J Clin Res Ped Endo 2011;3(2):89-94
DOI: 10.4274/jcrpe.v3i2.18 Original Article
Thyroid Functions in Long-Term Survivors of
Pediatric Hodgkin’s Lymphoma Treated with
Chemotherapy and Radiotherapy
Metin Demirkaya1, Betül Sevinir1, Halil Sa¤lam2, Lütfi Özkan3, Okan Akac›4
1Division of Pediatric Oncology, Department of Pediatrics, Uludag University, Medical Faculty, Bursa, Turkey
2Division of Pediatric Endocrinology, Department of Pediatrics, Uludag University, Medical Faculty, Bursa, Turkey
3Department of Radiation Oncology, Uludag University, Medical Faculty, Bursa, Turkey
4Department of Pediatrics, Uludag University, Medical Faculty, Bursa, Turkey
Introduction
ABSTRACT In parallel with enhanced survival rates of pediatric
Objective: Post-treatment endocrine disturbances are common in cancer Hodgkin’s lymphoma patients by current chemotherapy and
patients who have received radiotherapy or chemotherapy. The objective 
of this study was to evaluate the thyroid functions of long-term survivors of radiotherapy protocols, an increase in early and late complication
pediatric Hodgkin’s lymphoma treated with chemotherapy and radiotherapy. rates have also been noted. Common late complications of
Methods: Thyroid functions of 55 Hodgkin’s lymphoma patients (M/F:2.05/1) childhood cancers after treatment include neurological, cardiac,
in complete remission were evaluated retrospectively. pulmonary and gonadal disorders, reduction in bone mass,
Results: The mean age of the patients at diagnosis was 10.35±4.09
(range: 2.83-17) years and the mean follow-up period was 5.54±3.68 defective bone and soft tissue development, and increased 
(range: 0.92-13.92) years. All patients received chemotherapy; a total of susceptibility to secondary malignant tumors (1,2,3,4,5,6,7,8,9). 
50 patients (90.9%) underwent radiotherapy, 42 (76.4%) of whom
received neck/mantle radiotherapy. Thyroid function tests were abnormal Hyperthyroidism including Graves’ disease, thyroiditis,
in 14 (24.5%) patients and normal - in the remaining 41 (74.5%). A hypothyroidism, thyroid nodules and thyroid cancers are the
diagnosis of subclinical and overt hypothyroidism was made in 11 (78.6%)
and 3 (21.4%) patients with abnormal thyroid function tests, respectively. most commonly encountered thyroid gland disorders that are
Nearly one-fourth (21.4%) of all thyroid function disorders were detected known to be related with radiotherapy (6,10,11,12,13).
in the first year of follow-up. A statistically significant correlation was
found between the dose of mantle radiotherapy and thyroid function The objective of this study was to evaluate thyroid function
disorder (p=0.002). In addition, statistically significant correlations were in pediatric Hodgkin’s lymphoma patients in complete remission
established between thyroid examination or thyroid ultrasonography 
findings and thyroid functions (p <0.001 or p=0.006, respectively). with chemotherapy and radiotherapy.
Conclusions: Radiation-induced thyroid disorders may develop in pediatric
Hodgkin’s lymphoma patients in complete remission starting as early as the Methods
first year after treatment and are dose-dependent. Patients, particularly those
who have been exposed to radiotherapy of the neck, must be followed up
closely for occurrence of thyroid dysfunctions. In this retrospective study, we assessed the thyroid 
Key words: Hodgkin disease, children, late effect functions in 55 pediatric Hodgkin’s lymphoma patients in 
complete remission who were treated in the Department of
Conflict of interest: None declared
Received: 14.03.2001 Accepted: 23.04.2011 Pediatric Oncology at Uludag University Medical Faculty
between January 1995 and December 2008.  
Address for Correspondence
Metin Demirkaya MD, Division of Pediatric Oncology, Department of Pediatrics, Uludag University, Medical Faculty, 16059 Görükle, Bursa, Turkey
Tel: +90 224 295 04 32 Fax: +90 224 442 81 43 E-mail: demirkayametin@hotmail.com    
© Journal of Clinical Research in Pediatric Endocrinology, Published by Galenos Publishing.
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Thyroid Functions in Pediatric Hodgkin’s Lymphoma
Recurrence occurred only in 2 patients who received a Results
second treatment regimen and were then followed up in 
complete remission. Physical and thyroid examination  findings, Table 1 lists the demographic features of the 55 patients
thyroid stimulating hormone (TSH), free triiodothyronine (fT3), included in this study. The patients were classified according to
free thyroxine (fT4), total T3, and total T4 levels, thyroid imaging their thyroid function tests as normal (group 1) and abnormal
(ultrasonography and/or scintigraphy), thyroid antibody data, (group 2). The total study population consisted of 37 males
serum thyroglobulin and calcitonin levels were obtained from (67.3%) and 18 females (32.3%); male/female ratio was 2.05/1.
patient records and evaluated. Thyroid function tests were normal in 41 (74.5%) patients,
Age and gender of the patients, stage and histopathological while thyroid dysfunction was present in 14 (25.5%) patients.
subgroup of the disease, chemotherapy protocols, number of No statistically significant difference was found with regard to
cycles, radiotherapy region and dose, and follow-up durations thyroid dysfunction between genders.
were noted. Patients with hypothyroidism were divided into The mean ages of the patients at diagnosis and when the
two groups as subclinical hypothyroidism and overt study was performed were 10.35±4.09 (range: 2.83-17) years
hypothyroidism. and 15.84±3.91 (range: 6.91-24) years, respectively. The 
The study was approved by the local ethics committee. mean follow-up duration was 5.54±3.68 (range 0.92-13.92)
The following four chemotherapy protocols were used: i) years. No statistically significant difference was found with
ABVD (adriamycin 25 mg/m2 1st and 15th days, intravenously regard to gender distribution or follow-up duration between
(i.v.), bleomycin 10 mg/m2 1st and 15th days i.v., vinblastine 6 groups 1 and 2. 
mg/m2 1st and 15th days i.v., dacarbazine 375 mg/m2 1st and Thyroid examination was normal (grade 0) in 40 (72.7%)
15th days i.v.); ii) COPP (cyclophosphamide 600 mg/m2 1st and patients, while grade I, grade II, and grade III goiter was 
8th days i.v., vincristine 1.4 mg/m2 1st and 8th days i.v., detected in 9 (16.4%), 5 (9.1%), and 1 (1.8%) patient, 
procarbazine 100 mg/m2 1-14 days p.o., prednisolone 40 respectively. Thyroid ultrasonography  performed in 45 (81.8%)
mg/m2 1-14 days p.o.), iii) MOPP (mechlorethamine 5 mg/m2 out of 55 patients was normal in 41 (91.1%) and abnormal in 
1st and 8th days i.v., vincristine 1.4 mg/m2 1st and 8th days i.v., 4 (8.9%) patients (nodules in 3 patients and hypoechoic cyst in
procarbazine 100 mg/m2 1-14 days p.o., prednisolone 40 1 patient). 
mg/m2 1-14 days p.o.), iv) MOPP/ABVD or COPP/ABVD hybrid Thyroid functions were normal in 95% of patients with 
treatment protocol. normal thyroid examination findings, in 22.2% of patients with
The COPP, MOPP or hybrid protocols were applied to the grade I goiter and in 20% of patients with grade II goiter. One
patients between 1995 and 1997, while ABVD treatment patient with grade III goiter had abnormal thyroid functions.
protocol was given after 1997. All subjects, except for those Thyroid functions were significantly correlated with thyroid
who experienced recurrence, received 3-6 chemotherapy examination findings (p<0.001). 
cycles. Thyroid ultrasonography was performed in 87.8% and
Radiotherapy regions were grouped as: i) neck region and 64.3% of subjects in group 1 and 2, respectively. Thyroid 
mantle radiotherapy ii) mediastinum, iii) other regions. The
patients received a total dose of 2520 centigrays (cGy) mantle Table 1. Demographic features of the patients
radiotherapy with a daily dose of 180 cGy. The dose of Thyroid functions
radiotherapy was completed to 3060 or 3600 in patients with Normal Abnormal
remaining lymphadenopathy after standard dose 
chemotherapy and in those with residual disease after Number of patients [n, (%)] 41 (74.5) 14 (25.5)
radiotherapy, respectively. Gender [n, (%)]
Serum total T3, total T4, fT3, fT4 and TSH levels were 
analyzed by Immulite 2000 autoanalyzer using Male 26 (70.3) 11 (29.7)
chemiluminescent microparticle immunoassay (CMIA) method Female 15 (83.3) 3 (16.7)
(Abbott Laboratories).
The statistical analyses were performed using SPSS Age at diagnosis 10.45±4.2 10.07±3.89
(Statistical Package for the Social Sciences) for Windows 13.0 [(years), (mean ±SD)] (3.66-17) (2.83-16.41)
software. Comparisons of continuous variables in multiple
groups were made applying the Kruskal-Wallis test, while Age at time of study 16.1±4.11 15.07±3.27
comparisons between two groups were made using the [(years), (mean ±SD)] (6.91-24) (10.08-20.91)
Mann-Whitney U test. Inter-group differences of categorical
variables were determined by the Pearson’s chi-square test and Mean follow-up duration   5.78±4.08 5.01±2.83
Fisher’s exact test. Results were presented as mean±standard [(years), (mean ±SD)] (0.92-16.25) (0.92-11.33)
deviation (SD) values. A p-value of less than 0.05 was 
SD: standard deviation
considered statistically significant.
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Demirkaya M et al.
Thyroid Functions in Pediatric Hodgkin’s Lymphoma
functions were normal in 85.7% of patients with normal 13 (23.6%), 18 (32.7%), 19 (34.5%) and 5 (9.1%) patients were
ultrasonographic findings; in contrast, thyroid dysfunction was classified as having stages I, II, III, and IV, respectively.
found in all 4 patients with abnormal ultrasonographic findings. ABVD, COPP, and MOPP/ABVD hybrid protocols were
A significant correlation was observed between thyroid applied to 49 (89.1%), 2 (3.6%), and 4 (7.3%) patients, 
ultrasonography findings and thyroid functions (p=0.006). The 4 respectively. Three and 6 cycles of chemotherapy were given
patients in group 2 who showed abnormal ultrasonographic to 50.9% and 49.1% of all patients, respectively.
findings included 3 patients with nodules and one patient with Out of the 55 patients in our study, 50 (90.9%) received
a 12x17 mm hypoechoic cystic degeneration on the right radiotherapy, 42 (76.4%) of whom underwent neck/mantle
thyroid lobe. Hypothyroidism was present in all 4 patients. radiotherapy. Twenty-two (52.4%), 14 (33.3%), and 6 (14.3%)
Thyroglobulin levels in the case with hypoechoic cyst were patients received a total dose of 2520 cGy, 3060 cGy, and 3600
cGy neck/mantle radiotherapy, respectively. Twenty-two
higher than normal and the patient underwent thyroid surgery.
(52.4%) out of 42 patients who received neck/mantle 
The cyst was benign in nature on histopathological evaluation. 
radiotherapy also received radiotherapy to other regions, while
As shown in Table 2, histopathological typing revealed that the remaining 20 (47.6%) patients did not. 
the Hodgkin’s lymphoma was nodular sclerosing in 28 (50.9%) Statistical analysis revealed no differences with regard to
patients, mixed-cell in 23 (41.8%) and lymphocyte-rich in 4 thyroid function among the different histopathological groups,
(7.3%) patients. According to the Hodgkin’s lymphoma staging, nor among the various stage or chemotherapy groups. There
were also no differences detected among patients who 
Table 2. Clinical characteristics of the patients were exposed to 3 or to 6 cycles of treatment. Exposure or 
Thyroid functions non-exposure to radiotherapy or to radiotherapy to the
Normal (n=41) Abnormal (n=14) neck/mantle region also did not appear to lead to differences in
Histopathology [n, (%)] thyroid function. On the other hand, statistically significant 
differences were found regarding thyroid dysfunction among
nodular sclerosing  20 (71.4) 8 (28.6) patients receiving different doses of neck/mantle radiotherapy.
mixed-cell 17 (73.9) 6 (26.1) Thyroid function was normal in 72.7%, 92.9%, and 16.7% of
lymphocyte-rich 4 (100) - patients who received a total dose of 2520 cGy, 3060 cGy, and
3600 cGy neck/mantle radiotherapy, respectively. However,
Stage [n, (%)] binary comparisons of the three doses revealed statistically 
I 11 (84.6) 2 (15.4) significant differences between the 2520 cGy dose and the
II 12 (66.7) 6 (33.3) 3600 cGy dose (p=0.022) and also between the 3060 cGy dose
and 3600 cGy dose (p=0.002).
III 13 (68.4) 6 (31.6) Subclinical and overt hypothyroidism was diagnosed in 
IV 5 (100) - 11 (78.6%) and 3 (21.4%) patients with abnormal thyroid 
Chemotherapy [n, (%)] function tests, respectively. Table 3 lists the features in 
ABVD 35 (71.4) 14 (28.6) individual patients with abnormal thyroid function tests. Thyroid
dysfunction was detected after the first, second, third, fourth
COPP 2 (100) - and fifth year of treatment in 3, 2, 3, 4 and 2 patients, 
MOPP/ABVD 4 (100) - respectively. No statistically significant correlation was found
Number of cycles [n, (%)] between time passed after treatment and thyroid dysfunction. 
3 cycles 20 (71.4) 8 (28.6) Discussion
6 cycles 21 (77.8) 6 (22.2)
Radiotherapy [n, (%)] 36 (72) 14 (28) In parallel to enhanced survival rates of pediatric Hodgkin’s
lymphoma patients by current chemotherapy and radiotherapy
Neck/mantle region [n, (%)] 30 (71.4) 12 (28.6) protocols, an increase in early and late complication rates was
Neck/mantle dose* [n, (%)]         also noted (14,15,16). The risk of thyroid disorder development
was found to be 52% and 67% after 20 and 26 years of 
2520 cGy 16 (72.7) 6 (27.3)
survival, respectively, in a study including 1787 patients with
3060 cGy 13 (92.9) 1 (7.1) Hodgkin’s lymphoma (14). We found a thyroid disorder rate of
3600 cGy 1 (16.7) 5 (83.3) 25.5% within a mean follow-up duration of 5.54 years in our
study group of 55 patients, all in complete remission following
* p<0.05, SD: standard deviation, ABVD: adriamycin, bleomycin, vinblastine, 
dacarbazine, COPP: cyclophosphamide, vincristine, procarbazine, prednisolone, chemotherapy and radiotherapy. Of the 14 patients who
MOPP: mechlorethamine, vincristine, procarbazine, prednisolone showed abnormal thyroid function, 78.6% were diagnosed as
cGy: centigrays subclinical and 11.4% as overt hypothyroidism. 
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Subclinical hypothyroidism following exposure to low-dose (lower than 2600 rad) and high-dose (higher than 2600
radiotherapy has been reported to have a high incidence in rad) mantle radiotherapy to the neck, 
Hodgkin’s patients (17). Hunger et al (18) detected subclinical respectively. Since thyroid dysfunction occurred 18 and 31
chemical hypothyroidism in 9 (16%) out of 57 patients who months after low- and high-dose radiotherapy, respectively, it is
received a combination of chemotherapy and low-dose generally stated that it takes a time period of 3 to 5 years for
radiotherapy in their study with a mean follow-up duration of 6.7 thyroid function to be affected. In another study (6) with a mean
years. In another study (19), subclinical hypothyroidism was follow-up duration of 30 years, thyroid dysfunction, the most
found in 22 (63%) out of 35 patients with Hodgkin’s lymphoma common (17.1%) of which was hypothyroidism (p=0.0001),
who received mantle radiotherapy; some of these patients was detected in 34% of 1791 Hodgkin’s lymphoma patients
reportedly recovered within time. Periodical thyroid function who received chemotherapy and radiotherapy; the risk of
tests revealed altered levels of at least one thyroid hormone. hypothyroidism was increased by high-dose radiotherapy,
Elevation in TSH level was the most commonly encountered
disorder. In one study (20), a high TSH was reported in 29 advanced diagnosis age and female gender. Hyperthyroidism
(50%) out of 58 patients who had received chemotherapy and was detected in 5% of these patients - an 8-fold increased risk
low-dose (15-25 Gy) mantle radiotherapy. In our study, we also compared with controls (p=0.0001). The risk of thyroid nodule
observed a significant correlation between thyroid dysfunction development was 27-fold that of controls after a mean latent
and dose of the neck/mantle radiotherapy. period of 14 years in this same study and the risk of nodule
Radiotherapy dose, which was 44-45 Gy previously, was development was correlated with high dose radiotherapy 
reduced to 15-25.5 Gy due to late complications (1). In a study (higher than 2500 cGy) and female gender. 7% of the nodules
(21) on 119 Hodgkin’s lymphoma patients, TSH levels were were of malignant nature. In addition, thyroid cancer was found
found to be elevated in 17% and 78% of those who received in 20 survivors in that study, which is 18-fold of that expected
in a community.
Table 3. Features of patients with overt and subclinical hypothyroidism
Age at Gender Stage Chemotherapy Neck/mantle Thyroid Thyroid Thyroid
diagnosis protocol/number RT examination USG dysfunction 
(years) of cycles dose (cGy) grade time
Overt 
hypothyroidism
Patient 1    16.4 F 1 ABVD/3 2520 1 - 1st year
Patient 2 9.8 M 2b ABVD/3 3060 1 normal 5th year
Patient 3 10.8 M 1 ABVD/3 2520 1 nodule 3rd year
Subclinical
hypothyroidism
Patient 4 13.8 M 3sb ABVD/6 2520 1 normal 2nd year 
Patient 5 14.6 M 3 ABVD/6 3600 1 - 4th year
Patient 6 11.6 M 2b ABVD/3 3600 2 nodule 4th year
Patient 7 8.9 M 2 ABVD/3 3600 2 normal 3rd year 
Patient 8 9.2 F 2 ABVD/3 2520 2 normal 1st year 
Patient 9 2.8 M 3s ABVD/6 - 1 - >5th year
Patient 10 14.8 M 3sb ABVD/6 - 0 - 3rd year 
Patient 11 6.5 M 2 ABVD/3 2520 1 nodule 4th year
Patient 12 6.7 M 3s ABVD/6 3600 0 - 1st year 
Patient 13 9.2 M 3s ABVD/6 3600 2 normal 2nd year
Patient 14 5.8 F 2 ABVD/3 2520 3 cyst >5th year
ABVD: adriamycin, bleomycin, vinblastine, dacarbazine, F: female, M: male, RT: radiotherapy, cGy: centigrays
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Thyroid Functions in Pediatric Hodgkin’s Lymphoma
In a study (14) on 1677 patients with Hodgkin’s lymphoma completion of treatment. Thyroid dysfunction was found to 
who received radiotherapy to the thyroid gland region, at least statistically correlate with the dose of neck/mantle radiotherapy.
one nodule was detected in 2.6% of them. The risk of thyroid The reason why the rate of thyroid dysfunction in our study was
nodule development was found to be increased 27-fold in a smaller than those in other reports could be that we applied a
controlled study after a mean latent period of 14 years. 7% of lower dose as mantle radiotherapy. It is also known that the
the nodules were of malignant nature.  Independent risk factors rate of detection of thyroid nodules increases with duration of
were reported as female gender and high dose (higher than 25 follow-up. Thus, periodic evaluation of the thyroid gland in
Gy) of radiotherapy (6). The risk of benign or malignant thyroid Hodgkin’s lymphoma patients who received radiotherapy and
disease development subsequent to chemotherapy and chemotherapy needs to be started at an early period after 
radiotherapy is reported to be increased 1.74- or 36.4-fold, treatment and continued for many years. 
respectively. The length of duration after treatment and the age Conflict of Interest
at which the treatment was initiated increase this risk. Although No author of this paper has a conflict of interest, including
radiotherapy is significantly correlated with such risks, the risk specific financial interests, relationships, and/or affiliations 
caused by chemotherapy is not clear. However, it is generally relevant to the subject matter or materials included in this 
accepted that a combination of chemotherapy and radiotherapy manuscript.
further enhances the risk of benign or malignant thyroid 
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