Complications Post Transplant

Secondary thyroid carcinoma after allogeneic bone marrow transplantation during childhood


The aim of this study was to evaluate the incidence and risk factors related to secondary thyroid carcinoma (STC) in patients who have undergone allogeneic BMT during childhood. Data related to the primary hematological disorder and BMT procedure were obtained from the records of 113 patients (42 F; 71 M) who underwent BMT before the age of 18 (median 10.0 years; range 1.7–18.0) and survived more than 3 years after transplant with a median follow-up of 10.1 years (range 3.0–19.0). Sixteen received cranial radiation (CRT) during first-line treatment. Pre-transplant conditioning included TBI in 85 patients, TAI in two, while 26 children did not receive irradiation. The standardized incidence ratio of STC after BMT was significantly higher (P < 0.001) than that of the general population. STC was found in eight patients, 3.1 to 15.7 years after transplant. All received TBI and three also CRT. The Cox's regression analysis, although not statistically significant due to the small study population, showed an increased risk in those who had received a cumulative radiation dose higher than 10 Gy and in those who developed chronic GVHD. Careful follow-up of thyroid status including annual ultrasound examination is recommended for early detection of tumor.

Bone Marrow Transplantation (2001) 28, 1125–1128.


Bone marrow transplantation (BMT) has improved the prognosis of patients with hematological malignancies. Nevertheless, this procedure has been associated with early and late toxicity, mainly related to the pre-transplant chemotherapy and radiotherapy. The development of secondary tumors is the foremost complication in this group of patients.1

There have been a few studies dealing with the risk of secondary solid tumors after BMT2,3,4,5,6,7,8 and occasional ones after BMT for childhood leukemia.9 The risk of developing secondary thyroid tumor after BMT10,11 has only been marginally reported as part of retrospective multicenter studies.4,7,8,9

The aim of this study was to assess the risk of secondary thyroid cancer in patients who have undergone BMT during childhood, evaluating the incidence and treatment-related risk factors. This study reports eight patients who developed a second thyroid malignancy after BMT, who were detected out of 113 patients surviving more than 3 years after transplant and who underwent a routine late-effects surveillance work-up including ultrasound.

Patients and methods

From January 1981 to June 1997, 250 patients underwent allogeneic BMT before the age of 18 years, in two Italian centers (San Gerardo Hospital-Monza and San Martino Hospital-Genoa). The source of the stem cells was bone marrow in all cases. Patients with inborn susceptibility for developing tumors due to their primary disease, such as Fanconi's anemia (two patients) and thalassemia (two patients) were excluded beforehand from the study population. The 113 patients (71 M; 42 F) who survived more than 3 years after transplant were enrolled in the study. The median age at transplant was 10.0 years (range 1.7–18.0), and the median follow-up period after transplant was 10.1 (range 3.0–19.0 years).

Patient characteristics and the conditioning regimens used are shown in Table 1. None of the patients received T cell depletion as prophylaxis for graft-versus-host disease (GVHD) at transplant.

Table 1 Patient characteristics

The cohort was divided into three groups according to the pre-transplant conditioning regimen: the ‘non-irradiation’ group which included 25 patients who received either busulphan associated with cyclophosphamide (BuCy) or Cy-only treatment (the patient who received CRT during first-line treatment and BuCy for conditioning was excluded from this group); the ‘total body irradiation’ group which included 72 patients who received either fractionated total body irradiation (fTBI), single-dose total body irradiation (sTBI) or thoraco-abdominal irradiation (TAI) without previous cranial radiotherapy (CRT); and the ‘CRT’ group which included 16 patients who received CRT at the time of first-line treatment, 15 of whom also received TBI at conditioning and one who was conditioned with BuCy.

Since 1992 when the study surveillance began, all patients underwent thyroid function testing (TSH and fT4) and ultrasound at least once a year, following BMT.

Those factors considered as possible risks for secondary thyroid malignancies such as gender, primary disease, previous cranial irradiation, age at transplant, degree of HLA match, conditioning regimen (chemotherapy and radiotherapy), presence and degree of chronic GVHD and treatment with immunosuppressive agents were recorded for each patient on a standardized clinical record form and were taken into statistical consideration.

Gender-specific age-standardized incidence ratios (SIR) and their 95 confidence intervals (95% CI) were analyzed to estimate the risk of secondary thyroid cancer in BMT patients compared with the general population. SIRs were calculated using the Epilog Plus Statistics Package for Epidemiology and Clinical Trial Software.12 The expected number of cases was calculated by applying the 5 year age and gender-specific incidence rates for thyroid cancer reported by the Liguria Cancer Registry for the period 1988–199213 to the person years of observation (M = 670; F = 400). Cox's multiple regression analysis was used to quantify the relationships between time to thyroid cancer detection and each potential risk factor, while simultaneously accounting for the effects of patients' other characteristics. This analysis was carried out using the SPSS Statistical Package.14


Among the 113 patients who underwent BMT during childhood and who survived more than 3 years after this procedure, eight patients (4 F; 4 M) were found to have a secondary thyroid cancer (Table 2). Standardized incidence ratios were 1062 (95% CI = 289–2718) for males and 607 (95% CI = 165–1553) for females. All eight patients received irradiation at the time of pre-transplant conditioning (one patient received sTBI and the remaining seven received fTBI, three of whom were also exposed to CRT during first-line treatment) (Table 2). Three of the 16 patients who received CRT, developed secondary thyroid carcinoma. However, these patients also received TBI during the pre-transplant conditioning regimen. Since only seven out of the 113 patients had a matched unrelated or a mismatched related transplant, it was statistically impossible to verify the effect of the degree of HLA match on tumor development.

Table 2 Characteristics of patients who developed thyroid cancer after transplant

Although six of the eight patients had chronic GVHD (one extensive and five limited), none received azathioprine.

The presenting symptom in just one patient was a palpable thyroid nodule. Three patients had high TSH blood levels and a thyroid nodule was revealed by diagnostic ultrasound examination. The four remaining patients were asymptomatic, and tumor was detected by routinely performed US. Family history of thyroid disease was positive in only one patient whose mother had benign multinodular goiter. None of the patients diagnosed with thyroid cancer resides in a known iodine deficiency area.

All patients were alive at the time of the study, 0.5 to 9.0 years (median 4.5) after surgical treatment. Six patients also received radioactive iodine ablation therapy and are receiving hormone suppressive treatment with L-thyroxine.

The median interval between transplant and thyroid cancer diagnosis was 8.5 years (range 3.1–15.7) and histology confirmed the diagnosis of papillary cell carcinoma in six, and follicular type carcinoma in the two remaining patients.

Since none of the ‘non-irradiated’ patients developed a thyroid cancer during the follow-up period, the entire cohort was divided into two groups according to the cumulative radiation dose received (Table 1) in order to perform Cox's multiple regression analysis (Table 3). The following dichotomous covariates (and codes) were included in the Cox's regression model: gender (M = 0, F = 1), age at BMT (<10 years = 0; 10 years = 1), cumulative radiation dose (10 Gy = 0; >10 Gy = 1), chronic GVHD (none = 0; limited, moderate or extensive = 1). Although not statistically significant, the results from the Cox's regression analysis revealed an increased risk among females (RR = 1.58, 95% CI = 0.35–7.15, P = 0.55), in children who underwent BMT under 10 years of age (RR = 1.87, 95% CI = 0.39–8.79, P = 0.43), in those who received a cumulative radiation dose higher than 10 Gy (RR = 4.28, 95% CI = 0.67–7.27, P = 0.12) and in patients who developed chronic GVHD after BMT (RR = 2.14, 95% CI = 0.42–10.81, P = 0.35).

Table 3 Results from Cox's multiple regression analysis


Primary thyroid cancer in children is considered to be a rare event (3–5 cases/1000000 a year), constituting 2.9% of all childhood cancers and 3–5% of all thyroid cancers.13,15

This study shows that patients who underwent BMT during childhood have a significantly increased risk of developing secondary thyroid carcinoma (SIR = 1062 and 607 in males and females, respectively), compared to the general healthy population aged 0–29 years.

Neither of the risk factors studied was found to be statistically significant for the development of secondary thyroid carcinoma in our cohort, probably due to the small size of the study population. However, analyzing the possible risk factors, younger age at transplant, being female, cumulative radiation dose and chronic GVHD were all found to have an increased RR for the development of thyroid cancer. The major risk factor was related to radiation, since patients who received a cumulative radiation dose higher than 10 Gy had a four-fold increased risk of secondary cancer (RR = 4.28, 95% CI = 0.67–7.27). A pooled analysis of seven studies16 demonstrated that the thyroid gland is highly sensitive to the carcinogenic effect of irradiation doses as low as 0.1 Gy in children below 15 years of age, with excess relative risk apparent among subjects irradiated under the age of 5. During cranial radiotherapy the scattered radiation dose to the thyroid was measured as 0.13–1.32 Gy.17 As observed in other studies which have dealt with secondary solid tumors in general,4,6,8 patients with chronic GVHD were found to have an increased risk for developing thyroid tumors, with a RR value equal to 2.14. However, none of the patients received azathioprine, which has been shown to be one of the possible risk factors for secondary solid tumor development.4,6,8

While thyroid carcinoma is an expected event after neck irradiation in Hodgkin's patients,18,19 data on secondary thyroid cancer after chemotherapy in children with acute leukemia who did not undergo BMT, are scarce and show that this event is uncommon.20,21 Therefore, our study suggests that the BMT procedure constitutes an excess risk for thyroid carcinogenesis.

The relatively high incidence of secondary thyroid carcinoma found in our study compared to other multicenter studies2,3,4,5,6,7,8,9 can be related to the close attention of the endocrinological follow-up which consists of an annual routinely performed thyroid ultrasound examination in all patients, including asymptomatic patients with normal thyroid function tests. This approach was instituted after the observation of the first two cases of secondary thyroid carcinoma in our cohort.10 In fact, half of the patients found to have thyroid carcinoma were asymptomatic with normal TSH levels. Since five out of the eight patients who developed secondary thyroid carcinoma had normal TSH, it can be argued whether sub-clinical hypothyroidism, usually a benign and self-limited condition observed after BMT,22 should or should not be treated with L-thyroxine hormone replacement treatment, which has been suggested by others to be an indication for reducing the risk of carcinogenesis.23

Based on this study, we recommend that an annual routine thyroid ultrasound examination should be carried out on all BMT survivors, especially those who were transplanted at an early age. Ultrasound examination, a non-invasive and relatively inexpensive procedure, should also be performed at diagnosis or at least immediately before transplant for a base-line evaluation. Considering the elevated risk for developing thyroid cancer after transplant, fine needle aspiration is highly recommended in this group of patients when thyroid nodules are observed.


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We thank the nonprofit ‘Associazione CRESCI’ and ‘Comitato ML Verga’ for their help in the accomplishment of this study and Miss J Upton for linguistic consultancy and secretarial assistance.

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Correspondence to A Cohen.

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  • bone marrow transplantation
  • late effects
  • thyroid carcinoma
  • secondary tumors
  • children
  • irradiation

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