of newer variants, and terminology for urine cytology reporting.

PEA3/ETV4-related transcription factors coupled with active ERK signalling are associated with poor prognosis in gastric adenocarcinoma.

Background:Transcription factors often play important roles in tumourigenesis. Members of the PEA3 subfamily of ETS-domain transcription factors fulfil such a role and have been associated with tumour metastasis in several different cancers. Moreover, the activity of the PEA3 subfamily transcription factors is potentiated by Ras-ERK pathway signalling, which is itself often deregulated in tumour cells.Methods:Immunohistochemical patterns of PEA3 expression and active ERK signalling were analysed and mRNA expression levels of PEA3, ER81, MMP-1 and MMP-7 were determined in gastric adenocarcinoma samples.Results:Here, we have studied the expression of the PEA3 subfamily members PEA3/ETV4 and ER81/ETV1 in gastric adenocarcinomas. PEA3 is upregulated at the protein level in gastric adenocarcinomas and both PEA3/ETV4 and ER81/ETV1 are upregulated at the mRNA level in gastric adenocarcinoma tissues. This increased expression correlates with the expression of a target gene associated with metastasis, MMP-1. Enhanced ERK signalling is also more prevalent in late-stage gastric adenocarcinomas, and the co-association of ERK signalling and PEA3 expression also occurs in late-stage gastric adenocarcinomas. Furthermore, the co-association of ERK signalling and PEA3 expression correlates with decreased survival rates.Conclusions:This study shows that members of the PEA3 subfamily of transcription factors are upregulated in gastric adenocarcinomas and that the simultaneous upregulation of PEA3 expression and ERK pathway signalling is indicative of late-stage disease and a poor survival prognosis.

The search for lymph nodes; does a second search influence the staging and/or management in mesorectal cancer excisions?

Sir: The letter by Hughes et al. about the value of repeated lymph node searches in mesorectal cancer excision was a useful addition to the literature on this subject and larger studies are warranted to confirm their findings. However, we take issue with their assertion that most of the nodes found on additional searches were too small to be palpated because ‘the two-point discrimination of the human finger [is] 5 mm’. Twopoint discrimination refers to the minimum distance between two points at which they can be distinguished as separate points. This has no relevance to the minimum size of a single object that can be identified by palpation. It is easy to feel a grain of sugar, for example, much smaller than 5 mm diameter, on a smooth, flat surface. The ease of palpating small nodes within mesorectal fat depends mainly on the difference in firmness between the node and the surrounding fat. A node made firmer by a metastasis is usually easier to palpate, whereas induration of the surrounding fat will make identification of a node more difficult. The vigour with which palpation is carried out is also relevant, as fat will usually disintegrate and fragment more readily than will a lymph node. Difficulty in identifying nodes after neoadjuvant chemoradiotherapy may therefore be due to not only shrinkage of lymph nodes but also induration and fibrosis of the mesorectal fat making identification of small nodes more difficult. A combination of palpation and close visual inspection is therefore also more likely to improve lymph node yield.

Enlargement of the juxtaglomerular apparatus in insulin-dependent diabetes mellitus patients with microalbuminuria.

Abstract Kidney biopsies from 15 insulin-dependent diabetes mellitus (IDDM) patients with microalbuminuria were investigated to obtain quantitative data on the juxtaglomerular apparatus. The IDDM patients were young and normotensive with a mean duration of microalbuminuria of 2 years. Eight healthy kidney donors served as controls. Measurements taken by light microscopy, using 1-µm serial sections of epon blocks, included volumes of the juxtaglomerular apparatus and of glomeruli, areas of the macula densa and luminal area of the juxtaglomerular (afferent and efferent) arterioles at the level of the glomerular vascular pole. The volume of the juxtaglomerular apparatus was significantly larger in the IDDM group than in controls [6.08 (2.96–18.8) 104µm3 vs 3.48 (1.84–5.21) 104µm3, P=0.003, median and (range)], as was the volume of the juxtaglomerular apparatus relative to glomerular volume [1.89(1.28–4.21)% vs 1.48 (1.13–1.71)%, P=0.004]. The area of the macula densa was also larger in the IDDM patients (1370 µm2 vs 937 µm2, P=0.03). Luminal areas of the afferent and efferent arterioles and the ratio between them did not differ significantly between the two groups. In conclusion, the juxtaglomerular apparatus is enlarged more than would be expected from the glomerular hypertrophy in IDDM patients with microalbuminuria.

Lithium-induced Nephrotoxicity: A Case Report of Renal Cystic Disease Presenting as a Mass Lesion.

Lithium is an effective therapeutic agent used in the management of bipolar disorder. However, lithium is also associated with several side effects, including renal toxicity. We present a case of a symptomatic cystic mass lesion in the kidney of a patient who had a history of lithium therapy for the management of bipolar disorder.

W1726 ERK MAP Kinase Signalling and PEA3 are Synergistic in Predicting Adversity in Gastric Adenocarcinomas

Introduction The PEA3 sub family consists of 3 similar transcription factors, PEA3, ER81 and ERM. In gastric cancer cells PEA3 is activated by H pylori and it has been shown to regulate MMP-7 and invasion. PEA3 mRNA expression correlates with an adverse prognosis in gastric adenocarcinomas. We have previously shown that PEA3 and/or ER81 mRNA correlates with adverse the indicator, MMP-1 and MMP-7. Very high PEA3 protein expression in isolation is associated with tumour metastases. However tumours with PEA3 mRNA and lower protein expression did not correlate with prognostic markers. PEA3 is regulated by ERK MAP kinase signalling in oesophageal adenocarcinomas and we investigated if this pathway plays an important role in gastric adenocarcinomas. Methods Patients with gastric adenocarcinoma (37) and controls (11) were selected. Tissue microarrays were constructed for immunohistochemical studies of PEA3 and pERK. The t test and chi square test were used for statistical analysis. A p value Results In patients with gastric adenocarcinoma, active ERK signalling is present in 60%. From these, ERK signalling is associated with an advanced tumour stage (AJCC stage 1 67%, stage 2: 33%, stage 3: 21% stage 4: 80% p=0.04). Active signalling is present in stage 1 and 2 tumours (55%). Survival is significantly reduced in patients with active ERK signalling (41 vs 34 months P=0.05) on univariate analysis. Adenocarcinomas with PEA3 and pERK co-occurrence frequently have distant metastases 60% (T and N stage vs M stage p=0.048). Survival is worse in patients with combined pERK and PEA3 presence compared to PEA3 or pERK presence in isolation (12 vs 30 vs 63 months p=0.071). Conclusion Our results indicate that ERK MAP kinase signalling is an important marker of an advanced tumour stage and prognosis in gastric adenocarcinoma. The signalling pathway is frequently active in early stage (AJCC 1–3) tumours. Previous studies have shown poor results with MEK inhibition treatment in Pancreatic, Colon, Lung and Breast cancers. This may be due to the selection of heterogeneous tumours with an advanced disease stage or tumours with activation of alternative signalling pathways. Our results suggest consideration of trialling MEK inhibition treatment in patients with earlier stage disease in gastric adenocarcinoma. The more adverse outcome in patients with the combination of ERK MAP signalling and PEA3 indicates that a combined approach with inhibition of PEA3, could be considered in selected patients.

Long‐term studies of the juxtaglomerular apparatus in young microalbuminuric type 1 diabetic patients

Aim: To determine the long‐term changes of the juxtaglomerular apparatus in incipient diabetic nephropathy. Methods: Three renal needle biopsies were performed on 15 young type 1 diabetic patients with microalbuminuria; at baseline and after an average of 2.4 and 8.2 years. Using light microscopy, 1 μm serial sections of the plastic‐embedded biopsies were investigated and volumes of the juxtaglomerular apparatus and glomerulus and areas of the macula densa and lumina of the afferent and efferent arterioles were measured. Results: From baseline to second follow‐up there was a significant decrease in JGA relative to glomerular volume. There was an increase in luminal area of the efferent arteriole which was paralleled by (non‐significant) changes in the afferent arteriole. Conclusion: Over a period of 8.2 years JGA size remained stable, but decreased relative to glomerular size. Also, an increase in luminal area was noted in efferent arterioles. This may be due to increased single nephron blood flow secondary to nephron loss.