Thyroid lymphoma may be classified as primary, when neoplastic cells arise de novo within the thyroid gland, or secondary, when the gland is infiltrated by malignant lymphoid cells originating from other sites [1]. Both entities are rare. Primary thyroid lymphoma (PTL) accounts for approximately 2% of extranodal lymphomas and 1%‐5% of all thyroid malignancies [2]. Diagnosis is established by fine-needle aspiration or open biopsy [3]. Accurate subtype identification is essential, as treatment depends on the histologic variant. Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype, comprising more than half of reported cases [4], followed by mucosa-associated lymphoid tissue (MALT) lymphoma [5].

In addition, PTL is strongly associated with Hashimoto thyroiditis; several studies suggest that up to 80% of patients with PTL have a background of this autoimmune condition [6]. Prognosis varies according to the lymphoma subtype, with reported 5-year survival rates of up to 45% [7].

In contrast, secondary thyroid lymphoma is an even rarer entity. It may be misdiagnosed as other thyroid pathologies, such as primary lymphoma or intrathyroidal metastases. Definitive diagnosis relies on histopathological evaluation [8]. Takashima et al [9] reported older series in which thyroid involvement among patients with systemic lymphoma ranged from 11% to 27%. Among these, aggressive subtypes such as Burkitt lymphoma often present with rapid progression and poor prognosis if treatment is not initiated promptly [7].

Although the prevalence of both entities is low, early recognition of primary and secondary thyroid lymphomas is essential, as their therapeutic approaches differ substantially from those of other thyroid malignancies. However, published data on these conditions remain limited.

Given this knowledge gap, establishing a comprehensive database that compiles information reported in the literature would be valuable for assessing potential prognostic factors and determining optimal treatment strategies—an endeavor complicated by the rarity of these diseases. The aim of this scoping review is to examine the current literature on primary and secondary thyroid lymphomas and to identify key factors associated with improved patient outcomes

The proposed scoping review will be conducted in accordance with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) for scoping reviews.

The search was conducted on August 9, 2024, using Scopus (Elsevier), Embase, and Ovid, yielding a total of 1404 results. A comprehensive review of the manuscripts is expected to be completed by August 2025. All potential manuscripts will be imported into the reference management software Rayyan QCRI 23. This scoping review aims to identify and describe the clinical, histopathological, and molecular prognostic factors associated with survival and disease progression in adult patients with primary and secondary thyroid lymphomas.

A preliminary PRISMA flow diagram illustrating the identification, screening, eligibility, and inclusion process is provided in Figure 1.

Primary and secondary thyroid lymphomas are rare malignant neoplasms that account for only 2%‐5% of all thyroid cancers and approximately 2% of extranodal lymphomas [10,11]. This rarity underscores the need to analyze the various case reports and case series published over time to identify specific characteristics such as histologic subtypes, clinical manifestations, prognosis, and survival, among others [11]. Given their low incidence, the overarching goal is to identify shared features across different patient groups.

With this scoping review, we aim to compile the available observational evidence to determine which clinical factors—such as sex, age, presentation, comorbidities, and disease stage—have been associated with progression and/or survival in patients with thyroid lymphomas [12]. We also aim to identify histopathological characteristics, including histologic subtypes and immunohistochemical markers such as tumor protein p53 (p53) and marker of proliferation Ki-67 (Ki-67), that have been linked to prognosis. This will help confirm that the most frequent histologic subtypes of thyroid lymphoma are DLBCL and MALT, as described in multiple case series [6].

Additionally, we seek to characterize the most relevant and common clinical manifestations—such as dysphagia, hoarseness, and airway obstruction, particularly in rapidly growing masses [13]—to support earlier diagnosis when clinical suspicion arises. However, molecular evidence remains fragmented and heterogeneous, and prognostic factors for secondary thyroid lymphomas are even less consistent and infrequently reported.

Among the main findings, the most frequently evaluated variables across studies include age, the presence of compressive symptoms, a prior diagnosis or documented history of Hashimoto thyroiditis [14], and the different Ann Arbor stages. Certain factors appear to have a more consistent association with survival outcomes[15], including age, tumor size, and the presence of B symptoms [16]. Nonetheless, only a limited number of studies provide comprehensive data on comorbidities at diagnosis [14,17], diagnostic methods [7,17,18], clinical status, and other relevant variables [19].

Regarding the prognostic value of immunomarkers, Ki-67 is perhaps the most extensively studied and most consistently associated with disease aggressiveness. Other markers such as p53, B-cell lymphoma 2 (BCL2), and MYC proto-oncogene (MYC) show variable findings [20], and no adequately standardized protocol exists for their assessment. Molecular factors, including gene rearrangements, are infrequently reported in patients with thyroid lymphoma, making it even more challenging to evaluate somatic mutations or advanced genetic alterations in these tumors [21]. These findings often lack external validation [22], further limiting their incorporation into broader analyses.

This scoping review seeks to highlight the lack of standardization in the characterization of primary and secondary thyroid lymphomas. Examples include the frequent aggregation of primary and secondary cases in previous studies, differences in therapeutic management, and considerable variability in the cut-off values used for Ki-67 [23,24].

Among the strengths of this review, we identify the opportunity to expand the clinical, histologic, and molecular characterization of thyroid lymphomas by including studies with diverse designs and by identifying gaps that had not been clearly documented or systematically addressed in previous literature. Nevertheless, heterogeneity in study designs, sample sizes, and disease stages limits the ability to establish causal relationships. Most of the available evidence is derived from small retrospective series; however, these still contribute valuable insights and facilitate a more structured understanding of the current literature. One of the most significant limitations remains the scarcity of studies focusing specifically on secondary thyroid lymphoma.

These findings underscore the need for prospective multicenter studies that jointly evaluate clinical and molecular factors, standardize immunohistochemical markers and their quantification, and, in the long term, conduct comparative analyses to better establish prognostic differences between primary and secondary thyroid lymphomas.

We hope that disseminating this compiled information and publishing our results in open-access repositories and medical literature will support clinicians and pathologists seeking a deeper prognostic understanding of patients affected by this condition.

This scoping review, therefore, aims to emphasize the importance of clinical and histopathological factors as the predictors with the strongest available evidence in thyroid lymphomas, whereas molecular factors remain fragmented due to their low reporting frequency across studies, making them appear insufficiently explored. Although, as previously mentioned, methodological variability limits the ability to draw solid comparisons, this work constitutes an initial step toward identifying priority areas for standardization and knowledge gaps, providing a clearer path for future research and ultimately improving the prognostic characterization of this rare entity.