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Dental maturity assessment in children with acute lymphoblastic leukemia after cancer therapy
Forensic Science International 184 (2009) 10–14
Contents lists available at ScienceDirect
Forensic Science International journal homepage: www.elsevier.com/locate/forsciint
Dental maturity assessment in children with acute lymphoblastic leukemia after cancer therapy Niucha P.S. Vasconcelos, Eliana M.M. Caran, Maria Lucia Lee, Nilza N.F. Lopes, Rosa M.E. Weiler * Federal University of Sa˜o Paulo, Brazil
A R T I C L E I N F O
A B S T R A C T
Article history: Received 4 June 2008 Received in revised form 7 October 2008 Accepted 16 November 2008
Dental age is largely used in both forensic studies and clinical practice. All over the world, many studies have been made to determine chronological age using dental ages of individuals, but selecting individuals with no chronic or acute sickness as the study group. Cancer is the second most frequent cause of death in children, and acute lymphoblastic leukemia (ALL) is the most common type of cancer in childhood. Most of the children who survived childhood cancer experienced disturbances in dental development due to cancer therapy or to cancer itself. The aim of this study is to assess dental development in children and teenagers who had suffered from childhood leukemia and were submitted to chemotherapy isolated or associated with radiotherapy, by comparing the dental ages with those corresponding features in a healthy control group. Dental development was analyzed using panoramic radiographs of 92 children divided in two groups: 46 children between 5 and 12 years old, treated for ALL at GRAACC – IOP, UNIFESP, and as a control group, 46 healthy children treated for dental reasons at APCD, Sa˜o Paulo. The dental age of the subjects was estimated using the system of Demirjian et al. [A. Demirjian, H. Goldstein, J.M. Tanner, A new system of dental age assessment, Hum. Biol. 45(2) (1973) 211–227]. A significant difference was found between the chronological and dental age of patients submitted to antineoplasic therapy for ALL, when compared to those of the control group, but there were no significant differences between patients treated with different protocols for ALL. Conclusions: although the study was within a small group of patients, we could clearly conclude that antineoplastic therapy can interfere in the dental maturity of patients treated for childhood cancer by interfering in dental formation and root development. ß 2008 Elsevier Ireland Ltd. All rights reserved.
Keywords: Leukemia Chronological age Dental age Age estimation
1. Introduction Studies suggesting accurate techniques for age estimation have been widely documented over the past two decades, since age estimation has a major significance in clinical and forensic studies. In living humans, most of these studies involving age estimation have been made exclusively in healthy people, not considering the effects of disease in dental age and age estimation.
Abbreviations: ALL, acute lymphoblastic leukemia; IOP, institute of pediatric oncology (in Sa˜o Paulo, Brazil); GRAACC, grupo de apoio a adolescentes e crianc¸as com caˆncer (support group for teenagers and children with cancer in Sa˜o Paulo, Brazil); UNIFESP, universidade federal de Sa˜o Paulo (Federal University of Sa˜o Paulo, Brazil); APCD, associac¸a˜o paulista de cirurgio˜es dentistas (Dentists Association of Sa˜o Paulo, Brazil); BMT, bone marrow transplant. * Corresponding author at: UNIFESP – Federal University of Sa˜o Paulo, Brazil. Tel.: +55 11 3062 1723; fax: +55 11 3062 1723. E-mail address: [email protected] (Rosa M.E. Weiler). 0379-0738/$ – see front matter ß 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.forsciint.2008.11.009
Cancer represents the second most frequent cause of death in children under the age of 15 years old [1], with acute lymphoblastic leukemia (ALL) being the most common childhood malignancy [1–3]. Recent advances in cancer therapy over the past decades have transformed ALL from a rapidly fatal disease into one in which more than 70% of patients survive at least 5 years [2,4]. According to Dickerman [5] the number of long-term survivors of childhood cancer will continue to increase, and almost 75% will have a chronic health problem resulting from cancer therapy. As the patient’s lifespan increases, dental effects of oncology treatment become clinically significant [6]. Since oral health of children is frequently affected by antineoplasic therapy in almost all stages of treatment, dentists who treat children must become acquainted with all consequences of cancer treatments [3]. Neither chemotherapeutic agents nor radiation therapy can differentiate between neoplasic cells and metabolically active normal cells [6,7]. Considering that ALL is most predominant in children under 5 years of age and some permanent teeth are undergoing active
N.P.S. Vasconcelos et al. / Forensic Science International 184 (2009) 10–14
development in that age group, dental sequelae in patients treated for ALL are not surprising. This is why children younger than 5 years of age at diagnosis have abnormal dental development [7]. In the other hand, dental development may be affected by illness, trauma, chemotherapy and radiation therapy at any point prior to complete maturation [2]. Some factors such as age of the patient during treatment, treatment methods and the use and doses of radiation therapy will affect the extent of damage caused to tooth formation [2,7,8,10–12]. In the past years, many authors have listed the type of defects associated with childhood cancer and its treatment [2–4,6,8–15]. Dental abnormalities found in children after cancer therapy can be caused by chemotherapy alone [2,4,6–9,11,12,15], radiation therapy [2,6–9,11,13–15], and bone marrow transplant (BMT) [10]. Antibiotics and systemic disturbances such as fever and poor nutritional status may also be responsible [8]. According to Lopes et al. [15], dental abnormalities observed in children treated for cancer can be those of shape (microdontia, macrodontia, taurodontia), alterations in number (anodontia), and alterations in root formation (root shortening, blunting of the roots, root stunting). Dental maturity, often expressed as dental age, is an indicator of the biological maturity of growing children [16]. How dental maturity is influenced by cancer therapy still remains unclear. Pajari et al. [13] tried to assess the relationship between antineoplastic therapy on dental maturity and tooth development. In this study, 38 panoramic radiographs from children and adolescents who survived childhood cancer were observed, and dental age was estimated using the system of Demirjian et al. [16]. For these authors, the dental age of children after cancer therapy was different from those of a control group. The aim of this study is to determine the dental age of children with ALL who were submitted to chemotherapy with and without radiation therapy, using Demirjian et al. [16] method for dental age assessment. 2. Materials and methods This study consisted on the evaluation of dental development observed in panoramic radiographs of 92 children aged 4–12. The children were divided in two groups: 46 children (22 boys and 24 girls) aged 4–12 years (average age 8.9 years) who received antineoplasic therapy for ALL at GRAACC, UNIFESP, and a control group of 46 healthy children (23 boys and 23 girls), aged 4 to 12 (average age 8.3 years) from Associac¸a˜o Paulista de Cirurgio˜es Dentistas (APCD). We retrospectively reviewed the medical records and panoramic radiographs of the patients that were taken for dental reasons. The analysis of the panoramic radiographs was made by using the method introduced by Demirjian’s et al. [16] and based on the development of the seven left permanent mandibular teeth. In this method, tooth formation is divided into eight stages, and criteria for the stages are given for each tooth separately, in detailed written description and supplementary illustrations, and in this study we used a chart created and adapted by the author, from the original chart of Demirjian’s et al. [16]. For each stage of the seven teeth it is given a score according to a statistical model. Standards are given for each sex separately, and the sum of the scores of the seven teeth is the obtained dental maturity, that can be converted into dental age by use of conversion tables. In children treated for childhood cancer, we also reviewed information such as age of patient at diagnosis; use of radiation therapy; total time of cancer treatment and time out of treatment after cancer was eradicated. Exclusion criteria included patients who received BMT, those who did not have one or more mandibular permanent teeth, who received any kind of antineoplastic treatment in the last 12 months or died during this study. In the control group, we excluded from this study those patients who
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suffered from any disease that could affect the results (such as Down syndrome, hormonal dysfunctions and others), and those who did not have all seven left mandibular teeth (incisors, canine, first and second bicuspids and first and second molars). One examiner rated the radiographs, and the dental age of the subjects was estimated using a chart created and adapted by the author, from the original chart of Demirjian’s et al. [16] method of dental assessment (Figs. 1–3). Student’s t-test was used for the statistical analysis. 3. Results This study included 92 patients divided in two groups: 46 patients (22 boys and 24 girls) with ALL and 46 patients (23 boys and 23 girls) of the control group, as shown in Fig. 4. The age of the patients when the panoramic radiograph was taken varied from 4 to 12 years (average of 8.9 years for patients with ALL, and 8.3 years for the control group). Thirty-seven out of forty-six (80%) ALL patients were under 5 years of age at diagnosis. We found that the dental age of the ALL patients was advanced compared to the dental age in the control group, and this difference was found to be statistically significant, as seen in Table 1. Regarding the therapy method involved in the ALL group, we observed that the majority of patients received only chemotherapy, and a smaller group received chemotherapy combined with radiation therapy as seen in Table 2. When the t-test was applied to verify the difference between chronological and dental age in both groups of patients the difference was nonsignificant, as shown in Table 2. 4. Discussion The concept of physiological age is based on the degree of maturation of different tissue systems. Biological age can be assessed through different methods: skeletal age, morphological age, secondary sex character age and dental age [16]. In this study, dental age assessment was made using the method introduced by Demirjian’s et al. [16] and based on the development of the seven left permanent mandibular teeth. Various authors have used this method over the past 3 decades. Eid et al. [17] assessed the dental age of Brazilian children using Demirjian’s method, and analyzed the advantages of this method over other methods for age assessment. Dental development is an important indicator of disturbances during odontogenesis [13] and factors such as trauma, diseases, chemotherapy and radiation therapy can affect teeth at any phase prior to their complete formation and calcification [2,8,14]. In patients with ALL the effects of antineoplastic treatment on dental health are well known and widely documented. Studies suggest that teeth may be affected by crown or root alterations, and delayed or arrested tooth development. Root alterations include premature closure of apices [2,8,13,14]; blunting of roots [7,10,12–14]; foreshortening of roots [5,7–9,11–14]; delayed and arrested tooth development [4,8,12–14] and V-shaped or thinning of the roots [6,9,11,12,15]. Remmers et al. [18] observed that the influence of chemotherapy was not the same in all affected teeth in a particular patient, and in some patients, the size and form of the teeth were affected, whereas in others there was a reduction in size but no change in the form. Goho [6] gives an explanation to this fact since chemotherapy damage is related directly to doses and repetition of various agents, odontoblasts and ameloblasts are damaged easily in susceptible phases of cell cycle. Cells in nonproliferative, germinal stages (second or third molars in the infant) are unaffected and should develop normally. In accordance to this article, Rosenberg et al. [9], found that the first and second bicuspids were the most affected
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N.P.S. Vasconcelos et al. / Forensic Science International 184 (2009) 10–14
Fig. 1. Dental mineralization chart.
teeth with shortening roots, due to the age of the patients at treatment. Authors agree that dental sequelae are more severe in children that were exposed to cancer therapy in the first years of age with a low prevalence of defects in those children who had been treated after the amelogenesis of teeth was completed [2,10,12]. In our study, 80% of the patients with ALL were under the age of 5, and this is consistent with reports in the literature by McDonald and Avery [1], Kaste et al. [2], Curtis [3] and Minicucci et al. [12]. Either the presence of a malignancy, or the use of cytotoxic drugs during tooth development affects the developing tooth germ, leading to dental abnormalities, or they can also cause malformation of the roots [4]. Since dental maturity is based on the
measurements of the roots in mandibular teeth, it is expected that dental age will be influenced by cancer therapy. There are few studies on dental maturity in patients submitted to antineoplastic treatment. Kaste et al. [2] observed that 4% of the studied population had delayed exfoliation of the primary teeth and eruption of permanent dentition. Goho [6] stated that chemotherapy and radiation therapy might affect dental exfoliation and eruption. Since normal exfoliation of primary teeth is associated with the maturation and eruption of permanent teeth, any factor interfering with dental development can affect this process. Dahllo¨f et al. [7] studied 44 patients with cancer and treated with chemotherapy, and did not observe any relation between dental and chronological age when comparing patients
Fig. 2. Panoramic radiograph of an ALL female patient with chronological age of 8 years and dental age of 11 years and 1 month—note the short roots of the lower incisors and the premature closure of the apices in the lower first bicuspid.
Fig. 3. Panoramic radiograph of a female patient from the control group with chronological age of 8 years and dental age of 8 years and 1 month.
N.P.S. Vasconcelos et al. / Forensic Science International 184 (2009) 10–14
Fig. 4. ALL patients and control group distributed according to gender.
Table 1 t-Test applied to average chronological and dental ages of control group and patients with ALL.
ALL patients Control group
Number of patients
ACA
ADA
(DA-CA)
S.D.
S.E.
46 46
8.9 8.3
10.2 8.5
1.5 0.2
0.7 0.5
0.1 0.008
t-Value = 8.04; P-value = 0.000 where: ACA (average chronological age); ADA (average dental age); DA (dental age); CA (chronological age); S.D. (standard deviation); S.E. (standard error for the average). The results are expressed in years.
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agents is less well documented, says Duggal [10]. According to Jaffe et al. [8], the variety of chemotherapy agents administered to the patients does not permit an opportunity to assess their dentomaxillary effects. The method we used for age estimation in this study was based on root formation and apices closure in teeth. Since cancer therapy is responsible for the premature closure of apices [2,8,13,14], perhaps the method proposed by Demirjian’s et al. [16] for dental assessment is not suitable for this study. Cameriere and Ferrante [19] suggested that the study of the morphological parameters of teeth and wrist/ hand X-rays of children is more reliable than many other methods for age estimation, but we cannot forget that the subjects included in their study were healthy as in any other method to determine dental age. For this reason it is difficult to determine the best method to be used in individuals with diseases such as childhood cancer. In addition, when considering children with cancer, we cannot ignore the fact that the concomitant use of other medications during treatment, the disease itself and nutritional factors can interfere with tooth formation [8]. Demirjian’s method for dental assessment was used in this study only as a way of determining the dental age of ALL patients and was not used to acquire a precise dental age for this specific population. Various authors have used Demirjian’s et al. [16] method for dental assessment and they agree that this method should be adapted to different populations and that individual assessment parameters need to be included due to wide ethnic differences. 5. Conclusions
with cancer to the control group. Purdell-Lewis et al. [4] observed delayed dental eruption in 8 of 56 patients after cancer therapy. Pajari et al. [13] used Demirjian method to evaluate dental maturity in 38 children who received chemotherapy with or without radiation therapy to treat cancer. The results of this study showed an advanced average dental age when compared to the control group, but this difference was not statistically significant. In our study, when comparing dental and chronological age of patients with ALL to patients in the control group, we found that the average dental age in ALL patients was higher than the average chronological age, and this difference was statistically significant. When comparing treatment methods, we must remember that chemotherapy was used in different modalities in all patients, but radiation therapy was used only in 15 out of 46 patients. When we compared the dental age and chronological age of patients submitted to different methods of treatment (chemotherapy with or without concomitant use of radiation therapy), no significant relation was found. This is in agreement with the fact that radiation therapy for treatment of ALL is not specifically applied to head and neck. Authors have also suggested that the influence on root formation is caused by chemotherapy itself [4,7–9,11,12] and this may be one of the reasons why all patients treated for cancer therapy had a significant difference in the average dental age and chronological age. However, the potential mechanism whereby the developing tooth germ might be affected by chemotherapy
Table 2 t-Test applied to average chronological and dental age in the group that received chemotherapy alone and in the group that received chemotherapy plus radiation therapy.
Chemotherapy group Chemo + radiation therapy group
Number of patients
ACA
ADA
(DA-CA)
S.D.
S.E.
31 15
8.6 9.5
10 10.6
1.4 1.1
0.7 0.5
0.1 0.1
t-Value = 1.12; P-value = 0.269 where: ACA (average chronological age); ADA (average dental age); DA (dental age); CA (chronological age); S.D. (standard deviation); S.E. (standard error for the average). The results are expressed in years.
From dental assessment in ALL patients submitted to chemotherapy with or without the concomitant use of radiation therapy we can conclude that antineoplastic therapy can interfere in the dental maturity of these patients. According to the results of this study, and still considering the small group of patients used, we could find that there was a highly significant difference between chronological age and dental age of ALL patients compared to the control group. Dental formation can be used as an indicator or maturity; however, it is under the influence of external factors that they are common in patients with ALL, such as cancer therapy or other medications, systemic disturbances and nutritional factors. We found no significant differences between patients treated with different treatment protocols. The influence of the disease (ALL) per se in age estimation still remains unclear. References [1] B.J. Sanders, A.D. Shapiro, R.A. Hock, J.A. Weddell, Treatment of patients with medical problems: hematology, oncology, hepatitis and AIDS, in: R.E. McDonald, D.R. Avery (Eds.), Odontopediatrics, 2001, 434–445. [2] S.C. Kaste, K.P. Hopkins, D. Jones, D. Crom, C.A. Greenwald, V.M. Santana, Dental abnormalities in children treated for acute lymphoblastic leukemia, Leukemia 11 (1997) 792–796. [3] A.B. Curtis, Childhood leukemias: initial oral manifestations, Jada 83 (1971) 159–164. [4] D.J. Purdell-Lewis, M.S. Stalman, G.B. Humphrey, H. Kalsbeek, Long-term results of chemotherapy on the developing dentition: caries risk and developmental aspects, Commun. Dent. Oral Epidemiol. 16 (1988) 68–71. [5] J.D. Dickerman, The late effects of childhood cancer therapy, Pediatrics 119 (3) (2007) 554–568. [6] C. Goho, Chemoradiation therapy: effect on dental development, Pediatric Dent. 15 (1) (1993) 6–11. [7] G. Dahllo¨f, B. Rozell, C.M. Forsberg, B. Borgstro¨m, Histologic changes in dental morphology induced by high dose chemotherapy and total body irradiation, Oral Surg. Oral Med. Oral. Pathol. 77 (1994) 56–60. [8] N. Jaffe, B.B. Toth, R.E. Hoar, H.L. Ried, M.P. Sullivan, M.D. McNeese, Dental and maxillofacial abnormalities in long-term survivors of childhood cancer effects of treatment with chemotherapy and radiation to the head and neck, Pediatrics 73 (6) (1984) 816–823. [9] S.W. Rosenberg, H. Kolodney, G.Y. Wong, M.L. Murphy, Altered dental root development in long-term survivors of pediatric acute lymphoblastic leukemia: a review of 17 cases, Cancer 59 (1987) 1640–1648.
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[10] M.S. Duggal, Root surface areas in long-term survivors of childhood cancer, Oral Oncol. 39 (2002) 178–183. [11] A.L. Sonis, N. Tarbell, R.W. Valachovic, R. Gelber, M. Schwenn, S. Sallan, Dentofacial development in long-term survivors of acute lymphoblastic leukaemia: a comparison of three treatment modalities, Cancer 66 (1990) 2645–2652. [12] E.M. Minicucci, L.F. Lopes, A.J. Crocci, Dental abnormalities in children after chemotherapy treatment for acute lymphoid leukemia, Leukemia Res. 27 (2003) 45–50. [13] U. Pajari, P. Lahtela, M. Lanning, M. Larmas, Effect of anti-neoplasic therapy on dental maturity and tooth development, J. Pedodont. 12 (1988), pp. 266–274.14. [14] U. Pajari, M. Lanning, Developmental defects of teeth in survivors of childhood ALL are related to the therapy and age at diagnosis, Med. Pediatric Oncol. 24 (1994) 310–314.
[15] N.N.F. Lopes, A.S. Petrilli, E.M.M. Caran, C.M. Franc¸a, I. Chilvarquer, H. Lederman, Dental abnormalities in children submitted to antineoplastic therapy, J. Dentistry Child. 73 (3) (2006) 140–146 (6). [16] A. Demirjian, H. Goldstein, J.M. Tanner, A new system of dental age assessment, Hum. Biol. 45 (2) (1973) 211–227. [17] R.M.R. Eid, R. Simi, M.N.P. Friggi, M. Fisberg, Assessment of dental maturity of Brazilian children aged 6 to 14 using Demirjian’s method, Int. J. Pediatric Dent. 12 (2002) 423–428. [18] D. Remmers, J.P.M. Bo¨kkerink, C. Katsaros, Microdontia after chemotherapy in a child treated for neuroblastoma, Orthod. Craniofacial Res. 9 (2006) 206–210. [19] R. Cameriere, L. Ferrante, Age estimation in children by measurement of carpals and epiphyses of radius and ulna and open apices in teeth: a pilot study, Forensic Sci. Int. 174 (1) (2008 Jan 15) 60–63.
Contents lists available at ScienceDirect
Forensic Science International journal homepage: www.elsevier.com/locate/forsciint
Dental maturity assessment in children with acute lymphoblastic leukemia after cancer therapy Niucha P.S. Vasconcelos, Eliana M.M. Caran, Maria Lucia Lee, Nilza N.F. Lopes, Rosa M.E. Weiler * Federal University of Sa˜o Paulo, Brazil
A R T I C L E I N F O
A B S T R A C T
Article history: Received 4 June 2008 Received in revised form 7 October 2008 Accepted 16 November 2008
Dental age is largely used in both forensic studies and clinical practice. All over the world, many studies have been made to determine chronological age using dental ages of individuals, but selecting individuals with no chronic or acute sickness as the study group. Cancer is the second most frequent cause of death in children, and acute lymphoblastic leukemia (ALL) is the most common type of cancer in childhood. Most of the children who survived childhood cancer experienced disturbances in dental development due to cancer therapy or to cancer itself. The aim of this study is to assess dental development in children and teenagers who had suffered from childhood leukemia and were submitted to chemotherapy isolated or associated with radiotherapy, by comparing the dental ages with those corresponding features in a healthy control group. Dental development was analyzed using panoramic radiographs of 92 children divided in two groups: 46 children between 5 and 12 years old, treated for ALL at GRAACC – IOP, UNIFESP, and as a control group, 46 healthy children treated for dental reasons at APCD, Sa˜o Paulo. The dental age of the subjects was estimated using the system of Demirjian et al. [A. Demirjian, H. Goldstein, J.M. Tanner, A new system of dental age assessment, Hum. Biol. 45(2) (1973) 211–227]. A significant difference was found between the chronological and dental age of patients submitted to antineoplasic therapy for ALL, when compared to those of the control group, but there were no significant differences between patients treated with different protocols for ALL. Conclusions: although the study was within a small group of patients, we could clearly conclude that antineoplastic therapy can interfere in the dental maturity of patients treated for childhood cancer by interfering in dental formation and root development. ß 2008 Elsevier Ireland Ltd. All rights reserved.
Keywords: Leukemia Chronological age Dental age Age estimation
1. Introduction Studies suggesting accurate techniques for age estimation have been widely documented over the past two decades, since age estimation has a major significance in clinical and forensic studies. In living humans, most of these studies involving age estimation have been made exclusively in healthy people, not considering the effects of disease in dental age and age estimation.
Abbreviations: ALL, acute lymphoblastic leukemia; IOP, institute of pediatric oncology (in Sa˜o Paulo, Brazil); GRAACC, grupo de apoio a adolescentes e crianc¸as com caˆncer (support group for teenagers and children with cancer in Sa˜o Paulo, Brazil); UNIFESP, universidade federal de Sa˜o Paulo (Federal University of Sa˜o Paulo, Brazil); APCD, associac¸a˜o paulista de cirurgio˜es dentistas (Dentists Association of Sa˜o Paulo, Brazil); BMT, bone marrow transplant. * Corresponding author at: UNIFESP – Federal University of Sa˜o Paulo, Brazil. Tel.: +55 11 3062 1723; fax: +55 11 3062 1723. E-mail address: [email protected] (Rosa M.E. Weiler). 0379-0738/$ – see front matter ß 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.forsciint.2008.11.009
Cancer represents the second most frequent cause of death in children under the age of 15 years old [1], with acute lymphoblastic leukemia (ALL) being the most common childhood malignancy [1–3]. Recent advances in cancer therapy over the past decades have transformed ALL from a rapidly fatal disease into one in which more than 70% of patients survive at least 5 years [2,4]. According to Dickerman [5] the number of long-term survivors of childhood cancer will continue to increase, and almost 75% will have a chronic health problem resulting from cancer therapy. As the patient’s lifespan increases, dental effects of oncology treatment become clinically significant [6]. Since oral health of children is frequently affected by antineoplasic therapy in almost all stages of treatment, dentists who treat children must become acquainted with all consequences of cancer treatments [3]. Neither chemotherapeutic agents nor radiation therapy can differentiate between neoplasic cells and metabolically active normal cells [6,7]. Considering that ALL is most predominant in children under 5 years of age and some permanent teeth are undergoing active
N.P.S. Vasconcelos et al. / Forensic Science International 184 (2009) 10–14
development in that age group, dental sequelae in patients treated for ALL are not surprising. This is why children younger than 5 years of age at diagnosis have abnormal dental development [7]. In the other hand, dental development may be affected by illness, trauma, chemotherapy and radiation therapy at any point prior to complete maturation [2]. Some factors such as age of the patient during treatment, treatment methods and the use and doses of radiation therapy will affect the extent of damage caused to tooth formation [2,7,8,10–12]. In the past years, many authors have listed the type of defects associated with childhood cancer and its treatment [2–4,6,8–15]. Dental abnormalities found in children after cancer therapy can be caused by chemotherapy alone [2,4,6–9,11,12,15], radiation therapy [2,6–9,11,13–15], and bone marrow transplant (BMT) [10]. Antibiotics and systemic disturbances such as fever and poor nutritional status may also be responsible [8]. According to Lopes et al. [15], dental abnormalities observed in children treated for cancer can be those of shape (microdontia, macrodontia, taurodontia), alterations in number (anodontia), and alterations in root formation (root shortening, blunting of the roots, root stunting). Dental maturity, often expressed as dental age, is an indicator of the biological maturity of growing children [16]. How dental maturity is influenced by cancer therapy still remains unclear. Pajari et al. [13] tried to assess the relationship between antineoplastic therapy on dental maturity and tooth development. In this study, 38 panoramic radiographs from children and adolescents who survived childhood cancer were observed, and dental age was estimated using the system of Demirjian et al. [16]. For these authors, the dental age of children after cancer therapy was different from those of a control group. The aim of this study is to determine the dental age of children with ALL who were submitted to chemotherapy with and without radiation therapy, using Demirjian et al. [16] method for dental age assessment. 2. Materials and methods This study consisted on the evaluation of dental development observed in panoramic radiographs of 92 children aged 4–12. The children were divided in two groups: 46 children (22 boys and 24 girls) aged 4–12 years (average age 8.9 years) who received antineoplasic therapy for ALL at GRAACC, UNIFESP, and a control group of 46 healthy children (23 boys and 23 girls), aged 4 to 12 (average age 8.3 years) from Associac¸a˜o Paulista de Cirurgio˜es Dentistas (APCD). We retrospectively reviewed the medical records and panoramic radiographs of the patients that were taken for dental reasons. The analysis of the panoramic radiographs was made by using the method introduced by Demirjian’s et al. [16] and based on the development of the seven left permanent mandibular teeth. In this method, tooth formation is divided into eight stages, and criteria for the stages are given for each tooth separately, in detailed written description and supplementary illustrations, and in this study we used a chart created and adapted by the author, from the original chart of Demirjian’s et al. [16]. For each stage of the seven teeth it is given a score according to a statistical model. Standards are given for each sex separately, and the sum of the scores of the seven teeth is the obtained dental maturity, that can be converted into dental age by use of conversion tables. In children treated for childhood cancer, we also reviewed information such as age of patient at diagnosis; use of radiation therapy; total time of cancer treatment and time out of treatment after cancer was eradicated. Exclusion criteria included patients who received BMT, those who did not have one or more mandibular permanent teeth, who received any kind of antineoplastic treatment in the last 12 months or died during this study. In the control group, we excluded from this study those patients who
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suffered from any disease that could affect the results (such as Down syndrome, hormonal dysfunctions and others), and those who did not have all seven left mandibular teeth (incisors, canine, first and second bicuspids and first and second molars). One examiner rated the radiographs, and the dental age of the subjects was estimated using a chart created and adapted by the author, from the original chart of Demirjian’s et al. [16] method of dental assessment (Figs. 1–3). Student’s t-test was used for the statistical analysis. 3. Results This study included 92 patients divided in two groups: 46 patients (22 boys and 24 girls) with ALL and 46 patients (23 boys and 23 girls) of the control group, as shown in Fig. 4. The age of the patients when the panoramic radiograph was taken varied from 4 to 12 years (average of 8.9 years for patients with ALL, and 8.3 years for the control group). Thirty-seven out of forty-six (80%) ALL patients were under 5 years of age at diagnosis. We found that the dental age of the ALL patients was advanced compared to the dental age in the control group, and this difference was found to be statistically significant, as seen in Table 1. Regarding the therapy method involved in the ALL group, we observed that the majority of patients received only chemotherapy, and a smaller group received chemotherapy combined with radiation therapy as seen in Table 2. When the t-test was applied to verify the difference between chronological and dental age in both groups of patients the difference was nonsignificant, as shown in Table 2. 4. Discussion The concept of physiological age is based on the degree of maturation of different tissue systems. Biological age can be assessed through different methods: skeletal age, morphological age, secondary sex character age and dental age [16]. In this study, dental age assessment was made using the method introduced by Demirjian’s et al. [16] and based on the development of the seven left permanent mandibular teeth. Various authors have used this method over the past 3 decades. Eid et al. [17] assessed the dental age of Brazilian children using Demirjian’s method, and analyzed the advantages of this method over other methods for age assessment. Dental development is an important indicator of disturbances during odontogenesis [13] and factors such as trauma, diseases, chemotherapy and radiation therapy can affect teeth at any phase prior to their complete formation and calcification [2,8,14]. In patients with ALL the effects of antineoplastic treatment on dental health are well known and widely documented. Studies suggest that teeth may be affected by crown or root alterations, and delayed or arrested tooth development. Root alterations include premature closure of apices [2,8,13,14]; blunting of roots [7,10,12–14]; foreshortening of roots [5,7–9,11–14]; delayed and arrested tooth development [4,8,12–14] and V-shaped or thinning of the roots [6,9,11,12,15]. Remmers et al. [18] observed that the influence of chemotherapy was not the same in all affected teeth in a particular patient, and in some patients, the size and form of the teeth were affected, whereas in others there was a reduction in size but no change in the form. Goho [6] gives an explanation to this fact since chemotherapy damage is related directly to doses and repetition of various agents, odontoblasts and ameloblasts are damaged easily in susceptible phases of cell cycle. Cells in nonproliferative, germinal stages (second or third molars in the infant) are unaffected and should develop normally. In accordance to this article, Rosenberg et al. [9], found that the first and second bicuspids were the most affected
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Fig. 1. Dental mineralization chart.
teeth with shortening roots, due to the age of the patients at treatment. Authors agree that dental sequelae are more severe in children that were exposed to cancer therapy in the first years of age with a low prevalence of defects in those children who had been treated after the amelogenesis of teeth was completed [2,10,12]. In our study, 80% of the patients with ALL were under the age of 5, and this is consistent with reports in the literature by McDonald and Avery [1], Kaste et al. [2], Curtis [3] and Minicucci et al. [12]. Either the presence of a malignancy, or the use of cytotoxic drugs during tooth development affects the developing tooth germ, leading to dental abnormalities, or they can also cause malformation of the roots [4]. Since dental maturity is based on the
measurements of the roots in mandibular teeth, it is expected that dental age will be influenced by cancer therapy. There are few studies on dental maturity in patients submitted to antineoplastic treatment. Kaste et al. [2] observed that 4% of the studied population had delayed exfoliation of the primary teeth and eruption of permanent dentition. Goho [6] stated that chemotherapy and radiation therapy might affect dental exfoliation and eruption. Since normal exfoliation of primary teeth is associated with the maturation and eruption of permanent teeth, any factor interfering with dental development can affect this process. Dahllo¨f et al. [7] studied 44 patients with cancer and treated with chemotherapy, and did not observe any relation between dental and chronological age when comparing patients
Fig. 2. Panoramic radiograph of an ALL female patient with chronological age of 8 years and dental age of 11 years and 1 month—note the short roots of the lower incisors and the premature closure of the apices in the lower first bicuspid.
Fig. 3. Panoramic radiograph of a female patient from the control group with chronological age of 8 years and dental age of 8 years and 1 month.
N.P.S. Vasconcelos et al. / Forensic Science International 184 (2009) 10–14
Fig. 4. ALL patients and control group distributed according to gender.
Table 1 t-Test applied to average chronological and dental ages of control group and patients with ALL.
ALL patients Control group
Number of patients
ACA
ADA
(DA-CA)
S.D.
S.E.
46 46
8.9 8.3
10.2 8.5
1.5 0.2
0.7 0.5
0.1 0.008
t-Value = 8.04; P-value = 0.000 where: ACA (average chronological age); ADA (average dental age); DA (dental age); CA (chronological age); S.D. (standard deviation); S.E. (standard error for the average). The results are expressed in years.
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agents is less well documented, says Duggal [10]. According to Jaffe et al. [8], the variety of chemotherapy agents administered to the patients does not permit an opportunity to assess their dentomaxillary effects. The method we used for age estimation in this study was based on root formation and apices closure in teeth. Since cancer therapy is responsible for the premature closure of apices [2,8,13,14], perhaps the method proposed by Demirjian’s et al. [16] for dental assessment is not suitable for this study. Cameriere and Ferrante [19] suggested that the study of the morphological parameters of teeth and wrist/ hand X-rays of children is more reliable than many other methods for age estimation, but we cannot forget that the subjects included in their study were healthy as in any other method to determine dental age. For this reason it is difficult to determine the best method to be used in individuals with diseases such as childhood cancer. In addition, when considering children with cancer, we cannot ignore the fact that the concomitant use of other medications during treatment, the disease itself and nutritional factors can interfere with tooth formation [8]. Demirjian’s method for dental assessment was used in this study only as a way of determining the dental age of ALL patients and was not used to acquire a precise dental age for this specific population. Various authors have used Demirjian’s et al. [16] method for dental assessment and they agree that this method should be adapted to different populations and that individual assessment parameters need to be included due to wide ethnic differences. 5. Conclusions
with cancer to the control group. Purdell-Lewis et al. [4] observed delayed dental eruption in 8 of 56 patients after cancer therapy. Pajari et al. [13] used Demirjian method to evaluate dental maturity in 38 children who received chemotherapy with or without radiation therapy to treat cancer. The results of this study showed an advanced average dental age when compared to the control group, but this difference was not statistically significant. In our study, when comparing dental and chronological age of patients with ALL to patients in the control group, we found that the average dental age in ALL patients was higher than the average chronological age, and this difference was statistically significant. When comparing treatment methods, we must remember that chemotherapy was used in different modalities in all patients, but radiation therapy was used only in 15 out of 46 patients. When we compared the dental age and chronological age of patients submitted to different methods of treatment (chemotherapy with or without concomitant use of radiation therapy), no significant relation was found. This is in agreement with the fact that radiation therapy for treatment of ALL is not specifically applied to head and neck. Authors have also suggested that the influence on root formation is caused by chemotherapy itself [4,7–9,11,12] and this may be one of the reasons why all patients treated for cancer therapy had a significant difference in the average dental age and chronological age. However, the potential mechanism whereby the developing tooth germ might be affected by chemotherapy
Table 2 t-Test applied to average chronological and dental age in the group that received chemotherapy alone and in the group that received chemotherapy plus radiation therapy.
Chemotherapy group Chemo + radiation therapy group
Number of patients
ACA
ADA
(DA-CA)
S.D.
S.E.
31 15
8.6 9.5
10 10.6
1.4 1.1
0.7 0.5
0.1 0.1
t-Value = 1.12; P-value = 0.269 where: ACA (average chronological age); ADA (average dental age); DA (dental age); CA (chronological age); S.D. (standard deviation); S.E. (standard error for the average). The results are expressed in years.
From dental assessment in ALL patients submitted to chemotherapy with or without the concomitant use of radiation therapy we can conclude that antineoplastic therapy can interfere in the dental maturity of these patients. According to the results of this study, and still considering the small group of patients used, we could find that there was a highly significant difference between chronological age and dental age of ALL patients compared to the control group. Dental formation can be used as an indicator or maturity; however, it is under the influence of external factors that they are common in patients with ALL, such as cancer therapy or other medications, systemic disturbances and nutritional factors. We found no significant differences between patients treated with different treatment protocols. The influence of the disease (ALL) per se in age estimation still remains unclear. References [1] B.J. Sanders, A.D. Shapiro, R.A. Hock, J.A. Weddell, Treatment of patients with medical problems: hematology, oncology, hepatitis and AIDS, in: R.E. McDonald, D.R. Avery (Eds.), Odontopediatrics, 2001, 434–445. [2] S.C. Kaste, K.P. Hopkins, D. Jones, D. Crom, C.A. Greenwald, V.M. Santana, Dental abnormalities in children treated for acute lymphoblastic leukemia, Leukemia 11 (1997) 792–796. [3] A.B. Curtis, Childhood leukemias: initial oral manifestations, Jada 83 (1971) 159–164. [4] D.J. Purdell-Lewis, M.S. Stalman, G.B. Humphrey, H. Kalsbeek, Long-term results of chemotherapy on the developing dentition: caries risk and developmental aspects, Commun. Dent. Oral Epidemiol. 16 (1988) 68–71. [5] J.D. Dickerman, The late effects of childhood cancer therapy, Pediatrics 119 (3) (2007) 554–568. [6] C. Goho, Chemoradiation therapy: effect on dental development, Pediatric Dent. 15 (1) (1993) 6–11. [7] G. Dahllo¨f, B. Rozell, C.M. Forsberg, B. Borgstro¨m, Histologic changes in dental morphology induced by high dose chemotherapy and total body irradiation, Oral Surg. Oral Med. Oral. Pathol. 77 (1994) 56–60. [8] N. Jaffe, B.B. Toth, R.E. Hoar, H.L. Ried, M.P. Sullivan, M.D. McNeese, Dental and maxillofacial abnormalities in long-term survivors of childhood cancer effects of treatment with chemotherapy and radiation to the head and neck, Pediatrics 73 (6) (1984) 816–823. [9] S.W. Rosenberg, H. Kolodney, G.Y. Wong, M.L. Murphy, Altered dental root development in long-term survivors of pediatric acute lymphoblastic leukemia: a review of 17 cases, Cancer 59 (1987) 1640–1648.
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[10] M.S. Duggal, Root surface areas in long-term survivors of childhood cancer, Oral Oncol. 39 (2002) 178–183. [11] A.L. Sonis, N. Tarbell, R.W. Valachovic, R. Gelber, M. Schwenn, S. Sallan, Dentofacial development in long-term survivors of acute lymphoblastic leukaemia: a comparison of three treatment modalities, Cancer 66 (1990) 2645–2652. [12] E.M. Minicucci, L.F. Lopes, A.J. Crocci, Dental abnormalities in children after chemotherapy treatment for acute lymphoid leukemia, Leukemia Res. 27 (2003) 45–50. [13] U. Pajari, P. Lahtela, M. Lanning, M. Larmas, Effect of anti-neoplasic therapy on dental maturity and tooth development, J. Pedodont. 12 (1988), pp. 266–274.14. [14] U. Pajari, M. Lanning, Developmental defects of teeth in survivors of childhood ALL are related to the therapy and age at diagnosis, Med. Pediatric Oncol. 24 (1994) 310–314.
[15] N.N.F. Lopes, A.S. Petrilli, E.M.M. Caran, C.M. Franc¸a, I. Chilvarquer, H. Lederman, Dental abnormalities in children submitted to antineoplastic therapy, J. Dentistry Child. 73 (3) (2006) 140–146 (6). [16] A. Demirjian, H. Goldstein, J.M. Tanner, A new system of dental age assessment, Hum. Biol. 45 (2) (1973) 211–227. [17] R.M.R. Eid, R. Simi, M.N.P. Friggi, M. Fisberg, Assessment of dental maturity of Brazilian children aged 6 to 14 using Demirjian’s method, Int. J. Pediatric Dent. 12 (2002) 423–428. [18] D. Remmers, J.P.M. Bo¨kkerink, C. Katsaros, Microdontia after chemotherapy in a child treated for neuroblastoma, Orthod. Craniofacial Res. 9 (2006) 206–210. [19] R. Cameriere, L. Ferrante, Age estimation in children by measurement of carpals and epiphyses of radius and ulna and open apices in teeth: a pilot study, Forensic Sci. Int. 174 (1) (2008 Jan 15) 60–63.