Sorafenib, a tyrosine kinase inhibitor, is approved for the treatment of advanced differentiated thyroid carcinoma (DTC). Resistance to sorafenib may appear under treatment and may be associated with increased aggressiveness of the neoplasia. The present study reports the case of a 65‑year‑old male who underwent total thyroidectomy for a follicular thyroid carcinoma, Hürthle cell variant, in February 2005. Until January 2010, the patient received four consecutive 131I doses (total dose, 612 mCi) for increased serum thyroglobulin (Tg) and initial faint lung uptake (which eventually became undetectable). Subsequently, the patient developed several sequential bone (humerus, rib and skull), adrenal and lung metastases, the majority of which were surgically removed. Histological examination in all cases revealed evidence of DTC metastases that were strongly positive for Tg, as revealed by immunohistochemistry. In March 2014, sorafenib therapy was initiated, but it was discontinued 10 months later to allow an undelayable prostatectomy. Immediately upon surgery, the patient developed a large metastatic lesion in the right gluteal muscle, whose biopsy revealed undifferentiated neoplasia of epithelial origin, and the patient succumbed shortly afterwards. An extensive comparative search for biochemical and molecular markers was performed on all available tissues (primary tumor, and differentiated and undifferentiated metastases). The primary tumor and all the available metastases exhibited the same molecular oncogenic markers (namely, the RAS mutation p.Q61R and the telomerase promoter mutation C228T). In addition, the undifferentiated metastasis exhibited a p53 mutation. The present study reports a case of a sudden acceleration of DTC metastatic progression following sorafenib discontinuation, which could have been due to the emergence of sorafenib‑resistant undifferentiated p53‑positive tumor cell clones.
Papillary thyroid cancer (PTC) often co-occurs with Hashimoto's thyroiditis, an association that has long been reported in clinical studies, remaining controversial. Experimental evidence has recently shown that pre-existing thyroiditis has a beneficial effect on PTC growth and progression by a distinctive expansion of effector memory CD8 T cells. Although the link between inflammation and PTC might involve different components of the immune system, a deep characterization of them which includes T cells, B cells and tertiary lymphoid structures, Mye-loid cells, Neutrophils, NK cells and dendritic cells will be desirable. The present review article considers the role of the adaptive and innate immune response surrounding PTC in the context of Hashimoto's thyroiditis. This review will focus on the current knowledge by in vivo and in vitro studies specifically performed on animals' models; thyroid cancer cells and human samples including (i) the dual role of tumor-infiltrating lymphocytes; (ii) the emerging role of B cells and tertiary lymphoid structures; (iii) the role of myeloid cells, dendritic cells, and natural killer cells; (iv) the current knowledge of the molecular biomarkers implicated in the complex link between thyroiditis and PTC and the potential implication of cancer immunotherapy in PTC patients in the context of thyroiditis.
The association between Hashimoto thyroiditis (HT) and papillary thyroid carcinoma (PTC) has been originally suggested by retrospective pathological studies and has recently been re-evaluated and proposed on the basis of several fine-needle aspiration cytology (FNAC) studies. In FNAC studies, the association between HT and PTC is based on the comparison of anti-thyroid autoantibodies (ATA) (anti-thyroperoxidase [TPOAb] and anti-thyroglobulin [TgAb]), thyroid function (TSH), and cytology with histology of thyroid nodules and lymphocytic thyroid infiltration (LTI) of operated thyroid glands. Most of the pathological studies found a high prevalence rate of PTC in HT. In most FNAC studies, the risk ratio of PTC in HT patients was evaluated using multivariate statistical analysis: increased TSH levels represented the main and common independent risk factor of malignancy, although it resulted not consistently related to HT. On the other hand, several studies provided a positive relationship between ATA and PTC, particularly with TgAb. Two recent FNAC studies from the same referral center clearly demonstrated an independent risk for thyroid malignancy conferred by both TPOAb and TgAb, confirming the role of increased TSH levels, and found a significant association between PTC and ATA and diffuse LTI at histology. These studies are consistent with the hypothesis that autoimmune thyroid inflammation and increased serum TSH concentration may be involved in thyroid tumor growth. The complex relationship between HT and PTC, which involves immunological/hormonal pathogenic links, needs to be further investigated with prospective studies.
The pathogenesis of thyroiditis caused by immune-checkpoint inhibitors (ICIs) such as antiprogrammed death receptor-1 (PD-1) and anticytotoxic T lymphocyte antigen-4 (CTLA-4) is incompletely understood. To gain mechanistic insights, we developed a mouse model of ICI-related thyroiditis and assessed the clinical, hormonal, and cytokine profiles.
e15004 Background: Regorafenib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of patients with metastatic colorectal cancer failing fluoropyrimidine-based chemotherapy in combination with oxaliplatin and irinotecan, bevacizumab and anti EGFR antibodies (if RAS wild type).The toxicity profile includes several side effects which make challenging the use of regorafenib in the clinical practice. Among these, thyroid dysfunctions although uncommon, might be relevant for their clinical implications. Methods: From November 2015, 14consecutive patients (4 males and 10 females; mean age 64±8.1) with metastatic colorectal cancer were studied at the start of regorafenib and at monthly intervals. In all cases a full haemogram, LDH, phosphocalcic metabolism levels (calcemia, phosphorous, parathormon, albumin, Vitamin D), FT3, FT4 and TSH were measured together with clinical assessment and thyroid morphology. Results: Fatigue represented the most commonside effect: 13/14 patients (92.8%) presented G1-G3 fatigue. Among all 5 patients developing G3 fatigue we also observed hypothyroidism (TSH 5.8±3.1, range 18.47-6.99). Interestingly 40% of patients showing G3 fatigue and hypothyroidism developed TPO Antibodies. Furthermore, in these patients we observed a trend towards a reduced phosphoremia (range 3.0-2.7; (p = ns) associated with a reduction of 25OH- Vit D. All patients who developed hypothyroidism received hormone replacement therapy with a prompt improvement of clinical symptoms, without regorafenib interruptions or dose modifications. Conclusions: These preliminary data suggest that in a non-negligible proportion of patients developing severe fatigue during regorafenib an accompanying hypothyroidism may be present. An early diagnosis and management of hypothyroidism is therefore mandatory for an effective clinical control of fatigue in most of the cases, in order to prevent unnecessary regorafenib dose reductions and modifications. Further and larger data are needed to confirm this hypothesis through a closer collaboration with endocrinologists in clinical practice.
