Thyroid cancer (TC) constitutes 1% of all cancer cases (1–5). The incidence of TC has been increasing in most populations worldwide (6, 7). This increase may be attributed to advancements in clinical practices and/or changes in histological criteria, as well as potential alterations in environmental and hormonal factors (5, 8, 9). While TC is generally more prevalent in females, males have a higher likelihood of having a positive family history of malignancy (10). Treatment options for TC vary depending on the histology and extent of the disease, encompassing surgical intervention, radioactive iodine therapy, suppressive thyroid hormone therapy, and occasionally, external beam radiotherapy (11). Despite acknowledged ethnic variations, the prognosis for treated TC is favorable, with excellent overall survival (OS) rates (5, 12–14).

When considering the histologic subtypes, TC can be divided into five unique classifications: papillary TC (PTC), follicular TC (FTC), medullary TC (MTC), anaplastic TC, and miscellaneous subtypes (15). It is worth noting that the majority of TC, around 95%, originates from the follicular epithelium, manifesting in PTC, FTC, and anaplastic variations (16). In numerous surveyed countries, the most prevalent subtype is PTC, accounting for 70% or more of cases (14, 17, 18). The prognosis is highly favorable for PTC and FTC, whereas other histologic subtypes demonstrate a poorer prognosis and limited therapeutic options (19–22).

As the early cancer detection becomes more common, individuals who survive this disease are living longer, which may increase the risk of developing multiple primary neoplasms (MPN) (23). A limited number of investigations have been conducted to examine the potential risk of developing a second neoplasm following a diagnosis of TC, including comprehensive studies conducted in Europe and the United States (24–28). These studies have consistently demonstrated a rise in the occurrence of cancers subsequent to TC diagnosis. Additionally, it has been observed that TC can be diagnosed as a second primary neoplasm subsequent to other forms of cancer (25, 29–32).

The present study aimed to examine the cancers associated with TC and to compare survival rates between patients with thyroid-only cancers and patients with thyroid cancer as part of MPN. This may help shed light on common etiological factors affecting such a challenging group of patients.

This retrospective study utilized KHCC cohort of TC patients to explore patients who had MPN. A total of 30 patients were identified with MPN. Those patients were observed to have 68 neoplasms in total. Thirty-one of these were thyroid neoplasms and the remaining 37 were other malignancies. Demographic and clinicopathologic characteristics are shown in Table 1 .

Our research underscores an important finding regarding patients with MPN, revealing a notably lower survival rate. According to our study, MPN patients were diagnosed at an older age, displayed an elevated body mass index, and presented with increased thyroglobulin antibody levels, along with a more pronounced familial history of cancer.

The global rise in TC incidence is a widely recognized trend, largely attributed to the progress in clinical procedures, biochemical knowledge, and imaging technologies (38). The evolution of medical guidelines and practices, such as more thorough evaluations of the thyroid gland, has resulted in higher rates of TC detection. Progress in understanding the biochemical aspects of TC, including the identification of new biomarkers and genetic mutations linked to the disease, has also been a significant factor (39). Additionally, the widespread use of advanced ultrasound technology has facilitated the identification of small thyroid nodules, including thyroid microcarcinomas (38). In our MPN subcohort, imaging played a crucial role in the initial detection and evaluation of TC, underscoring the importance of ongoing clinical monitoring and multidisciplinary care for both cancer survivors and sufferers. However, advancements in therapeutic and diagnostic techniques have drawbacks, as previous research has linked the occurrence of secondary cancer and MPN to exposure to radiation (40, 41). While radiation therapy is effective in treating various types of cancer, it is also associated with an increased risk of developing additional primary malignancies. The carcinogenic impact of radiation on the thyroid gland primarily stems from the DNA damage caused by ionizing radiation, leading to genetic mutations and chromosomal abnormalities that initiate cancer formation. Additionally, exposure to radiation significantly heightens the likelihood of developing thyroid cancer, with the risk increasing in proportion to the dosage received, even at lower levels (40).

With regards to TC treatment, effective management strategies involve a multidisciplinary approach that incorporates surgical, oncological, medical, and radiological assessments (42). Surgical intervention has been found to reduce mortality and event rates in cases of operable TC, even when dealing with microcarcinomas (43). Furthermore, research has indicated that radioactive iodine therapy can significantly enhance survival outcomes for individuals with differentiated TC (44–47). For example, a large study involving 96,557 patients demonstrated that the use of radioactive iodine was linked to improved disease-specific survival in this population (48). Furthermore, radioactive iodine therapy has been shown to improve rates of recurrence-free survival, by eliminating residual thyroid tissue and microscopic disease (49). This treatment is particularly advantageous for patients with certain risk factors, such as extrathyroidal extension or lymph node involvement, as it reduces the likelihood of cancer recurrence (50).

MPN are infrequent, exhibiting a greater occurrence in older patients (51). The occurrence of MPN is predominantly noted in cancer survivors as well as in cancer subtypes that are associated with favorable outcomes. Therefore, the rising prevalence of TC and the favorable survival outcomes have resulted in a higher occurrence of MPN (52). However, MPN in survivors of TC may contribute significantly to mortality rates. This emphasizes the need for vigilant surveillance of MPN occurrence to enhance prognosis. In our study population consisting of 563 individuals, we identified 30 patients who developed MPNs, indicating a prevalence of approximately 5% at our institution, which closely aligns with prior findings from Taiwan (26). Lin et al. outlined that TC patients with MPN exhibit a lower female-to-male ratio, an older mean age, and more advanced TNM stages compared to those with only TC (26). These patients also receive higher doses of therapeutic radioactive iodine and have a higher total mortality rate (26). Notably, hematological malignancies and renal cell carcinoma are prevalent as secondary cancers in these patients, despite not being among the top ten common cancers in the general population of Taiwan, indicating a distinct pattern of secondary malignancies in thyroid cancer patients (26).

The possibility of being diagnosed with another neoplasm after surviving a first one is 14% higher for people who have previously had cancer compared to the general population (53). This percentage is anticipated to increase due to the growing number of cancer survivors. Consequently, there has been a rise in the occurrence of MPN among individuals who have overcome cancer, accounting for almost one-fifth of all newly diagnosed malignancies in recent studies (54).

With regards to MPN incidence, there is a notable variation in the reported incidence shared in current literature ranging from 1–37% (55). The variation observed in these findings can be attributed to the different methodologies used for calculations and the diverse ethnic populations studied. In the United States, the prevalence of primaries has been reported in percentages over time. For example, it was found to be 3.5% in New Mexico in 1977, 5.3% according to a study conducted in 1968, and finally 8% based on data from 1975–2001 (56–58). Similarly, in Western Europe, the occurrence of MPN varied across studies; it was recorded as 0.7% in a hospital registry in Scotland in 1972, 6.3% based on European cancer registries from 1995 to 1999, and reached up to 11.7% according to an autopsy series from Sweden in 1969 (59–61). The literature also shows variation in the numbers and types of multiple primaries in relation to the total number of cancer patients. For example, the incidence of three or more primaries ranged from 0.2% in a cancer center in Jordan (2006–2011) to 2.0% in a cancer center in France (1980–2009) (62–64). Similarly, metachronous primaries accounted for 3% in a recent study from the United States (2005–2012) which is equivalent to our obtained results (55).

Currently, there is a lack of a definitive risk factor that has been confirmed for the development of MPN. However, various factors have been previously investigated. It has been hypothesized that the presence of MPN in cancer survivors may be influenced by increased vigilance or can be a result of previous treatments, and could also be linked to mutual risk factors such as environmental factors, and genetic predisposition (60). In addition, ethnic background is a significant determinant of susceptibility to certain diseases (55). Various societies exhibit varying rates of occurrence for specific types of neoplasms (14). For instance, the Japanese population experiences a notable prevalence of gastric cancer, while having a relatively low incidence of prostate cancer (65). Conversely, the Jordanian population demonstrates a considerably higher occurrence of prostate and lung malignancies (66).

There is a strong correlation between obesity and the development of cancer in the general population, specifically in relation to breast cancer, genitourinary cancers, and gastrointestinal cancers (67). Therefore, obesity has been found to significantly increase the likelihood of developing MPN. This connection was observed in the current study, which found that patients with MPN were more likely to be obese than those with a single form of malignancy. In addition, the higher levels of baseline thyroglobulin antibodies in patients with MPN can point to the possibility of autoimmune thyroid disease. A recent cohort study by Chen et al. concluded that patients with autoimmune thyroid disease are more susceptible to developing various cancers, including breast, colorectal, and head and neck cancers (68). They also found that elderly patients with autoimmune thyroid disease can have an increased risk of developing thyroid and colorectal cancer compared with the general population (68). Therefore, clinicians must be aware of such associations in the clinical oncology care.

Family history is a significant risk factor for the development of MPN. There is a notable presence of familial clustering across almost all cancer sites, and this clustering is primarily observed in close relationships within families spanning multiple generations (69). The majority of hereditary cancers display an excess of multiple primary tumors and an early onset of the disease (67). This clustering phenomenon may be attributed to abnormal genes or gene variants. Various cancer predisposition genes, including BRCA1, BRCA2, and p16/CDKN2A, have already been identified in high-risk pedigrees (67, 69). Additionally, individuals with hereditary nonpolyposis colorectal cancer who have MPN often exhibit a higher frequency of mismatch repair genes, such as hMSH2 and hMLH1 (70). Moreover, cribriform variants of PTC were identified as being classically linked with familial adenomatous polyposis (71).

Breast cancer and TC are among the most prevalent forms of cancer in women (72). In our study, we found a higher incidence of breast cancer in MPN patients. Breast cancer was found to be the most common secondary cancer in patients with TC, occurring either simultaneously, prior to, or after the TC diagnosis. This bidirectional relationship between thyroid and breast cancer has been previously suggested in a retrospective study, which also found an increased risk of developing a MPN in patients with a history of breast or TC (73). Various factors, such as iodine transport, obesity, sex hormones, thyroid hormones, and cancer treatment, have been potentially implicated in the development of both types of cancer (73, 74). Lei et al. explored the prognosis of breast cancer patients who subsequently developed metachronous TC using information obtained from the Surveillance, Epidemiology, and End Results database (75). The study aimed to compare the prognosis of breast cancer patients who had a second primary thyroid cancer with those who did not, analyzing a wide range of clinicopathological and treatment characteristics, and evaluating the impact of second metachronous TC on breast cancer survival. The population studied included breast cancer patients diagnosed between 2000 and 2014, with a subset of these patients developing a second primary TC within this timeframe. The study found that the impact of other malignancies on TC prognosis (and vice versa) can vary depending on the type and timing of the secondary cancer, as well as the specific characteristics of the cancer itself. This study contributes significantly to understanding the complex interplay between primary and secondary malignancies, highlighting the importance of considering the type, timing, and specific characteristics of secondary cancers in the prognosis of the primary cancer (75).

The presentation of hematologic malignancy with a second primary neoplasm is most commonly observed during the follow-up period (76). Breast, lung, and TC are the most frequently occurring secondary tumors (76). Typically, secondary TC in these patients occurs at a later time. It has been established that radiotherapy administered at the early stages of lymphoma is linked to an increased risk of developing secondary TC (77). Another study demonstrated that prior radiotherapy of the head, neck, and upper diaphragm may also contribute to the development of TC (78). In lymphoma patients, a recent study found that diffuse large B-cell lymphoma was the most commonly observed hematologic malignancy alongside TC in MPN patients (76). Similar to our findings, PTC was the most coinciding malignancy discovered incidentally (76).

Based on our analysis, it was found that patients with MPN exhibited a lower survival rate. This is more in line with previous research findings, as MPN had shown a detrimental and statistically significant impact on the survival of patients with TC (52). Liou et al. found that the overall mortality rate in TC patients with MPN could be 4.4 times higher compared to those without MPN (79). Similarly, Lang et al. reported a considerable mortality rate of 43.5% in TC patients with nonsynchronous MPN (80).

This study faces several limitations, chiefly due to its retrospective nature, a limited number of patients, and being conducted at a single institution. Moreover, despite attempts to mitigate confounding variables through propensity score matching and the exclusion of genetic conditions, the retrospective approach may have compromised accurate final selection due to the lack of exhaustive details on genetic testing, thyroid marker assays, and laboratory analyses, among other factors. Despite this, the present study is the first to address this topic using propensity score-matching among MPN patients of Middle-Eastern ethnicity.

The onset of MPN can significantly influence the survival outcome of TC patients. The diagnosis of thyroid carcinoma at an older age, accompanied by elevated initial thyroglobulin antibody levels and a notable familial predisposition, may raise concerns about the potential occurrence of synchronous or metachronous neoplastic manifestations. Further analysis with larger patient cohorts is necessary to confirm the results of this study.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Institutional Review Board of King Hussein Cancer Center (KHCC) in Amman, Jordan (Registration number: 22 KHCC 131, 11 August 2022). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

A-AI: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. ASA: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Software, Writing – original draft, Writing – review & editing. DA-A: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Project administration, Writing – original draft, Writing – review & editing. EL: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Project administration, Software, Supervision, Writing – original draft, Writing – review & editing. AA-O: Conceptualization, Writing – original draft, Writing – review & editing. MA-M: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. YY: Conceptualization, Data curation, Formal Analysis, Writing – original draft, Writing – review & editing. NA-H: Writing – original draft, Writing – review & editing. IM: Writing – original draft, Writing – review & editing. SS: Writing – review & editing, Methodology, Writing – original draft. GS: Conceptualization, Formal Analysis, Methodology, Validation, Writing – original draft, Writing – review & editing.