Gyda Lolk Ottesen

Lobular Carcinoma In Situ of the Female Breast: Short-Term Results of a Prospective Nationwide Study

In a Danish nationwide prospective study of in situ carcinoma of the breast, 112 women with ductal carcinoma in situ, treated with excision only, were registered from 1982 to 1987. Within a median follow-up of 53 months, a crude recurrence rate of 22% (25 cases) was found, of which five cases recurred as invasive carcinomas and 20 cases as in situ carcinomas. The histopathologic review included a single-parameter analysis of histological growth pattern, size of lesion, nuclear size, presence of comedonecrosis, and subhistologic type. A strong inter-relationship was found for histological growth pattern, nuclear size, and comedonecrosis. These parameters were also significantly related to recurrence. Cases that had clinical symptoms had a high recurrence rate as compared with cases that were discovered by mammography only or incidentally.In a Danish nationwide prospective study of in situ carcinomas and atypical lesions of the breast, 88 women, comprising 69 patients with lobular carcinoma in situ (LCIS) and 19 patients with combined lobular and ductal carcinoma in situ (LCIS + DCIS), were accrued from 1982 through 1987. All cases were treated with excision only. Within a median follow-up time of 61 months, a recurrence rate of 17% (15 cases) was found, excluding nine cases of refinding of LCIS. No contralateral recurrences occurred. The recurrences were in eight cases invasive carcinomas (IC), in six cases LCIS + DCIS, and in one case DCIS alone. The recurrence rates among cases of LCIS and of LCIS + DCIS were not significantly different. The histopathological review included an estimate of the number of lobules with LCIS and nuclear size, both of which were significantly related to recurrence. The risk of developing IC was calculated to be increased by a factor 11 as compared with the reference population.

Nationwide study of sudden cardiac death in persons aged 1–35 years

AIMS The aim of this investigation was to study the incidence of sudden cardiac death (SCD) in persons aged 1-35 years in a nationwide setting (5.38 million people) by systematic evaluation of all deaths. METHODS AND RESULTS All deaths in persons aged 1-35 years in Denmark in 2000-06 were included. Death certificates were read independently by two physicians. The National Patient Registry was used to retrieve information on prior medical history. All autopsy reports were read and the cause of death was revised based on autopsy findings. We identified 625 cases of sudden unexpected death (10% of all deaths), of which 156 (25%) were not autopsied. Of the 469 autopsied cases, 314 (67%) were SCD. The most common cardiac cause of death was ischaemic heart disease (13%); 29% of autopsied sudden unexpected death cases were unexplained. In 45% of SCD cases, the death was witnessed; 34% died during sleep; 89% were out-of-hospital deaths. Highest possible incidence rate of SCD in the young was 2.8 per 100 000 person-years including non-autopsied cases of sudden unexpected death. Excluding those, the incidence rate declined to 1.9 per 100 000 person-years. CONCLUSIONS A total of 7% of all deaths in the young can be attributed to SCD, when including non-autopsied cases (autopsy ratio 75%). The incidence rate of SCD in the young of 2.8 per 100 000 person-years is higher than previously reported.

Incidence and etiology of sports-related sudden cardiac death in Denmark—Implications for preparticipation screening

BACKGROUND Studies on incidences of sports-related sudden cardiac death (SrSCD) are few and data are needed for the discussion of preparticipation screening for cardiac disease. OBJECTIVE We sought to chart the incidence and etiology of SrSCD in the young in Denmark (population 5.4 million) and to compare this to the incidence of sudden cardiac death (SCD) in the background population. METHODS All 5,662 death certificates for decedents in the period 2000 to 2006 in the age group 12 to 35 years in Denmark were read independently by 2 physicians to identify cases of SCD. Information from autopsy reports, selected hospital records, and multiple registries was used to identify cases of SCD and SrSCD. SrSCD was defined as SCD occurring during or within 1 hour after exercise in a competitive athlete. The size of the athlete population was estimated from national survey data. RESULTS Fifteen (range 0 to 5 per year) cases of SrSCD were found, 8 of which had antecedent symptoms. The incidence rate was 1.21 (95% confidence interval [CI]: 0.68 to 2.00) per 100,000 athlete person-years. The most common autopsy findings were arrhythmogenic right ventricular cardiomyopathy (n = 4), sudden unexplained death (n = 4), and coronary artery disease (n = 2). The incidence of SCD in the general population age 12 to 35 was 3.76 (95% CI: 3.42 to 4.14) per 100,000 person-years. CONCLUSION In Denmark, SrSCD is a rare occurrence and the incidence rate is lower than that of SCD in the general population. This may imply a low value of preparticipation screening of athletes in Denmark.

Carcinoma in situ of the female breast. 10 year follow-up results of a prospective nationwide study

In a Danish nationwide prospective study of in situ carcinoma of the breast, a total of 275 women, treated with excision alone, were registered from 1982 to 1989. The series included 142 cases of ductal carcinoma in situ (DCIS), 100 cases of lobular carcinoma situ (LCIS), 26 cases of DCIS+LCIS, and seven cases of atypical hyperplasia (AH). Within a median follow-up of 120 months, a crude recurrence rate of 28% (76 cases) was found, of which 53% (40 cases) recurred as invasive carcinomas (IC) and 47% (36 cases) as CIS. CIS recurrences appeared after median 18 months, compared to median 42 months for IC recurrences. No statistical difference was found with respect to development of IC between the three groups of DCIS, DCIS+LCIS, and LCIS. The majority of recurrences were ipsilateral, also for LCIS. Forty four of 49 recurrences following DCIS, and seven of nine recurrences following DCIS+LCIS occurred as local recurrences. Histopathologically, in DCIS a strong association was found between large nuclear size and comedonecrosis. Univariate analysis showed a significant association to recurrence for nuclear size, comedonecrosis, and size of the original lesion. Multivariate analysis showed that only comedonecrosis and size of lesion were independent predictors of recurrence, however, specimen margins were not included in the analysis, as this parameter could not be adequately evaluated in the present series. Nuclear size of original DCIS lesion was related to histologic grade of the IC recurrence. The recurrence rate for DCIS of small nuclear size increased from 6% at five years of follow-up to 16% at 10 years, possibly due to a slower growth rate and a continued but delayed risk. Similarities were found between LCIS and DCIS of small nuclear size, both showing a continued risk and comparable rate of recurrence. Further, progression of IC to similar, highly differentiated type was seen, indicating a linkage between biological behavior of the two histological types.

Sports-related sudden cardiac death in a competitive and a noncompetitive athlete population aged 12 to 49 years: Data from an unselected nationwide study in Denmark

BACKGROUND Preparticipation screening programs have been suggested to reduce the numbers of sports-related sudden cardiac deaths (SrSCD). OBJECTIVE The purpose of this study was to identify and characterize all SrSCD aged 12-49 years and to address the difference in incidence rates between competitive and noncompetitive athletes. METHODS All deaths among persons aged 12-49 years from 2007-2009 were included. Death certificates were reviewed. History of previous admissions to hospital was assessed, and discharge summaries and autopsy reports were read. Sudden cardiac deaths (SCDs) and SrSCD cases were identified. RESULTS In the 3-year period, there were 881 SCDs, of which we identified 44 SrSCD. In noncompetitive athletes aged 12-35 years, the incidence rate of SrSCD was 0.43 (95% confidence interval [CI] 0.16-0.94) per 100,000 athlete person-years vs 2.95 (95% CI 1.95-4.30) in noncompetitive athletes aged 36-49 years. In competitive athletes, the incidence rate of SrSCD was 0.47 (95% CI 0.10-1.14) and 6.64 (95% CI 2.86-13.1) per 100,000 athlete person-years in those aged 12-35 years and 36-49 years, respectively. The incidence rate of SCD in the general population was 10.7 (95% CI 10.0-11.5) per 100.000 person-years. CONCLUSION The incidence rates of SrSCD in noncompetitive and competitive athletes are not different. The study showed an increase in the incidence rate of SrSCD in persons aged 36-49 years in both noncompetitive and competitive athletes compared to those aged 12-35 years. Importantly, SCD in the general population is much more prevalent than is SrSCD in all age groups.

Burden of Sudden Cardiac Death in Persons Aged 1 to 49 Years Nationwide Study in Denmark

Background—Knowledge of the burden and causes of sudden cardiac death (SCD) is sparse in persons aged <50 years; better understanding is needed to lower the risk of SCD. The aim of this study was to report SCD incidence rates and autopsy findings in persons aged 1 to 49 years. Methods and Results—All deaths in persons aged 1 to 49 years were included in 2007 to 2009. Death certificates were reviewed by 2 physicians. History of previous admissions to hospital was assessed, and discharge summaries were read. Sudden unexpected death cases were identified and autopsy reports were collected. In the 3-year study period, there were 7849 deaths of which we identified 893 (11%) SCD cases. The annual incidence rate per 100 000 persons increased from 2.3 (95% confidence interval, 2.0–2.7) to 21.7 (95% confidence interval, 20.2–23.4) in persons aged 1 to 35 and 36 to 49 years, respectively. Coronary artery disease was the most common cause of death and was found in 158 (36%) autopsied cases, followed by 135 (31%) cases of sudden unexplained death. Conclusions—In a nationwide cohort of persons aged <50 years, the annual incidence rate of SCD was ≈10× higher in persons aged 36 to 49 years than in persons aged 1 to 35 years. Notably, coronary artery disease was the most common cause of SCD, followed by unexplained deaths. These findings may help in developing strategies to prevent SCD in the future.

Carcinoma in situ of the breast: correlation of histopathology to immunohistochemical markers and DNA ploidy

In a consecutive and unselected series of 178 cases of carcinoma in situ of the breast (CIS), comprising both ductal (DCIS) and lobular type (LCIS), and a series of 48 cases of invasive carcinoma (IC) with predominance of DCIS, the association between histopathology, immunohistochemical markers (ER, PgR, MIB-1, c-erbB-2, and p53), and DNA ploidy was investigated, in order to discriminate biologically different groups. In DCIS, significant correlation was shown between large nuclear size and comedonecrosis, both of which showed also strong association to DNA aneuploidy, high proliferation activity, low steroid receptor content, and overexpression of c-erbB-2 and p53 – factors that may indicate an aggressive behavior. Small nuclear CIS, whether LCIS or DCIS, on the contrary, were DNA diploid with low proliferation, and no cases showed overexpression of c-erbB-2 and p53. Heterogeneity with respect to the investigated parameters was also a frequent finding that may reflect a development complexity. In IC, comparison of the DCIS and the invasive component showed similar patterns. No significant differences were shown between DCIS without and with invasion. This may indicate that none of the investigated parameters on its own are essential for the event of invasion.

Genetic investigations of sudden unexpected deaths in infancy using next-generation sequencing of 100 genes associated with cardiac diseases

Sudden infant death syndrome (SIDS) is the most frequent manner of post-perinatal death among infants. One of the suggested causes of the syndrome is inherited cardiac diseases, mainly channelopathies, that can trigger arrhythmias and sudden death. The purpose of this study was to investigate cases of sudden unexpected death in infancy (SUDI) for potential causative variants in 100 cardiac-associated genes. We investigated 47 SUDI cases of which 38 had previously been screened for variants in RYR2, KCNQ1, KCNH2 and SCN5A. Using the Haloplex Target Enrichment System (Agilent) and next-generation sequencing (NGS), the coding regions of 100 genes associated with inherited channelopathies and cardiomyopathies were captured and sequenced on the Illumina MiSeq platform. Sixteen (34%) of the SUDI cases had variants with likely functional effects, based on conservation, computational prediction and allele frequency, in one or more of the genes screened. The possible effects of the variants were not verified with family or functional studies. Eight (17%) of the SUDI cases had variants in genes affecting ion channel functions. The remaining eight cases had variants in genes associated with cardiomyopathies. In total, one third of the SUDI victims in a forensic setting had variants with likely functional effect that presumably contributed to the cause of death. The results support the assumption that channelopathies are important causes of SUDI. Thus, analysis of genes associated with cardiac diseases in SUDI victims is important in the forensic setting and a valuable supplement to the clinical investigation in all cases of sudden death.

Genetic investigation of 100 heart genes in sudden unexplained death victims in a forensic setting

In forensic medicine, one-third of the sudden deaths remain unexplained after medico-legal autopsy. A major proportion of these sudden unexplained deaths (SUD) are considered to be caused by inherited cardiac diseases. Sudden cardiac death (SCD) may be the first manifestation of these diseases. The purpose of this study was to explore the yield of next-generation sequencing of genes associated with SCD in a cohort of SUD victims. We investigated 100 genes associated with cardiac diseases in 61 young (1–50 years) SUD cases. DNA was captured with the Haloplex target enrichment system and sequenced using an Illumina MiSeq. The identified genetic variants were evaluated and classified as likely, unknown or unlikely to have a functional effect. The criteria for this classification were based on the literature, databases, conservation and prediction of the effect of the variant. We found that 21 (34%) individuals carried variants with a likely functional effect. Ten (40%) of these variants were located in genes associated with cardiomyopathies and 15 (60%) of the variants in genes associated with cardiac channelopathies. Nineteen individuals carried variants with unknown functional effect. Our findings indicate that broad genetic investigation of SUD victims increases the diagnostic outcome, and the investigation should comprise genes involved in both cardiomyopathies and cardiac channelopathies.

Plakoglobin: A diagnostic marker of arrhythmogenic right ventricular cardiomyopathy in forensic pathology?

PurposeThe histopathological diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) can be challenging in forensic medicine. Immunohistochemical myocardial analysis for plakoglobin has been suggested as a new diagnostic test for ARVC. We examined this in the setting of forensic pathology, applying this method to forensic autopsy samples.MethodsWe performed immunohistochemical staining for plakoglobin on 40 myocardial samples with an autopsy diagnosis of ARVC. In addition, histopathological reevaluation was performed applying the revised 2010 task force criteria including morphometric analysis. Myocardial samples from 15 subjects without heart disease were used as controls.ResultsBased on the histopathological reevaluation, 38 out of 40 cases were categorized as ARVC. A marked reduction in the plakoglobin staining was seen in 26 out of 38 myocardial samples in the ARVC-group. Of the two samples categorized as not ARVC, one showed reduced plakoglobin staining and one sample had normal staining. No control samples showed reduced plakoglobin staining.ConclusionsIn conclusion, our study displayed reduced plakoglobin staining in approximately 2/3 of myocardial samples with ARVC. Our data suggests that immunostaining for plakoglobin might serve as an additional diagnostic marker of ARVC in forensic pathology, but additional validation is required.