Diagnostic accuracy of post-mortem CT with targeted coronary angiography versus autopsy for coroner-requested post-mortem investigations: a prospective, masked, comparison study.

BACKGROUND: England and Wales have one of the highest frequencies of autopsy in the world. Implementation of post-mortem CT (PMCT), enhanced with targeted coronary angiography (PMCTA), in adults to avoid invasive autopsy would have cultural, religious, and potential economic benefits. We aimed to assess the diagnostic accuracy of PMCTA as a first-line technique in post-mortem investigations. METHODS: In this single-centre (Leicester, UK), prospective, controlled study, we selected cases of natural and non-suspicious unnatural death referred to Her Majesty's (HM) Coroners. We excluded cases younger than 18 years, known to have had a transmittable disease, or who weighed more than 125 kg. Each case was assessed by PMCTA, followed by autopsy. Pathologists were masked to the PMCTA findings, unless a potential risk was shown. The primary endpoint was the accuracy of the cause of death diagnosis from PMCTA against a gold standard of autopsy findings, modified by PMCTA findings only if additional substantially incontrovertible findings were identified. FINDINGS: Between Jan 20, 2010, and Sept 13, 2012, we selected 241 cases, for which PMCTA was successful in 204 (85%). Seven cases were excluded from the analysis because of procedural unmasking or no autopsy data, as were 24 cases with a clear diagnosis of traumatic death before investigation; 210 cases were included. In 40 (19%) cases, predictable toxicology or histology testing accessible by PMCT informed the result. PMCTA provided a cause of death in 193 (92%) cases. A major discrepancy with the gold standard was noted in 12 (6%) cases identified by PMCTA, and in nine (5%) cases identified by autopsy (because of specific findings on PMCTA). The frequency of autopsy and PMCTA discrepancies were not significantly different (p=0·65 for major discrepancies and p=0·21 for minor discrepancies). Cause of death given by PMCTA did not overlook clinically significant trauma, occupational lung disease, or reportable disease, and did not significantly affect the overall population data for cause of death (p≥0·31). PMCTA was better at identifying trauma and haemorrhage (p=0·008), whereas autopsy was better at identifying pulmonary thromboembolism (p=0·004). INTERPRETATION: For most sudden natural adult deaths investigated by HM Coroners, PMCTA could be used to avoid invasive autopsy. The gold standard of post-mortem investigations should include both PMCT and invasive autopsy. FUNDING: National Institute for Health Research.

Overexpression of the Nek2 kinase in colorectal cancer correlates with beta-catenin relocalization and shortened cancer-specific survival.

The serine/threonine kinase Nek2 (NIMA-related kinase 2) regulates centrosome separation and mitotic progression, with overexpression causing induction of aneuploidy in vitro. Overexpression may also enable tumour progression through effects upon Akt signalling, cell adhesion markers and the Wnt pathway. The objective of this study was to examine Nek2 protein expression in colorectal cancer (CRC). Nek2 protein expression was examined in a panel of CRC cell lines using Western blotting and immunofluorescence microscopy. Nek2 and beta-catenin expression were examined by immunohistochemistry in a series of resected CRC, as well as their matched lymph node and liver metastases, and correlated with clinicopathological characteristics. Nek2 protein expression in all CRC lines examined was higher than in the immortalised colonocyte line HCEC. Nek2 overexpression was present in 86.4% of resected CRC and was significantly associated with advancing AJCC tumour stage and shortened cancer-specific survival. Elevated Nek2 expression was maintained within all matched metastases from overexpressing primary tumours. Nek2 overexpression was significantly associated with lower tumour membranous beta-catenin expression and higher cytoplasmic and nuclear beta-catenin accumulation. These data support a role for Nek2 in CRC progression and confirm potential for Nek2 inhibition as a therapeutic avenue in CRC.

Histological changes during extracorporeal perfusions of the porcine liver: implications for temporary support during acute liver failures.

Ex vivo perfused porcine livers have been used for temporary support during acute liver failure. The aim of this study was to assess both the histological changes and temporal pattern of the changes that occur during extracorporeal liver perfusions and to correlate these with factors that may influence them. Five porcine livers were harvested, preserved in cold ice and reperfused for 6 h in an extracorporeal circuit using autologous normothermic blood. Tissue biopsies were collected hourly. The Ishak score was used to quantify hepatic necrosis, and immunohistochemistry was used to evaluate apoptosis and regeneration. Liver weight, perfusion parameters, arterial blood gases and blood samples were also collected. The Ishak score peaked immediately before and 4 h after the start of reperfusion. Scattered necrosis, microvesicular steatotic vacuolization, sinusoidal dilatation and red cell extravasation were present. Anion gap acidosis was associated with the Ishak score. An inverse correlation was present between liver regeneration and necrosis, and between liver weight and regeneration. No changes were observed for apoptosis. Among the inflammatory cytokines evaluated, interleukin-6 and -8 levels increased significantly during the perfusions. Hepatic necrosis was always present during the extracorporeal perfusions, followed a definite pattern and was inversely correlated with regeneration. Apoptosis did not increase over baseline levels. The meaning of these findings and their correlation with clinical outcomes during acute hepatic failures deserve further investigation.

Inter-observer variability in the histological assessment of colorectal polyps detected through the NHS Bowel Cancer Screening Programme.

AIMS: Although effective clinical management of colorectal polyps detected through the National Health Service (NHS) Bowel Cancer Screening Programme (BCSP) is dependent on the quality of pathological diagnosis, there have been few attempts to formally evaluate inter-observer variability in histological assessment. The aim of this study was to examine the impact of inter-observer variability on the reported prevalence of prognostic features in a large series of screen-detected colorectal polyps. METHODS AND RESULTS: A retrospective series of 1329 screen-detected polyps (2008-10) was identified from computerized records at two histopathology departments participating in the NHS BCSP. Slides from a sample of 239 polyps were exchanged between centres for independent review and measurement of inter-observer (kappa) agreement. There were significant between-centre differences in the prevalence of polyps with high-risk histological features. Diagnostic review demonstrated good reliability with respect to the assessment of adenomatous change (κ = 0.83), excision margin status (κ = 0.74), high-grade dysplasia (0.61) and invasive malignancy (κ = 0.84). By contrast, there were significant inter-observer differences in the classification of villous lesions (0.18) despite recent efforts to standardize reporting practice. CONCLUSIONS: Inter-observer variability in the assessment of screen-detected colorectal polyps limits the prognostic value of histological subtyping and highlights the need for clarification of existing diagnostic criteria.

Can reference images improve interobserver agreement in reporting liver fibrosis?

Staging of fibrosis in medical liver biopsies has inherent interobserver variability. There are a number of disease-specific scoring systems available. While recognising the importance of these scoring systems, there is scope to consider how concordance amongst histopathologists could be improved using a generic fibrosis staging system.Using virtual slides, we approached both specialist liver histopathologists and general histopathologists from the UK to assess the degree of fibrosis against a proposed four-tiered reporting system. Example reference images were then produced and distributed to the same responders who were asked to rate a second set of slides to assess if the use of reference images improved concordance between pathologists.The use of reference images eliminated spread across three categories (from 15% to 0%). Overall, agreement was already good; our study showed an improved agreement amongst all participants for percentage agreement (67.79% to 70.08%) and interobserver agreement improved (Fleiss' Kappa 0.55 to 0.59).

Molecular screening for colon cancer in inflammatory bowel disease.

Prophylactic colectomy is an established method of bowel cancer prevention in high-risk patients such as familial adenomatosis polyposis coli (FAP) and hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in patients with longstanding ulcerative colitis or Crohn's disease. The decision to perform such a major procedure cannot be made lightly, and issues of timing are important. In inflammatory bowel disease (IBD), the trigger to carry out colectomy usually relates to detection of dysplasia, well recognized to be a premalignant lesion. Screening methods are aimed at detection of precursor lesions or clinically occult malignancies. In current clinical practice, such screening methods are either resource intensive (e.g. colonoscopy and biopsy) or of low sensitivity and specificity (e.g. faecal occult blood testing). We discuss the development of screening techniques based upon molecular technologies and the limitations engendered by our incomplete understanding of the natural history and molecular biology of colorectal neoplasia in IBD.

Patterns of histological changes following hepatic electrolytic ablation in an ex-vivo perfused model.

Electrolytic ablation (EA) destroys the liver by releasing toxic radicles and producing modifications in the local pH without increasing the tissue temperature. We assessed the histological changes produced by EA using an ex-vivo perfused model. Five porcine livers were harvested, preserved in ice and reperfused for six hours in an extracorporeal circuit using autologous normothermic blood. One hour after reperfusion EA was performed and liver biopsies collected at the end of the experiments. The main necrotic zone consisted of coagulative necrosis, sinusoidal dilatation and haemorrhage with an unusual morphological pattern. The coagulative necrosis and haemorrhage affected mainly the peripheral area of the lobule with relative sparing of the area surrounding the centrilobular vein. Contrasting with this sinusoidal dilatation appeared to be more prominent in the centrilobular area. EA produces patterns of tissue destruction that have not been observed with the more commonly used thermal techniques. Further studies should obtain more information about the influence of adjacent biliary and vascular structures so that appropriate clinical trials can be designed.

Influence of hepatic parenchymal histology on outcome following right hepatic trisectionectomy.

BACKGROUND: Histological abnormalities in the non-tumour-bearing liver (NTBL) may influence outcome following hepatectomy. Effects will be most pertinent following right trisectionectomy but have yet to be specifically examined in this context. This study aimed to investigate the influence of perioperative factors, including NTBL histology, on outcome following right trisectionectomy. METHODS: Pathological review of the NTBL of 103 consecutive patients undergoing right trisectionectomy between January 2003 and December 2009 was performed using established criteria for steatosis, non-alcoholic steatohepatitis (NASH), sinusoidal injury (SI), fibrosis and cholestasis. Perioperative and pathological factors were correlated with post-operative outcome (morbidity, major morbidity, hepatic insufficiency and mortality). RESULTS: Morbidity, hepatic insufficiency and major morbidity occurred in 37.9 %, 14.6 % and 22.3 % of cases, respectively. Ninety-day mortality rate was 5.8 %. NASH (P = 0.007) and perioperative blood transfusion (P = 0.001) were independently associated with hepatic insufficiency following trisectionectomy. NASH (P = 0.028), perioperative transfusion (P = 0.016), diabetes mellitus (P = 0.047) and coronary artery disease (P = 0.036) were independently associated with major morbidity. Steatosis, SI, fibrosis and cholestasis in the NTBL demonstrated no association with any adverse outcome. CONCLUSION: NASH, but not steatosis or SI, is associated with adverse outcome following right trisectionectomy and caution must be exerted when considering major hepatectomy in patients with NASH.

Clinical outcome of atypical endometrial hyperplasia diagnosed on an endometrial biopsy: institutional experience and review of literature.

The aims of this study were: (1) to review the rate of concurrent endometrial cancer in patients with a preoperative diagnosis of atypical endometrial hyperplasia (AEH); and (2) to determine the features of concurrent endometrial carcinoma and their impact on the subsequent management of AEH. We reviewed a retrospective series of 219 AEHs diagnosed locally in routine practice, over 24 years, and followed by a repeat biopsy or hysterectomy. Another series of 65 cases with a malignant diagnosis on preoperative sampling was included as a control group. Clinicopathologic parameters were obtained. In addition, published data on the risk of malignancy and features of malignant tumors after a diagnosis of AEH were collected and analyzed. This study reported on 2571 patients diagnosed in 31 published studies in addition to the current one. This showed a wide variation in the positive predictive value (PPV) of AEH in detecting endometrial cancer (6% to 63%) with an overall PPV of 37%. This variation is not only based on the differences among studies but also on the degree of atypia [mild/moderate (PPV 13%) or severe (PPV 50%)], the type of subsequent intervention (biopsy vs. hysterectomy), and more importantly the time period of diagnosis (around 20% in studies published before 1990s and up to 40% to 48% in recently published cases). Of the benign outcome cases, nearly 40% to 50% showed AEH with a potential risk of progressing to invasive carcinoma in 25% of cases. Malignant tumors after AEH diagnosis are associated with features of good prognosis with endometrioid morphology, lower grade, and early stage. Although the overall PPV of AEH is 37%, a figure of 40% to 48% is expected in the cases currently diagnosed in routine practice. Providing qualifying criteria for AEH will help identify its different associated risks and therefore should be included in routine pathology reports whenever possible. Unless there is a clinical contraindication, hysterectomy should be performed to treat concurrent carcinoma and to reduce the risk of subsequent carcinoma in nonmalignant cases with residual AEH.

Histopathology training schools 4 years on.

The initial three pilot histopathology senior house officer schools have improved training efficiency and effectiveness. Additional schools have been established to develop a national network of histopathology training schools. Their success provides lessons for the organization and delivery of structured training in other medical specialties.