agenesis and microdontia of permanent teeth as late adverse effects after stem cell transplantation...

Agenesis and Microdontia of Permanent Teeth as LateAdverse Effects after Stem Cell Transplantation inYoung Children

Paivi Holtta, D.D.S.1–3

Satu Alaluusua, D.D.S., Ph.D.1,2

Ulla M. Saarinen-Pihkala, M.D., Ph.D.3

Jaakko Peltola, D.D.S., Ph.D.4

Liisa Hovi, M.D., Ph.D.3

1 Department of Pedodontics and Orthodontics, In-stitute of Dentistry, University of Helsinki, Helsinki,Finland.

2 Department of Oral and Maxillofacial Diseases,Helsinki University Central Hospital, Helsinki, Fin-land.

3 Hospital for Children and Adolescents, Universityof Helsinki, Helsinki, Finland.

4 Department of Oral Radiology, Institute of Den-tistry, University of Helsinki, Helsinki, Finland.

Supported by research grants from the HelsinkiUniversity Central Hospital and the Finnish DentalSociety Apollonia.

The authors thank Jorma Torppa, M.Sc., for sta-tistical advice and Blackwell Publishing Ltd. forkind permission to use their material.

Address for reprints: Paivi Holtta, D.D.S., Instituteof Dentistry, P.O. Box 41, University of Helsinki,00014 Helsinki, Finland; Fax: (011) 358919127266; E-mail: [email protected]

Received August 5, 2004; revision received Sep-tember 21, 2004; accepted September 21, 2004.

BACKGROUND. The objective of the current study was to examine the occurrence of

tooth agenesis and microdontia in pediatric stem cell transplantation (SCT) recip-

ients.

METHODS. The impact of total body irradiation (TBI) and age at SCT on agenesis

and microdontia of permanent teeth was examined in 55 patients from panoramic

radiographs. Assessment A1 (for tooth agenesis and microdontia) excluded the

third molars, and assessment A2 (for tooth agenesis) included the third molars.

Patients were grouped according to TBI status (the TBI group vs. the non-TBI

group) and age at SCT (patients age � 3.0 years [Group Y], patients ages 3.1–5.0

years [Group M], and patients age � 5.1 years [Group O]).

RESULTS. From 1 to 12 teeth were missing in 77%, 40%, and 0% of patients

(assessment A1) in Groups Y, M, and O, respectively (Group Y vs. Group M, P

� 0.055; Group Y vs. Group O, P � 0.001; and Group M vs. Group O, P � 0.002),

increasing to 83%, 78%, and 43%, respectively, when the third molars were in-

cluded (assessment A2; P values were not significant). Correspondingly, 75%, 60%,

and 13%, respectively, of patients had 1–12 microdontic teeth (assessment A1:

Group Y vs. Group M, P � 0.306; Group Y vs. Group O, P � 0.001; and Group M vs.

Group O, P � 0.003). Recipient age at the time of SCT was found to have a negative

correlation with the number of missing teeth (P � 0.001) and microdontic teeth (P

� 0.005). TBI appeared to have little effect on the prevalence of tooth agenesis

(assessment A1: TBI group, 32%; non-TBI group, 29%; assessment A2: TBI group,

72%; non-TBI group, 46%; P values were not significant) or on the prevalence of

microdontia (assessment A1: TBI, 41%; non-TBI, 50%; P value was not significant).

A tendency toward an increased number of affected teeth was noticed in the group

of patients who received TBI.

CONCLUSIONS. Depending on their age at SCT, 50 –100% of pediatric SCT recipients

will later present with agenesis and/or microdontia of permanent teeth that may

jeopardize occlusal development. Young age (� 5.0 years) at SCT was found to be

a stronger risk factor than TBI, although TBI caused additive impairment. Cancer

2005;103:181–90. © 2004 American Cancer Society.

KEYWORDS: dental development, stem cell transplantation, late adverse effects,tooth agenesis, hypodontia, microdontia.

S tem cell transplantation (SCT) has an established role in thetreatment of selected malignant and nonmalignant diseases in

children. High-dose chemotherapy (HDC) and total body irradiation(TBI) used in the preparative regimens for SCT give rise to multiple,well known, acute and long-term adverse effects, also involving teeth.

Morphogenesis and calcification of teeth form a sequence ofevents that begins in utero and continues for 14 –15 years.1 Thereafter,

181

© 2004 American Cancer SocietyDOI 10.1002/cncr.20762Published online 11 November 2004 in Wiley InterScience (www.interscience.wiley.com).

the development of the third molars continues forseveral years. Abnormal events that occur during den-tal development have permanent sequelae that cannotbe corrected later. Dental late effects of chemotherapyand/or radiotherapy in childhood may involve severalkinds of developmental dental disturbances, includingtooth agenesis, microdontia, and disturbed root devel-opment. It is possible to predict future dental aberra-tions to some extent by placing the period of therapyon the schedule of tooth mineralization (Fig. 1).

Agenesis of teeth (other terms used include “apla-sia of teeth” and “hypodontia”) is a common dentalanomaly in a healthy population, and its prevalencereportedly ranges from 2.8%2 to 10%.3 In a healthyFinnish population, a hypodontia prevalence of 8.0%(third molars excluded) has been reported.4 Both ge-netic and environmental factors may result in toothagenesis. In most individuals, hypodontia has a ge-netic background, as shown in family studies5,6 or byidentifying the gene mutations involved.7–9 Some en-vironmental factors, such as multiagent chemother-apy and radiotherapy, are known to cause tooth agen-esis when used in pediatric anticancer therapy. Thepercentage of cancer patients with missing teeth isreported to range from 5–28% after conventional che-motherapy.10 –14 In several studies, the most extensivedental disturbances (agenesis, microdontia, and rootanomalies) have been reported in children who weretreated before the ages of 5– 6 years.11,12,15 There arefewer studies on SCT recipients. Those patientshave had more dental disturbances compared withpatients who were treated with conventional chemo-therapy.12,13

Information regarding the prevalence of micr-odontia among healthy populations is scarce, withvarying criteria used in assessments. A 1.7% preva-lence of small, peg-shaped, upper lateral incisors hasbeen reported.5 A microdontia prevalence of 1.9% wasreported in healthy Japanese schoolchildren whenteeth with 3.5 standard deviations below the gender-specific mean mesiodistal crown size were recorded.16

Microdontia, registered from panoramic radiographsis more frequent after pediatric anticancer therapy,10 –

13,15,17,18 ranging from 10% after conventional chemo-therapy for hematologic malignancies12 to 78% afterSCT in patients with neuroblastoma.18

In the current study, we examined 1) the preva-lence of tooth agenesis and microdontia and 2) thenumber of missing and microdontic teeth in the per-manent dentition of SCT recipients. We also analyzedthe roles of TBI and age at SCT in dental adverseeffects.

MATERIALS AND METHODSPatientsFifty-six SCT recipients were examined for agenesisand microdontia of permanent teeth at the Institute ofDentistry, University of Helsinki (Helsinki, Finland).The patients had undergone SCT at the Hospital forChildren and Adolescents, University of Helsinki, be-tween 1980 and 1999. The eligibility criteria requiredthat children were age � 10 years at the time theyunderwent SCT and that the minimum follow-up was1 year. Of the 85 consecutive survivors, 56 patientsvolunteered to take part in the examination. One pa-tient was later excluded from the analysis because shehad no definable teeth due to her very young age atthe time of the dental examination. The final studygroup was comprised of 55 patients, including 28males and 27 females, who underwent SCT at ages1.0 –9.4 years (mean, 4.3 years) and who were followedafter SCT for 1.0 –20.6 years (mean, 7.4 years). Themean patient age at the time of dental examinationwas 11.7 years (range, 4.7–25.7 years).

The underlying diagnoses of the patients are listedin Table 1. Thirteen patients underwent SCT due torecurrent disease. The treatment period between di-agnosis and SCT varied from 0.2 years to 2.6 years(mean, 0.8 years). With the exception of only onepatient, all patients were in continuous disease remis-sion at the time of the dental examination.

Informed consent was obtained from the patients

FIGURE 1. The chronology of mineralization of permanent teeth.

Reprinted with the permission of Blackwell Publishing Ltd. from Koch G,

Thesleff I. Developmental disturbances in number and shape of teeth and

their treatment. In: Koch G, Poulsen S, editors. Pediatric dentistry—a

clinical approach, 1st ed. Copenhagen: Munksgaard, 2001:253–271.

182 CANCER January 1, 2005 / Volume 103 / Number 1

and/or their guardians. The Institutional ReviewBoard of the Hospital for Children and Adolescents,University of Helsinki, approved the study protocol.

Treatment of the Patients Prior to SCTConventional chemotherapy was given to patientswith acute lymphoblastic leukemia (ALL), acute my-eloid leukemia (AML), and non-Hodgkin lymphomaaccording to Nordic protocols19,20: For most patients,this included prednisolone, vincristine, doxorubicin,methotrexate, L-asparaginase, cyclophosphamide, cy-tosine arabinoside, and 6-mercaptopurine. Patientswith neuroblastoma (NBL) received multiagentchemotherapy with vincristine, cyclophosphamide,dacarbazine, cisplatin, and doxorubicin with the ad-dition of ifosfamide and etoposide in some patients.21

The five patients with Wilms tumor were treated ac-cording to National Wilms Tumor Study-like protocolswith vincristine, actinomycin D, cyclophosphamide,and doxorubicin. The one patient with rhabdomyosar-coma received vincristine, actinomycin D, cyclophos-phamide, doxorubicin, ifosfamide, and etoposide. Theone patient with yolk sac tumor received etoposide,bleomycin, and cisplatin. The only chemotherapeuticagent given to the two patients with chronic myeloidleukemia was hydroxyurea, whereas the patients withmyelodysplastic syndrome and severe aplastic anemiadid not receive any cytostatic chemotherapy prior toSCT.

Radiotherapy was administered to 17 patients, ei-

ther to the tumor bed or to local metastases. Twopatients with AML received cranial irradiation of 12grays (Gy), and 1 patient with ALL received 24 Gy.Local irradiation was given to 3 patients with NBL formetastases in the skull area. One patient received 20Gy to the left frontal bone, the second patient received20 Gy to the right orbital area, and the third patientreceived 6 Gy to the left temporal bone. Eleven pa-tients received radiation either to the tumor bed or tometastases outside the head. None of those radiationfields covered the jaws, and this radiotherapy was notconsidered significant with regard to dental develop-ment.

Conditioning for SCTThe preparative regimen for SCT included TBI at adose of 10 –12 Gy either in a single fraction (n � 1patient) or in 5– 6 fractions (n � 38 patients; the TBIgroup). The remaining 16 patients belonged to thenon-TBI group (Table 1). The mean age at SCT did notdiffer between the groups (in the TBI group, the meanage was 4.4 years [range, 1.1– 9.4 years] and in thenon-TBI group, the mean age was 4.1 years [range,1.0 –7.9 years]; P � 0.657). The chemotherapeuticagents with dosages used for HDC are provided inTable 1.

Dental ExaminationsThe clinical and radiologic examinations of all but twopatients were performed at the Institute of Dentistry,

TABLE 1Key Characteristics of 55 Pediatric Stem Cell Transplantation Recipients

Diagnosis

No. of patients

Mean age inyrs at SCT(range)Total

TBI HDC

Yes No Ara-C Cy Mel VMP ECT

NBL 19 11 8a 5 13 1 2.9 (1.0–7.9)ALL 12 12 0 7 2 3 4.9 (1.1–6.3)AML 9 9 0 3 5 1 5.2 (2.2–9.0)Wilms tumor 5 0 5 5 5.4 (4.2–6.4)CML 2 2 0 1 1 (5.2–5.5)Lymphoma 2 2 0 1 1 (5.7–6.4)MDS 2 2 0 2 (2.2–9.4)SAA 2 1 1b 2 (3.9–6.1)RMS 1 0 1 1 4.7Yolk sac tumor 1 0 1 1 2.5Total 55 39 16 12 13 14 13 3 4.3 (1.0–9.4)

TBI: total body irradiation; HDC: high-dose chemotherapy; SCT: stem cell transplantation; Ara-C: cytosine arabinoside (3 g/m2 � 12); Cy: cyclophosphamide (120 –200 mg/kg); Mel: melphalan (140 –180 mg/m2);

VMP: etoposide (300 mg/m2), melphalan (140 � 70 mg/m2), and cisplatin (90 mg/m2); ECT: etoposide (250 mg/m2 � 3), carboplatin (500 mg/m2 � 3), and thiotepa (300 mg/m2 � 3); NBL: neuroblastoma; ALL:

acute lymphoblastic leukemia; AML: acute myeloid leukemia; CML: chronic myeloid leukemia; MDS: myelodysplastic syndrome; SAA: severe aplastic anemia; RMS: rhabdomyosarcoma.a One patient in the non-total body irradiation-group received TBI that excluded the head.b The patient in the non-total body irradiation-group received total lymph node irradiation.

Tooth Agenesis and Microdontia after SCT/Holtta et al. 183

University of Helsinki. Panoramic radiographs (PRGs)from two patients were obtained from local healthcenters. One author (P.H.) performed all clinical ex-aminations and radiographic assessments. PRGs wereused to study agenesis and microdontia of permanentteeth.

The prevalence of tooth agenesis and the numberof missing teeth were recorded in 2 assessments, A1and A2, using the following criteria. For assessmentA1, third molars were excluded (52 patients with amean age of 4.5 years at SCT were analyzed; the meanfollow-up after SCT was 7.6 years). For assessment A2,third molars were included (29 patients with a meanage of 4.8 years at SCT were analyzed; the mean fol-low-up after SCT was 9.4 years).

Recordings were performed taking into accountthe different calcification schedules of teeth. Becausecalcification in permanent incisors, canines, and firstmolars begins at birth or soon after birth, these teethalways were recorded. Agenesis of the first premolarswas registered if no sign of tooth development wasobserved at age 5 years. The corresponding age for thesecond premolars and the permanent second molarswas 6 years. Because the third molars develop late,and the mineralization schedule shows wide varia-tion,22 their agenesis was not recorded until age 12years.

All 55 patients were included in the microdontiastudy. Commonly used criteria for the microdontiaassessment of PRGs are not available; therefore, re-cording was based on subjective visual judgmentwhen the size of a tooth crown was � 50% of the sizeconsidered “normal” (Fig. 2A,B). Of the two assess-ments, A1 and A2, only assessment A1 results arepresented because only three third molars in one pa-tient were found to be microdontic, and the results ofthe assessments were nearly identical.

The underlying factors behind tooth agenesis andmicrodontia also were analyzed by dividing the pa-tients into a TBI group and a non-TBI group and into

3 categories according to age at SCT: age � 3.0 years(Group Y), ages 3.1–5.0 years (Group M), and age � 5.1years (Group O). The numbers and percentages ofpatients who had received TBI in Group Y, Group M,and Group O were 10 of 16 patients (63%), 11 of 15patients (73%), and 18 of 24 patients (75%), respec-tively (P � 0.675).

Statistical AnalysisThe Statistical Package for the Social Sciences (SPSSfor Windows), version 10.0 (SPSS, Inc., Chicago, IL)was used in statistical analyses. The statistical signifi-cance of categoric variables between the groups werestudied with the Pearson chi-square test or the Fisherexact test, and continuous variables were studied withthe Mann–Whitney U test. Linear regression analysesand Pearson correlation coefficients were used tostudy associations of TBI and age at SCT with thedental outcome. P values � 0.05 were considered sig-nificant.

RESULTSTooth AgenesisFifty-two SCT recipients were analyzed for agenesis ofpermanent teeth, which occurred in 16 of 52 patients(31%) in assessment A1 (third molars excluded). Themost frequently missing teeth were second premolars(58%; 45 of 78 missing teeth), followed by secondmolars (28%), first premolars (10%), and upper lateralincisors (4%). Other permanent incisors as well as allcanines and first molars were present. When all teethwere included (assessment A2; n � 29 patients), toothagenesis occurred in 19 of 29 SCT recipients (62%).The agenesis prevalence in third molars alone was52% (15 of 29 patients).

The prevalence of tooth agenesis did not differstatistically between the TBI group and the non-TBIgroup, although, in assessment A2, the prevalenceamong patients in the TBI group (72%) tended to behigher compared with the prevalence among patients

FIGURE 2. Example of tooth agenesis and microdontia recording. Microdontia was recorded when the size of a tooth crown was approximately � 50% of the

size considered “normal.” (A) The crowns of the first premolar (short arrow), the second premolar (arrowhead), and the permanent first molar (long arrow) are

considered “normal.” (B) The crown of the first premolar (short arrow) is microdontic, the second premolar (arrowhead) is missing, and the crown of the permanent

first molar (long arrow) is “normal.”


in the non-TBI group (46%) (Table 2). Tooth agenesiswas most prevalent in the youngest group (Group Y)(Table 2). In assessment A1, the difference was highlysignificant compared with Group O, in which no teethwere missing (P � 0.001). The frequency of toothagenesis in Group M also exceeded the frequency inGroup O (P � 0.002) (Table 2). In assessment A2, theagenesis prevalence was 83%, 78%, and 43%, respec-tively, in Group Y, Group M, and Group O. In Group O,the percentage indicated the prevalence of third mo-lar agenesis, because no other teeth were missing(Table 2).

The Number of Missing TeethThe mean number and range of missing teeth per SCTrecipient was 1.5 teeth (range, 0 –11 teeth) and 2.9teeth (range, 0 –12 teeth), respectively, in assessmentsA1 and A2. If only the patients with tooth agenesiswere included, then the mean number of missingteeth was 4.8 teeth in assessment A1 (16 patients) and4.7 teeth in assessment A2 (18 patients). A mean of 5.0teeth (range, 2–11) were missing in all patients age � 2years at the time of SCT (n � 7 patients).

Patients in the TBI group were affected moreseverely than patients in the non-TBI group withregard to the number of missing teeth in assessmentA2 (P � 0.031) (Table 2, Fig. 3). The mean number ofmissing teeth was highest in Group Y: increasingfrom 3.9 teeth in assessment A1 to 4.7 teeth in

assessment A2. In Group M, the increase was from1.8 to 4.9 teeth. Both younger groups (Groups Y andM) differed significantly from Group O in both as-sessments (Table 2).

Patient age at the time of SCT was found to havea negative correlation with the number of missingteeth (R � � 0.580; P � 0.001). Age at SCT aloneexplained approximately 34% of the variation, irre-spective of whether the third molars were included orexcluded (assessment A1 or assessment A2). TBI wascorrelated negatively with the number of missing teethin assessment A2 (R � � 0.439; P � 0.017) but not inassessment A1 (R � � 0.164; P � 0.246).

MicrodontiaMicrodontia was present in 44% of the 55 patientsanalyzed, including 41% of patients in the TBI groupand in 50% of patients in the non-TBI group (assess-ment A1, third molars excluded; P � 0.377) (Table 3).The most frequently microdontic permanent teethwere first premolars (46%; 28 of 64 microdontic teeth),followed by second premolars (26%), and secondmolars (23%). Other teeth seldom were involved.Microdontia prevalence was high in the younger SCTrecipients, with rates of 75% in Group Y and 60% inGroup M, percentages that were significantly highercompared with Group O (13%) (Table 3).

TABLE 2The Prevalence of Tooth Agenesis and the Mean Number of Missing Teeth in Pediatric Stem CellTransplantation Recipients According to Total Body Irradiation and Age at Stem Cell Transplantation

Variable

No. of patients with tooth agenesis/no. of patients studied (%)

Mean no. of missing teeth per patient(range)

A1 (n � 52) A2 (n � 29) A1 (n � 52) A2 (n � 29)

Irradiation groupTBI 12/38 (32) 13/18 (72) 1.7 (0–11) 4.1 (0–12)Non-TBI 4/14 (29) 5/11 (46) 0.8 (0–4) 1.1 (0–4)P valuea 0.560 0.148 0.503 0.031b

Age at SCT� 3.0 yrs (Group Y) 10/13 (77) 5/6 (83) 3.9 (0–11) 4.7 (0–8)3.1–5.0 yrs (Group M) 6/15 (40) 7/9 (78) 1.8 (0–8) 4.9 (0–12)� 5.1 yrs (Group O) 0/24 (0) 6/14 (43) 0 (0) 0.9 (0–4)

P valuesa

Group Y vs. Group M 0.055 0.659 0.08 0.955Group M vs. Group O 0.002c 0.111 0.038b 0.011b

Group Y vs. Group O 0.001d 0.119 0.001d 0.015b

A1: assessment with third molars excluded; A2: assessment with third molars included; TBI: total body irradiation; SCT: stem cell transplantation.a The Fisher exact test was used for categoric variables, and the Mann–Whitney U test was used for continuous variables.b P � 0.05.c P � 0.01.d P � 0.001.


The Number of Microdontic TeethThe mean number of microdontic teeth was 1.4, with1.5 teeth found in the TBI group and 1.1 teeth in thenon-TBI group (P � 0.821) (Table 3, Fig. 4). The lowestmean number of microdontic teeth (0.2) was recordedin Group O (P � 0.001 and P � 0.005 compared withGroup Y and Group M, respectively) (Table 3). A neg-ative correlation was found between the number ofmicrodontic teeth and patient age at SCT (R � �0.375; P � 0.005). Patient age at SCT explained only

14% of the variation in the dependent variable. Therewas no correlation found between TBI and the num-ber of microdontic teeth (R � 0.077; P � 0.578).

Summarized Tooth Agenesis and/or MicrodontiaSummarized agenesis and/or microdontia were ob-served in 51% and 69%, respectively, of the SCT recip-ients for assessments A1 and A2. In assessment A1, theTBI and non-TBI groups were affected equally (51% vs.50%, respectively). The difference was not significantin assessment A2 either (72% vs. 64%, respectively; P� 0.694).

A very high prevalence (94%) of summarizedagenesis and/or microdontia was found in assess-ment A1 among the patients age � 3.0 years at SCT(Group Y). All age groups (Groups Y, M, and O)differed significantly from one another (assessmentA1: Group Y vs. Group M, P � 0.033; Group Y vs.Group O, P � 0.001; Group M vs. Group O, P� 0.007) (Fig. 5). All patients in Group Y were af-fected in assessment A2; whereas, in the least af-fected group (Group O), only 50% of patients pre-sented with agenesis and/or microdontia (Group Yvs. Group O, P � 0.044). Group M with the angensisand/or microdontia prevalence of 78% did not differfrom Groups Y and O.

The mean number of affected teeth per patientappeared greater in the TBI group than in the non-TBIgroup (3.3 teeth vs. 1.8 teeth in assessment A1 and 5.2teeth vs. 2.1 teeth in assessment A2), but the differ-ences were not significant (assessment A1, P � 0.447;assessment A2, P � 0.095.). With regard to the meannumber of affected teeth per patient in the 3 agegroups, Groups Y and M scored significantly higherthan Group O (in assessment A1: Group Y vs. Group O,P � 0.001 and Group M vs. Group O, P � 0.005; in

TABLE 3The Prevalence of Microdontia and the Mean Number of MicrodonticTeeth in Pediatric Stem Cell Transplantation Recipients According toTotal Body Irradiation and Age at Stem Cell Transplantation

Variable

Assessment A1 (n � 55 patients)

No. of patients withmicrodontia/no. ofpatients studied (%)

Mean no. of microdonticteeth per patient (range)

Irradiation groupTBI 16/39 (41) 1.5 (0–12)Non-TBI 8/16 (50) 1.1 (0–3)P valuea 0.377 0.821

Age at SCT� 3.0 yrs (Group Y) 12/16 (75) 1.9 (0–4)3.1–5.0 yrs (Group M) 9/15 (60) 2.8 (0–12)� 5.1 yrs (Group O) 3/24 (13) 0.2 (0–2)

P valuesa

Group Y vs. Group M 0.306 0.861Group M vs. Group O 0.003b 0.005b

Group Y vs. Group O 0.001c 0.001c

A1: assessment with third molars excluded; TBI: total body irradiation; SCT: stem cell transplantation.a The Fisher exact test was used for categoric variables, and the Mann–Whitney U test was used for

continuous variables.b P � 0.01.c P � 0.001.

FIGURE 3. The number of missing teeth (third molars included;

assessment A2) is shown in individual patients (n � 29 patients)

according to their age at the time they underwent stem cell transplan-

tation (SCT). Patients in the total body irradiation (TBI) group are indicated

by dark triangles, and patients in the non-TBI group are indicated by

white triangles.


assessment A2: Group Y vs. Group O, P � 0.002 andGroup M vs. Group O, P � 0.016) (Fig. 6).

DISCUSSIONThe results of the current study concerning pediatricSCT recipients emphasize the role of young age at SCT

as a risk factor for late dental adverse effects, which wedefined as tooth agenesis and microdontia. Ageseemed to be a stronger risk factor than TBI, althoughTBI caused additive impairment.

Numerous signal molecules that are used repeat-edly in complicated interactions between surface ep-ithelium and the underlying mesenchyme mediate the

FIGURE 4. The number of microdontic teeth (third molars excluded;

assessment A1) is shown in individual patients (n � 55 patients)

according to their age at the time they underwent stem cell transplan-

tation (SCT). Patients in the total body irradiation (TBI) group are indicated

by black triangles, and patients in the non-TBI group are indicated by

white triangles.

FIGURE 5. The percentages of patients with tooth agenesis (solid bars),

microdontia (open bars), and summarized agenesis and/or microdontia (shaded

bars) are shown for the youngest age group (Group Y) (age � 3 years at the

time of stem cell transplantation [SCT]; n � 16 patients), the middle age group

(Group M) (ages 3.1–5.0 years at the time of SCT; n � 15 patients), and the

oldest age group (Group O) (age � 5.1 years at the time of SCT; n � 24

patients). Third molars were excluded (assessment A1). The prevalence of

agenesis and microdontia in Group O differed significantly from that in Groups

Y and M (agenesis: Group Y vs. Group O, P � 0.001 and Group M vs. Group

O, P � 0.002; and microdontia: Group Y vs. Group O, P � 0.001 and Group M

vs. Group O, P � 0.003). Each group differed from the others when agenesis

and/or microdontia were summarized (Group Y vs. Group M, P � 0.033; Group

Y vs. Group O, P � 0.001; and Group M vs. Group O, P � 0.007).

FIGURE 6. The mean number of missing (solid bars), microdontic (open

bars), and summarized mean number of missing and/or microdontic (shaded

bars) teeth per patient is shown in the youngest age group (Group Y) (age � 3

years at the time of stem cell transplantation [SCT]; n � 16 patients), the

middle age group (Group M) (ages 3.1–5.0 years at SCT; n � 15 patients), and

the oldest age group (Group O) (age � 5.1 years at SCT; n � 24 patients). Third

molars were excluded (assessment A1). The mean number of affected teeth in

Group O differed significantly from the other groups in terms of agenesis (Group

Y vs. Group O, P � 0.001 and Group M vs. Group O, P � 0.038), microdontia

(Group Y vs. Group O, P � 0.001 and Group M vs. Group O, P � 0.005), and

summarized agenesis and/or microdontia (Group Y vs. Group O, P � 0.001 and

Group M vs. Group O, P � 0.005).


developmental stages of teeth from initiation to mor-phogenesis and, furthermore, to the differentiation oftooth-specific cells, mineralization, and root forma-tion.23,24 Pediatric anticancer therapy may affect toothdevelopment either by a direct toxicity toward theodontogenic cells, or by interfering with the delicatesignaling network between ectoderm and mesen-chyme or within one tissue layer. To our knowledge,the exact molecular mechanisms of the anticancertreatment that result in dental aberrations are notknown.

Proliferating preodontoblasts and their precursorsusually are more sensitive than mature, functioningcells, as shown in biochemical and histologic studiesof developing rat or hamster teeth. Disturbed odonto-genesis has been reported after the administration ofseveral chemotherapeutic agents, such as cyclophos-phamide,25–27 vincristine,28,29 actinomycin D,30,31

doxorubicin,32,33 and daunorubicin.34 Typical, dose-dependent findings include, for example, dentinniches (reduced thickness of the dentin wall); con-strictions (reduction in the tooth width); and, at highdoses, interrupted odontogenesis and degeneration oftooth-forming cells. The same agent that kills a cell athigh doses by directly inhibiting a vital metabolic pro-cess, resulting in necrosis (straight toxicity), at lowerdoses, may trigger the apoptotic pathway.31,34

The dental effects of radiation therapy are knownwell. although to our knowledge the minimum radia-tion dose that is harmful to developing teeth remainsuncertain. Teeth exposed to a dose as low as 4 Gy haveshown some abnormality in patients treated for softtissue sarcomas of the head and neck.35 The typicalclinical consequences of irradiation on developing hu-man teeth include microdontia, agenesis, and dwarf-ing of the roots.36 Dentine niches identical to thoseobserved after chemotherapy also have been de-scribed.37,38 The dental consequences depend on thecell sensitivity and the radiation dose.

The 31% prevalence of permanent tooth agenesisin the SCT group (third molars excluded) was 4-foldgreater compared with the prevalence of 8% reportedin a population of healthy Finns,4 indicating a consid-erable effect of chemotherapy and/or radiotherapy ontooth development in children. According to the samestudy, the most frequently missing teeth were man-dibular second premolars (42%), followed by maxillarysecond premolars (29%) and maxillary lateral incisors(19%). Missing of permanent second molars was veryrare (1.4%). Compared with these percentages, therewere striking differences in the distribution of missingpermanent teeth among patients in the SCT group.For instance, only 4% of the missing teeth were max-illary lateral incisors, and a high percentage (28%) was

recorded for second molars. These percentages, whichclearly differ from the rates of “genetic hypodontia,”further stress that agenesis in the SCT group resultedmainly from the toxicity of anticancer therapy. A ma-jor difference between the healthy population and theSCT recipients also was seen in the third molar agen-esis rate. Haavikko4 reported that at least 1 of the thirdmolars was missing in 21% of healthy Finns, com-pared with 52% among the SCT recipients in ourstudy.

The preparative regimens for SCT have causedtooth agenesis at a frequency that reportedly rangesfrom 56 –58%12,13 to 80%.18 To our knowledge, thecurrent series of SCT patients is the largest reported todate with an agenesis prevalence of 31%, which islower than the prevalence reported previously.12,13,18

The present results are not easy to compare with ear-lier studies due to variations in methodology, age ofthe patients, and treatment protocols. In the study byNasman et al.,12 all patients who underwent SCT re-ceived TBI in a single fraction, whereas only 71% ofpatients in the current study received TBI that wasfractionated in all but 1 patient. The underlying dis-eases also have been different (e.g., poor-risk NBLpatients versus patients with mainly hematologic ma-lignancies).12,13,18 The current study included severaldiagnoses (Table 1).

According to our study, TBI alone was not foundto increase the prevalence of tooth agenesis signifi-cantly. Quantitatively more serious consequenceswere observed, especially when the third molars wereincluded: The maximum number of missing teeth perpatient was 4 teeth in the non-TBI group and 12 teethin the TBI group (Table 2; Fig. 3).

Young age at the time of SCT predisposes a toothgerm to permanent destruction prior to its mineral-ization due to the chemotherapy or chemoradiationtherapy. A high prevalence of patients with toothagenesis and high numbers of missing teeth per pa-tient in the youngest age groups (Groups Y and M; age� 5 years) indicate a high risk of developmental dentaldisturbances at young age. At age 5 years, the perma-nent teeth already are in the mineralization phase,except for the third molars, which begin their miner-alization as late as at ages 9 –10 years.22 Consequently,children age � 5 years at the time of SCT had anagenesis prevalence of 43% for the third molars,whereas all other teeth were present.

Furthermore, the clinical significance of toothagenesis was remarkable in the youngest children. Theresulting gaps were situated more anteriorly on thealveolar ridge than the gaps that resulted from thirdmolar agenesis. Primary molars often are able to sub-stitute the missing premolars for some time; however,


after their exfoliation, the mastication ability is de-creased. The third molar agenesis alone did not ap-pear to jeopardize occlusion in the oldest patients(Group O).

Information regarding microdontia prevalence isscarce, and there are no solid diagnostic criteria for itsassessment on PRGs. Measurements of horizontal dis-tances on PRGs, such as the mesiodistal crown size af-fected in microdontia, are not considered as reliable asthe vertical measurements.39,40 Thus, radiographic micr-odontia assessments after pediatric anticancer treat-ment have been based on clinical judgment.10–13,15,17,18

In the current study, only distinctly small teeth, maxi-mally half of a “normal” size, were considered micr-odontic. The prevalence would have been higher thanthe rate of 44% found in our study if dental plaster castscould have been used for accurate crown size measure-ments. However, in young children such as those in thecurrent study, many unerupted teeth, already seen inradiographs, are nonmeasurable from dental casts. Nev-ertheless, the microdontia prevalence among SCT recip-ients clearly exceeded the microdontia prevalence of1.9% among healthy Japanese schoolchildren as mea-sured from dental casts.16

Nasman et al.12 reported a microdontia preva-lence of 68% in SCT recipients (n � 19 patients) whohad a mean age of 6.5 years at diagnosis and 75% in 16SCT recipients who had a mean age of 6.3 years at thestart of treatment.13 These percentages are higherthan what was found in the current study (44% amongrecipients with a mean age of 4.3 years at SCT), despitethe fact that our patients were younger and moresusceptible to dental aberrations. The subjective cri-teria for the microdontia assessment may explain thedifference. Calculated from the material of 16 SCTrecipients with a mean age of 7.1 years at SCT, themicrodontia prevalence was 25%,15 which is more inaccordance with the prevalence rate determined ac-cording to our data.

Although the prevalence of microdontia wasfound to be greatest in patients age � 3.0 (Group Y) atthe time of SCT, the most severely affected patients,with � 4 microdontic teeth, were ages 3.1–5.0 years(Group M) at the time of SCT and belonged to the TBIgroup. This is understandable because fewer teethwere missing in Group M compared with Group Y,leaving more teeth vulnerable to microdontia.

Tooth agenesis and microdontia often occurredsimultaneously after SCT. With the third molars in-cluded, 100% of patients age � 3 years at the time ofSCT, 78% of patients ages 3.1–5.0 years, and 50% of thepatients age � 5.0 years were affected, often resultingin clinically significant occlusal disturbances. Properdental care and rehabilitation, from the beginning of

the treatment until adulthood, play one part in achiev-ing a good quality of life for this increasingly largergroup of children.

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agenesis and microdontia of permanent teeth as late adverse effects after stem cell transplantation...

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