Ivo Steiner

Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study

BACKGROUND Knowledge about the distribution of human papillomavirus (HPV) genotypes in invasive cervical cancer is crucial to guide the introduction of prophylactic vaccines. We aimed to provide novel and comprehensive data about the worldwide genotype distribution in patients with invasive cervical cancer. METHODS Paraffin-embedded samples of histologically confirmed cases of invasive cervical cancer were collected from 38 countries in Europe, North America, central South America, Africa, Asia, and Oceania. Inclusion criteria were a pathological confirmation of a primary invasive cervical cancer of epithelial origin in the tissue sample selected for analysis of HPV DNA, and information about the year of diagnosis. HPV detection was done by use of PCR with SPF-10 broad-spectrum primers followed by DNA enzyme immunoassay and genotyping with a reverse hybridisation line probe assay. Sequence analysis was done to characterise HPV-positive samples with unknown HPV types. Data analyses included algorithms of multiple infections to estimate type-specific relative contributions. FINDINGS 22,661 paraffin-embedded samples were obtained from 14,249 women. 10,575 cases of invasive cervical cancer were included in the study, and 8977 (85%) of these were positive for HPV DNA. The most common HPV types were 16, 18, 31, 33, 35, 45, 52, and 58 with a combined worldwide relative contribution of 8196 of 8977 (91%, 95% CI 90-92). HPV types 16 and 18 were detected in 6357 of 8977 of cases (71%, 70-72) of invasive cervical cancer. HPV types 16, 18, and 45 were detected in 443 of 470 cases (94%, 92-96) of cervical adenocarcinomas. Unknown HPV types that were identified with sequence analysis were 26, 30, 61, 67, 69, 82, and 91 in 103 (1%) of 8977 cases of invasive cervical cancer. Women with invasive cervical cancers related to HPV types 16, 18, or 45 presented at a younger mean age than did those with other HPV types (50·0 years [49·6-50·4], 48·2 years [47·3-49·2], 46·8 years [46·6-48·1], and 55·5 years [54·9-56·1], respectively). INTERPRETATION To our knowledge, this study is the largest assessment of HPV genotypes to date. HPV types 16, 18, 31, 33, 35, 45, 52, and 58 should be given priority when the cross-protective effects of current vaccines are assessed, and for formulation of recommendations for the use of second-generation polyvalent HPV vaccines. Our results also suggest that type-specific high-risk HPV-DNA-based screening tests and protocols should focus on HPV types 16, 18, and 45.

Lymphatic vasculature is increased in heart valves, ischaemic and inflamed hearts and in cholesterol-rich and calcified atherosclerotic lesions.

Eur J Clin Invest 2011; 41 (5): 487–497

Bone formation in cardiac valves: a histopathological study of 128 cases

In a series of 1,177 patients with surgical valve resection, there were 128 (10.9%) patients with the histological finding of bone and/or cartilage formation (bony metaplasia; heterotopic ossification) in the excised valve (119 aortic, 9 mitral). The incidence was higher in men (12.8%) than in women (8.5%). The bony metaplasia was always associated with valvular calcification. The metaplastic changes were encountered in all types of calcific aortic valve disease (senile, bicuspid valve, post-rheumatic). The marrow of the heterotopic lamellar bone was mostly composed of adipose tissue. Frequently, it showed chronic inflammation with polyclonal plasmocytic infiltration. Complete haematopoiesis was present only rarely.

Isolated thoracic aortitis: clinicopathological and immunohistochemical study of 11 cases.

Isolated thoracic aortitis (ITA) is diagnosed in a variable proportion of patients operated on for dilation/aneurysm of ascending aorta. The etiopathogenesis of ITA remains unclear. We studied 11 cases of ITA in order to determine the role of IgG4-mediated immune responses in its pathogenesis. The series included nine women and two men aged 52-79 years. All patients developed aortic incompetence due to dilation/aneurysm of ascending aorta. None of the patients had a history of IgG4-related disease neither did they develop features of such disease during the follow-up period. The microscopic findings included the presence of lymphoplasmacellular fibrosing infiltrate of varied intensity involving the adventitia and media of aorta. This inflammation was associated with severe medial elastic fiber defects. Obliterative phlebitis of the vasa vasorum was absent. Immunohistochemically, the inflammatory infiltrate comprised T- and B-lymphocytes as well as plasma cells. The plasma cell population was polyclonal with a predominance of IgG-producing cells. In all the cases, IgG4-producing plasma cells were detected. In five cases, the count exceeded 20 cells per high-power field. The IgG4/IgG ratio ranged from 0.07 to 0.98 (median 0.55). In six cases with the ratio >0.50, severe adventitial fibrosis was present. To the best of our knowledge, ours is the first study focused on investigating the role of IgG4-positive plasma cells in the development of ITA. Our results suggest that a subset of ITA may represent aortic manifestation of IgG4-related disease. Further research is necessary in order to clarify this issue.

Myocardial sleeves of pulmonary veins and atrial fibrillation: a postmortem histopathological study of 100 subjects

Atrial fibrillation (AF) is triggered by ectopic beats originating from extensions of the left atrial myocardium over the pulmonary veins (PVs), so-called myocardial sleeves. A total of 100 hearts (393 PVs) obtained at autopsy were studied. Of these, 50 were from patients with chronic AF and 50 from controls in sinus rhythm. Out of a total of 393 PVs studied, a sleeve was present in 349 PVs (88.8%). The myocardial sleeves frequently harboured senile atrial amyloid and scarring. These two changes were evaluated semi-quantitatively (grade 0–3). Amyloidosis was found in 68% of all hearts and in 55% of all sleeves. It was more frequent in patients with AF (58.5%) than in those without (51.7%), however, without statistical significance (p values 0.948, 0.306, 0.166 and 1). Scarring was present in all 349 sleeves studied. It was significantly more severe in patients with AF (average grade 2.44) than in those without (average grade 2.00) (p values <0.001, <0.1, <0.05 and <0.01). In conclusion, amyloidosis and particularly scarring of the myocardial sleeves of the pulmonary veins, appear to be common in the elderly population as an arrhythmogenic substrate for AF.

Persistence of spongy myocardium with embryonic blood supply in an adult

Gross presence of the embryonic pattern of myoarchitecture and of a sinusoid blood supply was found in the apical part of the left ventricle in a man who had been diagnosed with nonobstructive hypertrophic cardiomyopathy during life and who died suddenly at age 21 years. This is a first description of this finding in an adult with an otherwise normal heart and coronary arteries. The features of the cardiac lesions provide support for the current embryological views on ontogenesis of human myocardial structure and blood supply.

Calcific aortic valve stenosis: Immunohistochemical analysis of inflammatory infiltrate

Calcific aortic valve disease is considered a form of atherosclerosis and, like the latter, possibly of inflammatory origin. The aim of our work was to study the pattern of cellular infiltrate in calcific aortic valve stenosis (CAS). Fifteen operatively excised calcified aortic valves were examined by histology and immunohistochemistry (CD20, CD79α, CD3, CD4, CD8, CD68, CD138, CD117, BJK, BJL, IgA, IgD, IgG, IgG4 and IgM). The findings revealed that in CAS, there were chronic inflammatory features with infiltrates comprising lymphocytes, polyclonal plasma cells, histiocytes and mast cells. In T-lymphocytes, CD4 prevailed over CD8. In B-lymphocytes, there was a slight preponderance of CD20 over CD79α. The BJL (lambda)-positive plasma cells prevailed over the BJK (kappa) ones. The CD138-positive plasma cells comprised 24% IgA-, 20% IgD-, 41% IgG- (including 11% of IgG4-) and 15% IgM-positive cells. CAS did not fulfill the criteria of the recently described clinicopathological entity IgG4-related sclerosing systemic disease. The inflammatory process was the same in both subsets of CAS - those with trileaflet (normally formed) valves and those with congenitally bicuspid valves.

The Association of Atrial Tachyarrhythmias with Isolated Atrial Amyloid Disease: Preliminary Observations in Autopsied Heart Specimens

Objective: Isolated atrial amyloidosis (IAA) is associated with atrial tachyarrhythmias. However, only a few studies have appraised atrial tachyarrhythmias and atrial depolarization abnormalities in connection with high-grade IAA. We conducted a collaborative retrospective study to assess this association. Methods: One hundred consecutive autopsied hearts were studied histologically for IAA. To increase the specificity for atrial depolarization abnormalities in this preliminary study, we excluded those specimens with intermediate amyloid involvement, i.e. IAA grades 1 and 2 (grade 0 = absent or trivial deposits; grade 1 = small deposits; grade 2 = moderate deposits; grade 3 = dense, large deposits). We then screened for baseline, premortem electrocardiograms (ECGs) to assess rhythm. In those with sinus rhythm, the P wave axis, duration, dispersion and terminal force in V1 were determined under magnification. Results: Of the 27 premortem ECGs corresponding to the autopsy specimens with grades 3 (sample) or 0 (controls) IAA, 9 showed sinus rhythm, 13 showed atrial fibrillation, 1 showed atrial flutter and 4 were uninterpretable. Fourteen autopsied hearts (52%) were positive for grade 3 IAA. Ten of those had atrial tachyarrhythmias (9 atrial fibrillation and 1 atrial flutter) compared to 4 of the 13 hearts with grade 0 IAA (72 vs. 31%, respectively; p = 0.03). Although there was excellent interobserver agreement using intraclass correlation coefficients, there were no significant differences in P wave measurements among the small number of patients with sinus rhythm for grade 3 versus grade 0 IAA. Conclusion: In a collaborative, preliminary, pilot assessment of autopsied hearts for which premortem ECGs were necessarily screened retrospectively, significantly more hearts with high-grade IAA were associated with atrial tachyarrhythmias compared to those with low-grade IAA. A larger study with an appropriately matched autopsy control group is needed to confirm these and previous observations.

Histopathology of aspirated thrombi during primary percutaneous coronary intervention in patients with acute myocardial infarction.

Thrombus aspiration in the setting of primary percutaneous coronary intervention is a recently recommended technique that facilitates thrombus removal from the culprit lesions in acute myocardial infarction (AMI) patients. Thrombectomy specimens from 50 patients with symptoms of AMI lasting usually not more than 12 h were examined by methods of routine histology, immunohistochemistry (IHC), and electron microscopy (ELMI). In 36 patients, there were fresh thrombi, in 10 older thrombi (8 of them with simultaneous presence of a fresh thrombi) and in 3 atheroma material only (in additional 7 patients atheroma material was admixed to the thrombi), and in one patient, there was carcinoma embolus. To help to distinguish between fresh and older thrombi, we recommend IHC (presence of macrophages and endothelia) and ELMI (loss of density of the erythrocyte matrix and presence of macrophages). On the other hand, changes of neutrophils (IHC degranulation/lysis) and of platelets (ELMI degranulation) appear early and thus contribute little to distinguishing between fresh and older thrombi. It could be concluded that, in a substantial proportion of patients with AMI, there is a discrepancy between duration of the symptoms and microscopic picture of the coronary thrombus. The thrombus may apparently be symptomless for a period of days or even weeks.

Nonbacterial thrombotic versus infective endocarditis: A necropsy study of 320 cases☆

The precise relationship between nonbacterial thrombotic endocarditis (NBTE) and infective endocarditis (IE) remains to be clearly established, some believing that IE might develop from NBTE once the latter becomes secondarily infected during bacteremia. To compare the features of the two lesions, 175 cases of NBTE and 145 cases of IE encountered in more than 25,000 autopsies performed over a period of 24 years (1970-1993) were reviewed, and the relevant clinical, pathological, and bacteriological findings assessed. The results show that IE is a genuine suppurative infection of cardiac valves ab initio, whereas, in NBTE, inflammation is lacking and the lesion is a result of a usually paraneoplastic disturbance of thrombosis/thrombolysis.