October 2006
ANATOMIC PATHOLOGY
The pathology of Myocardial Infarction in the Era of Interventional
Cardiology: Introduction
[MINI-SYMPOSIUM]
The modern management of acute myocardial infarction has been associated with substantial changes in the pattern of disease which pathologists encounter in the post mortem room. The role of the pathologist is no longer restricted to the mere confirmation of the clinical diagnosis, which in the majority of cases was beyond reasonable doubt. In many centres this lack of doubt has been one reason for the falling rate of post mortem examinations in patients admitted to coronary care units. There are, of course, very few pathologists who specialise specifically in cardiovascular diseases and the largest number of these are based in centres in which heart and lung transplantation are performed. Nevertheless all pathologists who undertake autopsy examinations must have a sound knowledge of cardiac pathology. To address this need the Association for European Cardiovascular Pathology has been established. We hold biannual freestanding educational meetings and in alternate years organise symposia as part of the meetings of the European Society of Pathology (ESP). This mini-symposium is adapted from presentations made at a recent ESP meeting in Paris 2005.
In an important paper published in this journal in 1999, Eloisa Arbustini and her colleagues from Pavia reported on their findings in a series of nearly 300 patients who died in a coronary care unit and who had not received thrombolysis. All but six patients had histological evidence of an acute coronary thrombosis and in 10% of cases a thrombus was present in two major epicardial arteries. Plaque ruptures were more common than erosions, but the exact nature of the causative coronary lesion did not influence the pattern of the associated myocardial infarction.
In the first presentation in this symposium Professor Arbustini describes the myocardial pathology that is now seen in patients who have undergone thrombolysis or angioplasty after an acute event. The classical descriptions of myocardial infarction as found in textbooks are no longer relevant. We seldom see pale transmural infarcts, the coagulative necrosis that generations of students have learnt about. The range of pathological complications is now very different.
In the second article Mark Kockx and Michael Knappen from Antwerp discuss how coronary arterial plaques enlarge, the importance of macrophage infiltration, and the role of matrix metalloproteins. This group has particular expertise in the assessment of cell death and apoptosis in the myocardium and coronary arteries.
The third contribution is from the Department of Cardiovascular Pathology in Padua. Cristina Basso and Gaetano Thiene describe the pathology of reperfusion injury in the myocardium. Their contribution describes what we should look for in patients treated by interventionalists, but most importantly highlights what can be learnt from careful assessment of post mortem material.
In many countries post mortem rates are falling, or post mortems are performed for coroners or other medicolegal officers who do not value histological examination. We know from a recent meta-analysis that many post mortem diagnoses made without histology are inaccurate, and the three papers in this symposium demonstrate amply what careful microscopy can and should contribute.
Almost all pathologists in large centres are now subspecialists and this is likely to extend to the majority of hospitals. This is largely driven by the detailed protocols required for the examination of cancer resections and the close collaboration between pathologists and the wide range of colleagues involved in the management of patients with malignancy. Training in cardiovascular pathology has also undergone a renaissance and is now under active discussion in Europe and North America. Cardiac pathology cannot be understood without appreciating what cardiologists are attempting to do. We hope that this symposium will demonstrate what can be learnt, especially when pathologists collaborate closely with cardiologists.
British Heart Journal, 92(1) November 2006
The Pathology of Myocardial Infarction In The Pre- And Post-Interventional Era
[MINI-SYMPOSIUM]
The clinical diagnosis of myocardial infarction (MI) relies on symptoms, electrocardiographic findings, and biochemical markers (troponin, serum creatine kinase, creatine kinase-MB). Acute ischaemic syndromes are now classified as unstable angina/non-ST-elevation MI (UA/NSTEMI) and acute ischaemic syndromes with ST-elevation MI (STEMI). The new diagnostic criteria and markers are leading to increased proportions of acute ischaemic syndromes being recognised as acute MI. Obviously, elevated troponin concentrations are not, by themselves, synonymous with acute MI and can occur in a variety of cardiac and non-cardiac disorders (for example, sepsis or septic shock, pulmonary embolism, acute exacerbation of chronic obstructive pulmonary disease). Therefore, the diagnosis of acute MI relies on the combination of all clinical and biochemical tools, each providing its own diagnostic contribution.
The pathological hallmark of acute MI is coagulative necrosis of the myocardium. All recent advances in the definition, diagnostic work-up and treatment of MI are essential to perform an informative pathological investigation. In fatal MI, the pathological study must be performed at the appropriate technical and interpretative level to confirm, extend and improve information useful for the clinical understanding of the event (why one infarction proves fatal while other clinically similar MIs are not) and, eventually, contribute towards improving knowledge that may help future research in the MI setting.
PATHOLOGY
The pathological diagnosis of MI relies on the identification of coagulative necrosis in the myocardium, or of repairing features according to the age of the MI, or, if death occurred before the time necessary for coagulative necrosis to become visible at routine histopathology, on the detection of occlusive coronary thrombosis of an epicardial coronary artery (International classification of diseases, 9th revision (ICD-9) classification 410, 411). When coronary thrombosis is not detected at autopsy in individuals with MI who did not receive reperfusion, plaque complications such as rupture and haemorrhage can be considered the potential substrate of an acute thrombotic event that spontaneously thrombolysed. In less than 5% of cases, MI is reported as not being associated with coronary atherosclerotic plaques. Coronary spasm (toxic, drug-induced (Kounis syndrome) or associated with systemic disease), coronary emboli, and myocardial bridges have been considered as exceptional causes of MI; for these coronary substrates, the pathologic identification of the culprit lesion may be difficult. Cases with clinically diagnosed MI in which neither coagulative necrosis nor acute events in the culprit plaque are found at autopsy are exceptional.
Most patients with acute MI who are admitted to coronary care units (CCUs) and coronary interventional labs shortly after the onset of the ischaemia have a favourable prognosis. In the modern cardiology setting, fatal MIs are usually those occurring out of the hospital, or are seen in patients who came late to the CCU, did not receive appropriate treatments, or died suddenly from life-threatening arrhythmias.
With respect to transmural versus subendocardial MI, the recent identification of small intramural foci of coagulative necrosis, clinically recognised with the additional information derived from troponin measurements (Fig 1), indicates the need for modified investigation protocols at autopsy with extensive search for microfoci of necrosis in multiple myocardial samples. These MIs are unlikely to be fatal unless the acute ischaemia triggers life-threatening arrhythmias and, in any case, the corresponding clinical phenotype should be UA/NSTEMI.
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Figure 1. Small foci of coagulative necrosis can be recognised on haematoxylin and eosin (H&E) stained sections: ischaemic myocytes typically show the hypereosinophilia that characterises early phases of coagulative necrosis. (A) The ischaemic myocytes are located in the left side of the panel; (B) the ischaemic myocytes are positioned bottom left; (C) low magnification view showing a small area of acute myocardial infarction in which granulocyte infiltration is clearly visible among the myocytes showing coagulative necrosis (squared area and (D), inset at higher magnification). The front of the myocardial ischaemia is in the top half of the figure. |
PRE-INTERVENTIONAL AND PRE-THROMBOLYTIC ERA
Non-reperfused MI shows typical ischaemic coagulative necrosis. During the first 30-40 minutes of ischaemia, the changes are visible only at electron microscopy and are reversible. The macroscopic appearance depends on the interval of time between the onset of MI and death. A macroscopic early diagnosis (few hours from onset) relies on the immersion of the infarcted myocardium in a solution of triphenyltetrazolium chloride. This histochemical stain imparts a brick-red stain to the non-infarcted area preserving the dehydrogenase enzymes. From 12 to 24 hours the myocardium appears as dark mottling; from days 1 to 3, the mottling is centred by a yellow-tan core; from days 3 to 7 the central yellow-tan softening area is surrounded by hyperaemic borders; from days 7 to 10, the infarction area is yellow-tan and soft, and the margins are red-tan and depressed; from 10–14 days, the borders assume a red-grey colour; from 2 to 8 weeks the scar starts to develop from the periphery to the centre; after the second month, the scarring process should be completed.
Although the microscopic appearance before 12 hours is poorly informative, hypereosinophilic changes of the myocyte sarcoplasms are present before neutrophilic infiltrates (Fig 1A,B). The so-called waviness may be seen at the border of the ischaemic MI. Isolated myocyte waviness (without other findings such as hypereosinophilia of the sarcoplasms or contraction bands and coagulative necrosis) do not have diagnostic value. Focal waviness of single myocytes or groups of these cells can be seen in hearts of patients who died from proven non-cardiac causes; they constitute the morphologic expression of terminal changes in pre-agonic and agonic phases. The lack of significance of isolated myocyte waviness has been experimentally demonstrated.
After 12 hours, coagulative necrosis starts and progresses with loss of the nuclei (days 1 to 3), neutrophilic infiltration (early days 1 to 3) (fig 1C,D, Fig 2A,B), myocyte fragmentation (days 3 to 7) and early phagocytosis at the border of the MI (days 3 to 7) after the first week; the granulation tissue progresses and evolves through loose (week 2) and progressively dense collagen deposition (from 3 to 8 weeks) and scar that is completed by the second month. After that date, the scar becomes acellular and collagen appears dense and compact. The above time intervals indicate the onset and peaks of the features but do not reflect the ending. In large transmural MI, layers of necrotic myocytes can be observed after intervals longer than two months.
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Figure 2. (A and B) Typical, non-reperfused myocardial infarction: the basophilic areas indicate the front of granulocyte infiltration. In non-reperfused MI the repair starts at the borders of the MI and the front progresses from the periphery to the centre. (C and D) Typical reperfusion pattern of a consolidated myocardial infarction: note the extensive haemorrhagic invasion of the myocardium with coagulative necrosis and the absence of haemorrhage in subendocardial layers with morphologically viable myocytes. |
Coronary arteries
A culprit plaque with acute thrombosis is found at autopsy in more than 90% of patients who have died from MI and were not treated with either thrombolysis or percutaneous transluminal coronary angioplasty (PTCA). The plaque substrate for thrombosis is rupture in about 75% of the cases and erosion in a minority of cases, mostly women and smokers. The typical culprit lesion is a large atherosclerotic plaque with cap ulceration and superimposed acute thrombosis. The acute thrombus is red, with a small platelet-rich small head, a fibrin- and red cell-rich body, and a red cell-rich tail.
POST-THROMBOLYTIC AND POST-PTCA ERA
Reperfusion in MI restores the coronary flow interrupted by the acute coronary event. It can be obtained using thrombolysis or mechanical interventions such as PTCA with or without stenting. The greatest effectiveness is obtained with PTCA which dramatically modifies the natural history of MI and is now available in nearly all tertiary cardiologic centres in Europe.
Thrombolysis and percutaneous coronary interventions (PCI) with or without stenting is usually performed when the interval between the onset of symptoms and opening of the culprit coronary artery is less than 12 hours (the gold standard is six hours, while the benefit derived from reperfusion between 12 to 24 hours is debatable). Guidelines for STEMI indicate 12 hours after onset of symptoms, and then distinguish the indications on the basis of the presence or absence of a PCI centre in the hospital. In hospitals where a PCI centre is active, all patients with STEMI should undergo primary PCI. If the interval between onset of symptoms and arrival at a hospital without a PCI centre is between 3 to 12 hours, the patient should be immediately transferred to a hospital with an active PCI centre. If the interval is < 3 hours, then thrombolysis can be performed.
Myocardium
Reperfusion strategies are introduced in the cardiopathological setting for the so-called reperfusion-associated pathologies, whose clinical manifestations include arrhythmias and prolonged ischaemic dysfunction, the pathological evidence for which includes myocardial haemorrhage with contraction bands, myocyte reperfusion injury distinct from, and additional to, coagulative necrosis, and small vessel damage. Contraction bands are seen in irreversibly injured myocytes: their morphology is characterised by intensely eosinophilic transverse bands comprising closely packed hypercontracted sarcomeres. The macroscopic appearance of reperfused MI is typically haemorrhagic. Microscopic examination of reperfused infarction areas shows myocytes with coagulative necrosis surrounded by red cell infiltration (Fig 2C,D), contraction band necrosis and small vessels which are either damaged or showing small thrombo- or athero-emboli. Small vessel damage may further worsen the haemorrhagic invasion of the myocardium and leads to endothelial cell swelling which is potentially occlusive (especially at the capillary level), thus preventing local reperfusion of ischaemic myocardium. This phenomenon is known as no-reflow. If reperfusion is done before irreversible necrosis, the blood flow restoration of the area at risk may rescue the entire ischaemic myocardium. Alternatively, the rescued area is proportional to the interval elapsed between onset of ischaemia and blood flow restoration. Scars of reperfused MI show more angiogenesis processes than non-reperfused MI. In the majority of cases, the result of reperfusion is a limitation of the infarct area and size, with improvement of short and long term function and prolonged survival.
Coronary arteries
In reperfused MI the culprit lesion is expected to be patent: it may show ulceration with haemorrhagic invasion of the core or mural thrombus layered over the plaque ulceration. Pultaceous material and thrombotic fragments may reach the small vessels of the area around the culprit vessel. This deleterious consequence of infarct-related artery reperfusion can be addressed by the upstream use of glycoprotein IIb/IIIa inhibitors, which were found to improve microcirculatory function and clinical outcome. Alternatively, new filters or aspirating devices are being used in clinical practice to collect or suck up both plaque and thrombus derived fragments in order to limit small vessel impairment. However, these devices were not found to sufficiently antagonise the no-reflow phenomenon and improve clinical results.
MYOCARDIAL INFARCTION COMPLICATIONS
Acute pulmonary oedema
Pulmonary oedema is associated with a 20 to 40% 30-day mortality rate, even in the fibrinolytic era. Pulmonary oedema may occur as an acute event with the onset of STEMI or reinfarction, or as the culmination of slowly progressive congestive heart failure during the first days after MI.
Heart rupture
The main risk factors for heart rupture include longstanding hypertension, female sex, advanced age, and no history of prior infarction.
Left ventricular free-wall rupture: Cardiac rupture occurs in 1 to 6% of all patients admitted with STEMI. The frequency of cardiac rupture shows two peaks: one early within 24 hours, and one late from 3 to 5 days after STEMI. Risk factors for cardiac rupture include: first MI, anterior infarction, old age, female sex, hypertension during the acute phase of STEMI, lack of prior angina and MI, lack of collaterals, Q waves on the ECG, symptoms of pericarditis, peak MB creatine kinase > 150 IU/l, intake of corticosteroids or non-steroidal anti-inflammatory drugs, and fibrinolytic therapy more than 14 hours after onset of symptoms. The most important determinants in preventing rupture are successful early reperfusion and the presence of collateral circulation.
Ventricular septal rupture: During the reperfusion era the frequency of acute rupture of the interventricular septum has declined. It occurs in less than 1% of patients with STEMI. In patients treated with fibrinolytic therapy, the highest risk is within the first 24 hours after MI. The rupture site can rapidly expand and cause sudden haemodynamic collapse, even in patients who appear to be clinically stable with normal left ventricular function.
Papillary muscle rupture: Papillary muscle rupture occurs in less than 1% of cases. The diagnosis is made on the basis of clinical and imaging findings.
Left ventricular aneurysm
Aneurysm after STEMI usually occurs in the left anterior wall, in association with left anterior descending occlusion and a wide infarcted area. Patients with STEMI treated with fibrinolytic therapy and a patent infarct-related artery have a significantly reduced incidence of left ventricular aneurysm compared with those who do not (7.2%v 18.8%).
Ventricular pseudoaneurysm
Ventricular pseudoaneurysm is a rare complication. It occurs as a consequence of rupture of the ventricular free wall and is contained by overlying, adherent pericardium, producing what has been termed a false aneurysm or pseudoaneurysm of the left ventricle. The pathologic features depend on the interval of time elapsed from onset of MI and death and from the extent of haemorrhage between the pericardium and the myocardial wall. The myocardial wall shows interruption or fissuring. The myocardial changes include coagulative necrosis with or without reperfusion pattern, according to the administered treatments. Most pseudoaneurysms are formed within seven days after an AMI, only exceptionally forming later.
Arrhythmias
Cardiac arrhythmias are common in patients with STEMI and occur most frequently early after the development of symptoms. The mechanisms for ventricular tachyarrhythmia include loss of transmembrane resting potential, re-entrant mechanisms due to dispersion of refractoriness in the border zones between infracted and non-ischaemic tissues, and the development of foci of enhanced automaticity. Reperfusion arrhythmias likely involve washout of toxic metabolites and various ions such as lactate and potassium.
Lethal arrhythmias/sudden death
Ventricular arrhythmias are one of the most frequent causes of death in non-hospitalised patients with acute MI. They are the most common form of sudden ischaemic death.
Cardiogenic shock
Cardiogenic shock in patients with STEMI is commonly (75%) caused by extensive left ventricular dysfunction. Other relevant causes include mechanical complications (acute severe mitral regurgitation, ventricular septal rupture, and subacute free-wall rupture with tamponade). Cardiogenic shock may be mimicked by aortic dissection and haemorrhagic shock.
Mitral regurgitation
After STEMI, mitral regurgitation (MR) may occur as a result of infarction of the papillary muscle, infarction involving the lateral wall, large infarction with left ventricular dilation, and displacement/dysalignment of the papillary muscle. Severe MR with cardiogenic shock has a poor prognosis. In the SHOCK trial registry, approximately 10% of patients with shock presented with severe MR (overall hospital mortality 55%). When severe MR is caused by infarction of the papillary muscle and wall, the area of infarction tends to be less extensive than in patients in whom the MR is caused by papillary displacement/dysalignment and severe left ventricular dysfunction. The presence of acute pulmonary oedema or cardiogenic shock in posterior/posterolateral STEMI should point to the possibility of acute MR caused by papillary muscle rupture.
Pericarditis
Pericarditis occurs in transmural STEMI involving the full thickness of the myocardial wall to the epicardium. Patients with pericarditis have larger infarcts, lower ejection fraction and higher incidence of congestive heart failure. Pericarditis may appear up to several weeks after STEMI. The Dressler syndrome (post-MI syndrome) has essentially disappeared in the reperfusion era.
Acute pulmonary haemorrhage
This is a rare complication that may occur in patients who undergo primary PTCA and are treated with glycoprotein IIb/IIIa inhibitors. When it occurs, it is difficult and costly to treat and may result in death. The pathologic diagnosis is essential to confirm the alveolar invasion by red blood cells (Fig 3A,B). Bleeding complications are higher in women than in men. In pooled analysis of the results from EPIC, EPILOG and EPISTENT, major bleeding rates were 3% and 1.3% (p = 0.004) and minor bleeding rates were 6.7% and 2.2% (p < 0.001) in women and men, respectively. Rare intracranial and gastrointestinal haemorrhages have also been reported.
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Figure 3. Light micrographs showing (A) typical pulmonary oedema (H&E stain) versus (B) pulmonary haemorrhage in a patient who died of acute adult-type respiratory distress related to abciximab (peroxidase-antiperoxidase; anti-glycoforin A immunostain). |
CONCLUSIONS
The pathology of MI in the post-interventional era includes specific features mostly resulting from the reperfusion of necrotic myocardium. The contribution of the pathologic study should add information to the clinical data and should match new sensitive diagnostic markers. The complication scenario is also modified: prevalence and evolution are significantly different in non-reperfused and reperfused MI.
British Heart Journal Volume 92(11), November 2006, pp 1552-1556
Histopathologic indicators of recurrence in
meningiomas: correlation with clinical and genetic parameters.
Kim YJ, Ketter R, Henn W, Zang KD et al
Meningiomas in general are circumscribed slow-growing tumors. However, despite gross total resection, tumor relapse and patients' outcome are still an issue. Risk stratification based on histomorphology alone remains problematic. This study explored the independent prognostic value of potential risk factors among 206 patients who underwent meningioma resection and followed-up until death or a median of 44 months. The statistical analysis considered clinical data, histomorphologic parameters, cytogenetic findings, Ki-67 immunoreactivity, and activity of tissue non-specific alkaline phosphatase (ALPL). Recurrence-free survival estimates were computed and prognostic factors were identified using Cox proportional hazards model. Independent predictors of recurrence included (1) anaplasia; (2) mitotic index >/=20/10 high-power fields; (3) subtotal tumor resection; (4) loss of short arm of chromosome 1 (1p-); and (5) Ki-67 labeling index (LI) >12%. Among totally resected WHO grade I meningiomas, neither histopathologic nor clinical parameters were predictive, whereas 1p- was the only independent prognostic factor. ALPL did not reach significance in the multivariate modeling, however, the fast and low-cost histochemical detection of ALPL expression could be proved as a highly sensitive screening method for 1p-. In particular, biologically aggressive meningiomas of histologically benign or "borderline" phenotype could be therefore identified by ALPL detection followed by 1p in situ hybridization.
Virchows Arch. 2006 Oct 3; [Epub ahead of print]
Transformation in lymphomas--morphological,
immunophenotypic and molecular features.
Prochorec-Sobieszek M, Majewski M, Sikorska A et al
During the course of lymphoma, a clinically more aggressive process with different morphology may develop, referred to as lymphoma transformation. Clonal relationship and pathogenic mechanism of this process are widely debated. The aim of the study was to evaluate morphology, immunophenotype (including EBV status) and clonal relationship in nine cases of lymphoma transformation. Among the six patients with low grade B-cell lymphomas three transformed into high grade B-cell lymphomas (two into diffuse large B-cell lymphoma, one into Burkitt lymphoma) and three into Hodgkin lymphoma. Three other patients with Hodgkin lymphoma presented with transformation into diffuse large B-cell lymphoma in two patients and peripheral T-cell lymphoma in one patient. In all cases there was a sudden clinical change as well as change in morphology and phenotype. In five of the nine patients studied EBV-LMP1 was demonstrated by immunohistochemistry in large transformed lymphoma cells. In two cases molecular studies revealed a different pattern of immunoglobulin gene rearrangement in the large transformed cells as compared to the small cells of primary indolent lymphoma. Thus, they represented secondary, arising de novo neoplasm.
Pol J Pathol. 2006;57(2):63-70.
Immunohistochemical characterization of endocervical papillary serous carcinoma
Nofech-Mozes, S., Rasty, G., Ismiil, N. et al
Endocervical adenocarcinomas are rare and aggressive neoplasms. Papillary serous endocervical adenocarcinomas are the rarest form of endocervical adenocarcinomas. This tumor exhibits morphologic similarities to its counterparts commonly seen in the endometrium, fallopian tubes, ovaries, and peritoneum, which are known to have an aggressive behavior. Because of the rarity of this tumor, little is known about its immunophenotyping. In this study, we included ten cases of papillary serous carcinomas arising from the uterine cervix (PSCC) diagnosed in the absence of a primary endometrial malignancy. We studied their immunohistochemical profile, using a panel of antibodies against Ki67, bcl-2, p53, carcinoembryonic antigen (CEA), and CD10, and compared them to 20 consecutive cases of cervical adenocarcinoma of conventional cell subtypes (CAC) (15 mucinous, 3 adenosquamous, and 2 endometrioid). Immunostaining was recorded semiquantitatively. Patients with PSCC ranged in age from 27 to 79 years (mean = 51.6 +/- 19.1), while the conventional cell subtypes control group were 28-90 years old (mean = 47.5 +/- 16.9). Only p53 and CEA immunostaining significantly correlated with the PSCC morphology (P= 0.001 and P= 0.016, respectively) as shown by Cochran-Mantel-Haenszel Statistics (Modified Ridit Scores). PSCC is a distinctive immunophenotypic subtype of endocervical adenocarcinoma with significantly higher p53 and lower CEA reactivity than other more common histologic subtypes.
International Journal of Gynaecological Cancer 16(Supplement 1):286-292, 2006
Lipofuscin pigment can be used
as a prognostic marker in prostatic adenocarcinoma.
Mahmoodi M, Zhang S, Salim S, Hou JS, Garcia FU.
Lipofuscin, known as the "wear and tear" pigment, is seen in cells undergoing regressive changes, the seminal vesicles and the ejaculatory ducts. It is also present in prostatic adenocarcinoma. The purpose of this study is to evaluate the prognostic significance of lipofuscin in prostatic adenocarcinoma. Lipofuscin was evaluated in 736 hematoxylin-eosin-stained slides from 60 conventional and whole-mounted consecutive radical prostatectomies from December 1996 to February 2002. The adenocarcinoma cases were divided into lipofuscin-positive group and lipofuscin-negative group. The Gleason score and pathologic stage were compared between the 2 groups. Percentage of cells positive for p53 and MIB-1 was also compared. Lipofuscin pigment was found in 17 (31%) of 60 prostatic adenocarcinomas as random, sparse, fine, yellow-brown intracytoplasmic granules staining positive for cathepsin D and negative for S-100 protein. Using logistic regression to exclude age as a confounding factor, lower Gleason scores and pathologic stages were demonstrated in the lipofuscin-positive group. There was also a significant difference between the 2 groups in tumor volume, degree of capsular invasion, and positive margins. The difference in seminal vesicle invasion and vascular invasion between the 2 groups was not statistically significant. Lipofuscin in prostatic adenocarcinoma correlates with both lower Gleason score and pathologic stage. Lipofuscin probably indicates slow cellular turnover as suggested by the low proliferation rate and p53 expression. The value of lipofuscin in biopsy as a predictor separating aggressive from indolent disease needs further investigation.
Ann Diagn Pathol. 2006 Oct;10(5):257-62.
Heat Shock Proteins (HSP70 and HSP27) as
Markers of Epithelial Dysplasia in Oral Leukoplakia.
Seoane JM, Varela-Centelles PI, Ramirez JR et al
Heat shock proteins (HSPs) play a significant role in cell proliferation,
differentiation, and oncogenesis. HSP70 and HSP27 are constitutively and
gradually expressed in a broad range of normal tissues and neoplasms, and their
expression has been assessed as markers for oral epithelial dysplasia. The
study involved 43 patients with oral leukoplakia (OL): 23 were categorized as nondysplastic
and 20 as dysplastic OLs. Immunohistochemistry was carried out with the
monoclonal antibodies HSP70 and HSP27. The presence of epithelial dysplasia and
its histologic grading was evaluated according to the World Health Organization
classification: mild, moderate, and severe squamous epithelial dysplasia.
Expression of HSPs within the epithelium was also evaluated. The difference in
the percentage of HSP70 positive nuclei in nondysplastic and dysplastic OL
reached statistical significance (Equation is included in full-text article.)
95% confidence interval = 17.74-43.82; P = 0.000). None of the 43 specimens
analyzed showed positive nuclear immunostaining for anti-HSP27 antibody. No
significant difference for HSP27 cytoplasmic expression could be identified
between OL with or without epithelial dysplasia(Equation is included in
full-text article.)95% confidence interval = 0.44-3.95; P = 0.89). It is
concluded that the nuclear HSP70 immunoexpression could be an objective marker
for the presence of the epithelial dysplasia in OL.
Am J Dermatopathol. 2006 Oct;28(5):417-422.
MICROBIOLOGY
New HIV Test Approved
David G. Fairchild, MD, MPH, Editor-in-Chief
The FDA yesterday approved an assay for detecting HIV-1 RNA.
The Aptima HIV-1 RNA Qualitative Assay has similar sensitivity to the PCR-based viral load tests used in monitoring patients. Unlike the viral load tests, however, the assay has been approved as an alternative to Western blot both for confirming chronic HIV infection and for detecting acute infection when antibody test results are negative.
Asked to comment, Dr. Paul Sax, editor-in-chief of AIDS Clinical Care, said, "Tests such as this one are likely to be particularly helpful in diagnosing patients with recent high-risk exposures, or in suspected acute HIV infection, since such patients may have negative HIV antibody tests. Aptima could replace quantitative viral-load testing for this purpose, which is known to have low but significant false-positive rate. Whether this new test is used more broadly will depend on its cost and its performance in more widespread clinical use."
Physicians First Watch, 6th October, 2006
Faster Diagnosis of MDR-TB
The microscopic-observation drug-susceptibility assay is faster and more sensitive than existing methods for diagnosing TB and multidrug-resistant TB.
TB kills 1.7 million people worldwide every year. Conventional methods for Mycobacterium tuberculosis culture and susceptibility testing are barriers to rapid detection of TB and multidrug-resistant TB (MDR-TB), especially in resource-limited settings. The microscopic-observation drug-susceptibility (MODS) assay, which relies on early microscopic detection of typical cord formation in broth culture, has been shown in preliminary studies to be rapid and sensitive for TB and MDR-TB detection. Now, investigators have compared this assay against two conventional diagnostic methods in Lima, Peru.
From April 2003 through July 2004, sputum samples were collected from 1570 consecutive patients with suspected TB at 10 government clinics, 253 patients prescreened for high risk of TB and MDR-TB, and 157 hospitalized HIV patients at 2 hospitals. All samples were processed by three methods: MODS assay, Löwenstein-Jensen (L-J) culture, and automated mycobacterial culture using the MBBacT broth system.
Of 3760 samples, 401 (10.7%) yielded cultures positive for M. tuberculosis. The MODS assay was more sensitive than either the automated mycobacterial culture or the L-J culture (98% vs. 89% and 84%; P<0.001) and showed shorter median time to culture positivity (7 days vs. 13 and 26 days; P<0.001). The addition of a second sputum sample for MODS did little to improve sensitivity, especially for the group prescreened for high TB risk. Susceptibility results for the MODS assay were >92% concordant with reference testing for each of the four drugs examined (isoniazid, rifampin, ethambutol, and streptomycin).
Comment: The MODS assay is an affordable, rapid method for culture-based detection of TB, including MDR-TB. As an editorialist points out, however, manipulating broth cultures requires a TB laboratory with biosafety level 3 standards. Bringing more such laboratories into countries with a high prevalence of TB and MDR-TB is necessary before this assay’s advantages can be fully realized.
— Daniel J. Diekema,
Journal Watch Infectious Diseases October 11, 2006
Elevated soluble thrombomodulin
in the febrile stage related to patients at risk for dengue shock syndrome.
Butthep P, Chunhakan S, Tangnararatchakit K et al
BACKGROUND: Children with dengue hemorrhagic fever (DHF) are at risk to develop
dengue shock syndrome (DSS) for which neither marker has been
demonstrated.
OBJECTIVE: The study was designed to investigate the markers of vascular endothelial cell injuries and dysfunction that might be used as early predictors of the subsequent manifestation of DSS.
METHODS: The blood samples from 111 patients with dengue fever, DHF and other febrile illness (OFI) were collected daily from the day of admission until discharge and at convalescent stage. The sample from the day of defervescence was defined as day 0, 1 day before defervescence was defined as day -1 and so on. Also, 1 day after defervescence was defined as day +1 and so on.
RESULTS: Increased soluble thrombomodulin (sTM) was demonstrated in dengue-infected patients via an enzyme-linked immunosorbent assay. Patients with DSS (DHF grades III and IV) had higher concentrations of sTM than those with dengue fever, DHF grade I, II and OFIs from day -3 until day +2. Increased circulating endothelial cells were detected from day 0 until day +2 in DSS patients as compared with other groups. In addition, increased soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1 and soluble E-selectin were also found in dengue virus-infected patients as compared with OFIs.
CONCLUSION: Blood sTM may be useful as an early predictor of DSS in dengue infected patients in the febrile stage. However, a further evaluation in a large prospective series is needed.
Pediatr Infect Dis J. 2006 Oct;25(10):894-7.
A meta-analysis of the diagnostic performance of the direct agglutination test and rK39 dipstick for visceral leishmaniasis
François Chappuis, Suman Rijal, Alonso Soto et al
Objective To compare the performance of the direct agglutination test and rK39 dipstick for the diagnosis of visceral leishmaniasis.
Data sources Medline, citation tracking, January 1986 to December 2004.
Selection criteria Original studies evaluating the direct agglutination test or the rK39 dipstick with clinical visceral leishmaniasis as target condition; adequate reference classification; and absolute numbers of true positive, true negative, false positive, and false negative observations available or derivable from the data presented.
Results 30 studies evaluating the direct agglutination test and 13 studies evaluating the rK39 dipstick met the inclusion criteria. The combined sensitivity estimates of the direct agglutination test and the rK39 dipstick were 94.8% (95% confidence interval 92.7% to 96.4%) and 93.9% (87.7% to 97.1%), respectively. Sensitivity seemed higher and more homogenous in the studies carried out in South Asia. Specificity estimates were influenced by the type of controls. In phase III studies carried out on patients with clinically suspected disease, the estimated specificity of the direct agglutination test was 85.9% (72.3% to 93.4%) and of the rK39 dipstick was 90.6% (66.8% to 97.9%).
Conclusion The diagnostic performance of the direct agglutination test and the rK39 dipstick for visceral leishmaniasis is good to excellent and seem comparable.
BMJ 2006;333:723 (7 October)