A UK-based investigation of inter- and intra-observer reproducibility of Gleason grading of prostatic biopsies.

AIMS: The frequency of prostatic core biopsies to detect cancer has been increasing with more widespread prostate specific antigen (PSA) testing. Gleason score has important implications for patient management but morphological reproducibility data for British practice are limited. Using literature-based criteria nine uropathologists took part in a reproducibility study. METHODS: Each of the nine participants submitted slides from consecutive cases of biopsy-diagnosed cancer assigned to the Gleason score groups 2-4, 5-6, 7 and 8-10 in the original report. A random selection of slides was taken within each group and examined by all pathologists, who were blind to the original score. Over six circulations, new slides were mixed with previously read slides, resulting in a total of 47 of 81 slides being read more than once. RESULTS: For the first readings of the 81 slides, the agreement with the consensus score was 78% and overall interobserver agreement was kappa 0.54 for Gleason score groups 2-4, 5-6, 7, 8-10. Kappa values for each category were 0.33, 0.56, 0.44 and 0.68, respectively. For the 47 slides read more than once, intra-observer agreement was 77%, kappa 0.66. The study identified problems in core biopsy interpretation of Gleason score at levels 2-4 and 7. Patterns illustrated by Gleason as 2 tended to be categorized as 3 because of the variable acinar size and unassessable lesional margin. In slides with consensus Gleason score 7, 13% of readings were scored 6 and in slides with consensus 6, 18% of readings were scored 7. CONCLUSIONS: Recommendations include the need to increase objectivity of the Gleason criteria but limits of descriptive morphology may have to be accepted.

A study of Gleason score interpretation in different groups of UK pathologists; techniques for improving reproducibility.

AIMS: To test the effectiveness of a teaching resource (a decision tree with diagnostic criteria based on published literature) in improving the proficiency of Gleason grading of prostatic cancer by general pathologists. METHODS: A decision tree with diagnostic criteria was developed by a panel of urological pathologists during a reproducibility study. Twenty-four general histopathologists tested this teaching resource. Twenty slides were selected to include a range of Gleason score groups 2-4, 5-6, 7 and 8-10. Interobserver agreement was studied before and after a presentation of the decision tree and criteria. The results were compared with those of the panel of urological pathologists. RESULTS: Before the teaching session, 83% of readings agreed within +/- 1 of the panel's consensus scores. Interobserver agreement was low (kappa = 0.33) compared with that for the panel (kappa = 0.62). After the presentation, 90% of readings agreed within +/- 1 of the panel's consensus scores and interobserver agreement amongst the pathologists increased to kappa = 0.41. Most improvement in agreement was seen for the Gleason score group 5-6. CONCLUSIONS: The lower level of agreement among general pathologists highlights the need to improve observer reproducibility. Improvement associated with a single training session is likely to be limited. Additional strategies include external quality assurance and second opinion within cancer networks.

Henoch Schönlein purpura with nephritis in adults: adverse prognostic indicators in a UK population.

BACKGROUND: Henoch Schönlein purpura with nephritis (HSN) in adults may cause severe organ injury, but its rarity has contributed to a lack of data. AIM: To evaluate clinical outcomes and risk factors in adult HSN patients. DESIGN: Retrospective analysis. METHODS: Thirty-seven patients with adult HSN attending the Regional Vasculitis Clinic between 1974 and 2004 were assessed. For inclusion, a renal biopsy showing predominant mesangial IgA immune deposits was required, plus at least two of: purpuric rash, arthralgia, abdominal pain. RESULTS: Ten patients (27%) progressed to end-stage renal failure (ESRF). Renal failure rates were highest in the first decade, with survival rate 72% at 5 years, 68% at 10 years and 46% at final review. Risk factors for ESRF were: proteinuria > or =1 g/day during follow-up (RR 83.8, p = 0.0006); hypertension at presentation (RR = 53.3, p = 0.0045) and during follow-up (RR = 5.9, p = 0.05); renal impairment at presentation (RR 8.0, p = 0.0015); age <30 years (RR 7.6, p = 0.02); and male sex (RR = 6.0, p = 0.05). Biopsies frequently showed crescents, mostly affecting <50% of glomeruli; their presence predicted ESRF, as did interstitial fibrosis and tubular atrophy. Renal remission, in contrast, was also high (43%). Cytotoxics were used in 32%, with no clear effect on outcome. Relapses affecting the classical extra-renal systems were common, but were not associated with declines in renal function. A high proportion of patients (41%) also suffered vasculitic organ injuries outside the classical systems. DISCUSSION: HSN in adults is a serious relapsing disease, causing renal failure as frequently as in small-vessel ANCA-positive vasculitides. Prognosis and risks differed in this series from those in other countries, including a higher risk of ESRF than in previous series. Distinct groups developed either ESRF, or remitted. The absence of clear benefit suggests that corticosteroids should be reserved for patients with serious disease, and that cytotoxics may not be merited for those at high risk of renal failure.

Actin filaments in human renal tubulo-interstitial fibrosis: significance for the concept of epithelial-myofibroblast transformation.

Epithelial-myofibroblast transformation has been argued as playing a role in tubulo-interstitial fibrosis. To investigate this hypothesis, we examined 9 renal biopsy specimens from patients with chronic renal disease by light and electron microscopy. In all cases, electron microscopy confirmed light microscope observations in relation to tubulo-interstitial fibrosis-tubular atrophy, accumulation of extracellular matrix and of mesenchymal interstitial cells, and infiltration by inflammatory cells. Tubular epithelial cells (TECs) contained bundles of actin filaments: mostly lacking the focal densities typical of smooth-muscle myofilaments. The interstitium contained collagen and inflammatory cells. Some endothelial cells showed bundles of myofilaments. Free mesenchymal cells in the matrix were spindled and had sparse rough endoplasmic reticulum (rER), small attachment plaques, few actin filaments and no lamina. In one case, myofibroblasts (defined by abundant rER, myofilaments and fibronexuses) were present. Most of the mesenchymal cells, therefore, did not correspond to myofibroblasts, nor to classical fibroblasts because of the sparse rER and the presence of actin filaments. We therefore called these cells myoid stromal cells, regarding them as stromal mesenchymal elements showing partial activation towards a smooth-muscle phenotype. This paper demonstrates a greater phenotypic complexity of actin-containing stromal cells in the interstitium than previously appreciated, with only a minority conforming to true or fully differentiated myofibroblasts. The widespread presence of actin (as filaments or immunoreactivity) in both TECs and interstitial cells, combined with the absence of evidence of intermediate forms or of migration from epithelium into interstitium, may point to epithelium and interstitium as separate targets for actin upregulation as an alternative hypothesis to epithelial-myofibroblast transformation.

Incomplete excision of basal cell carcinoma: a prospective multicentre audit.

The audit of incomplete excision of basal cell carcinoma can be used as a parameter for clinical governance in plastic surgery units. However, there are no national standards, and all the previous reports from the UK have been retrospective and from regional units only. This 1 year prospective audit was undertaken simultaneously in the plastic surgery units of three different categories of hospital: a regional plastic surgery unit (University Hospital of South Manchester), a supraregional cancer hospital (Christie Hospital) and a district general hospital (Royal Bolton Hospital). A total of 757 lesions were excised from 600 patients, with 34 lesions (4.5%) being incompletely excised. The incidences of incomplete excision were similar in the regional unit (3.2%) and the district general hospital (3.1%), but higher in the supraregional cancer hospital (7.5%). The commonest site for incomplete excision was the eyebrow, followed by the postauricular area, the nose and the temple. There were no statistically significant differences in the distributions of the age and sex of the patients, the site and size of the lesions or the methods of repair between the three hospitals. However, there were significant differences in the distribution of syndromal, multiple and recurrent lesions, the grade of surgeon, and the clinical and histological subtypes. When the various confounding factors were adjusted by logistic regression, the variables most likely to have affected the incidence of incomplete excision were found to be grade of surgeon, minimal excision margin and histological subtype.

A field based evaluation of household arsenic removal technologies for the treatment of drinking water.

Seven household treatment technologies for the removal of arsenic (Alcan, BUET, DPHE/DANIDA, Garnet, Sono, Stevens, Tetrahedron) were each evaluated using water from 63 different tube wells taken from 3 different regions of Bangladesh. The technologies that were evaluated were chosen from those that appeared user friendly, readily available and whose promoters were open to participate in the study. Arsenic concentrations in feed and treated waters were analysed by the PeCo 75 arsenic field test kit, AA-hydride generation and ICP-AES. Feed water arsenic concentrations were found to be up to 600 microg l(-1). The more advanced treatment methods using: activated alumina (Alcan, BUET); metallic iron (Sono); anionic exchange resin (Tetrahedron) and iron coagulation (Stevens) were found to be most easily used and efficiently reduced arsenic concentrations to below the Bangladesh drinking water standard (0.05 mg As l(-1)). The use of aluminium sulphate coagulants and permanganate oxidants in the DPHE/DANIDA technology introduced unacceptably high concentrations of aluminium and manganese into the treated waters and are not recommended in household water treatment applications. While arseric concentrations were initially considered to be of paramount importance, it became clear that such technologies can increase the risk of bacterial contamination in the treated water and this needs serious consideration as this could create a hazard much greater than the arsenic contained in the water. Ground waters sampled during the course of this study were mostly found to be bacteria free. To minimize any risks relating to bacterial contamination the addition of hypochlorite or the boiling of water is necessary.

Incidence of incomplete excision in surgically treated basal cell carcinoma: a retrospective clinical audit.

All the patients who had excision of basal cell carcinoma at the regional plastic surgery unit at Manchester over a period of 2 years from January 1995 to December 1996 were included in a retrospective audit. A total of 879 lesions were excised in 754 patients. In 41 lesions (4.7%) the tumour was incompletely excised, 16 of these lesions were further excised; the rest were managed by regular follow-up. The mean age of the incomplete excision group was slightly higher. The site where the incomplete excision rate was highest was the scalps followed by the ear, canthi,eyebrows and nose. There was a higher incidence of squamous differentiation and presence of foci of squamous cell carcinoma in the lesions excised incompletely. There was no statistically significant difference among the different groups of surgeons but in individual grades the rate was lower where more wounds were repaired by direct closure. The concept of a complexity ratio (number of wounds repaired by other methods/number of wounds repaired by direct closure) can be helpful in comparing the incomplete excision rates of different grades of surgeons or departments. The excision of basal cell carcinoma is one of the commonest procedures performed by all grades of surgeons in a plastic surgery department. Incomplete excision leads to further surgery or prolonged follow-up, thus significantly affecting the outcome. As the incidence of incomplete excision can be precisely monitored, it may be a useful tool for clinical governance.

Neuroendocrine differentiation and prognosis in prostatic adenocarcinoma.

OBJECTIVES: To assess the prognostic importance of neuroendocrine differentiation in conventional (non-small cell) prostatic adenocarcinoma. MATERIALS AND METHODS: Ninety-two samples from patients with prostatic adenocarcinoma were studied retrospectively. The immunohistochemical analysis of chromogranin A and neuron-specific enolase in formalin-fixed, paraffin wax embedded prostatic tissue chips was related to other prognostic variables and patient survival. RESULTS: Neuroendocrine differentiation was detected in 48 cases; there was a significant correlation with worsening tumour differentiation, the presence of bone metastases and with worsening survival, but no independent effect of neuroendocrine differentiation on survival. CONCLUSION: The detection of neuroendocrine differentiation in conventional prostatic adenocarcinoma is not an independent indicator of prognosis.

Interstitial myofibroblasts: predictors of progression in membranous nephropathy.

AIMS: To determine the role of interstitial myofibroblasts in the progression of membranous nephropathy; and to assess the predictive value of quantifying myofibroblasts in determining long term renal outcome. METHODS: All cases of membranous nephropathy, diagnosed by renal biopsy at University Hospital of South Manchester between 1984 and 1987, were studied retrospectively. The biopsy specimens (n = 26) were reviewed and analysed morphometrically to measure interstitial volume as a proportion of the total volume of renal cortex, and numbers of interstitial myofibroblasts (cells positive for alpha-smooth muscle actin within the interstitium). Clinical data, with a follow up of seven to eight years, was available for 24 patients, and renal outcome was correlated with pathological changes in the initial diagnostic biopsy specimen. RESULTS: The number of myofibroblasts and interstitial volume were inversely correlated with creatinine clearance at the initial biopsy, and at the end of follow up. Percentage sclerosed glomeruli or stage of glomerular disease, assessed by electron microscopy, did not correlate with renal function at initial biopsy or during follow up. The number of myofibroblasts, but not interstitial volume, correlated with severity of proteinuria at initial biopsy. Of 15 biopsy specimens showing no or mild interstitial fibrosis, four showed a notable increase in the number of interstitial myofibroblasts. All of these patients developed chronic renal failure, compared with three of 11 patients whose specimens showed no or a mild increase in myofibroblast numbers. CONCLUSIONS: Interstitial myofibroblasts play a role in the development of interstitial fibrosis and progressive renal failure in membranous nephropathy. Increased numbers of myofibroblasts in biopsy specimens showing only mild fibrosis may predict subsequent chronic renal failure.

Loss of HLA class I expression in prostate cancer: implications for immunotherapy.

OBJECTIVES: There is currently no reliable predictor of the metastatic potential of apparently localized prostate cancer in an individual patient or satisfactory treatment for patients with advanced disease. One of the factors that may influence tumor progression is the cellular arm of the immune response, and central to this is the human leukocyte antigen (HLA) system, which acts to restrict T-cell recognition of potential tumor antigens. It has been reported in some cancers that down regulation of HLA class I expression by the tumor cells is associated with poor prognosis. In this report, HLA class I and II expression have been investigated in both benign and malignant prostate disease, first to define the extent of altered HLA expression and second to assess whether HLA expression may be related to disease progression. METHODS: HLA expression was assessed by immunohistochemistry utilizing a set of monoclonal antibodies that recognize both monomorphic determinants and the commoner HLA class I allelic products. RESULTS: In contrast to the normal HLA class I expression of the benign tissue, complete loss of HLA class I expression occurred in 34% of primary prostate cancers and 80% of lymph node metastases. When individual allelic expression was assessed, the minimum estimate of down regulation was 85% in the primary prostate cancers and 100% of the metastases. CONCLUSIONS: This investigation has demonstrated a higher rate of HLA class I loss than has been reported in other tumors and would suggest that the immune system may have an important role in the progression of prostate cancer, as well as having implications for the design and success of immunotherapy regimens in advanced disease.

Can histopathologists diagnose bronchopneumonia?

OBJECTIVES: To assess histopathologists' ability to accurately diagnose bronchopneumonia, both on naked eye and microscopic examination; to extrapolate from the error rate to determine whether the role of the necropsy in monitoring the epidemiology of clinical error might be compromised. METHODS: Review of archival histological sections and necropsy reports from two teaching hospitals in Manchester. The main outcome measures identified were the proportions of macroscopic diagnoses of bronchopneumonia which were confirmed by the original pathologist on histological examination, and which could be confirmed on histological review by independent pathologists, together with the proportion of discrepant diagnoses remedied in the final report by the original pathologist. RESULTS: Of 279 cases where a macroscopic diagnosis of bronchopneumonia had been noted in the original provisional necropsy report, the original histopathologist described bronchopneumonia in only 206 (73.8%) in the subsequent final report, which took histology into account. Bronchopneumonia could be confirmed on independent histological review in only 193 (69.2%) of these cases. The original histopathologist diagnosed 74 cases of bronchopneumonia on histological grounds only, of which only 57 (77.0%) could be confirmed on review. Of a total of 160 discrepancies between the original naked eye diagnoses and the final reviewed diagnoses, only 130 (81.3%) had been remedied by the original pathologist. CONCLUSIONS: There is a considerable discrepancy rate between naked eye diagnoses of bronchopneumonia at necropsy and diagnoses confirmed on microscopy. If this discrepancy rate is extrapolated to other common lesions, then the role of the necropsy in clinical audit may be compromised. Pathologists need to take steps to monitor and improve their own diagnostic standards.

Altered saccharide sequences in two groups of patients with metastatic prostatic carcinoma.

OBJECTIVE: To investigate the hypothesis that primary prostatic carcinomas with metastases to different sites (lymph nodes or bone) show varying expression of cell surface and cytoplasmic glycoconjugates. PATIENTS AND METHODS: A group of 14 patients with primary prostatic carcinoma with lymph node metastases but no bone metastases has previously been shown to have an increased survival time. This group was compared with a control group of 14 patients with lymph node-negative, bone metastasis-positive primary prostatic carcinoma using a panel of biotinylated lectins revealed by the avidin-biotin peroxidase complex method. The results were analysed semi-quantitatively and differences in binding patterns between the two groups were sought. RESULTS: No significant differences were seen using the LCA, LTA, UEA-1, WFA, VVA or SBA lectins. The group with bone metastases but no lymph node involvement showed significantly increased binding for the ECA and AHA lectins, both before and after neuraminidase pre-treatment, compared with the lymph node-positive group. CONCLUSIONS: These results suggest that tumours lacking or having a reduced affinity for binding sites for both Gal beta 1-3GalNac (Type I oligosaccharide structures--AHA) and Gal beta 1-4GlcNac (Type II oligosaccharide structures--ECA) sequences are more likely to develop lymph node metastases and less likely to develop bone metastases and thereby increasing the patient's chances of survival. This is further evidence that the metastatic potential of tumours per se and the ultimate site of distal metastases from such tumours is affected in part by the glycoconjugates expressed on their cell surfaces and indicates that metastatic phenotypes for prostatic carcinoma exists.

Secondary polycythaemia associated with bilateral renal lymphocoeles.

A patient with a 15 year history of secondary polycythaemia due to renal erythropoietin hypersecretion is presented. Subsequent spontaneous development of bilateral renal lymphocoeles, which contained high erythropoietin levels, was shown by computerized tomography. The lymphocoeles were successfully treated by bilateral peritoneal marsupialization. No cause for the persistent polycythaemia or lymphocoeles was found at laparotomy or on renal biopsy.

Temporomandibular ganglion or synovial cyst? A case report and literature review.

A ganglion of the temporomandibular joint is a rare finding but it is important in the differential diagnosis of a preauricular swelling. This case report illustrates the usefulness of ultrasound in attempting to establish a preoperative diagnosis of a preauricular swelling. This article also illustrates the histologic techniques that may be used to distinguish a true ganglion from a synovial cyst or bursa.

Value of electron microscopy in diagnosis of renal disease.

AIMS: To assess the role and value of electron microscopy in the diagnosis of renal disease. METHODS: Retrospective evaluation of 88 renal biopsy specimens received for primary diagnosis by assessment of the contribution of electron microscopy to the final diagnosis in the knowledge of the light microscopy and immunofluorescence findings. RESULTS: Electron microscopy had an important diagnostic role in 75% of cases and was essential or necessary for diagnosis in 25%. In 25% of cases electron microscopy was considered unhelpful in diagnosis. CONCLUSION: Electron microscopy has an integral role in the diagnosis of renal disease, and tissue should be taken for electron microscopy in all cases if possible. In some selected cases once the light microscopy and immunofluorescence findings are known it may be possible to forego electron microscopic examination. Electron microscopy is particularly useful in the differential diagnosis of minimal change disease and the nephrotic syndrome.