Residential Radon and Risk of Lung Cancer in Eastern Germany
Kreuzer, Michaela*†; Heinrich, Joachim*; Wölke, Gabi*; Rosario, Angelika Schaffrath*‡; Gerken, Michael§; Wellmann, Juergen¶; Keller, Gert∥; Kreienbrock, Lothar*; Wichmann, H-Erich*‡
From the *GSF-National Research Center for Environment and Health, Institute of Epidemiology, Neuherberg, Germany; †BfS-Federal Office for Radiation Protection, Institute of Radiation Hygiene, Neuherberg, Germany; ‡Department of Epidemiology, Ludwig-Maximilians-University of München, Munich, Germany; §Tumor Center Regensburg, University of Regensburg, Regensburg, Germany; ¶University of Muenster, Institute of Epidemiology and Social Medicine, Münster, Germany; ∥Saar University, Biophysics Unit, Homburg, Germany; **Hannover School of Veterinary Medicine, Department of Biometry, Epidemiology and Information Processing, Hannover, Germany
Submitted 9 April 2002; final version accepted 28 February 2003.
Financial support for this article was provided by the Federal Office for Radiation Protection, Salzgitter, Germany (Grant St SCH 4006, 4112, 4237).
Correspondence: H-Erich Wichmann, GSF-Institute of Epidemiology, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany. E-mail: email@example.com.
Background: There is suggestive evidence that residential radon increases lung cancer risk. To elucidate this association further, we conducted a case-control study in Thuringia and Saxony in Eastern Germany during 1990-1997.
Methods: Histologically confirmed lung cancer patients from hospitals and a random sample of population controls matched on age, sex and geographical area were personally interviewed with respect to residential history, smoking, and other risk factors. One-year radon measurements were performed in houses occupied during the 5-35 years prior to the interview. The final analysis included a total of 1,192 cases and 1,640 controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression.
Results: Measurements covered on average 72% of the exposure time window, with mean radon concentrations of 76 Bq/m3 among the cases and 74 Bq/m3 among the controls. The smoking- and asbestos-adjusted ORs for categories of radon (50-80, 80-140 and >140 Bq/m*3, compared with 0-50 Bq/m3) were 0.95 (CI = 0.77 to 1.18), 1.13 (CI = 0.86 to1.50) and 1.30 (CI = 0.88 to 1.93). The excess relative risk per 100 Bq/mł was 0.08 (CI = −0.03 to 0.20) for all subjects and 0.09 (CI = −0.06 to 0.27) for subjects with complete measurements for all 30 years.
Conclusions: Our data indicate a small increase in lung cancer risk as a result of residential radon that is consistent with the findings of previous indoor radon and miner studies.
It is well established that exposure to the radioactive gas radon (222Rn) and its progeny increases risk of lung cancer among workers in the uranium or other mining industry.1,2 The major radioactive exposure of public health concern, however, is long-term exposure of the general population to the much smaller concentrations of radon in homes. A direct transfer of risk estimates derived from studies of miner to residential environments is not possible due to substantial differences in the levels of radon exposure, confounding factors (eg, dust, arsenic, asbestos, smoking), differences in age and sex of affected subgroups, and differences in other physical factors such as breathing rate, the size distribution of aerosol particles, the unattached fraction of radon progeny and others. In the past decade a series of well-conducted epidemiological studies has investigated the risk of lung cancer in relation to indoor radon exposure directly via case-control studies.3-16 Some of these studies have found a statistically significant increased lung cancer risk, and other studies have not. Uncertainty in assessment of exposure, low statistical power and a limited range of radon concentrations have to varying degrees impeded these studies.17
From 1990 to 1996, a case-control study of lung cancer and indoor radon (comprising 1,449 cases and 2,297 controls) was conducted in Western Germany. There was no association between lung cancer and radon exposure across the entire study area.14,18 The study area was characterized by overall low radon exposures. When analyzes were restricted to subjects living in radon-prone areas, a 13% excess risk for an increase of 100 Bq/m3 was observed. In parallel, a case-control study using identical methods was conducted in Thuringia and Saxony in Eastern Germany, an area with increased radon levels.19 In this area, with many centuries of ore mining as well as uranium mining, the concentrations in homes are elevated due to natural background radiation and also due to mining activities. This paper provides results on the relation of indoor radon and lung cancer from the East German study.
Lung Cancer Cases
Reporting to the cancer registry of the former government of East Germany (German Democratic Republic, or GDR) dramatically dropped after the reunification of Germany in 1990. We therefore identified cases from each of the 5 hospitals in Thuringia and Saxony where investigation and treatment of lung cancer are carried out (Gera, Chemnitz, Coswig, Bad Berka, and Zschadrass). The recruitment period was from October 1990 to March 1997. Incident cases of lung cancer were included only if the diagnosis was histologically or cytologically ascertained by the clinical pathologist and metastases secondary to other tumors had been excluded. Further inclusion criteria for eligible cases were (i) current residence within study area, (ii) living in Germany since 1965, (iii) age less than 76 years, (iv) never having worked in the uranium mining industry, (v) an interview within 3 months after first diagnosis, (vi) no carcinoid tumors, (vii) an adequately good health status to face a personal interview of approximately 1-hour duration, and (viii) no initial evidence of tuberculosis. The proportion of eligible cases that consented to take part in the study was 73%.
Following the World Health Organization classifications, we coded cell subtype into three groups: small cell lung cancer, squamous cell carcinoma and adenocarcinoma. Because of small numbers we combined large cell carcinomas, mixed types and tumors for which no classification was possible, into the category “others”. Approximately 31% of the diagnoses from the clinical pathologist were derived from histology only, 13% were derived from cytology only and 56% were derived from both. A diagnosis from cytology was used only if a diagnosis from histology was not present. To ensure that cell subtypes were classified uniformly, the original pathologic material was additionally reviewed by two reference pathologists, one for cytologic and one for histologic material, without any knowledge of the tumor type diagnosed by the clinical pathologist. This material was obtained for approximately 61% of all cases’ tumors. When available, we used the diagnoses from the reference pathologist, with missing reference pathology replaced by the diagnosis from the clinical pathologist.
Controls were recruited as a two-stage population sample, in the same time period as the cases (1990–1997). In the first stage, a random sample of approximately 30,000 people was selected from the central registration office of the former GDR (status October 2, 1990). Based on this first sample, controls were randomly selected and frequency-matched to the cases by sex, age (six 5-year classes) and region (10 matching areas based on administrative districts). The inclusion criteria (i–iv) and (viii) were the same as those for the cases. A total of 4,244 controls fulfilled the requirements, of whom 1,933 were interviewed (46%) and 2,311 (54%) did not wish to participate.
Information on Potential Confounders
After subjects provided informed consent, trained staff conducted face-to-face interviews at the bedside of the patients or at home for controls. They used a standardized questionnaire, identical to the one in the West German study.14 Detailed information was collected on demographic characteristics, residential history, active and passive smoking history, occupational history, dietary habits and the personal and familial medical history. Subjects were defined as smokers if they had ever smoked regularly (at least one cigarette per day, four cigarillos per week or three cigars or pipes per week) for at least 6 months. Smoking exposure was explored in a series of phases, where a new phase was defined by a change in amount or type of tobacco product smoked. In each phase, information was available on the type of tobacco, amount smoked, duration of years, times of cessation and use of filter or nonfilter cigarettes. Current smokers were defined as smoking within the last 2 years before interview. Occupational exposures were evaluated on the basis of the lifelong job history including all jobs held for at least 6 months. Subjects who reported a job with a potential lung cancer risk were asked in more detail about working conditions and especially about exposure to asbestos.
Radon Dosimetry and Exposure Assessment
Residential history for each subject included information on all houses occupied for at least 1 year during the 5–35 years prior to interview. For each residence, information was gathered on the exact addresses, the time period of residence, housing conditions, radon-relevant alterations of the house, floor levels of the bedroom and main living room, and for both rooms the ventilation habits and average occupancy patterns. Attempts were made to measure radon concentrations in the current home and in the previous homes of the participants. To correct for differences in housing conditions and ventilation habits between study participants and the present inhabitants, a short questionnaire concerning these radon-relevant factors was administered to each of the present inhabitants.
Radon measurements were carried out using solid state nuclear alpha-track detectors that consist of a polycarbonate foil (Makrofol; Bayer AG, Leverkusen, Germany) inside a Kernforschungszentrum Karlsruhe (KfK)-type capsule. The detectors were placed for 1 year in the living room and bedroom in each of the identified houses by either trained field staff or the participants themselves, following a standard protocol. Six months after placement of the detectors, participants were requested by a letter to check whether dosimeters were in place. After 12 months, supplies were sent to each household for returning the detectors by mail to the Biophysics Unit at the Saar University in Homburg. Because annual radon concentrations of more than 400 Bq/m3 require shorter measurement periods than 1 year, spot measurements were conducted with activated charcoal detectors to identify relevant houses. In this case, several α-track measurements, equally distributed over the year, were carried out. For details on type of dosimeter, methods of radon exposure measurement and calibration techniques see Kappel et al20 and Kreienbrock et al.14,21
Radon exposure was quantified as follows. First, we calculated the weighted average of the radon concentrations in the living room and the bedroom of each home, using the proportion of time spent in each room as weights. Information on the average hours spent in each room in each residence was collected individually for each subject. If the bedroom measurement was missing, the living room measurement was substituted and multiplied by a correction factor of 0.94 (given by the median ratio of bedroom and living room measurements), and vice versa. Second, the time-weighted average (TWA) radon concentration during the exposure window 5–35 years prior to interview was calculated based on the radon concentrations over all addresses, weighted by the number of years spent on each address. We accounted for reconstruction of the building, changes in temporal (occupancy rates) and spatial mobility (floor level) or in ventilation habits within one residence period, as well as between present inhabitants and study participants, by applying correction factors based on a multiplicative model.22 For the time periods for which no valid measurement was available, missing data were imputed by the study-specific mean of radon concentrations measured in the homes of the control subjects.23 To avoid seasonal effects we included only those measurements that were conducted for 10–14 months.
A total of 1,815 confirmed lung cancer cases and 1,933 population controls were interviewed. Because of incomplete smoking history, 24 cases and 7 controls were excluded. To avoid excessive imputation, the present analysis was restricted to subjects with at least one valid radon measurement in the exposure time window 5 to 35 years prior to interview. This reduced the study population for analysis to 1,192 cases (66%) and 1,640 controls (85%).
Odds ratios (OR) and asymptotic 95% confidence intervals (CI) were calculated via conditional logistic regression with strata for sex, age in 6 classes, and 10 matching areas. Using previous definitions, we categorized the exposure to residential radon concentration with cutoff points at 50, 80 and 140 Bq/m3.14 Linear trends were estimated by treating radon exposure as a continuous variable and determining excess relative risks (ERR) (approximated by OR–1), per additional exposure of 100 Bq/m3. All odds ratios were adjusted for smoking and asbestos exposure, the 2 main confounders. Cigarette smoking was taken into account by “log (pack-years + 1)” and “years since quitting” in 4 categories (current smokers/quit less than 2 years ago; quit 2–5 years ago, quit 5–10 years ago, quit &;gt10 years ago), with smoking of other tobacco products as a separate category. Occupational exposure to asbestos was included via a binary variable. In a sensitivity analysis we also included other potential confounders such as additional occupational exposure, exposure to environmental tobacco smoke, nutrition, and social status. Because these factor had no material impact on the estimated radon risks, we omitted them from the final risk models. The statistical analysis was carried out using the PHREG procedure of the SAS® software, Rel. 6.12,24 under a UNIX system.
Table 1 shows the main demographic characteristics of the study population. Approximately 12% of the cases and 14% of the controls were women. The mean age was 61 years for men and 60 years for women. Among men the most common histologic cell type was squamous cell carcinoma (41%), followed by small cell lung cancer (29%) and adenocarcinoma (26%), whereas among women adenocarcinoma was predominant (55%). The educational level of men tended to be higher among controls as compared with cases.
The proportion of men who were lifelong nonsmokers was 2% among cases and 26% among controls. Among women, 51% of cases and 77% of controls had never smoked (Table 1). The OR for lung cancer for smokers compared with lifelong nonsmokers was 18 (CI = 12–29) among men and 2.8 (CI = 1.7–4.8) among women, respectively. Among smokers, substantially more cases than controls were current smokers. Cases had smoked more cigarettes per day and over a longer period than the controls, resulting in strong exposure-disease relationships in the risk analyzes. For example, among men the ORs (adjusted for asbestos) for smokers compared with nonsmokers in the categories of less than 20, 20–40, 40 or more cumulative pack-years were 8.8 (CI = 5.5–14.1), 31 (CI = 19–49) and 58 (CI = 34–100), respectively. Among women, the corresponding risk estimates were 2.0 (CI = 1.2–3.3) for less than 20 pack-years and 14 (CI = 4.5–41) for 20 or more pack-years. Among men, occupational asbestos exposure was reported by 30% of cases and 28% of controls. Among women only a negligible proportion of cases and controls was found to be exposed to asbestos.
The study subjects had not moved frequently within the time period 5–35 years before interview (Table 2). Among the cases and controls the average number of homes occupied in this time period was 2.3 and 2.4, respectively, yielding a total of 2,767 and 3,968 addresses. Measurements were obtained in 1,415 of the addresses of the cases and 1,992 of the addresses of the controls. On average, radon measurements covered 21.3 years of the 5–35 year period among the cases and 21.6 years among the controls, or 71% and 72% of the exposure window, respectively.
We found considerably higher radon concentrations in the living room than in the bedroom (Table 3). The highest mean radon concentrations were found for houses with no or partial basement, or poorly insulated basement, and for houses built before 1900. Half-timbered houses, single-family homes, houses in rural areas, and rooms in the basement or on the ground floor were also associated with an elevated radon concentration. Cases and controls spent on average 7.7 hours in the bedroom and 6.0 hours in the living room per day. Taking into account holidays and other periods of absence from home, cases and controls spent on average 53% of their time at home. The occupancy-weighted average of the 1-year measurements in the living room and bedroom followed an approximately log-normal distribution. The quartiles of the distribution occurred at 34, 52 and 83 Bq/m3 among the cases and 37, 52 and 79 Bq/m3 among the controls.
After imputation of missing radon measurements, the time-weighted average (TWA) radon concentrations within 5 to 35 years prior to interview showed an arithmetic mean of 76 Bq/m3 among the cases and 74 Bq/m3 among the controls. Table 4 displays the odds ratios for lung cancer and residential radon, based on the TWA of radon concentrations. The ORs adjusted for smoking and asbestos were 0.95 (CI = 0.77–1.18), 1.13 (CI = 0.86–1.50) and 1.30 (CI = 0.88–1.93) for 50–80, 80–140 and over 140 Bq/m3, respectively, compared with the reference category of 0-50 Bq/m3. The adjusted linear trend test showed an elevated excess relative risk of 0.08 (CI = –0.03, 0.20) for an increase of 100 Bq/m3 in the radon concentration.
To investigate the effect of imputing missing radon concentrations, we limited the analyzes to subjects with complete radon measurements in the time period 5–35 years (427 cases and 536 controls). No major differences were observed (OR = 0.09; CI = –0.06 to 0.27) (Table 5). A similar pattern of risk estimates was observed when we considered the time period 5–25 years (or 5–15 years) before interview and limited the study population to subjects with complete measurements in the corresponding time period.
The lung cancer risk in relation to TWA residential radon exposure with respect to the three main histologic subtypes is given in Table 6. Elevated odds ratios in the highest exposure category (140 or more Bq/m3) were observed for all major histologic types. The strongest evidence for a trend in risk was for small cell lung cancer (ERR = 0.23 per increase of 100 Bq/m3; CI = 0.02 to 0.47).
The aim of the present study was to examine the relation between residential radon and lung cancer risk. The study was carried out in an area in Germany with high concentrations of residential radon. We collected detailed information on residency and individual occupancy in the current and previous homes and on the main confounders by standardized questionnaires with patients and controls themselves, without using next-of-kin interviews. One-year measurements using α-track detectors were performed in the living rooms and bedrooms of the homes occupied 5–35 years prior to interview. The analysis included a large number of cases (n = 1,192) and controls (n = 1,640). We collected radon measurements in residences comprising over 2/3 of the 30-year exposure period, thus representing a considerable amount of lifetime residential exposure. All cases were confirmed histologically or cytologically as a primary tumor of the lung. In accordance with previous studies, our data indicated a small increase in lung cancer risk with increasing residential radon exposure, an increase that was most pronounced for small cell lung cancer.
Some potential weaknesses of our study should be discussed. The recruitment of lung cancer patients in Eastern Germany has to be done via hospitals, because there has been no complete cancer registry since 1990. In analyzes based on data of the former East German cancer registry we estimated a coverage of about 50% for our study area. Thus, the representativeness of our cases to all cases is not directly measurable. An advantage of our approach (in contrast to radon studies that recruited cases via cancer registries), was that patients were alive at interview. Thus, all information (eg, on residency, occupancy, smoking history, etc.) could be gathered from the patients themselves, and a large part of radon measurements could be done in their own homes under their own living circumstances.
A possible classification bias of cell subtype due to different clinical pathologists should be small, since we used the diagnoses from the reference pathologist. Although a reference pathology report was missing for approximately 39% of the study subjects, there should be little bias, because the proportion of the cell types diagnosed by the clinical pathologist and subsequently confirmed by the reference pathologist was high (89% for small cell lung cancer, 72% for squamous cell carcinoma and 81% for adenocarcinoma).
Another possible source of bias was the low response rate among controls (46%). The effect of a potential selection bias could not be ruled out, since we had no information on sociographic or other factors among nonresponders. A nonresponder analysis in the West German radon study14 demonstrated that the major reason for not participating in that study was the time-consuming interview and the requirement to conduct a 1-year radon measurements in the home. In the West German study, higher educated people tended to be more willing to participate. When we additionally adjusted for years of school attendance in the various models in the present study, there were no major changes in the risk estimates. We also compared smoking habits reported by participating controls with data of national surveys conducted in 199125 and 199826 in East Germany. Based on these data and taking into account the age distribution of our controls the proportion of never-smokers in 1991 was estimated to be 21% among men and 80% among women and 32% and 74%, respectively, in 1998. This is in good agreement with our data (26% among men and 77% among women).
Another problem concerns the exclusion of 33% of the interviewed cases and 14% of the controls due to missing radon measurements. This could possibly introduce a bias, if responders and nonresponders differed with respect to radon exposure. The larger proportion of excluded subjects among the cases than the controls is due to a higher number of missing measurements in the current home caused by death during the measurement period. Therefore, bias due to selectively missing radon data is unlikely. Since subjects with small cell carcinoma have a shorter survival time and their tumors are suspected to be more likely radiation-induced,1 we compared the proportion of small cell lung cancers among study participants with that of nonparticipants, and found no major differences (28% vs. 27%).
Given the weak associations between lung cancer and residential radon, special attention was given to smoking as a confounder. Lifelong smoking exposure was documented with information on intensity, duration and other characteristics within phases of constant smoking habits. Information was obtained in personal interviews by regularly trained interviewers. Underreporting of smoking is unlikely. As stated before, smoking data of controls were in good agreement with external population data. No such official statistics exist for lung cancer patients. The observed risk estimates, however, are comparable with results from other European studies that investigated the association between smoking and lung cancer.27 Moreover, in a European validation study using cross-interviews with next-of-kin Nyberg et al28 had shown that misclassification of nonsmoking status is likely to be negligible. To reduce the possibility of residual confounding due to smoking in the risk model, we tested several models using different combinations of smoking variables. When we combined the variables pack-years, years of quitting smoking, and type of tobacco product, we achieved the best fit. Smoking acted as a negative confounder, as observed in other studies.9-11
Another source of potential bias is the inaccuracy of exposure assessment. Much effort was invested to quantify individual exposure in an appropriate way. Radon detectors were installed for one year in the living room and bedroom. Detailed information was gathered on retrospective individual spatial and temporal mobility as suggested by Field et al29,30 A multiplicative model has been developed to derive internal correction factors for alterations to the house or changes in living habits (such as ventilation habits, occupancy rates and spatial mobility).22 Results of a series of intercomparisons of radon detectors under field conditions showed a high accuracy for the German radon detectors. Generally the coefficient of variation was less than 10%.21 Another potential limitation of our study (and most other indoor radon studies) is that radon exposures outside from home (outdoors or at the workplace) were not taken into account. Radon measurements conducted close to ground levels in 11 residential areas in Thuringia and Saxony showed mean radon concentrations ranging from 10 to 27 Bq/m3, which is approximately one third the indoor levels.31 The failure to link the radon concentrations with the subject’s movement outside the home may increase exposure misclassification and lead to underestimation of risk, as reported in the Iowa radon study.32
We also investigated the impact of choosing different cut-points for the categorical analyzes of radon exposure and applying different types of estimators for linear trend. The referent category of less than 50 Bq/m3 in our study is in accordance with several other studies.10,11,14,32 When we used quintiles of the exposure of controls, a similar pattern of risk estimates was obtained. The same holds true when a logarithmic scale was applied. The odds ratios were 0.98 (CI = 0.80–1.21) for 50–100 Bq/m3, 1.20 (CI = 0.86–1.66) for 100–200 Bq/m3, 0.89 (CI = 0.46–1.72) for 200–400 Bq/m3 and 2.20 (CI = 0.76–6.37) for > 400 Bq/m3 compared with the reference category. To reduce the influence of extreme values, we calculated a trimmed estimator discarding the 1% highest radon values. This yielded a similar ERR per 100 Bq/m3 of 0.07 (CI = −0.16;0.35), but with wider confidence intervals. Similar results were obtained with a categorical trend estimator with 5 (ERR = 0.11; CI = –0.09 to 0.35) or 8 (ERR = 0.08; CI = −0.09 to 0.27) categories as described in Schaffrath Rosario et al.33
We found a moderate increase in lung cancer risk as a result of residential radon, which is in agreement with the results of previous studies that included direct, long-term measurement of radon using alpha-track detectors (Table 7). Some of these studies reported a statistically significant ERR for an increase of 100 Bq/m3,10,13,16 some observed an elevated ERR that did not achieve statistical significance,3,7,9,11,12,15 whereas no clear effect was found in the remaining studies.4,5,8,14 Uncertainty in exposure assessment may have contributed to some of the negative results. In most studies, the complete time window of interest could not fully be covered by radon measurements. Gaps as well as imputation of missing data contribute to measurement error and have been suggested to lead to odds ratios that are biased towards 1.0.34,35 Other sources of measurement error concern a high variability of radon levels when measurements were repeated in the same residence in the same time period, as well as systematic changes in the radon levels over the years. Statistical models have been developed to analyze data with measurement error.35,36 After application of these models to data in three previous indoor studies, an increase in risk estimates because of radon exposure was observed.12,16,32 Another method of possibly minimizing inaccurate measurements in previous residences is to measure the long-term cumulative exposure by analyzing glass objects in the household via surface monitors.8,37,38
When we explored the effect of radon by histologic types of lung cancer, the largest risk estimates were obtained for small cell lung cancer, followed by squamous cell carcinoma, while no association was present with adenocarcinoma of the lung. Inconsistent results have been reported in previous indoor radon studies. A stronger effect of radon exposure in small cell lung cancer compared with all others was obtained in the West German study and the British study.12,14 The Stockholm study9 provided evidence for stronger effects among small cell lung cancer and squamous cell carcinoma, while the Swedish nationwide study10 found the largest effects among small cell lung cancer and adenocarcinoma. Other studies showed an association with radon exposure mainly for adenocarcinoma or large cell carcinoma,7,13 whereas more or less similar risk estimates for each of the histologic types were found in other studies.4,8,11 Among uranium miners, small cell carcinoma represented the majority of lung cancer cases,1,39 although with increasing follow-up time squamous cell carcinoma may become more predominant.1,40,41
In conclusion, we examined the relation of residential radon and risk of lung cancer in an area in Germany with elevated radon levels. Our findings suggest a moderate increase in lung cancer risk, which is most pronounced among small cell lung cancer. Overall, our risk estimates are similar in magnitude to those from other residential radon studies, and also to extrapolations from underground miners studies.
We acknowledge the contributions of Drs. Wiesner and Bonnet (Bad Berka); Drs. Al-Zand and Weber (Zschadrass); Drs. Baudrexl, Matthiessen, Selbitschka, and Schmidt (Coswig); Drs. Heil and Neudeck (Gera); and Drs. Schaarschmidt and Schmidt (Chemnitz) for identifying lung cancer cases. The authors thank the clinical pathologists Dr. Schmidt (Bad Berka), Prof. Haupt (St. Georg), Dr. Schieck (Grimma), Prof. Justus, Dr. Kunze (Dresden-Friedrichstadt), Dr. Urban, Dr. Perzlin (Gera), and Dr. Habeck (Chemnitz). We also give special thanks to the pathologic reviewer Prof. Mueller (Bochum) and Profs. Attay and Topalidis (Hannover).
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