- Email: [email protected]
Increased incidence of papillary thyroid cancer among total thyroidectomies in Crete
Otolaryngology–Head and Neck Surgery (2007) 136, 560-562
ORIGINAL RESEARCH
Increased incidence of papillary thyroid cancer among total thyroidectomies in Crete Emmanuel P. Prokopakis, MD, PhD, Vassilios A. Lachanas, MD, George A. Velegrakis, MD, PhD, Dimitrios D. Tsiftsis, MD, PhD, Joanna Moschandreas, PhD, and Georgios E. Chalkiadakis, MD, PhD, Crete, Greece OBJECTIVE: To investigate the increased incidence of papillary thyroid cancer as found in specimens of total thyroidectomies and potential correlation with etiological factors. STUDY DESIGN AND SETTING: A retrospective study on patients who underwent total thyroidectomy, from 1990 to 2004, in an academic tertiary referral medical center. Patients’ records were placed in a database, which included medical condition, history, and demographics. Histopathological slides were reviewed with special focus on papillary cancer. RESULTS: Our series consisted of 2379 patients. Thyroid cancer was confirmed in 354 patients (14.88%). Papillary carcinoma represented the most frequent type (316 patients, 89.26%). Increased incidence of papillary carcinomas was noticed after 1995, reaching the maximum value in the year 2000. After 2000, there was a descending trend and then a plateau. CONCLUSION: The increased incidence of papillary thyroid cannot be attributed to dietary patterns or increased diagnostic and therapeutic activity. It is likely to be associated with increased radiation and may be associated with the Chernobyl fallout. © 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
investigate the demographics of thyroid cancer as found in specimens of total thyroidectomies performed in an academic tertiary referral medical center during the last 15 years. Emphasis is given to the potential correlation with the nuclear accident at Chernobyl in 1986, as well as with nutrition pattern and possible surgical overtreatment.
MATERIALS AND METHODS
number of studies show upward incidence trends of thyroid cancer associated with radiation,1-3 dietary patterns,4-6 and increased diagnostic activity because of more sensitive diagnostic tests or surgical overtreatment.7 The island of Crete is the southernmost part of the European continent and is located in the eastern Mediterranean Sea. It has an area of 8261 km2 and according to the latest census has 800,000 inhabitants. The purpose of this study is to
A retrospective study was conducted on patients who had undergone thyroid surgery from January 1990 to December 2004 in three departments (Department of Surgery, Department of Surgical Oncology, and Department of Otolaryngology–Head and Neck Surgery) of an academic tertiary referral medical center (University Hospital of Crete, School of Medicine, Heraklion, Crete, Greece). All patients’ records were placed in a database, which included patients’ medical condition, history, and demographics. Histopathological slides were also reviewed thoroughly in all cases, with a special focus on papillary cancer because this type of thyroid cancer is the most frequent type. We classified papillary cancer into two categories: (1) silent carcinomas: defined as single or multifocal microcarcinomas with a tumor diameter ⱕ1 cm, and (2) clinical carcinomas: defined as tumors with a diameter ⬎1 cm. Data were assessed by using the Poisson dispersion test. The Poisson dispersion test was applied on the null hypothesis that the risk of occurrence of papillary carcinoma in
From the Departments of Otolaryngology–Head and Neck Surgery (Drs Pokopakis, Lachanas, and Velegrakis); Surgical Oncology (Dr Tsiftsis); Social Medicine (Dr Moschandreas); and General Surgery (Dr Chalkiadakis); University Hospital of Crete, Heraklion.
Reprint requests: George E. Chalkiadakis, MD, PhD, University Hospital of Crete, Department of General Surgery, 2nd Building, 3rd Floor, Heraklion-Crete, Greece, PO Box 1352. E-mail address: [email protected].
A
0194-5998/$32.00 © 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2006.10.014
Prokopakis et al
Increased incidence of papillary thyroid cancer . . .
561
Table 1 Incidence of thyroid cancer histological types, on patients who had undergone thyroid surgery from January 1990 to December 2004 Histological type of thyroid cancer
Total
Papillary Follicular Medullary Other Total
316 22 7 9 354
patients undergoing thyroidectomy does not change over time. Under the null hypothesis, the number of cases appearing in different time intervals follows a Poisson distribution.8 The study protocol was approved by the University Hospital of Heraklion review board.
Figure 1 Time course curves showing the incidence of papillary carcinomas as well as both clinical and silent subtypes. The curves represent the proportion of papillary carcinoma and the silent and clinical subtypes to the number of thyroidectomies performed for each year.
RESULTS
0.0001) and also when the silent types were considered separately (214 ⫽ 56.2, P ⬍ 0.0001).
Our series consisted of 2379 patients, 368 men (mean age, 52.8 years) and 2011 women (mean age, 44.3 years). Thyroid cancer was confirmed by histological examination in 354 (14.88%) of them (Table 1). Papillary carcinoma represents the most frequent type and was found in 316 patients (89.26%). The mean age of those patients was 27.7 years (female/male ratio: 2.6/1). Clinical subtype was identified in 203 patients (64.24%), whereas the remaining 113 patients (35.76%) represent the silent subtype. Time course curves showing the incidence of papillary carcinomas, as well as both clinical and silent subtypes were obtained (Table 2 and Fig 1). Curves represent the proportion of papillary carcinoma and the silent and clinical subtypes to the number of thyroidectomies performed for each year from 1990 to 2004. Variability in the occurrence of papillary carcinoma in excess of that expected if the risk were constant over time was detected (214 ⫽ 142.4, P ⬍ 0.0001). From the data, it can be seen that there is an increase in papillary carcinomas, including both clinical and silent subtypes after 1995, reaching the maximum value in the year 2000. After 2000, there is a descending trend and then a plateau. Excess variability was also detected when only the clinical cases were considered (214 ⫽ 100.0, P ⬍
DISCUSSION The increase in incidence of thyroid cancer noticed on the island of Crete corresponds to an increase in the papillary form of thyroid cancer, whereas no changes in the other subtypes were noticed. One explanation for the lack of an increase in the other types of thyroid cancer is that there were very few of these cases (so chance fluctuations play a bigger role). Among the risk factors for thyroid cancer, the most established is ionizing radiation. Data obtained from studies involving patients subjected to external radiation, the fallout of nuclear bombs, or, more recently, the Chernobyl accident show that radiation plays an important role in thyroid carcinogenesis9,10 and principally in papillary thyroid cancer.11 In Greece, there was remarkable geographical variability of the contamination caused by the Chernobyl accident on April 26, 1986. The evaluated ground activity because of 137Cs of Chernobyl origin deposition ranged between 0.01 and 137 kBq/m2. Because the island of Crete was not included in the polluted regions in 1986 (evaluated ground activity because of 137Cs 0.01
Table 2 Incidence of papillary thyroid carcinoma, clinical and silent subtype, and thyroidectomies performed, for each year from 1990 to 2004 Year
90
91
92
93
94
95
96
97
98
99
00
01
02
03
04
Total
Papillary total Silent papillary Clinical papillary Thyroidectomies
4
4 3 1 172
6 1 5 158
2 1 1 134
9 2 7 190
15 5 10 142
17 8 9 138
24 8 16 163
37 12 25 142
36 12 24 119
48 18 30 271
40 11 29 199
28 10 18 173
24 15 9 144
22 7 15 159
316 113 203 2379
4 75
562
Otolaryngology–Head and Neck Surgery, Vol 136, No 4, April 2007
kBq/m2),12 no radiation evaluation has been performed in our region since then. Nevertheless, radiation contamination in our region may be correlated with the increased rainfall volume noticed during the period after the Chernobyl accident. It is noticeable that rainfall volume in May 1986 (33.5 mm) was 2.54 times higher than the average (13.16 mm) of the last 50 years, according to Hellenic Meteorological Service records. Radiation contamination in our region may be correlated with another interesting phenomenon to be addressed, the “colored rain phenomenon.” This is a rain originating in clouds that contain dust from the Sahara desert and North Africa region.13,14 This phenomenon is very common, especially in May, in Crete because of its proximity to Africa. Furthermore, it has been documented that the Chernobyl fallout has contaminated the North African coast and Sahara desert.15,16 Radioactivity of the colored rain dust containing radionuclides, which originated from the Chernobyl accident, has also been confirmed.13,14 We believe that there are strong indications correlating our results with radiation. The increased cases of thyroid papillary carcinoma, as noticed in our series after 1995, reaching peak values in the year 2000, are likely to represent the effect of the Chernobyl fallout. After that year, there is a decrease in cases of papillary thyroid cancer, whereas the number of thyroidectomies displays a decreasing trend from 2000 to 2003. This decrease is even more obvious in the clinical subtype than the silent one. A silent subtype case of papillary cancer represents an accidental finding with no clinical suspicion and sometimes possibly reflects an over diagnosis. Further investigations will show the possibility of correlation between “colored rain phenomenon,” radiation contamination, and incidence of thyroid cancer in our area. Dietary patterns have been associated with the etiology and increased incidence of thyroid cancer. Seafood, because of its high content of iodine, and cruciferous vegetables, because of their goitrogenic nature, have been associated with increased risk of follicular thyroid cancer.4-6 Most Greek dietary patterns, which are rich in raw vegetables, are protective against thyroid cancer, whereas no association with the papillary thyroid carcinoma was found.4 It should also be mentioned that the available salt in our country is iodine enriched. Thus, association between nutrition and increase of thyroid cancer cannot be established. Upward incidence trends of thyroid cancer worldwide have also been associated with increased diagnostic activity because of more sensitive diagnostic tests.7 In our series, silent papillary carcinoma subtype indicates the increased diagnostic and therapeutic activity. The increased incidence trend of papillary carcinoma observed in our series was not because of the rise in silent carcinomas. There was a proportional increase in both clinical and silent subtypes. To
our knowledge (Medline search), this is the first survey reporting potential correlation among thyroid cancer and radiation caused by the Chernobyl fallout in southeastern Europe. In conclusion, the increased incidence of papillary thyroid cancer noticed on the island of Crete cannot be attributed to dietary patterns or increased diagnostic and therapeutic activity. It should be mainly attributed to increased radiation and can be associated with the Chernobyl fallout.
REFERENCES 1. Remontet L, Esteve J, Bouvier AM, et al. Cancer incidence and mortality in France over the period 1978-2000. Rev Epidemiol Sante Publique 2003;51:3–30. (Grade B). 2. Niedziela M, Korman E, Breborowicz D, et al. A prospective study of thyroid nodular disease in children and adolescents in western Poland from 1996 to 2000 and the incidence of thyroid carcinoma relative to iodine deficiency and the Chernobyl disaster. Pediatr Blood Cancer 2004;42:84 –92. (Grade B). 3. Verger P, Catelinois O, Tirmarche M, et al. Thyroid cancers in France and the Chernobyl accident: risk assessment and recommendations for improving epidemiological knowledge. Health Phys 2003;85:323–9. (Grade D). 4. Markaki I, Linos D, Linos A. The influence of dietary patterns on the development of thyroid cancer. Eur J Cancer 2003;39:1912–9. (Grade B). 5. Kolonel LN, Hankin JH, Wilkens LR, et al. An epidemiologic study of thyroid cancer in Hawaii. Cancer Causes Control 1990;1:223–34. (Grade B). 6. Ron E, Kleinerman RA, Boice JD, et al. A population-based casecontrol study of thyroid cancer. J Natl Cancer Inst 1987;79:1–12. (Grade B). 7. Verkooijen HM, Fioretta G, Pache JC, et al. Diagnostic changes as a reason for the increase in papillary thyroid cancer incidence in Geneva, Switzerland. Cancer Causes Control 2003;14:13–7. (Grade B). 8. Armitage P, Berry G. Statistical methods in medical research. 2nd ed. Oxford: Blackwell Scientific Publications, 1987:211–2, 479 – 80. (Grade D). 9. Ron E, Lubin JH, Shore RE, et al. Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies. Radiat Res 1995;141:259 –77. (Grade B). 10. Williams ED, Pacini F, Pinchera A. Thyroid cancer following Chernobyl. J Endocrinol Invest 1995;18:144 – 6. (Grade D). 11. Moretti F, Nanni S, Pontecorvi A. Molecular pathogenesis of thyroid nodules and cancer. Baillieres Best Pract Res Clin Endocrinol Metab 2000;14:517–39. (Grade D). 12. Simopoulos SE. Soil sampling and 137Cs analysis of the Chernobyl fallout in Greece. Int J Rad Appl Instrum 1989;40:607–13. (Grade D). 13. Papastefanou C, Manolopoulou M. The radioactivity of coloured rain in Thessaloniki, Greece. Sci Total Environ 1989;80:225–7. (Grade D). 14. Papastefanou C, Manolopoulou M, Stoulos S, et al. Coloured rain dust from Sahara Desert is still radioactive. J Environ Radioact 2001;55: 109 –12. (Grade D). 15. Baggoura B, Noureddine A, Benkrid M. Level of natural and artificial radioactivity in Algeria. Appl Radiat Isot 1998;49:867–73. (Grade B). 16. Shawky S, el-Tahawy M. Distribution pattern of 90Sr and 137Cs in the Nile delta and the adjacent regions after Chernobyl accident. Appl Radiat Isot 1999;50:435– 43. (Grade C).
ORIGINAL RESEARCH
Increased incidence of papillary thyroid cancer among total thyroidectomies in Crete Emmanuel P. Prokopakis, MD, PhD, Vassilios A. Lachanas, MD, George A. Velegrakis, MD, PhD, Dimitrios D. Tsiftsis, MD, PhD, Joanna Moschandreas, PhD, and Georgios E. Chalkiadakis, MD, PhD, Crete, Greece OBJECTIVE: To investigate the increased incidence of papillary thyroid cancer as found in specimens of total thyroidectomies and potential correlation with etiological factors. STUDY DESIGN AND SETTING: A retrospective study on patients who underwent total thyroidectomy, from 1990 to 2004, in an academic tertiary referral medical center. Patients’ records were placed in a database, which included medical condition, history, and demographics. Histopathological slides were reviewed with special focus on papillary cancer. RESULTS: Our series consisted of 2379 patients. Thyroid cancer was confirmed in 354 patients (14.88%). Papillary carcinoma represented the most frequent type (316 patients, 89.26%). Increased incidence of papillary carcinomas was noticed after 1995, reaching the maximum value in the year 2000. After 2000, there was a descending trend and then a plateau. CONCLUSION: The increased incidence of papillary thyroid cannot be attributed to dietary patterns or increased diagnostic and therapeutic activity. It is likely to be associated with increased radiation and may be associated with the Chernobyl fallout. © 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
investigate the demographics of thyroid cancer as found in specimens of total thyroidectomies performed in an academic tertiary referral medical center during the last 15 years. Emphasis is given to the potential correlation with the nuclear accident at Chernobyl in 1986, as well as with nutrition pattern and possible surgical overtreatment.
MATERIALS AND METHODS
number of studies show upward incidence trends of thyroid cancer associated with radiation,1-3 dietary patterns,4-6 and increased diagnostic activity because of more sensitive diagnostic tests or surgical overtreatment.7 The island of Crete is the southernmost part of the European continent and is located in the eastern Mediterranean Sea. It has an area of 8261 km2 and according to the latest census has 800,000 inhabitants. The purpose of this study is to
A retrospective study was conducted on patients who had undergone thyroid surgery from January 1990 to December 2004 in three departments (Department of Surgery, Department of Surgical Oncology, and Department of Otolaryngology–Head and Neck Surgery) of an academic tertiary referral medical center (University Hospital of Crete, School of Medicine, Heraklion, Crete, Greece). All patients’ records were placed in a database, which included patients’ medical condition, history, and demographics. Histopathological slides were also reviewed thoroughly in all cases, with a special focus on papillary cancer because this type of thyroid cancer is the most frequent type. We classified papillary cancer into two categories: (1) silent carcinomas: defined as single or multifocal microcarcinomas with a tumor diameter ⱕ1 cm, and (2) clinical carcinomas: defined as tumors with a diameter ⬎1 cm. Data were assessed by using the Poisson dispersion test. The Poisson dispersion test was applied on the null hypothesis that the risk of occurrence of papillary carcinoma in
From the Departments of Otolaryngology–Head and Neck Surgery (Drs Pokopakis, Lachanas, and Velegrakis); Surgical Oncology (Dr Tsiftsis); Social Medicine (Dr Moschandreas); and General Surgery (Dr Chalkiadakis); University Hospital of Crete, Heraklion.
Reprint requests: George E. Chalkiadakis, MD, PhD, University Hospital of Crete, Department of General Surgery, 2nd Building, 3rd Floor, Heraklion-Crete, Greece, PO Box 1352. E-mail address: [email protected].
A
0194-5998/$32.00 © 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2006.10.014
Prokopakis et al
Increased incidence of papillary thyroid cancer . . .
561
Table 1 Incidence of thyroid cancer histological types, on patients who had undergone thyroid surgery from January 1990 to December 2004 Histological type of thyroid cancer
Total
Papillary Follicular Medullary Other Total
316 22 7 9 354
patients undergoing thyroidectomy does not change over time. Under the null hypothesis, the number of cases appearing in different time intervals follows a Poisson distribution.8 The study protocol was approved by the University Hospital of Heraklion review board.
Figure 1 Time course curves showing the incidence of papillary carcinomas as well as both clinical and silent subtypes. The curves represent the proportion of papillary carcinoma and the silent and clinical subtypes to the number of thyroidectomies performed for each year.
RESULTS
0.0001) and also when the silent types were considered separately (214 ⫽ 56.2, P ⬍ 0.0001).
Our series consisted of 2379 patients, 368 men (mean age, 52.8 years) and 2011 women (mean age, 44.3 years). Thyroid cancer was confirmed by histological examination in 354 (14.88%) of them (Table 1). Papillary carcinoma represents the most frequent type and was found in 316 patients (89.26%). The mean age of those patients was 27.7 years (female/male ratio: 2.6/1). Clinical subtype was identified in 203 patients (64.24%), whereas the remaining 113 patients (35.76%) represent the silent subtype. Time course curves showing the incidence of papillary carcinomas, as well as both clinical and silent subtypes were obtained (Table 2 and Fig 1). Curves represent the proportion of papillary carcinoma and the silent and clinical subtypes to the number of thyroidectomies performed for each year from 1990 to 2004. Variability in the occurrence of papillary carcinoma in excess of that expected if the risk were constant over time was detected (214 ⫽ 142.4, P ⬍ 0.0001). From the data, it can be seen that there is an increase in papillary carcinomas, including both clinical and silent subtypes after 1995, reaching the maximum value in the year 2000. After 2000, there is a descending trend and then a plateau. Excess variability was also detected when only the clinical cases were considered (214 ⫽ 100.0, P ⬍
DISCUSSION The increase in incidence of thyroid cancer noticed on the island of Crete corresponds to an increase in the papillary form of thyroid cancer, whereas no changes in the other subtypes were noticed. One explanation for the lack of an increase in the other types of thyroid cancer is that there were very few of these cases (so chance fluctuations play a bigger role). Among the risk factors for thyroid cancer, the most established is ionizing radiation. Data obtained from studies involving patients subjected to external radiation, the fallout of nuclear bombs, or, more recently, the Chernobyl accident show that radiation plays an important role in thyroid carcinogenesis9,10 and principally in papillary thyroid cancer.11 In Greece, there was remarkable geographical variability of the contamination caused by the Chernobyl accident on April 26, 1986. The evaluated ground activity because of 137Cs of Chernobyl origin deposition ranged between 0.01 and 137 kBq/m2. Because the island of Crete was not included in the polluted regions in 1986 (evaluated ground activity because of 137Cs 0.01
Table 2 Incidence of papillary thyroid carcinoma, clinical and silent subtype, and thyroidectomies performed, for each year from 1990 to 2004 Year
90
91
92
93
94
95
96
97
98
99
00
01
02
03
04
Total
Papillary total Silent papillary Clinical papillary Thyroidectomies
4
4 3 1 172
6 1 5 158
2 1 1 134
9 2 7 190
15 5 10 142
17 8 9 138
24 8 16 163
37 12 25 142
36 12 24 119
48 18 30 271
40 11 29 199
28 10 18 173
24 15 9 144
22 7 15 159
316 113 203 2379
4 75
562
Otolaryngology–Head and Neck Surgery, Vol 136, No 4, April 2007
kBq/m2),12 no radiation evaluation has been performed in our region since then. Nevertheless, radiation contamination in our region may be correlated with the increased rainfall volume noticed during the period after the Chernobyl accident. It is noticeable that rainfall volume in May 1986 (33.5 mm) was 2.54 times higher than the average (13.16 mm) of the last 50 years, according to Hellenic Meteorological Service records. Radiation contamination in our region may be correlated with another interesting phenomenon to be addressed, the “colored rain phenomenon.” This is a rain originating in clouds that contain dust from the Sahara desert and North Africa region.13,14 This phenomenon is very common, especially in May, in Crete because of its proximity to Africa. Furthermore, it has been documented that the Chernobyl fallout has contaminated the North African coast and Sahara desert.15,16 Radioactivity of the colored rain dust containing radionuclides, which originated from the Chernobyl accident, has also been confirmed.13,14 We believe that there are strong indications correlating our results with radiation. The increased cases of thyroid papillary carcinoma, as noticed in our series after 1995, reaching peak values in the year 2000, are likely to represent the effect of the Chernobyl fallout. After that year, there is a decrease in cases of papillary thyroid cancer, whereas the number of thyroidectomies displays a decreasing trend from 2000 to 2003. This decrease is even more obvious in the clinical subtype than the silent one. A silent subtype case of papillary cancer represents an accidental finding with no clinical suspicion and sometimes possibly reflects an over diagnosis. Further investigations will show the possibility of correlation between “colored rain phenomenon,” radiation contamination, and incidence of thyroid cancer in our area. Dietary patterns have been associated with the etiology and increased incidence of thyroid cancer. Seafood, because of its high content of iodine, and cruciferous vegetables, because of their goitrogenic nature, have been associated with increased risk of follicular thyroid cancer.4-6 Most Greek dietary patterns, which are rich in raw vegetables, are protective against thyroid cancer, whereas no association with the papillary thyroid carcinoma was found.4 It should also be mentioned that the available salt in our country is iodine enriched. Thus, association between nutrition and increase of thyroid cancer cannot be established. Upward incidence trends of thyroid cancer worldwide have also been associated with increased diagnostic activity because of more sensitive diagnostic tests.7 In our series, silent papillary carcinoma subtype indicates the increased diagnostic and therapeutic activity. The increased incidence trend of papillary carcinoma observed in our series was not because of the rise in silent carcinomas. There was a proportional increase in both clinical and silent subtypes. To
our knowledge (Medline search), this is the first survey reporting potential correlation among thyroid cancer and radiation caused by the Chernobyl fallout in southeastern Europe. In conclusion, the increased incidence of papillary thyroid cancer noticed on the island of Crete cannot be attributed to dietary patterns or increased diagnostic and therapeutic activity. It should be mainly attributed to increased radiation and can be associated with the Chernobyl fallout.
REFERENCES 1. Remontet L, Esteve J, Bouvier AM, et al. Cancer incidence and mortality in France over the period 1978-2000. Rev Epidemiol Sante Publique 2003;51:3–30. (Grade B). 2. Niedziela M, Korman E, Breborowicz D, et al. A prospective study of thyroid nodular disease in children and adolescents in western Poland from 1996 to 2000 and the incidence of thyroid carcinoma relative to iodine deficiency and the Chernobyl disaster. Pediatr Blood Cancer 2004;42:84 –92. (Grade B). 3. Verger P, Catelinois O, Tirmarche M, et al. Thyroid cancers in France and the Chernobyl accident: risk assessment and recommendations for improving epidemiological knowledge. Health Phys 2003;85:323–9. (Grade D). 4. Markaki I, Linos D, Linos A. The influence of dietary patterns on the development of thyroid cancer. Eur J Cancer 2003;39:1912–9. (Grade B). 5. Kolonel LN, Hankin JH, Wilkens LR, et al. An epidemiologic study of thyroid cancer in Hawaii. Cancer Causes Control 1990;1:223–34. (Grade B). 6. Ron E, Kleinerman RA, Boice JD, et al. A population-based casecontrol study of thyroid cancer. J Natl Cancer Inst 1987;79:1–12. (Grade B). 7. Verkooijen HM, Fioretta G, Pache JC, et al. Diagnostic changes as a reason for the increase in papillary thyroid cancer incidence in Geneva, Switzerland. Cancer Causes Control 2003;14:13–7. (Grade B). 8. Armitage P, Berry G. Statistical methods in medical research. 2nd ed. Oxford: Blackwell Scientific Publications, 1987:211–2, 479 – 80. (Grade D). 9. Ron E, Lubin JH, Shore RE, et al. Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies. Radiat Res 1995;141:259 –77. (Grade B). 10. Williams ED, Pacini F, Pinchera A. Thyroid cancer following Chernobyl. J Endocrinol Invest 1995;18:144 – 6. (Grade D). 11. Moretti F, Nanni S, Pontecorvi A. Molecular pathogenesis of thyroid nodules and cancer. Baillieres Best Pract Res Clin Endocrinol Metab 2000;14:517–39. (Grade D). 12. Simopoulos SE. Soil sampling and 137Cs analysis of the Chernobyl fallout in Greece. Int J Rad Appl Instrum 1989;40:607–13. (Grade D). 13. Papastefanou C, Manolopoulou M. The radioactivity of coloured rain in Thessaloniki, Greece. Sci Total Environ 1989;80:225–7. (Grade D). 14. Papastefanou C, Manolopoulou M, Stoulos S, et al. Coloured rain dust from Sahara Desert is still radioactive. J Environ Radioact 2001;55: 109 –12. (Grade D). 15. Baggoura B, Noureddine A, Benkrid M. Level of natural and artificial radioactivity in Algeria. Appl Radiat Isot 1998;49:867–73. (Grade B). 16. Shawky S, el-Tahawy M. Distribution pattern of 90Sr and 137Cs in the Nile delta and the adjacent regions after Chernobyl accident. Appl Radiat Isot 1999;50:435– 43. (Grade C).