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Journal of Clinical Oncology, Vol 25, No 17 (June 10), 2007: pp. 2449-2454 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.9276 Risk for Secondary Thyroid Carcinoma After Hematopoietic Stem-Cell Transplantation: An EBMT Late Effects Working Party Study
From the Department of Pediatrics, University of Genova, Polo del Ponente, San Paolo Hospital, Savona; Bone Marrow Transplantation Unit, Department of Pediatrics, University of Milano-Bicocca, San Gerardo Hospital, Monza; Epidemiology and Biostatistics, Department of Cancer Etiology and Prevention, National Cancer Research Institute; Centro Trapianti di Midollo, San Martino Hospital; Department of Hematology-Oncology, Gaslini Children's Hospital, Genova, Italy; Department of Pediatrics, Leiden University Medical Center, the Netherlands; Division of Hematology, University Hospital, Basel, Switzerland; and the Service d'Hématologie Greffe de Moelle, Hospital Saint Louis, Paris, France Address reprint requests to Amnon Cohen, MD, Department of Pediatrics, San Paolo Hospital, Via Genova 31, 17100 Savona, Italy; e-mail: a.cohen{at}asl2.liguria.it
Purpose The effects of hematopoietic stem-cell transplantation (HSCT) on thyroid carcinogenesis needs to be determined in a large population. This study evaluates the incidence and the risk factors contributing to secondary thyroid carcinoma (STC) in patients who receive transplantation. Patients and Methods We performed a retrospective investigational study, comparing data obtained by means of a two-step questionnaire from the 166 centers who replied, and data reported to the European Group for Blood and Marrow Transplantation (EBMT) registry on their transplantation activity. During the follow-up period (1985 to 2003), 32 instances of STC were found within the EBMT cohort of 68,936 patients who received transplants. These patients were then compared with age- and sex-specific incidence rates in the European population and risk factors for STC were analyzed. Results The standardized incidence ratios (SIRs) of STC in the population who underwent transplantation was 3.26, in comparison with the European population. Multivariate analysis revealed that young age at transplantation was the strongest risk factor for STC (relative risk [RR], 24.61 for age 0 to 10 years; RR, 4.80 for age 11 to 20). Other risk factors were irradiation (RR, 3.44), female sex (RR, 2.79), and chronic graft-versus-host disease (RR, 2.94). Nine patients showed no clinical signs of thyroid illness at diagnosis. Total thyroidectomy and iodine ablation was the standard treatment for the majority of patients, and only one patient died due to STC progression. Conclusion Long-term survivors of HSCT are at risk for STCs. These results should promote efforts in screening for early detection and treatment guidelines of secondary thyroid cancer after HSCT, especially in patients who receive transplants during childhood and adolescence.
Hematopoietic stem-cell transplantation (HSCT) is recognized as an effective treatment for hematologic malignancies, solid tumors, and some nonmalignant diseases.1 However, this procedure has been associated with early and late complications involving different organs, with varying severity, prognosis, and impact on the quality of life.2 In particular, there is growing concern about the development of secondary cancers resulting either from irradiation and high-dose chemotherapy for conditioning or from immunosuppression and immunological complications after HSCT.3-13 Several studies have described the risk of secondary solid tumors after HSCT, but only a limited number of secondary thyroid carcinomas (STC) have been reported, mainly as anecdotal case reports or as a single institution's experience.8-14 Since some authors felt that STC might be more frequent14 than actually estimated, this could constitute a significant problem in the surveillance programs for long-term survivors. Given the need to define evidence-based guidelines for monitoring, diagnosing, and treating STC in this population who has received transplants, the European Group for Blood and Marrow Transplantation (EBMT) Late-Effects Working Party undertook this study to attain a better knowledge of the epidemiology, presenting symptoms, related risk factors, and treatment of STC in a large cohort of patients who underwent transplantation.
Study Design This retrospective investigational study was carried out utilizing a two-step questionnaire approach. The first questionnaire was sent to 422 EBMT centers asking for the number of patients who developed STC at each single center. One hundred sixty-six (39.3%) centers completed and returned the questionnaire. A total of 79,928 patients were registered by these 166 centers in the EBMT registry between 1985 and 2003. Data on this cohort were obtained from the Med-A form (minimum essential data) used by the EBMT registry. This included data collection on patient identification, primary disease, type of transplantation, conditioning regimen, presence or absence of graft-versus-host disease (GVHD), and survival status of the patient at latest follow-up. The status of each patient was ascertained from the EBMT registry file during the follow-up period from January 1, 1985, to January 1, 2004. Eight thousand fifty-five registered patients (10%) were excluded from the study because of insufficient key data. Patients with Fanconi's anemia and thalassemia (N = 1,014) were also excluded from the study because of their increased risk for developing cancer and the high incidence of thyroid abnormalities due to iron overload, respectively. The remaining 70,859 patients, contributing to 316,616 person-years of observation, were included in this study. Table 1 shows the distribution of the selected covariates between the studied population and the excluded group of patients. The follow-up was performed at each center according to EBMT guidelines and local protocols.
Seventeen of 166 centers reported a total of 35 instances of STC (online-only Appendix). The second questionnaire was then sent to the 17 centers asking for specific data related to thyroid carcinoma. It included questions regarding irradiation therapy used during first-line treatment (between diagnosis and pre-HSCT conditioning), transplantation-related data not reported to the EBMT registry, and thyroid-related data which included symptoms and laboratory evaluation at STC diagnosis, thyroid ultrasound, histology, treatment (surgery, iodine ablation), and follow-up.
Statistical Analysis
The characteristics of the 70,859 patients included in the study are presented in Table 1. The median follow-up period from transplantation was 12.7 years (25th and 75th percentiles, 10.3 and 16.5 years, respectively). Of the 35 patients with STC reported in the first questionnaire, two patients were excluded because their primary data had not been previously reported to the EBMT registry and one additional patient was excluded because thyroid carcinoma was diagnosed immediately after transplantation and was not therefore considered to be a transplantation-related secondary tumor. The characteristics of the 32 patients (21 female; 11 male) are summarized in Table 2. Median age at transplantation was 11.2 years (range, 1.7 to 51.3 years). The primary disease was nonmalignant severe aplastic anemia (SAA) in three patients; solid tumors in five patients (four neuroblastoma; one breast cancer), and hematologic malignancies in the remaining 24 patients (10 acute lymphoblastic leukemia; seven chronic myelogenous leukemia; four acute myeloid leukemia; one myelodysplastic syndrome; one non-Hodgkin's lymphoma; one unclassified acute leukemia).
Nine patients received autologous and 23 allogeneic HSCT (21 from matched siblings; two from an unrelated donor). Conditioning consisted of chemotherapy alone in seven patients, and a combination of chemotherapy and irradiation in the remaining 24 patients (23 total body irradiation; one thoracoabdominal irradiation). Four of the patients conditioned with total body irradiation received 18 to 24 Gy of cranial irradiation during first-line treatment. The source of stem cells was unmanipulated bone-marrow except in one patient who received peripheral blood stem cells. The majority of patients who underwent allogeneic transplantation received cyclosporine alone or in combination with methotrexate as prophylaxis for GVHD. None received T-cell depleted stem cells. Of the 23 allogeneic patients, 14 developed grade 1 to 2 GVHD and only one had grade 3 to 4 acute GVHD. Limited chronic GVHD was observed in eight patients and extensive chronic GVHD in five. The median follow-up period after transplantation was 15.4 years (range, 5.4 to 22.2). The median interval between HSCT and STC was 8.5 years (range, 0.6 to 18.5) with a median age at diagnosis of STC of 23.5 years (range, 8.8 to 52.2). The presenting symptom in 18 patients (56%) was a palpable thyroid nodule. Three patients had thyroid goiter while one developed recurrent left laryngeal nerve palsy. Nine patients (28%) did not show any clinical signs of thyroid disease and diagnosis was based on routine ultrasound examination. Clinical data was not reported for one patient. Twenty-one patients (66%) had normal thyroid function and the suspicion of STC was based on clinical (15 patients) and routine thyroid ultrasound examination (six patients). High thyroid-stimulating hormone (TSH) blood levels were found in only nine patients, five of whom had a palpable nodule, one with a goiter, and three who were asymptomatic (thyroid function tests were not reported in two patients). Family history of thyroid disease was positive in just one patient whose mother had benign multinodular goiter. Histology confirmed the diagnosis of papillary carcinoma in 23 patients, and follicular type carcinoma in the remaining nine. The median interval between transplantation and the diagnosis of STC in the papillary group was 11.2 years (range, 0.9 to 18.5) compared with 6.2 (range, 2.6 to 15.9) in the follicular group. Surgical treatment consisted of total thyroidectomy in 25 patients, subtotal in five, partial and lobectomy in one each. Twenty-three patients received radioactive iodine ablation therapy (19 total and 4 subtotal thyroidectomy). Twenty-nine patients are alive and disease free after a median period of 5.5 years from STC diagnosis (range, 0.3 to 11.5). They are receiving hormone suppressive treatment with L-thyroxine. Two patients died from relapse of the primary disease and only one died due to STC progression. SIRs for STC after HSCT among EBMT patients are presented in Table 3 for all subjects and for males and females, respectively. A three-fold increased SIR was detected among all HSCT patients (SIR, 3.26; 95% CI, 2.23 to 4.60), with higher SIR in males (SIR, 4.12; 95% CI, 2.05 to 7.37) than in females (SIR, 2.94; 95% CI, 1.82 to 4.49).
A significantly higher SIR for STC was observed in patients who received transplants before the age of 20 years and not for patients who underwent transplantations after the age of 20 (Table 4), with a nine-fold increased SIR among those ages 11 to 20 years at HSCT (SIR, 9.04; 95% CI, 3.31 to 19.64) and a 61-fold increased SIR (SIR, 61.30; 95% CI, 34.93 to 99.23) in patients younger than 10 years at transplantation.
Higher SIR was observed among irradiated patients (SIR, 7.63; 95% CI, 4.88 to 11.34), patients who underwent allogeneic transplantation (SIR, 6.45; 95% CI, 4.08 to 9.67), and those who developed chronic GVHD (SIR, 9.68; 95%CI, 5.14 to 16.51). Unexpectedly, patients with SAA showed a higher SIR value (SIR, 7.59; 95% CI, 1.56 to 22.18) than the hemato-oncological group (SIR, 2.93; 95% CI, 1.88 to 4.36). SIR value was equal to 4.04 (95% CI, 1.31 to 7.43) for the solid tumor group. Multivariate analysis (Table 5) confirmed age at transplantation as the most important risk factor for developing STC, with relative risk (RR) increasing with decreasing age (RR, 4.80; 95% CI, 1.13 to 20.44 and RR, 24.61; 95% CI, 4.45 to 136.25 for age at transplantation 11 to 20 years and younger than 10 years, respectively) compared with the group of patients who were older than 20 years at transplantation. Figure 1 shows the cumulative incidence accounting for the effect of competing mortality on the probability of developing STC across the follow-up (Fig 1A) and the cumulative incidence accounting for competing mortality for STC by age at transplantation (Fig 1B).
Irradiation was associated with a three-fold increased risk of STC (RR, 3.44; 95% CI, 1.41 to 8.37). Females had a three-fold higher risk of STC compared with males (RR, 2.79; 95% CI, 1.34 to 5.79), and patients who developed chronic GVHD had an increased risk compared with those who did not (RR, 2.94; 95% CI, 1.21 to 7.15). Nevertheless, the RR values of the latter three factors, although statistically significant, were lower than that associated with age at transplantation. The age at diagnosis of STC showed a moderate, nonstatistically significant upward trend (RR, 1.03; 95% CI, 0.99 to 1.08) indicating a 3% increased risk associated with each 5-year age interval.
This retrospective multicenter survey among the EBMT-affiliated centers is the largest series of STC in patients who underwent HSCT ever reported. The relatively high number of patients who developed STC suggests that the risk of thyroid cancer after HSCT has been underestimated so far. Transplantation recipients were at significantly higher risk of STC than the general population, with a ratio of observed to expected cases of 3.26 (95% CI, 2.23 to 4.60). In the general population thyroid cancer is more frequent in females.17-19 Our findings confirm the increased susceptibility of females who underwent transplantation to developing STC (RR, 2.79) compared with males. Our analysis of 32 instances of STC out of the more than 70,000 HSCT recipients shows that patients who received transplants at younger age (< 10 years) are at extremely high risk of developing thyroid carcinoma (RR, 24.61). Other statistically significant risk factors were irradiation, female sex, and chronic GVHD. This confirms results shown in other studies on secondary malignancies after HSCT—the younger the age of the patient at transplantation, the higher the risk of developing secondary tumors.9 The role of younger age at transplantation as a risk factor for developing STC is further emphasized by the fact that thyroid carcinomas in the general population are rare in children and adolescents (median age at diagnosis, 45 to 50 years).17 The relatively short interval between HSCT and the diagnosis of STC (median, 8.5 years) suggests a more aggressive mechanism of thyroid cells in malignant transformation in this group of patients, as compared with both the general population and patients exposed to other types of irradiation treatment (eg, irradiation for thymus enlargement).20 However, this relationship seems to be similar to that observed in patients with Hodgkin's disease.21-26 The reduced latency period might also be due in part to the thorough follow-up examination program usually applied to cancer patients which may result in early detection of secondary cancers. In particular, follicular carcinoma developed soon after transplantation (median interval of 6.2 years compared with 11.2 in the papillary group) indicating a more aggressive behavior of this type of STC. Furthermore, while 90% of thyroid carcinoma in children who received irradiation is papillary,25 our series shows a higher incidence of follicular-type carcinoma (26%). Patients with primary isolated thyroid carcinoma rarely have abnormalities in thyroid function tests (serum TSH and thyroxin levels) at diagnosis. In this cohort of patients who underwent transplantation and developed STC, laboratory tests were also found to be of limited value at the time of diagnosis. In fact, high TSH concentrations were found in only nine patients, and four had positive thyroid specific antibodies, meaning that thyroid laboratory evaluation add little to the suspicion and diagnosis of STC in patients who underwent transplantation. However, the majority of patients (22 patients) had clinically detectable signs of thyroid disease (palpable thyroid nodule, goiter, and recurrent left laryngeal nerve palsy). Six patients did not have either clinical signs or laboratory thyroid test dysfunction, and STC was discovered during annual routine ultrasound examination included in the surveillance program at their center. This should be considered when formulating long-term follow-up programs for late-effects screening after HSCT. Radiation treatment is a well-known risk factor for developing primary and secondary malignancies. This risk has been particularly acknowledged in relation to the development of thyroid carcinoma,19 and the pediatric age group has been reported as the most susceptible because the excess risk of thyroid carcinoma in children exposed to a dose of 1 Gy to the thyroid is of 7.7.20 Surprisingly however, seven of 32 patients who developed STC never had radiation therapy and the univariate analysis revealed that patients with SAA who did not receive irradiation were found to have a SIR value of 7.59, which is more than double that of patients with hemato-oncological diseases. Nevertheless, this higher SIR for SAA in the univariate analysis failed to show a significant role in the multivariate analysis (RR for SAA, 1.11; 95% CI, 0.32 to 3.93 compared with the hematologic cancer category as reference level). Furthermore, considering the fact that conditioning regimens that do not include irradiation were only introduced over the past decade, these patients may represent a sentinel which highlights the need for continued follow-up and surveillance in all patients who receive transplantation, irrespective of the conditioning regimen applied. Chronic GVHD is considered to be another important risk factor in the development of secondary tumors after HSCT.3 Our data confirm the role of chronic GVHD in inducing STC. Almost all centers followed the gold-standard treatment modality for STC which includes total thyroidectomy and iodine ablation.18,27-29 Early detected primary thyroid carcinoma usually has an excellent prognosis with a 25-year survival rate of 95% for papillary and 66% for follicular carcinoma.17 In our series, only one patient died because of early-aggressive STC progression. This outcome of STC is similar to that of primary thyroid cancer in previously healthy population.17,18 In conclusion, this study shows that long-term survivors of HSCT are at risk for secondary thyroid carcinomas. These results should promote efforts in screening for early detection and treatment guidelines of secondary thyroid cancer after HSCT, especially in patients undergoing transplantation during childhood and adolescence. The cost effectiveness of any diagnostic procedure, such as ultrasound or fine needle aspiration, should therefore be addressed in further specific studies, considering also the associated distress to the patient and invasiveness of the procedures.
The author(s) indicated no potential conflicts of interest.
Conception and design: Amnon Cohen, Attilio Rovelli, Domenico Franco Merlo, Maria Teresa van Lint, Marcello Ceppi, Vittorio Bocchini, André Tichelli, Gerard Socié Provision of study materials or patients: Amnon Cohen, Attilio Rovelli, Maria Teresa van Lint, Edoardo Lanino, Dorine Bresters, André Tichelli, Gerard Socié Collection and assembly of data: Amnon Cohen, Attilio Rovelli Data analysis and interpretation: Amnon Cohen, Domenico Franco Merlo, Marcello Ceppi, Vittorio Bocchini Manuscript writing: Amnon Cohen, Attilio Rovelli, Domenico Franco Merlo, Maria Teresa van Lint, Edoardo Lanino, Dorine Bresters, Marcello Ceppi, Vittorio Bocchini, André Tichelli, Gerard Socié Final approval of manuscript: Amnon Cohen, Attilio Rovelli, Domenico Franco Merlo, Maria Teresa van Lint, Edoardo Lanino, Dorine Bresters, Marcello Ceppi, Vittorio Bocchini, André Tichelli, Gerard Socié
Participating Centers Department of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem, Israel (Shimon Slavin); Servicio de Hematologia, Hospital Regional [Reina Sofia], Cordoba, Spain (Pedro Gomez); Service d'Hématologie, Centre Hospitalier Universitaire, Besançon Cedex, France (Eric Deconinck, Jean-Yves Cahn); Cliniques Universitaires Saint-Luc, UCL, Bruxelles, Belgium (Augustin Ferrant); Clinic of Pediatric Hematology Oncology, University of Padova, Italy (Simone Cesaro, Chiara Messina); Service de Maladies du Sang, Hopital Claude Huriez, Lille, France (JP Jouet); Klinikum Nurenberg, Medizinische Klinik 5, BMT-Unit, Nurenberg, Germany (Kerstin Schaefer–Eckar,Hannes Wandt); Klinik für Kinder- und Jugendmedizin, Klinikum der Friedrich-Schiller-Universität Jena, Germany (Felix Zintl, Dietlinde Fuchs); Department of Pediatrics, Leiden University Medical Center, the Netherlands (R. Maarten Egeler, J.M.J.J. Vossen); Department of Pediatrics, University of Genova - Polo del Ponente, San Paolo Hospital, Savona, Italy (Alberto Gaiero, Roberta Mulas); Bone Marrow Transplantation Unit, Department of Pediatrics, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy (Cornelio Uderzo, Paola Corti); Centro Trapianti di Midollo, San Martino Hospital, Genova, Italy (Andrea Bacigalupo, Anna Maria Raiola); Department of Hematology-Oncology, Gaslini Children's Hospital, Genova, Italy (Giorgio Dini, Maura Faraci); Division of Hematology, University Hospital, Basel, Switzerland (Jacob Pasweg, Alicia Rovò, André Tichelli); Service d'Hématologie Greffe de Moelle, Hospital Saint Louis, Paris, France (Eliane Gluckman, Agnes Devergie, Gerard Socié); and The Children's Hospital at Westmead, Oncology Unit, Sidney, Australia (Peter Swan).
We thank Joanna Upton for her review of the manuscript.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
