Incidence and prognostic factors of primary thyroid lymphoma and construction of prognostic models for post-chemotherapy and postoperative patients: a population-based study

Primary thyroid lymphoma (PTL) is an unusual malignancy, which is defined as an extra-nodal lymphoma confined to the thyroid without any involvement of other areas, comprising approximately 5% of all thyroid malignant tumors and fewer than 3% of all extra-nodal lymphomas, intrinsically related to Hashimoto’s thyroiditis [1]. It is 2–8 times more common in women than in men. Most of the tumors are B-cell-derived non-Hodgkin’s lymphoma; Hodgkin’s lymphoma and T-cell lymphoma are rare [2]. Patients usually show rapid enlargement of the neck mass and may develop hoarseness, expiratory dyspnea, or less commonly, B symptoms such as fever, night sweats, or weight loss [3]. Fine-needle aspiration cytology is not a dependable method for diagnosing PTL, and the main diagnostic method is ultrasound-guided puncture biopsy or surgical biopsy [4]. Combination chemotherapy and radiotherapy has become the standard practice today, surgery alone proved to have recurrence [5]. However, due to the rarity of PTL, no standardized treatment regimen has been established.

Most of the studies on PTL involve case series and case reports, whereas large-scale retrospective population studies are limited. This is currently the largest and most recent prognostic study of PTL patients using the US Surveillance, Epidemiology, and End Results (SEER) database, as the last study of PTL patients using the SEER database was conducted in 2009 by Graff-Baker et al. [6]. In our study, we also explored the incidence of PTL using the SEER database at the beginning, constructed the nomograms for patients after chemotherapy and after surgery, and visualized the prognostic models to achieve the effect that can be used clinically.

We observed that the incidence of PTL initially increased from 1975 to 1994 and then decreased to 2017, and this trend was particularly evident in the female population (68.8% of the PTL patients included in our study were female). Studies have shown that similar to Hashimoto’s thyroiditis, thyroid lymphoma incidence in women is 2:1 higher than in men, and even in some studies, it can be as high as 14:1 [5, 7]. The rise and fall in incidence may be related to the continuous improvement and implementation of PTL diagnostic tools, chemotherapy and radiotherapy techniques. Earlier studies have reported that it is difficult to distinguish thyroid lymphoma from undifferentiated thyroid cancer. However, in 1994–2004, the ability to distinguish and diagnose thyroid lymphoma dramatically increased due to new immunocytochemical staining techniques and increased knowledge of cytopathology [8]. This may be the reason why our study showed that 1994 was a turning point in the incidence of PTL. The occurrence of PTL goes hand in hand with chronic Hashimoto’s thyroiditis, studies have shown that chronic autoimmune (Hashimoto’s) thyroiditis has a higher risk of PTL and an increased relative risk of at least 60-fold compared with patients without thyroiditis [9]. It is important to consider the diagnosis of PTL in patients with enlarged neck masses and a history of Hashimoto’s thyroiditis [10]. Clinically, PTL is often used as a differential diagnosis of rapidly enlarging goiter or shortness of breath in patients with thyroiditis, and chemotherapy is started immediately after pathological diagnosis of PTL to avoid airway emergencies [11]. In recent years, some progress has been made in the diagnosis and treatment of Hashimoto’s thyroiditis, which could be conducive to reducing the incidence of PTL [12].

Our study also showed that although female patients had a high incidence of PTL, there was no correlation between gender and prognosis. However, married status is beneficial to the prognosis of PTL patients in our study. Previous studies have shown that marriages with lower lethal cancers (oral and pharyngeal, kidney and renal pelvis, thyroid, and lymphoma) have greater benefits to conditional relative survival, with higher relative survival rates in married patients, and relative survival rates in patients who are separated or divorced or widowed were the lowest [13]. Our study also shows that race has no significant impact on the prognosis of PTL, and no previous studies have reported a correlation between race and PTL prognosis.

The most prevalent type of lymphoma in our study was aggressive B-cell lymphoma, and the most common pathological type was diffuse large B-cell lymphoma (DLBCL), accounting for 57.4% of all PTL pathological types. According to previous case reports, more than 90% of PTL patients present with rapidly expanding goiter, and DLBCL is more aggressive than other PTL subtypes [11]. The second most common pathological type is MALT, an indolent lymphoma, which is a result of chronic inflammation and lymphoplasmacytic infiltration in Hashimoto’s thyroiditis, both of which are closely related [5], a substantial number of patients had thyroiditis history, especially thyroid MALToma. Reports have shown that the prognosis of PTL is associated with pathological subtypes and lymphoma Ann Arbor stage [6, 14, 15]. In our study, different pathological types of lymphoma influence the OS and CSS of PTL patients. The best prognostic pathological type is HL. The prognosis of DLBCL, which accounts for the largest proportion of pathological types, is not as good as MALT in terms of OS or CSS. This is related to the aggressiveness of DLBCL, which grows faster than MALT lymphoma, which often causes local obstructive symptoms, sometimes accompanied by cervical lymph node lesions [15]. In terms of lymphoma Ann Arbor stage, people at lower stages have better prognosis than those at high stages, which is concordant with the findings of a previous study [5].

The current standard chemotherapy regimen is CHOP (Cyclophosphamide, Halotestin, Oncovin, and Prednisone) [16]. DLBCL responds well to chemotherapy, and tumors may shrink within hours after corticosteroid injection [17]. Our results suggest that post-chemotherapy PTL patients treated with radiotherapy have better OS and CSS. In the cohort of chemotherapy patients, age, conjugal status, surgery, and radiotherapy were self-reliant prognostic elements for OS. Surgery and radiotherapy were beneficial for the prognosis of post-chemotherapy PTL patients, while the advantages of radiotherapy were more reflected in CSS. In chemotherapy patients, age, lymphoma Ann Arbor stage, and radiotherapy were independent prognostic factors for CSS. We constructed a nomogram for independent prognostic factors.

In terms of surgical treatment, some studies have shown that chemotherapy and radiotherapy are the mainstream means of PTL treatment, and surgery alone has a certain risk of recurrence [5]. Studies have shown that surgical treatment has a limited effect and that surgery does not significantly improve the OS of patients, which is somewhat inconsistent with our findings that surgery can improve the OS and CSS of PTL [17]. Surgery is rarely beneficial in DLBCL and mixed large cell subtypes because the disease is usually aggressive and disseminated, and it is impossible to surgically remove all lesions; however, thyroidectomy may be associated with great long-term remission and lower incidence [18]. Studies have shown that surgical treatment of PTL patients of the MALT subtype still has good results [8, 14]. The disease-free survival rate of patients with MALT lymphoma treated by surgery alone could be as high as 100% [15, 19]. In consideration of the fact that over half PTL patients in our study had been treated surgically, we also conducted a prognostic study and constructed nomograms of PTL patients who underwent surgical treatment. We reveal that age, conjugal status, lymphoma Ann Arbor stage, surgical procedure, and radiotherapy were independent prognostic factors in the post-operative cohort of patients with PTL.

For PTL patients, our results show that surgery, chemotherapy, and radiotherapy can improve the prognosis of PTL. According to Zhou et al., comprehensive treatment based on radiotherapy or (and) chemotherapy and assisted by surgery can improve efficacy in PTL patients [20]. Multimodal therapy is important for PTL patients, especially those with more aggressive subgroups and extensive local or distant disease; for patients with MALT lymphoma, the benefits of multimodal therapy are less than the risks, which highlights the importance of accurately defining histological subtypes before deciding on treatment options, and the need to consider histology and staging of tumors [10, 18]. Targeted therapies such as rituximab against CD20 on B-cell surface, which is a major advancement in the treatment of lymphoma, have been used in the treatment of DLBCL, but the application of R-CHOP (Retuximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) therapy in PTL has not been much studied, some literature shows that rituximab has been applied in the treatment of thyroid DLBCL [21‐23]. There are also some case reports showing that R-CHOP has a good therapeutic effect on PTL [24, 25]. In recent years, there are also some emerging therapies such as molecular detection, although there is a need to further explore their clinical applications and prognostic effects.

The C-index of the nomograms that were constructed in this study is considerable in both post-chemotherapy and postoperative PTL patients, which is more complete than the prognosis assessed by lymphoma Ann Arbor stage alone, and the calibration curve also reflects the good uniformity between the predicted and actual survival. Of course, our study also has shortcomings. This is a retrospective study, which will lead to some bias in our results, and some potential prognostic factors are missing in the SEER database, or our researchers are not included. Because the dynamic medication status of patients was not included in the SEER database, we could not make use of the fact that advances in medication, such as the molecular targeted drug rituximab, and other effects on prognosis, the patients who were diagnosed with lymphoma too long to draw a single conclusion about the treatment. However, compared with previous studies, our study used SEER database to reveal the trend of PTL incidence rising first and then decreasing, then we investigated the morbidity and prognostic elements of PTL, as well as visualized the prognostic model of post-chemotherapy and postoperative PTL patients for potential clinical application and also provided a certain reference for future research.

In sum, the incidence of PTL showed an upward and then downward trend, which was most prominent in female patients. Age, marital status, lymphoma Ann Arbor stage, histological types, surgery, radiotherapy, and chemotherapy have certain effects on the prognosis of PTL patients. Younger age, radiotherapy and lower lymphoma Ann Arbor stage, as well as less aggressive lymphoma pathological subtypes, are beneficial to the survival of post-chemotherapy and postoperative PTL patients. We constructed nomograms for their respective independent prognostic factors, and validated that they have good predictive ability.