In many institutions, initial handling of bloody aspirates, which can be voluminous, entails expressing the specimen into preservative or fixative liquid media. Later recovery of cellular particles is achieved by either clotting or centrifugation.
We recently discovered a simple and effective alternative method for the initial handling of a large volume of blood...]]>
A patient with hypertension, ischaemic heart disease, atrial fibrillation and recurrent strokes was admitted for acutely worsening abdominal distension and breathlessness. There was a history of persistent abdominal distension and diarrhoea, which were treated conservatively. Endoscopy done had shown reflux oesophagitis, peptic ulceration and right-sided ischaemic colitis. Per-rectal examination revealed blood clots mixed with mucus. CT of the abdomen and pelvis showed no evidence of mesenteric vascular occlusion or masses.
The patient subsequently became hypotensive and underwent emergency laparotomy. Intraoperatively, ischaemic changes of left colon and patchy oedema of the mesentery were noted. Left hemicolectomy with colostomy was performed. Postoperatively, the patient was found...]]>
'Safety indicators' in the anticoagulant management of atrial fibrillation (AF) are listed in the UK NHS Improvement Document, ‘Anticoagulation for AF’, aiming to promote quality services. Acceptable clinical event rates are not quantified in the document.
To provide clinical evaluation of the relevant safety indicators using data from a recent large European Action on Anticoagulation (EAA) study.
469 clinical events were recorded in 5839 outpatients in the EAA study. The safety indicators listed in the NHS Improvement Document were related to these patients with AF. The relevance of the ‘safety indicators’ is confirmed by the EAA study for patients starting oral anticoagulation and for those already receiving oral anticoagulation, and quantified.
The EAA clinical study provides a quantitative basis for the safety indicators' in AF listed in the NHS Commissioning Support Document and emphasises the importance of the document.
Triple antibody cocktail immunohistochemical staining is routinely used as an ancillary method to establish a diagnosis of prostate cancer in biopsies with small foci of atypical glands. Crush artefact can distort surgical margins in radical prostatectomy specimens, occasionally making it difficult to diagnose a positive margin.
To investigate the ability of a cocktail stain to distinguish carcinoma from benign prostatic glands at the edge of crushed margins in prostatectomy specimens.
10 radical prostatectomy specimens with crushed benign glands at the surgical margins, and 20 with crushed margins positive for carcinoma were retrieved from the pathology archives. The latter included 16 (80%) with positive apical margins, 2 (10%) incised intraprostatic margins, and 1 (5%) soft tissue margin. Two-colour triple antibody stain using a cocktail of antibodies against α-methylacyl coenzyme A racemase (AMACR), high molecular weight keratin and p63 was performed on all the selected cases.
In 10/10 specimens with crushed benign glands, basal cell staining continued to be detectable, while AMACR staining was negative in all cases (0/10). In the positive margin cases, none of the crushed glands expressed basal cell marker staining (0/20), whereas 14/20 (70%) of the cases showed variable levels of AMACR positivity at the inked margin.
Two-colour triple antibody cocktail stain is useful in the assessment of most, but not all, surgical margins with crushed artefact in prostatectomy specimens by helping to establish whether glands are malignant or benign.
We had previously reported similar findings of primary ovarian mucinous carcinomas having the highest prevalence of HER2 genomic amplification and protein overexpression among the various EOC histological subtypes and had proposed that ovarian mucinous carcinomas represent a...]]>
The medical regulator in the UK, the General Medical Council, requires curricula and assessments for postgraduate training to be blueprinted to its regulatory statement, Good Medical Practice. A similar document, Tomorrow's Doctors (2009), covers undergraduate education and training. Good Medical Practice, originally designed to regulate medical practice, is not optimally worded as an educational document. The Royal College of Physicians and Surgeons of Canada's physician competency framework known as CanMEDS is designed with education more centrally in mind.
The wordings of Good Medical Practice and Tomorrow's Doctors (2009) were compared with CanMEDS using ‘word clouds’, a textual analysis tool which provides a display of word frequency, revealing the emphasis in the wording of documents.
Good Medical Practice places much greater emphasis on the regulatory rather than the educational aspects of medical practice when compared with CanMEDS and is therefore less suitable for blueprinting curricula, especially in disciplines with high science content such as pathology.
Good Medical Practice is less suitable for an educational role and the General Medical Council should consider developing a more specific educational document around these principles.
The TNM classification for renal cell cancer (RCC) should accurately predict and assign prognostic information for patients. In this study the recent 2010 revision to the TNM classification was compared with the previous 2002 classification with regard to survival outcomes.
All patients having radical nephrectomy for RCC in the 5-year period 2004–8 at a tertiary referral centre were included. Pathological and radiological records were reviewed to identify TNM stage (2002 and 2010 classification) and survival data were captured.
345 patients with RCC were identified. Based on the 2002 TNM staging system and using outcomes in T1 staged tumours as a baseline, statistically significant differences in disease-specific survival were noted between patients with T1 and T3b tumours (log rank p<0.001) but not between those with T1 and T3a tumours (p=0.33). However, when tumour stage was reassigned according to the 2010 classification, patients with T3a tumours were also found to do statistically worse than T1 staged disease (p<0.001).
In our cohort, the new 2010 TNM reclassification of T3 tumours showed better correlation with predicting worsening outcomes compared with localised disease.
The hereditary non-polyposis colorectal cancer (HNPCC) subset of tumours can broadly be divided into tumours caused by an underlying mismatch-repair gene mutation, referred to as Lynch syndrome, and those that develop in families with similar patterns of heredity but without disease-predisposing germline mismatch repair mutations, referred to as familial colorectal cancer type X (FCCTX). Recognition of HNPCC-associated colorectal cancers is central since surveillance programmes effectively reduce morbidity and mortality. The characteristic morphological features linked to Lynch syndrome can aid in the identification of this subset, whereas the possibility to use morphological features as an indicator of FCCTX is uncertain.
To perform a detailed morphological evaluation of HNPCC-associated colorectal cancers and demonstrate significant differences between tumours associated with FCCTX and Lynch syndrome.
The morphological features associated with Lynch syndrome, that is, right-sided tumour location, poor differentiation, expansive growth pattern, tumour-infiltrating lymphocytes, peritumorous lymphocytes, Crohn-like reactions, and lack of dirty necrosis, were significantly less often observed in FCCTX tumours.
The less typical morphology in FCCTX implies that family history of cancer needs to be taken into account since these tumours cannot readily be recognised based on histopathological features.
Electron microscopy (EM) remains essential to delivering several specialist areas of diagnosis, especially the interpretation of native renal biopsies. However, there is anecdotal evidence of EM units struggling to survive, for a variety of reasons. The authors sought to obtain objective evidence of the extent and the causes of this problem.
An online survey was undertaken of Fellows of the Royal College of Pathologists who use EM in diagnosis.
A significant number of EM units anticipate having to close and hence outsource their EM work in the coming years. Yet most existing units are working to full capacity and would be unable to take on the substantial amounts of extra work implied by other units outsourcing their needs. Equipment and staffing are identified by most EM units as the major barriers to growth and are also the main reasons cited for units facing potential closure.
In the current financial climate it seems unlikely that units will be willing to make the large investment in equipment and staff needed to take on extra work, unless they can be reasonably confident of an acceptable financial return as a result of increased external referral rates. The case is thus made for a degree of national coordination of the future provision of this specialist service, possibly through the National Commissioning Group or the new National Commissioning Board. Without this, the future of diagnostic EM services in the UK is uncertain. Its failure would pose a threat to good patient care.
Increased β-oxidation of branched-chain fatty acids provides an additional metabolic advantage for cancer cells thereby enhancing tumour development and progression. Alpha-methylacyl coenzyme A racemase (AMACR) is an enzyme essential for the catabolism of branched-chain fatty acids that allows their subsequent β-oxidation and thus plays an important role in generating biological energy. However, the expression of AMACR has never been systemically investigated in gallbladder carcinoma. This study evaluated the expression status, associations with clinicopathological variables and prognostic implications of AMACR in a well-defined cohort of gallbladder carcinoma and confirmed their expression status in gallbladder carcinoma cells.
AMACR immunostaining was assessable in 89 cases on tissue microarrays of gallbladder carcinoma, and it was correlated with clinicopathological factors and patient survival. In three gallbladder carcinoma cell lines and one non-tumorigenic cholangiocyte, AMACR mRNA expression was measured by real-time reverse transcription PCR and the endogenous expression of AMACR protein was analysed by western blotting.
AMACR overexpression was significantly associated with an advanced primary tumour status (p=0.027) and American Joint Committee on Cancer stage (p=0.027), an increased histological grade (p=0.002) and vascular invasion (p=0.017). Importantly, AMACR overexpression independently predicted worse disease-specific survival (p=0.0452, RR 1.887). Expression levels of AMACR mRNA and total protein in various cells were comparable. The abundance of AMACR expression increased in tumour cells and was even higher in the metastatic cell line.
In primary gallbladder carcinoma, AMACR overexpression was correlated with important prognosticators and independently portended worse outcomes, highlighting the potential prognostic and therapeutic utility of AMACR in gallbladder carcinoma.
Well-differentiated follicular thyroid carcinoma usually has a favourable prognosis and metastases are rare. Toll-like receptors (TLRs) that take part in adaptive and innate immunity have, in many tumours, both apoptotic and antiapoptotic effects, making their role in tumourigenesis controversial. Chronic inflammation is involved in many cancers.
To examine the clinical relevance of TLR-2, TLR-4, and CD45 in follicular thyroid neoplasias.
The authors studied the immunohistochemical expression of TLR-2 and TLR-4 in 127 follicular thyroid neoplasms, both in adenomas and in carcinomas including oxyphilic tumours. Their degree of chronic inflammation was evaluated by a count of CD45-positive lymphocytes within and adjacent to the tumourous tissue.
Both high TLR-4 expression and lack of TLR-4 expression in carcinomas were associated with metastatic and aggressive disease. In oxyphilic tumours, both in adenomas and in carcinomas, TLR-4 expression was significantly stronger. TLR-2 expression was stronger in adenomas than in carcinomas but without any correlation with clinical variables. Degree of chronic inflammation outside the primary tumour was lower for metastasized carcinomas than for non-metastasised carcinomas.
Varying expression of TLR-4 and lack of inflammation are indicators of aggressive disease among follicular thyroid cancer.
Lymphoepithelioma-like carcinoma (LELC) of the liver is extremely rare. To our knowledge, only 16 cases of pure LELC or LELC with ordinary adenocarcinoma arising in the hepatobiliary tract have been reported in the English literature.
After reviewing 207...]]>
The book is divided into 10 anatomical sections: nasal cavity and paranasal sinuses, pharynx (nasal, oro-, hypo-), larynx and trachea, oral cavity, salivary glands, jaw, ear and temporal bone, neck (soft tissue and lymph nodes), thyroid gland and parathyroid glands along with an antibody index. These sections are subdivided into their...]]>
Dicer and Drosha are components of the miRNA-producing machinery and their altered expression may play a role in cancer progression. The main purpose of this study was a detailed investigation of Dicer and Drosha expression and localisation in triple-negative breast cancers.
Thirty-one triple-negative breast cancers and several breast cancer cell lines were investigated. Expression of Dicer and Drosha was evaluated at the mRNA level by quantitative reverse transcription PCR and at the protein level by immunohistochemistry or western blot.
Compared with normal breast tissues, a wide variation of Dicer and Drosha mRNA levels was detected in triple-negative breast cancers. As a group, Drosha mRNA levels in triple-negative breast cancers were significantly higher than those in normal breast tissues. Immunohistochemical data confirmed higher expression of Drosha protein in triple-negative breast cancers. In normal breast tissues Dicer was detectable predominantly in the cytoplasm of basal/myoepithelial cells only. In contrast, in the majority of triple-negative breast cancers, intense Dicer staining was detectable also in the nuclear compartment. Detection of Dicer and Drosha mRNA and protein levels in breast cancer cell lines confirmed the nuclear localisation of Dicer, suggesting, in addition, that the steady-state protein levels could be controlled by post-mRNA regulatory events.
These findings indicate that Dicer and Drosha expression is deregulated in triple-negative breast cancers.
Recent studies have shown that phosphorylation of p120-catenin (p120) promotes progression and invasion of oral squamous cell carcinoma (OSCC) cells. The objective of the current study was to evaluate the usefulness of phosphorylated p120-catenin (pp120) as a biomarker for predicting clinical behaviour in the carcinogenesis of potentially malignant oral lesions.
In a retrospective follow-up study, the expression pattern of pp120 protein was determined using immunohistochemistry in samples from 68 patients with potentially malignant oral lesions, including patients with untransformed lesions (n=38) and patients with malignant transformed lesions (n=30). Analysis of corresponding post-malignant lesions (OSCCs) was also performed.
There was high expression of pp120 in 35 of 68 (51.5%) of general potentially malignant oral lesions and 23 of 30 (76.7%) of OSCCs compared with expression in normal oral mucosa. Kaplan–Meier analysis revealed that patients with potentially malignant oral lesions expressing high levels of membranous pp120 had a significantly higher incidence of OSCC than those expressing low expressing pp120 (p=0.002; log-rank test). Cox regression analysis revealed that this pp120 expression pattern was significantly associated with a 3.43-fold increase in the risk of malignant progression (p=0.007). In addition, there was a significant correlation between high levels of membranous expression of pp120 in pre-malignant lesions and cytoplasmic expression in post-malignant lesions (p=0.028).
The data indicated that a high level of membranous expression of pp120 in potentially malignant oral lesions is an early event during oral carcinogenesis, and that the mislocalisation of expression of pp120 from the cell membrane to the cytoplasm is associated with oral cancer progression. pp120 may serve as a useful marker for the identification of a high risk of potentially malignant oral lesions progressing to OSCC.
To determine the frequency, pattern and distribution of stromal keratin expression in phyllodes tumours if any, which may impact diagnostic approaches.
The clinicopathological features of 109 phyllodes tumours comprising 70 (64.2%) benign, 30 (27.5%) borderline and nine (8.3%) malignant grades were evaluated, and the immunohistochemical expression of a keratin panel (MNF116, 34βE12, CK7, CK14, AE1/3, Cam5.2), p63 and CD34 in their stromal component was assessed.
There was focal and patchy cytoplasmic keratin staining in 1–5% of stromal cells in 13 (11.9%), 24 (22%), 31 (28.4%), 2 (1.8%), 9 (8.3%) and 2 (1.8%) cases for MNF116, 34βE12, CK7, CK14, AE1/3, Cam5.2, respectively. CD34 was expressed in 79 (72.5%) cases. There was no stromal staining for p63. Stromal MNF116, 34βE12 and Cam5.2 reactivity was significantly associated with phyllodes tumour grade (p=0.027, p=0.034, p=0.009 respectively), while MNF116 stromal staining was observed in tumours with increasing cellularity (p=0.036), necrosis (p=0.015) and cystic change (p=0.048). Contrary to common understanding, these findings confirm that stromal cells in phyllodes tumours can sometimes express keratins, albeit focal and in a patchy distribution. In comparison, fibromatosis and dermatofibrosarcoma were uniformly negative for the same keratin panel, while spindle cell components of eight metaplastic carcinomas expressed at least two or more keratins in a wider distribution of up to 90% of positively stained spindle cells. All eight spindle cell sarcomas were negative for keratins.
The use of keratins as an adjunctive immunohistochemical diagnostic tool in the differential work-up of spindle cell tumours of the breast has to be interpreted with caution especially on limited core biopsy material.
A 73-year-old woman who presented with anaemia and gastroscopy revealed a 30 mm firm ulcer with raised edges at the lesser curve of the stomach. A CT scan revealed features within the ulcer that were suspicious for malignancy. She was treated with a proton pump inhibitor and sucralfate but the ulcer failed to heal over a 1-year period. Three sets of biopsies from the ulcer edge during this time revealed benign changes only. There was no history of non-steroidal anti-inflammatory drug usage and urinary salicylate estimation was negative. The serum gastrin concentration was not raised. Her medical history included insulin-dependent diabetes mellitus and ischaemic heart disease. There was no history of a systemic inflammatory disorder. Due to the continued concern of occult malignancy she proceeded to laparotomy with partial gastrectomy, after which she made an uneventful recovery.
Macroscopic examination of the resection specimen revealed a 30 mm mucosal ulcer with slightly raised...]]>
Mucinous adenocarcinoma (MAC) of the colorectum has been known and studied for many years. The prognostic significance of this histological subtype remains controversial. The authors reviewed the prognostic significance of mucinous differentiation in colorectal cancer.
A systematic web-based search was performed using Web of Knowledge and Medline. Articles published in English, German or French which used the WHO definition of MAC and described cohort studies, case–control studies or cross-sectional studies comparing survival in patients with MAC and adenocarcinoma (AC) not otherwise specified were included. Data on first author, year of publication, country, number of patients included, prevalence of MAC, % stage IV disease, % disease located in the proximal colon, mean age at presentation, % male patients and 5-year overall survival were extracted from individual studies. A fixed-effects meta-analysis model was used for analysis. The primary outcome was survival, expressed as the HR. Differences between categorical outcome parameters were quantified using the RR and corresponding 95% CI.
44 studies and 222 256 patients were included. The RR for proximal disease versus distal disease was 1.55 (95% CI 1.53 to 1.58). Mucinous differentiation was less frequent in male subjects (RR 0.93 (95% CI 0.91 to 0.94)). Interestingly, the prevalence of stage IV disease was similar in MAC and AC (RR 0.99 (95% CI 0.96 to 1.02)). Thirty-five articles were included in the survival analysis. A worse survival in MAC versus AC was demonstrated (HR 1.05 (95% CI 1.02 to 1.08)). Conversely, three out of four studies reported a better survival in MAC with microsatellite instability (MSI). Due to heterogeneity a meta-analysis on the effect of MSI was not possible.
MAC more often originates from the right colon and is less frequent in male subjects. The authors did not identify a difference in the proportion of stage IV patients at presentation. Mucinous differentiation results in a 2–8% increased hazard of death, which persists after correction for stage. More research is needed to define the interaction between mucinous differentiation, MSI and outcome.
Isolated aortitis (IA) is a newly recognized condition, but its differentiation from Takayasu arteritis (TA) is still a challenge. This study aims to explore the characteristics of IA.
The clinical and pathological data of 965 cases with excised ascending aortas were obtained by chart and slide review. IA cases were compared with TA cases and examined for CD3, CD4, CD8, CD20, CD68, CD138 and IgG4 of the infiltrates using immunohistochemistry.
24 cases of IA and eight cases of TA were identified. IA cases tended to be older than TA cases (mean 46.3 vs 33.9 years). Both groups had the same male/female ratio (1.0). IA cases tended to have a bigger aortic diameter (mean 59.7 vs 47.6 mm), statistically less intimal thickening (mean 678 vs 1101 μm), fewer lesions outside the ascending aorta (8% vs 100%), a lower erythrocyte sedimentation rate (mean 14.6 vs 27.0 mm/h) and more active aortitis (75.0% vs 62.5%) than TA cases. The number of CD3+ cells was equal to CD20+ cells in the media but fewer than CD20+ cells in the adventitia of IA cases. Their CD4/CD8+ ratio ranged from 1.0 to 1.8 while the number of CD68+ macrophages varied largely. IgG4+ cells ranged from 0 to 40 (mean 4) cells/HPF and the IgG4+/CD138+ ratio ranged from 0 to 0.36 (mean 0.06) in IA cases.
Cases of IA tend to have more histologically active inflammation except for a relatively normal erythrocyte sedimentation rate, localised lesions and milder intimal fibrosis than cases of TA. IgG4 abnormality may not be the main cause of IA.
Acinar cell carcinomas (ACCs) are rare tumours of the exocrine pancreas accounting for about 1–2% of all pancreatic neoplasms in adults. It is therefore difficult to come across a large number of ACC cases in a single medical institution, and only a few serial studies have been published. Since ACCs present a wide variety of morphological patterns, immunohistochemical analysis is useful. In this study, the authors established a novel monoclonal antibody 2P-1-2-1 by means of a subtractive immunisation method.
Immunohistochemical staining was performed using 50 primary pancreatic tumors, including 7 ACCs, 7 neuroendocrine tumours (NETs), 5 solid-pseudopapillary neoplasms (SPNs), and 31 ductal carcinomas and organs other than the pancreas.
Non-neoplastic acinar cells were stained diffusely, but epithelial cells of the pancreatic duct and the islets of Langerhans were not stained. In pancreatic tumours, all the seven ACCs were diffusely positive for the 2P-1-2-1 antibody. However, no positive staining was found in other pancreatic tumours including NETs, SPNs and ductal adenocarcinomas. The sensitivity and specificity of the 2P-1-2-1 antibody for ACCs were both 100%. In other organs studied, positive staining was observed only in the ectopic pancreas.
It was shown that the 2P-1-2-1 antibody specifically stained the pancreatic acinar cells and tumours of acinar cell origin, such as ACCs. Although it remains unclear at this time to which proteins the monoclonal antibody 2P-1-2-1 is directed, it is suggested to be useful for the pathological diagnosis of ACCs and for the exclusion of other pancreatic tumours.
Animal data suggest that Toll-like receptors (TLR) may play an important role in colon carcinogenesis. Studies in humans to support that hypothesis are scarce.
To evaluate the expression of TLR2, TLR4 and TLR5, and the expression of several other related molecules, in different human colonic lesions.
Colon biopsy samples from normal mucosa, normal mucosa adjacent to lesion, adenoma or sporadic carcinoma were obtained from 35 consecutive patients undergoing colonoscopy. Quantification of TLR2, TLR4, TLR5, Toll-interacting protein (TOLLIP), peroxisome proliferator-activated receptor (PPAR-), nuclear factor B, tumour necrosis factor (TNF) α, cyclooxygenase (COX) 1 and 2 mRNA was performed by real-time reverse transcription PCR. TLR2, TLR4 and TLR5 protein expression was quantified by immunohistochemistry.
When compared with normal mucosa (1.0 arbitrary unit (AU)), adjacent normal mucosa presented higher expression of COX-2 (1.86±0.3 AU, p=0.01) and TNFα (1.44±0.18 AU, p=0.04) and lower TOLLIP expression (0.75±0.05 AU, p=0.004). Adenomas and carcinomas presented higher expression of COX-2 (1.63±0.27 and 1.38±0.14 AU, p=0.03 and p=0.05, respectively) and lower expression of TOLLIP (0.44±0.04 AU, p<0.001), with diffuse and higher TLR protein expression (p<0.001). Carcinomas also expressed higher TLR2 (2.31±0.32 AU, p=0.006) and lower PPAR- (0.56±0.12 AU, p=0.003). There was a trend towards decreased TOLLIP (p<0.001) and PPAR- (p=0.05) from normal mucosa to adenoma/carcinoma.
Persistently positive TLR expression and lower expression of TLR inhibitors was associated with higher TLR protein levels throughout the spectrum of lesions of colon carcinogenesis. Increasing activation of these receptors by bacteria may play a crucial role in colon carcinogenesis and tumour progression.
Pleomorphic adenoma (PA) is the most common salivary gland tumour. Although classified as benign, it has a tendency to recur (recurrent pleomorphic adenomas (RPA)), as well as the ability to undergo malignant transformation. It has been suggested that mutations in various families of growth factors and growth factor receptions are involved in the autonomous growth of tumour cells. The aim of the present study was to investigate the participation of platelet-derived growth factor (PDGF)-A, PDGF-B, PDGF-Rα, fibroblast growth factor (FGF)-2, Flg and BEK in PA, RPA and recurrent pleomorphic adenoma with malignant transformation (TRPA).
18 cases of PA, 16 cases of RPA and two cases of RPA with focal malignant transformation (TRPA) were analysed for growth factor expression utilising immunohistochemical techniques via tissue microarray.
There was a significant difference in PDGF-A, PDGF-B, PDGF-Rα, FGF-2, Flg and BEK expression in all groups. When comparing non-recurrent with recurrent tumours, PDGF-A, PDGF-B, PDGF-Rα, FGF-2, Flg and BEK reactivity in RPA was stronger than that observed in PA. All proteins were highly expressed in TRPA.
This research suggests that PDGF-A, PDGF-B, PDGF-Rα, FGF-2, BEK and Flg can be related to the recurrence of PA. In addition, this study shows that TRPA cells overexpress all growth factors, which has been reported in association with the malignant transformation.
To study and compare the anatomical and clinical pathology of first ribs in patients with Paget–Schroetter Disease (PSD) with first ribs in patients without the disease.
In a case–control study, normal human cadaver first ribs were compared with first ribs from patients with PSD. Ribs, intraoperative videos of transthoracic en bloc surgical resection of the first rib, and preoperative and postoperative dynamic upper extremity venograms were reviewed.
Fifteen first ribs were from patients with PSD and seven normal first ribs were from human cadavers. In all patients (100%) with PSD there was a bony tubercle that corresponded to the area of the subclavian vein groove in the normal ribs. In all controls (100%), there was a normal subclavian groove without the presence of a tubercle. On preoperative venograms in patients with PSD, the tubercle accounted for an extrinsic protuberance that compressed the subclavian vein (100%). Intraoperatively, the abnormal bony tubercle accounted for the extrinsic compression of the subclavian vein in all (100%) patients with PSD. Venograms of the upper extremity obtained after first rib resection showed the disappearance of the extrinsic compression on the subclavian vein (100%) and a patent subclavian vein with elevation of the arm in all patients.
A bony tubercle at the site of the subclavian vein groove in patients with PSD causes extrinsic compression of the subclavian vein at rest.
To evaluate the role of p53, p21 and cyclin D1 expression in patients with penile cancer (PC).
Paraffin-embedded tissues from PC specimens from six pathology departments were subjected to a central histopathological review performed by one pathologist. The tissue microarray technique was used for immunostaining which was evaluated by two independent pathologists and correlated with cancer-specific survival (CSS). -statistics were used to assess interobserver variability. Uni- and multivariable Cox proportional hazards analysis was applied to assess the independent effects of several prognostic factors on CSS over a median of 32 months (IQR 6–66 months).
Specimens and clinical data from 110 men treated surgically for primary PC were collected. p53 staining was positive in 30 and negative in 62 specimens. -statistics showed substantial interobserver reproducibility of p53 staining evaluation (=0.73; p<0.001). The 5-year CSS rate for the entire study cohort was 74%. Five-year CSS was 84% in p53-negative and 51% in p53-positive PC patients (p=0.003). Multivariable analysis showed p53 (HR=3.20; p=0.041) and pT-stage (HR=4.29; p<0.001) as independent significant prognostic factors for CSS. Cyclin D1 and p21 expression were not correlated with survival. However, incorporating p21 into a multivariable Cox model did contribute to improved model quality for predicting CSS.
In patients with PC, the expression of p53 in the primary tumour specimen can be reproducibly assessed and is negatively associated with cancer specific survival.
Bile duct changes in the form of intraepithelial neoplasia or dysplasia have been well studied in chronic biliary tract diseases. It is important to analyse the morphologic spectrum of bile duct changes in non-biliary diseases as a link has been reported between intrahepatic cholangiocarcinoma and chronic liver disease associated with viral hepatitis, metabolic syndromes and with alcohol abuse.
The authors retrospectively reviewed liver explants of alcoholic liver disease (ALD)-, hepatitis C virus- and non-alcoholic fatty liver disease-related end-stage liver diseases to analyse morphologic changes in large intrahepatic bile ducts. Diagnostic criteria of biliary intraepithelial lesions at end-stage disease are discussed.
Majority of explants exhibited reactive changes. Normal cuboidal epithelium of septal bile ducts was observed in minority of cases. Low-grade biliary intraepithelial neoplastic lesions were identified in all cases with variable frequency. None of the cases were associated with cholangiocarcinoma. Nuclear hyperchromasia, cellular polarity and presence o inflammation were considered as differentiating points between reactive and neoplastic lesions.
At end stage of liver disease, large septal bile ducts rarely show normal morphology. Presence of low-grade biliary dysplasia at end stage signifies its frequent occurrence probably in response to alcohol/viral/metabolic syndrome-related injury.
Observational analysis of large bile ducts in non-biliary diseases of varied aetiology has not been discussed from this part of world where incidence of cholangiocarcinoma is low. Identifying these lesions correctly is important. The frequency of these lesions is not uncommon especially at the end-stage liver disease.
PAX8 is a cell lineage-specific transcription factor which plays a crucial role in the organogenesis of the kidney, thyroid gland and Müllerian duct. A previous study showed that PAX8 is a specific and sensitive marker for both renal and ovarian carcinomas. The purpose of this study is to investigate PAX8 expression using a new monoclonal PAX8 antibody in a larger number of renal epithelial neoplasms including clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma and renal oncocytoma.
PAX8 immunohistochemical staining was performed on tissue microarrays containing 84 cases of clear cell renal cell carcinoma, 66 cases of chromophobe renal cell carcinoma, 57 cases of papillary renal cell carcinoma and 16 cases of renal oncocytoma.
PAX8 expression was detected in 93% (78/84) of cases of clear cell renal cell carcinoma, 80% (53/66) of cases of chromophobe renal cell carcinoma, 95% (54/57) of cases of papillary renal cell carcinoma and 94% (15/16) of cases of renal oncocytoma.
PAX8 is expressed in the majority of renal epithelial neoplasms including renal cell carcinomas and oncocytomas and the monoclonal PAX8 antibody is more sensitive than polyclonal antibody to detect chromophobe renal cell carcinoma. These results showed that PAX8 is a valuable marker for nephric neoplasms.
Current guidelines for the investigation of sudden unexpected death in infancy (SUDI) include full neuropathological examination with recommendations for brain fixation for 1–2 weeks. Little evidence is available regarding the yield of such examination in determining cause of death in clinical practice. This study examines the frequency of neuropathological findings determining cause of death at postmortem examination in SUDI in relation to clinical and macroscopic features.
All postmortem examinations performed for the indication of SUDI at a single specialist centre over a 14-year period were reviewed, including clinical history, macroscopic and neuropathological findings.
6% of postmortem examinations performed for cases of SUDI demonstrated a neuropathological cause of death; in almost all (>90%) the clinical history and/or macroscopic examination suggested the cause of death. In 2% of all cases the cause of death was determined by histological neuropathological examination, but there were no cases in which histological neuropathological examination of a macroscopically normal brain revealed the cause of death in the absence of a ‘neurological history’. Macroscopic brain abnormalities and the presence of a ‘neurological history’ were significantly more likely to yield histological brain abnormalities (11-fold and fourfold, respectively).
Histological neuropathological examination rarely determines the cause of death in SUDI in the absence of macroscopic abnormalities or neurological clinical history. A macroscopically abnormal brain and the presence of a clinical history of possible neurological disease or of inflicted injury are significantly more likely to be associated with significant histological brain abnormalities.
The examination of ciliary ultrastructure in a nasal sample remains a definitive diagnostic test for primary ciliary dyskinesia (PCD).
The quantitative assessment of ciliary ultrastructure in the diagnosis of PCD over a 20-year period was reviewed.
During this period, 1182 patients were referred for ciliary ultrastructural analysis, 242 (20%) of whom were confirmed as having the disease. The two main causes of PCD identified were a lack of outer dynein arms (43%) and a lack of both inner and outer dynein arms (24%). Other causes included transposition, radial spoke and inner dynein arm defects. No specific ultrastructural defects were detected in 33 patients (3%) diagnosed as having PCD on the basis of their clinical features and screening tests that included a low nasal nitric oxide concentration or slow saccharine clearance and abnormal ciliary beat frequency or pattern.
Electron microscopy analysis can confirm but does not always exclude a diagnosis of PCD.
Epidermal growth factor receptor (EGFR) gene copy number evaluated by fluorescence in situ hybridisation (FISH) can discriminate among KRAS wild-type patients those with better outcome to EGFR-targeted therapy in metastatic colorectal cancer, further enhancing selection of patients. Nevertheless, enumeration of gene copies is challenging and the lack of analytical standardisation has limited incorporation of the test into the clinical practice. We therefore assessed EGFR FISH interlaboratory consensus among five molecular diagnostic reference centres.
A set of 12 colorectal cancer samples circulated among laboratories, and samples were scored according to commonly agreed guidelines. Reproducibility was quantified using the standard error of measurement (SEM).
A SEM of 0.865 and a within-subject coefficient of variation (WSCV) of 26.8% for mean EGFR gene/nuclei and a SEM of 0.235 and a WSCV of 19.4% for the mean EGFR gene/CEP7 ratio were observed. Measurement of the fraction of cells displaying chromosome 7 polysomy showed WSCV of 46.6%, 34.0% and 51.0% for percentage of cells displaying ≤2, ≥3 and ≥4 EGFR signals, respectively. Among different slides of the same specimen, the WSCV was 6.1% for mean EGFR gene/nuclei and 3.9% for mean of EGFR gene/CEP7 ratios.
Molecular diagnosis of EGFR gene copy number by FISH varied largely among pathology centres, with fluctuations covering the whole range of proposed cut-offs of predictive usefulness from literature. Definition of a detailed scoring system and implementation of comprehensive training programmes for laboratories are therefore necessary before including the test into clinical practice.
Fascin is an actin-binding protein that potentiates migratory and invasive behaviour in neoplastic cells and has been shown to be upregulated in various malignancies. In this study fascin expression was assessed in adenocarcinoma in situ (ACIS) and invasive adenocarcinoma of the endocervix, and the results were correlated with tumour growth patterns (papillary, glandular or infiltrative).
Fascin immunoreactivity was assessed in 10 cases of ACIS and in 34 cervical adenocarcinomas, 15 of which also included an in situ component. Staining within normal epithelium and stromal elements was also noted.
Normal endocervical epithelium and 23/25 ACIS lesions were fascin-negative. Most invasive tumour elements were also unstained but 13/32 adenocarcinomas that exhibited a glandular growth pattern showed focal fascin immunoreactivity mainly towards the basal aspect of the larger tumour glands. These fascin-positive cells often showed a morphological alteration similar to that seen in infiltrative tumour areas. None of the papillary tumour elements, present in 12 cases, was fascin-positive. Twenty adenocarcinomas included a focal infiltrative component, often distributed at the advancing or deep tumour margin (invasive front), and these tumour cells were usually fascin-positive. Staining was also observed in normal parabasal squamous cells, endothelial and dendritic cells.
Novel fascin expression occurs during the development and progression of some endocervical neoplasms. Fascin immunoreactivity within infiltrative neoplastic elements suggests that this protein may have an important role in areas of active tumour invasion.
One problem encountered by the authors in their analysis of archival paraffin-embedded tumour tissues was that these frequently showed low-level contamination with Y chromosomal material and therefore it was necessary to use a relative quantitative PCR technique to establish reliable cut-off values between genuine and spurious levels of Y chromosome content. Although this...]]>
The size of the clonal field is crucial to support the leap from monotypy at an X-inactivation assay to monoclonality, as a large clonal field size may confound assessment of tumour clonality with X-inactivation assays.
Another important caveat perpetuated is that all neoplasias are clonal. At present, all the definite evidence is on the side of polyconal tumour origin. Colon tumours, for example, have been proved...]]>
Deregulated chromatin remodelling often leads to aberrant gene expression in cells, thereby implicating tumour development and progression. As a subunit of remodelling and spacing factor complex, Rsf-1 (HBXAP), a novel nuclear protein with histone chaperon function, mediates ATPase-dependent chromatin remodelling and confers tumour aggressiveness in common carcinomas. However, the expression of Rsf-1 has never been reported in nasopharyngeal carcinoma (NPC). This study aimed at evaluating the expression status, associations with clincopathological variables and prognostic implications of Rsf-1 in a well-defined cohort of NPC.
Rsf-1 immunoexpression was retrospectively assessed in biopsies of 108 consecutive NPC patients without initial distant metastasis and treated with consistent guidelines. The results were correlated with the clinicopathological features, therapeutic response, local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and disease-specific survival (DSS).
Present in 49 cases (45%), Rsf-1 overexpression was associated with N2,3 status (p=0.016), American Joint Committee on Cancer stage 3, 4 (p=0.004), and incomplete therapeutic response (p=0.041). In multivariate analyses, Rsf-1 overexpression not only emerged as the sole independent adverse prognosticator for LRFS (p=0.0002, RR 5.287) but also independently predicted worse DMFS (p=0.0011, RR 3.185) and DSS (p<0.0001, RR 4.442), along with T3,4 (p=0.0454) and N2,3 (p=0.0319), respectively.
Rsf-1 overexpression is common and is associated with adverse prognosticators and therapeutic response, which confers tumour aggressiveness through chromatin remodelling, and represents a potential prognostic biomarker in NPC.
A persistent problem in gynaecological differential diagnosis is the differentiation of primary ovarian mucinous carcinoma from metastatic disease either in the ovary or disseminated throughout the abdomen and pelvis from extragenital organs. Traditionally, there has been a tendency to vary treatment depending on a perception of origin in the ovary, secondary müllerian system
Further, the distinction between a primary ovarian mucinous carcinoma arising in either the background of borderline change or as a carcinoma within a teratoma, although admittedly both are unusual, and a metastasis, for example, from a bowel...]]>
The biomarkers representing the metastatic potential of well-differentiated thyroid carcinoma remain to be established. A study was undertaken to find whether the expression status of neural cell adhesion molecule (NCAM) and/or ovarian cancer immunoreactive antigen domain containing 1 (OCIAD1) is associated with the metastatic potential of differentiated thyroid carcinoma.
NCAM and OCIAD1 were analysed by immunohistochemistry on tissue microarrays.
Among 214 well-differentiated thyroid carcinomas, 68 patients had distant metastases. Immunohistochemical analyses showed that the majority of benign thyroid lesions expressed NCAM while a significant proportion of thyroid carcinomas lost or had reduced NCAM expression. Both follicular and papillary carcinomas with distant metastasis had a significantly higher frequency of preserving NCAM expression. Hierarchical clustering analysis showed that OCIAD1 had significant differential expression between benign and malignant thyroid lesions. The overall metastatic-to-localised tumour ratio was higher in NCAM-expressing clusters, but the difference between ratios of OCIAD1-positive and OCIAD1-negative subclusters was not significant.
These analyses suggest that the preservation of NCAM expression in well-differentiated thyroid carcinoma is an indicator for a higher risk of distant metastasis. OCIAD1 is a potential biomarker of thyroid carcinoma but had no significant additive effect on the risk of distant metastasis. Further elucidation of the molecular mechanisms underlying the NCAM-mediated cellular processes will be beneficial for the development of effective treatments against the metastasis of thyroid carcinoma.
Coeliac disease (CD) diagnosis requires the detection of characteristic histological alterations of small bowel mucosa, which are prone to interobserver variability. This study evaluated the agreement in biopsy interpretation between different pathology practice types.
Biopsies from community hospitals (n=46), university hospitals (n=18) and commercial laboratories (n=38) were blindly assessed by a pathologist at our institution for differences in histopathology reporting and agreement in diagnosis of CD and degree of villous atrophy (VA) by analysis.
Agreement for primary diagnosis was very good between this institution and university hospitals (=0.888), but moderate compared with community hospitals (=0.465) or commercial laboratories (=0.419). Diagnosis differed in 26 (25%) cases, leading to a 20% increase in CD diagnosis after review. Among those diagnosed with CD by both institutions (n=49), agreement in degree of VA was fair (=0.292), with moderate agreement between the authors and commercial laboratories (=0.500) and fair with university hospitals (=0.290) or community hospitals (=0.211). The degree of VA was upgraded in 27% and downgraded in 2%. Within different Marsh score categories, agreement was poor (<0.0316) for scores 1 and 2, both missed at other centres, and fair or moderate for scores 3a and 3b. Information regarding degree of VA and intraepithelial lymphocytosis was lacking in 26% and 86% of reports and non-quantifiable descriptors, eg, ‘blunting’ or ‘marked atrophy’ were prevalent.
CD-related histological changes are underdiagnosed in community-based hospitals and commercial pathology laboratories. Because incorrect biopsy interpretation can cause underdiagnosis of CD, greater CD awareness and uniformity in small bowel biopsy reporting is required among pathologists.
To investigate HER2 status in a cohort of 109 gastric adenocarcinomas also including unusual variants, such as 14 hepatoid (HAS) and 9 mitochondrion-rich (MRC), characterised by an opposing clinical behaviour.
Using HercepTest (DAKO) and FISH test (pharmDx DAKO), HER2 overexpression/amplification was encountered in 23 of 109 (21.10%) of all gastric adenocarcinomas. A progressive increase in HER2 overexpression was observed moving from the poorly cohesive histotype to MRC, tubular adenocarcinomas and HAS. A statistically significant difference was found between poorly cohesive carcinomas and the others; a similar significant difference was encountered between HAS and all other variants of adenocarcinoma. HER2 overexpression was significantly associated with high grade, advanced stage, high Ki-67 labelling index value and death from gastric cancer. Multivariate analysis identified HER2 overexpression as an independent unfavourable prognostic variable for adenocarcinomas as a whole and also for the HAS variant.
Trastuzumab has been confirmed as an additional useful therapeutic standard option for patients with HER2-positive advanced gastric cancers, and also in aggressive variants of adenocarcinomas such as HAS.
Classically it presents in young men with acroparasthesia, skin phenomena (angiokeratoma and hypohydrosis), gastrointestinal symptoms and renal failure.
Breast-conserving surgery currently focuses on improving margin clearance and excision volume, the main pathology report parameters for oncological and cosmetic outcomes.
To quantitatively evaluate discrepancies in surgical and pathological estimates of breast specimen sizes, including the influence of formalin fixation.
This prospective multicentre study included 68 breast specimens of consecutive patients undergoing breast-conserving surgery for breast cancer in three affiliated hospitals between November 2010 to May 2011. Specimens were weighed immediately after excision. Specimen volumes were calculated from the length, width and height. Actual specimen volumes were measured using volume displacement. Specimens were weighed once again after arrival at the pathology department, and volumes recalculated. The smallest pre- and post-fixation distances to the tumour-free margin were compared.
The mean surgical specimen weight was 47.7 g and was approximately similar to the actual specimen volume of 49.8 cm3. The weights of specimens immediately following surgery and on pathological appraisal were equal (p=0.94). The calculated volumes differed significantly from the actual specimen volumes (p>0.05). The mean distance to the closest tumour-free margin, 0.35 cm, was not altered by formalin fixation (p=0.1).
No evidence was found to suggest that surgical breast specimens shrink in the period between the surgical procedure and pathological examination, or following formalin fixation. The pathological appraisal of specimen margins and volumes is not affected by changes in specimen size. As calculations of specimen volumes are unreliable, the use of water displacement or the more readily available specimen weight is recommended for accurate volume measurement. Pathologists should be encouraged to always measure and record specimen weight.
The lecture hall is full,
The students are keen,
It's the last lecture
And there are tips to glean.
The lecturer aware of the expectant air
Is careful to choose his words with care.
Correct the papers, pass or fail? First class honours the holy grail Some answers too long, full of packing, Others too short, facts sadly lacking. Occasionally, a student bright Lights up a page like a shaft of light! Easy to read, straight to the core, Harmony and logic like a Mozart score.
Time for a viva, one last time, Have to decide who's first past the line. Gaze in turn at each nervous face And wonder if they will stick the pace. The Extern, aloof and steely eyed, As I present our best with pride.
Like a tennis match he begins the game, Answers vary, questions the same! Some unsure start to bluff Others love to strut their stuff. Serve and volley across the table, Some students, extremely able Return answers with a smash, First class honours, game, set, match!!
Teaching pathology has been...]]>
The principal folate in man is 5-methyltetrahydrofolic acid and food folates are tetrahydrofolates with either methyl or formyl adjuncts, so the measurement of total folate has been appropriate except in rare cases of inherited metabolic disease. When I was contributing to the British guidelines on the diagnosis of folate and cobalamin deficiency
Now, with folic acid supplementation widely used, either by medication or as a food additive, and with concerns in some quarters about the latter, natural food folate is not always the major ingested folate; therefore, it may be time to reconsider what we...]]>
Our study revealed that subspecialist GI pathologists were more likely to report higher VI detection rates than their...]]>
To examine the clinicopathological features of a series of penile melanomas and screen for mutations in the BRAF and KIT genes, which are seen in melanomas from other sites.
12 patients with penile melanoma were identified over a 10-year period in two supra-regional networks in the UK. The 2- and 5-year survival was 61% and 20%, respectively. Half the patients had lymph node involvement at presentation; this was a poor prognostic indicator. KIT exons 11, 13, 17 and 18, and BRAF codons 600 and 601 were analysed for mutations by Sanger sequencing and pyrosequencing, respectively. None of the tumours showed either KIT mutations or the BRAF V600E mutation.
Penile melanomas are extremely rare and have a similar prognosis to melanomas elsewhere, but they often present late, leading to a poor outcome. The mutations seen in melanomas from other sites appear to be rarely present in these tumours.
Ovarian cancer represents the fifth most common cancer to affect women in the UK, with approximately 6700 cases diagnosed annually. The majority of ovarian cancers are serous epithelial ovarian cancers (sEOCs), with mucinous epithelial ovarian cancers (mEOCs) forming around 12% of diagnosed cases, and hence comparatively rare.
Evolving evidence has demonstrated distinct histopathological and clinical contrasts between mEOC and sEOC, as discussed further in this issue, leaving oncologists questioning the current blanket approach to their treatment. Loco-regionally advanced sEOC and mEOC (the most prevalent presentation) is treated with a combination of chemotherapy and debulking surgery. However, there is evidence to suggest that mEOCs may be less sensitive to platinum based chemotherapy and the low prevalence of mEOC patients within randomised controlled trials...]]>
At the time of admission to our hospital just 4 months later from the initial operation, her serum β subunit of human chorionic gonadotropin (β-HCG) was 258.6 mIU/ml, and other tumour markers were normal. Her serum parathyroid hormone (PTH) was 88.6 pg/ml (normal 5~70 pg/ml), but serum calcium level was normal.
The pathology slides from her first operation were reviewed. The tumour was composed of two different components, most of which consisted of poorly differentiated medium to large tumour cells with enlarged round or oval nuclei arranged in...]]>
Although traditionally regarded as the second most common type of primary ovarian carcinoma following serous carcinoma, recent studies have illustrated that primary ovarian mucinous carcinomas are rather uncommon neoplasms representing approximately 3% of primary malignant ovarian epithelial tumours.
Aims: To extend the BMS cut up role to include gastrointestinal category D colorectal cancer resection specimens and to address issues of quality and safety by presenting performance data from the first 50 BMS cut up specimens in comparison to national guidelines and pathologist performance over the same timeframe.
Methods: Close mentoring and consultant supervision was carried out for every case with adherence to standard operating procedures and following colorectal cancer dataset guidelines as published by the RCPath. Performance targets were audited including anticipated spread of Duke’s stage, targets for mean lymph node harvest, percentage extramural vascular invasion and serosal involvement, and mean tumour blocks sampled. Histological pre-reporting of 20 cases was encouraged and time spent by BMS and consultant at all stages of specimen reporting was noted.
Results: Performance targets were all exceeded by the BMS and compared favourably with pathologist performance. A measure of consultant cut up and histology reporting time saved was identified.
Conclusions: Benefits of extending the BMS role to category D specimens may include BMS professional advancement, efficient use of consultant time, and development of a team approach to cancer reporting. Achievement of colorectal cancer performance targets and favourable comparison with pathologist performance implies there was no perceived detrimental effect on quality or safety and hence patient management.
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