Risk of Lymphoma and Leukemia in Thyroid Cancer Patients: A Retrospective Cohort Study in Germany

Abstract

Thyroid cancer is the ninth most common cancer worldwide. While differentiated thyroid cancer (DTC) has a high survival rate, concerns arise regarding optimal treatment strategies and potential long-term risks, including second primary malignancies (SPMs), associated with therapies such as radioiodine (RAI). The aim of the present study was to investigate the association between thyroid cancer and the incidence of subsequent lymphoma and leukemia in Germany. This retrospective cohort study used the IQVIA TM Disease Analyzer database and included adults with a first documented diagnosis of thyroid cancer between January 2005 and December 2021 as well as propensity score matched individuals without thyroid cancer in 1284 general practices. Univariate Cox regression models were performed to examine the association between thyroid cancer and the incidence of subsequent lymphoma and leukemia. A total of 4232 thyroid cancer patients (mean age: 54.2 years; 73.6% female) and 21 160 controls (mean age: 54.2 years; 72.6% female) were available for analyses. Thyroid cancer was significantly associated with a higher lymphoma incidence (HR: 3.35, 95% CI: 2.04–5.52), especially in men (HR: 5.37) and those aged 61–70 years. Leukemia incidence was not significantly associated with thyroid cancer (HR: 1.79, 95% CI: 0.91–3.53), although associations were notable in younger age groups. Thyroid cancer is positively associated with a risk of subsequent lymphoma, highlighting the need for vigilant surveillance and tailored treatment strategies. While the association with leukemia is less pronounced, close surveillance remains critical, especially in younger patients.

Keywords

thyroid cancer - secondary primary malignancy - lymphoma - leukemia

Introduction

According to the International Agency for Research on Cancer’s GLOBOCAN 2020 Cancer Incidence and Mortality database, thyroid cancer is the ninth most common cancer worldwide, with 43 646 new cases in 2020 [11]. The number of new cases in the U.S. increased steadily from 1978 to 2009 and has now reached a relatively stable plateau. At the same time, the overall very good 5-year survival rate has improved from 93.22% to 98.59% [22]. Although thyroid cancer can occur in people of any gender, the incidence is three times higher in women than in men [11] [22]. Notably, this gender distribution shows no regional differences [11]. Mortality is also almost twice as high in women as in men [22]. The peak incidence of thyroid cancer is between the ages of 50 and 64 [22]. Interestingly, thyroid cancer is the second most common malignancy in female adolescents and adults between the ages of 15 and 39, and the fourth most common in men [22]. Histopathologically, thyroid cancer is broadly classified into differentiated thyroid cancer (DTC), undifferentiated thyroid cancer (UTC), and medullary thyroid cancer (MTC) [33]. DTCs include papillary thyroid carcinoma, which is the most common malignant thyroid tumor (approximately 84%), follicular thyroid carcinoma (FTC, approximately 4%), and oncocytic thyroid carcinoma (approximately 2%). In contrast, biologically aggressive UTCs such as anaplastic thyroid carcinoma (ATC, about 2%) and medullary thyroid carcinoma originating from parafollicular C-cells (about 4%) are less common. While surgical resection with lymphadenectomy is the mainstay of treatment for all localized thyroid cancers, the therapeutic options for ATC and MTC that have metastasized outside the neck or are unresectable are very limited and include radiochemotherapy for ATC or combined BRAF/MEK inhibitor therapy in the presence of a BRAFV600E mutation and treatment with tyrosine kinase inhibitors for MTC [33] [44].

For a long time, complete thyroidectomy followed by ablation of all remaining thyroid tissue with radioiodine (RAI) therapy was considered the best treatment for DTC [55] [66]. However, this paradigm has changed in recent years in some countries. According to the American Thyroid Association (ATA), DTCs are classified into low, intermediate, and high risk tumors based on specific characteristics and the associated risk of recurrence [77]. Although adjuvant RAI improves overall survival and disease-free survival in advanced DTC, most studies show little or no benefit of RAI in low and intermediate risk tumors [88], where 5-year recurrence-free survival without RAI is already 97% [99]. While approximately 54% of all patients with DTC are in a low-risk situation for which routine RAI therapy is not recommended according to ATA recommendations, it is suggested under certain conditions for intermediate-risk situations (< 38%) and even recommended for high-risk patients (< 8%). In this context, the goal of RAI therapy is the ablation of residual thyroid tissue, adjuvant therapy, or the treatment of manifest tumor disease. However, since the introduction of RAI therapy, concerns have been raised about a possible carcinogenic effect. A meta-analysis of 13 studies [1010] found an increased incidence of secondary primary malignancies (SPMs) in patients with DTC, which may be related to disease-specific therapy or genetic predisposition. In addition, the results of a previous meta-analysis that included 2 multicenter studies [1111] suggest that the occurrence of SPMs in DTC may be associated with the use of RAI. As thyroid cancer is one of the most common tumors, especially in adolescents and adults between 15 and 39 years of age, these patients could be particularly affected by the consequences of a SPM.

Given the lack of population-based studies on this topic, the aim of our retrospective cohort study was to investigate the association between thyroid cancer and the incidence of subsequent lymphoma and leukemia.

Materials and Methods

Database

The study is based on data from the Disease Analyzer database (IQVIA), which contains drug prescriptions, diagnoses, and basic medical and demographic data obtained directly and anonymously from the computer systems used in the practices of general practitioners and specialists [1212]. The database includes approximately 1300 general practices in Germany. The panel of practices included in the Disease Analyzer database has previously been shown to be representative of general and specialist practices in Germany [1212]. Finally, this database has been used in previous studies focusing on cancer [1313] [1414].

Study population

This retrospective cohort study included adults (≥18 years) with a first documented diagnosis of thyroid cancer (ICD-10: C73) in 1284 general practices in Germany between January 2005 and December 2021 (index date; [Fig. 1Fig. 1]). A further inclusion criterion was an observation period of at least 12 months prior to the index date. Patients with other cancer diagnoses (ICD-10: C00-C97 excl. C73) before or on the index date were excluded.

Fig. 1 Fig. 1 Selection of study patients.

Thyroid cancer patients were matched (1:5) to non-thyroid cancer patients using nearest neighbor propensity scores based on age, sex, index year, and annual visit frequency during follow-up. Because thyroid cancer patients have much higher consultation frequency, and higher consultation frequency may increase the likelihood of documentation of other diagnoses, we included consultation frequency per year in the matching.

Non-thyroid cancer individuals were included only if they had an observation period of at least 12 months prior to the index date and no cancer diagnoses in their medical history before or on the index date. For non-thyroid cancer patients, the index date was the date of a randomly selected visit between January 2000 and December 2021 ([Fig. 1Fig. 1]).

Study outcomes

The study outcome was the incidence of lymphoma and leukemia within 10 years of the index date as a function of thyroid cancer. Lymphomas included Hodgkin lymphoma (ICD-10 C81), follicular lymphoma (ICD-10 C82), non-follicular lymphoma (ICD-10 C83), mature T/NK cell lymphoma (ICD-10 C84), other specified and unspecified types of non-Hodgkin’s lymphoma (ICD-10 C85), other specified types of T/NK-cell lymphoma (ICD-10 C86), malignant immunoproliferative disorders, and certain other B-cell lymphomas (ICD-10 C88). Leukemias included lymphoid leukemia (ICD-10 C91), myeloid leukemia (ICD-10 C92), monocytic leukemia (ICD-10 C93), other leukemia of specified cell type (ICD-10 C94), leukemia of unspecified cell type (ICD-10 C95).

Statistical analyses

Differences in sample characteristics between those with and without thyroid cancer were tested using the Wilcoxon signed-rank test for continuous variables, the McNemar test for categorical variables with two categories, and the Stuart–Maxwell test for categorical variables with more than two categories. Univariate Cox regression models were performed to examine the association between thyroid cancer and the incidence of subsequent lymphoma and leukemia diagnoses. These models were performed separately for four age groups, women, and men. To address the issue of multiple comparisons, p-values <0.01 were considered statistically significant. Analyses were performed with SAS version 9.4 (SAS Institute, Cary, USA).

Results

Baseline characteristics of the study cohort

The present study included 4232 individuals with thyroid cancer (mean age: 54.2 years; 73.6% female) and 21 160 individuals without thyroid cancer (mean age: 54.2 years; 72.6% female). Baseline characteristics of the study patients are shown in [Table 1Table 1]. On average, patients visited their primary care physician 7.9 times per year during the follow-up period.

Table 1 Table 1 Basic characteristics of the study sample (after 1:5 propensity score matching).

Variables	Proportion affected among individuals with thyroid cancer (%) N=4232	Proportion affected among individuals without thyroid cancer (%) N=21160	p-Value
Age (Mean, SD)	54.2 (15.4)	54.2 (15.4)	1.000
Age≤50	840 (19.9)	4200 (19.9)	1.000
Age 51–60	877 (20.7)	4385 (20.7)
Age 61–70	1,034 (24.4)	5170 (24.4)
Age>70	1481 (35.0)	7405 (35.0)
Women	3113 (73.6)	15 359 (72.6)	0.194
Men	1119 (26.4)	5801 (27.4)
Yearly consultation frequency during the follow-up period	7.9 (4.1)	7.9 (4.1)	1.000
Year of index date
2005–2008	489 (11.6)	2542 (12.0)	0.206
2009–2012	806 (19.1)	3834 (18.1)
2013–2016	1141 (27.0)	5529 (26.1)
2017–2021	1796 (42.4)	9255 (43.7)

Proportions of patients in% given, unless otherwise indicated. SD: standard deviation.

Association between thyroid cancer and lymphoma incidence

[Fig. 2Fig. 2] shows the Kaplan–Meier curves for the time to first lymphoma diagnosis with an incidence of 1.29 cases per 1000 person-years in patients with thyroid cancer and 0.39 cases per 1000 person-years in patients without thyroid cancer. The most common lymphoma diagnosis was other specified and unspecified non-Hodgkin’s lymphoma (ICD-10 C85) (57.1% of lymphoma cases in the thyroid cancer cohort and 62.9% in the non-thyroid cancer cohort). In Cox regression analyses, thyroid cancer was strongly and significantly associated with lymphoma incidence [Hazard ratio (HR): 3.35; 95% CI: 2.04–5.52]. This association was stronger in men (HR: 5.37; 95% CI: 2.22–12.98) than in women (HR: 2.67; 95% CI: 1.45–4.94). In the age-stratified analysis, the strongest association was observed in the age group 61–70 years but did not reach the predefined significance level of p<0.01 ([Table 2Table 2]).

Fig. 2 Fig. 2 Kaplan–Meier curves for time to lymphoma diagnosis in individuals with and without thyroid cancer.

Table 2 Table 2 Association between thyroid cancer and the incidence of lymphomas and leukemias in individuals followed in general practices in Germany (Cox regression models).

	Lymphomas		Leukemias
Patient group	HR (95% CI)	p-Value	HR (95% CI)	p-Value
Total	3.35 (2.04–5.52)	<0.001	1.79 (0.91–3.53)	0.087
Age≤50	1.11 (0.11–11.03)	0.928	4.19 (0.59–29.87)	0.153
Age 51–60	4.33 (1.25–15.00)	0.021	4.47 (0.28–71.63)	0.290
Age 61–70	5.45 (1.46–20.34)	0.012	1.35 (0.36–5.03)	0.653
Age>70	3.13 (1.67–5.88)	<0.001	1.61 (0.63–4.11)	0.322
Women	2.67 (1.45–4.94)	0.002	1.33 (0.53–3.33)	0.546
Men	5.37 (2.22–12.98)	<0.001	2.81 (1.00–7.93)	0.051

Association between thyroid cancer and leukemia incidence

[Fig. 3Fig. 3] shows the Kaplan–Meier curves for the time to first leukemia diagnosis with an incidence of 0.55 cases per 1000 person-years in patients with thyroid cancer and 0.31 cases per 1000 person-years in patients without thyroid cancer. Overall, the number of patients with a leukemia diagnosis was very small (12 cases in the thyroid cancer cohort and 28 cases in the non-thyroid cancer cohort), with lymphoid leukemia being the most common leukemia diagnosis (58.3% of leukemia cases in the thyroid cancer cohort and 35.7% in the non-thyroid cancer cohort). In Cox regression analyses, thyroid cancer was not significantly associated with the incidence of leukemia (HR: 1.79; 95% CI: 0.91–3.53). The nonsignificant association was strong in the age groups≤50 years (HR: 4.19; 95% CI: 0.59–29.87) and 51–60 years (HR: 4.47; 95% CI: 0.28–71.63), but due to the small number of patients with leukemia, the associations were not significant ([Table 2Table 2]).

Fig. 3 Fig. 3 Kaplan–Meier curves for time to leukemia diagnosis in individuals with and without thyroid cancer.

Discussion

Our results show a significant association between thyroid cancer and the incidence of lymphoma, which was particularly high among men. However, this association was also observed in women and in different age groups, although with different statistical significance. The incidence of lymphoma was significantly higher in thyroid cancer patients than in controls, suggesting a possible link between thyroid cancer and the subsequent development of lymphoma. This finding also underscores the importance of careful monitoring and tailored surveillance strategies for thyroid cancer patients, particularly for the early detection of lymphoma.

Conversely, the study found no significant association between thyroid cancer and the incidence of leukemia, although there was a trend toward an increased incidence, especially in younger age groups. However, it should be noted that the small number of leukemia cases may have reduced the statistical power to detect significant associations. Nevertheless, the observed trend suggests the need for further investigation of the possible association between thyroid cancer and leukemia, especially in younger patient populations.

The incidence of thyroid cancer has increased worldwide in recent decades, disproportionately affecting women and East Asia more than other regions [1515]. Numerous studies have shown that this global increase in thyroid cancer incidence is due in large part to the improved detection of small, low-risk papillary thyroid cancers made possible by the widespread use of thyroid ultrasound [1515] [1616].

As a result of diagnostic and therapeutic advances in the treatment of thyroid cancer, including RAI therapy for DTC, overall survival from thyroid cancer has improved significantly over the past two decades, with the 5-year survival rate increasing from 93.22% in 1978 to 98.59% in 2009 [22]. In parallel with the growing number of cancer survivors [1717] in recent decades, the incidence of SPMs has also been rising [1818]. In a large population-based study, Donin and colleagues demonstrated that one in twelve survivors of a common cancer developed a SPM, with lung cancer being the most commonly diagnosed SPM [1919]. Furthermore, in this group, more than half (55%) died from their SPM, exceeding the proportion of patients with only one cancer who died from it [1919].

Thus, the burden of SPMs in a growing and aging population of primary cancer survivors has increased significantly in recent decades. Cancer survivors may be predisposed to the development of SPMs by a variety of factors, including cancer predisposition syndromes or specific tumor characteristics, environmental exposures, and late effects of therapies [2020]. Knowledge of the predisposition to develop a SPM and its type is relevant for tailoring tumor follow-up. Thus, the meta-analysis of 13 studies published by Subramanian et al. showed that the incidence of SPMs in the form of non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM), and leukemia was significantly increased in thyroid cancer survivors [1010]. However, the results of individual studies are very heterogeneous. While some studies found an increased risk of Hodgkin’s lymphoma (HL), NHL, and leukemia after thyroid cancer [2121], others reported either an association with NHL and leukemia [2222] or even an association with subsequent leukemia but not lymphoma [2323]. Some of these studies also examined whether there was an association between the use of RAI and the incidence of lymphatic and hematopoietic malignancies [2121] [2323]. Brown et al. showed an increased risk of MM and HL after RAI, while patients who did not receive RAI were more likely to develop leukemia [2121]. Rubino and colleagues, on the other hand, described an increased relative risk of leukemia after RAI [2323]. A study published in 2017 demonstrated that in the group of patients with DTC who frequently developed ALL or MM after surgery alone, the risk of developing AML, CLL or CML was increased by RAI [2424]. In this context, there appears to be a dose dependence, as a recent nationwide population-based study from South Korea showed that RAI above 100 mCi was strongly associated with the development of leukemia, whereas this was not the case for lower RAI doses [2525]. Given the favorable survival rates of patients with DTC and the concerns about the potentially adverse effects of RAI, physicians should weigh the benefits and risks of RAI before choosing this therapeutic strategy. A useful tool for determining the risk of recurrence and therefore the benefit of adjuvant RAI is the ATA recommended risk classification of DTCs [77].

Interestingly, however, only the study by Brown et al. examined the association between thyroid cancer and lymphatic or hematopoietic tumors separately for men and women and in different age groups [2121]. In contrast to this study, we were able to demonstrate a stronger association in men. However, the observation that the incidence of developing SPM was increased when thyroid cancer was diagnosed in middle age was comparable.

In addition to RAI, environmental factors such as low-dose radiation used in diagnostic procedures have also been associated with an increased risk of thyroid cancer as well as lymphatic and hematopoietic tumors [2626]. Although DTCs certainly account for the highest proportion of thyroid cancers in our cohort, but are known to have a low mutational burden [2727], genetic factors may also explain the association we observed.

A major strength of our study is the large sample size. In fact, our study is one of the largest population-based studies on this topic and the only one to date that specifically examined the outpatient setting. In addition, our study excluded individuals with other tumor diagnoses on the index day. Moreover, the cohort was matched to the control cohort with respect to age, sex, index year, and even the average number of consultations per year. In particular, including of consultation frequency in matching reduces the influence of confounding factors such as utilization patterns.

But we must also note that our study has several limitations, especially in the study design. As diagnoses are based on ICD codes, misclassification cannot be excluded. Unfortunately, we were also unable to differentiate between the common histopathologic subtypes of thyroid cancer. Furthermore, as the database only contains data from outpatients, and no data from hospitals and procedures performed in hospitals are available, so no conclusions can be drawn about the performance or extent of surgery or the use of RAI. However, it should be noted that thyroidectomy is still the standard treatment for thyroid cancer in Germany and that patients with DTC in Germany are often treated postoperatively with ablative RAI therapy. However, a new German guideline for the treatment of thyroid cancer, which recommends a less aggressive treatment approach in the context of surgery and RAI therapy, is in progress. Another limitation of our study is that due to the small number of cases for some subtypes of the respective lymphatic and hematopoietic tumor diseases, we could only roughly classify them as lymphoma or leukemia. There is also a lack of detailed information on some other risk parameters associated with the tumorigenesis of thyroid cancer, lymphoma, or leukemia that could represent potential confounders (e. g., external radiation exposure, genetic factors). As a result, our study is only able to show an association, not a cause-and-effect relationship. Nevertheless, this study represents an important contribution to the literature, as other authors have only included patients from hospitals [2323] or tumor registries [2121] [2222] [2424], and the outpatient setting of general practitioners and specialists has not yet been studied.

Conclusion

In conclusion, our study provides valuable insights into the complex interplay between thyroid cancer and hematologic malignancies. The results underscore the importance of individualized risk assessment and surveillance strategies for thyroid cancer patients to effectively detect and treat potential SPMs. Further research is needed to elucidate the mechanisms underlying the observed associations and to develop optimal treatment strategies for these patients.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 16 March 2024

Accepted after revision: 02 May 2024

Article published online:
13 June 2024