Preexisting or Concomitant Thyroiditis in Papillary Thyroid Cancer: Something More Than a Mere Issue of Timing? Free

The mouse model in which papillary thyroid cancer (PTC) and autoimmune thyroiditis (AT) develop in a predictable manner is a relevant tool to clarify the longstanding debate on the clinical association between AT and PTC. By exploiting this model, Pani et al (1) demonstrated that the tumor phenotype profoundly differs according to the timing of AT development (preceding as opposed to coinciding with the onset of PTC). Mice with preexisting AT experience a less aggressive tumor, as assessed by histopathological features, and undergo longer survival, compared with those having a concomitantly occurring thyroiditis. The fact that PTC develops less frequently in mice with preexisting thyroiditis (33%) compared to those with concomitant (100%) or without thyroiditis (100%) is a further argument supporting a protective effect exerted by thyroiditis when it precedes the onset of PTC. Besides the relevance of the present experimental findings, this newly established animal model will certainly contribute to 1) providing more insights into the long-standing debate of whether AT is a risk factor for the development of PTC; and 2) improving our understanding of the role of the inflammatory tumor microenvironment in driving the clinical course of thyroid malignancies.

Indeed, PTC specimens from mice with preexisting AT show a more prominent mononuclear cell infiltrate. The favorable outcome of PTC in these mice was ascribed to the extent and composition of the lymphoid infiltrate, suggesting a tumor-controlling effect of thyroid inflammation. Furthermore, the contribution of T and B lymphocytes in determining the clinical course of PTC was highlighted.

Infiltrating immune cells are the histopathological hallmark of thyroiditis, which may result from a primary autoimmune process (ie, chronic autoimmune thyroiditis) as well as from the proinflammatory cascade elicited by malignant transformation of thyroid cells. Previous studies have indicated that the oncogenic background of malignant thyroid cells leads to the expression of a large set of genes involved in inflammation and tumor invasion (2). The early demonstration that the RET/PTC1 oncogene activates a proinflammatory program was then extended to other genetic abnormalities found in PTC, including the v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation. Thus, evidence for the existence of a direct link between oncogenes, inflammation, and malignant behavior was provided (2).

Not only the number of infiltrating Inflammatory cells but also, and likely more relevantly, their functional characteristics play a role as prognostic determinants influencing the clinical behavior of PTC. In this regard, the chemokine milieu within the tumor inflammatory microenvironment is crucially involved in determining both the amount and the specific phenotype of infiltrating immune cells (3, 4). Chemokines are small chemotactic molecules involved in many physiopathologic processes including inflammation and autoimmunity. Chemokines are one of the soluble components of the tumor microenvironment, being secreted both by tumor cells and by infiltrating immune cells, which also express their receptors (3, 4). A wide spectrum of chemokines is secreted in the tumor microenvironment, and the balance between the protumorigenic and the antitumorigenic ones ultimately determine a more or less aggressive biological behavior of the malignancy (4).

Our group has long been involved in this field of research, focusing its attention on the role of specific chemokines in autoimmune or in tumor-related inflammation. Different proinflammatory cytokines, which in turn sustain the secretion of specific chemokines, are involved in the 2 types of immune-inflammatory process (5). More specifically, when interferon-γ (IFNγ) activity prevails, the inflammatory microenvironment is enriched in chemokine (C-X-C motif) ligand 10 (CXCL10), a chemokine known to exert anticancer activities, which in turn, promotes a Th-1 cell infiltration typical of thyroid autoimmunity (4, 6). On the other hand, when tumor necrosis factor-α prevails, the inflammatory microenvironment is enriched in chemokine (C-X-C motif) ligand 8 (CXCL8), a chemokine specifically involved in tumor-related inflammation (4, 5). With regard to PTC, CXCL8 also plays a crucial role in determining more aggressive tumor behavior, the mechanisms involved being the epithelial-mesenchymal-transition and the promotion of the metastatic spread (7). Going back to the mouse model by Pani and colleagues (1), the more favorable course of PTC in mice with preexisting thyroiditis might, at least in part, be attributed to high levels of Th-1–oriented chemokines, such as CXCL10. On the other hand, protumorigenic chemokines, such as CXCL8, might prevail when PTC develops concurrently or before thyroiditis, this immunological profile being associated with faster tumor growth rate and worse prognosis.

The experimental findings just described (1) might have clinical implications by shedding light on the long-standing controversy on AT as a protective as opposed to a favorable condition for the development of PTC. In this regard, Pani et al (1) discussed clinical studies supporting their experimental findings. A recent longitudinal study evaluating the possible development of PTC in more than 500 patients with AT proven to be free of thyroid cancer at baseline should also be considered (8). During a 10-year thyroid ultrasound follow-up, a few new nodules developed, but none of them proved to be malignant. Yet, the issue is still widely debated, because several clinical studies reported controversial findings with AT either reducing or increasing the incidence, pathological aggressiveness, and clinical severity of PTC. The experimental observation that AT would be protective or not, according to whether it preexists or follows the onset of PTC, might provide a unifying hypothesis.

In conclusion, the study by Pani et al (1) is a further step toward a better understanding of the complex relationship between autoimmunity, inflammation, and thyroid cancer. Since the role of AT as a risk factor for PTC is still widely debated in clinical research, we believe that this new mouse model will help us to give some definitive answers, at least from a physiopathologic point of view. The next experimental task to be pursued would be to assess the role of specific chemokines in establishing the cellular immune infiltrate in this mouse model and its relationship with the clinical course of thyroid cancer.

Abbreviations

Abbreviations
 
• AT

  autoimmune thyroiditis

 
• BRAF

  v-Raf murine sarcoma viral oncogene homolog B

 
• CXCL8

  chemokine (C-X-C motif) ligand 8

 
• CXCL10

  chemokine (C-X-C motif) ligand 10

 
• IFNγ

  interferon-γ

 
• PTC

  papillary thyroid cancer

Financial Support

The authors received no financial support for the research, authorship, and/or publication of this article.

Disclosures

The authors have nothing to disclose.

Data Availability

Data sharing is not applicable to this article because no data sets were generated or analyzed during the present study.

References