The unambiguous effect of coexisting CLT has always been under debate, due to conflicting data of CLT and risk of malignancy. The contradiction could be attributed to different definition of CLT, contradicted effects of CLT in different age groups, poor pathologic reports of coexistent CLT (29) or variation of statistical approaches. In this study, multivariate analysis was performed to indicate that histopathologically confirmed CLT was independently associated with several aggressive pathologic features in patients < 55 years to some extent, which could suggest in a way that autoimmune thyroiditis harbored unfavorable impacts on PTC progress.
It has been indicated in previous abundant data that PTC coexistent with CLT was nearly three times more frequent than non-CLT (30). Our study has showed that 29.6% of PTC patients had coexistent CLT, which was a consistent frequency with statistics in other reports (0.5–38%) (18, 31–33). Meanwhile, our study also presented that coexistent CLT was more prevalent in female PTC patients, which was similar to conclusions in other reports (34). In our entire studied sample, coexistent CLT didn’t show significant association with any aggressive features in malignancy, except that CLT-coexisted group had a mild trend to have lesions > 1 cm. However, we found that in patients < 55 years, those with coexistent CLT tended to have more extrathyroidal extension and significantly a less frequency of small lesions. While in patients ≥ 55 years, the presence of CLT was associated with none of the clinical or pathologic features.
Our analyzed results indicated that CLT independently predicted macroscopic ETE and larger lesions (minimum lesion size > 1 cm) in patients < 55 years, and this trend was consistent with several previous reports. Babli et al. (25) concluded that the presence of CLT could be in association with unfavorable pathologic features, including ETE in young patients. Nam et al. (26) observed the larger lesions in CLT-coexisted patients. In contrast, however, CLT played a protective role in cancer development concluded from some other investigations. According to the study from Kim et al. (27), CLT was an independent predictor for low frequency of ETE and CLNM. We observed that the greater lesion size (Dmin>1 cm) served as an independent risk factor of gross ETE in patients and was associated with high-risk recurrence stratification in all age cohorts. Besides, ETE and greater lesion size mutually promoted the progression of each other, which had also been supported by other investigations that, according to Kim et al. (27), greater tumor size was independently associated with gross ETE, and vice versa. According to Castro et al. (35), larger lesion size was one of the best predictors of persistence/recurrence. Our observation was in accordance with studies from Lee et al. (36), that larger tumor size was one of the independent risk factors of gross ETE, which could partly explain the unfavorable prognosis. Apart from the authoritative statement in ATA guideline, gross ETE has been a longtime recognized adverse pathologic predictive factor of worse outcome in many other studies, and the extent of macroscopic ETE appeared to be a potential determinant of PTC recurrence. The macroscopic (gross) extrathyroidal extension has been proposed to be a well-established key variable and of more importance in PTC prognosis stratifications, compared with microscopic ETE (37). However, it has to be underlined that pathological and clinical features in 2015 ATA risk stratification systems are often diagnosed subjectively and vary in different institutions, so the definite approach to estimating high-risk recurrence still needs further observation so that it can play a part in bettering clinical management.
The results of CLT’s role in initial recurrence risk estimation from the whole studied group didn’t show significance. Interestingly, when divided in different age groups, CLT showed evident prognosis value but only in patients aged 35–44 years. No previous investigation has demonstrated CLT’ s role in recurrence risk stratification, especially in different age groups respectively. In that case, our observation could give a hint in regard to subsequent clinical management, of which the focus could be placed on patients in middle age.
In fact, the association between CLT and PTC outcome has remained controversy for over two decades. It is still ambiguous and unexplained partly because of the hesitation in answering whether it is the concurrence or causality between them. One hypothesis elucidated in previous studies pointed out that the lymphocytes migration around tumor lesions (known as “peritumoral infiltration”) was trying to restrict malignancy progression (38). This phenomenon, however, is distinct from the diffused lymphocyte infiltration in CLT with follicle effacement. Kamma et al. (39) observed that lymphocyte infiltration, predominantly around the tumor, was correlated with more aggressive cases. They supposed that surrounding lymphocyte infiltration was followingly induced by the antigen expression on tumor cells, which aroused the necessary but insufficient immune attack. Other hypotheses were addressed in different ways that the coexisting CLT contributed to cancer progression. Notably, thyroid follicular epithelial cells can show oncocytic changes extensively, exhibiting crowding, irregular contours and large nucleus, which resembled features of papillary carcinoma (40). According to Giordano et al. (41), the follicular cells in CLT background intensely expressed Fas/FasL due to abundant interleukin-1 beta (IL-1βd), which activated the apoptosis pathway to cause the destruction of normal thyroid tissue, promoting carcinoma growth and malignancy. Despite the abundant reports with regard to the association between CLT and PTC, the exact mechanism is still under debate and in need of further research.
The limitations of our study should be considered that it is a retrospective study, and CLT diagnosis was confirmed on the basis of histopathological examination on thyroid tissue from thyroidectomy, which concealed the real chronological and further causal relationship between PTC and CLT. Besides, we simply estimate recurrence risks using initial postoperative stratification system, the robust association between CLT and recurrence needs factual prospective outcomes. The significant results were only applied to patients < 55 years and the prognosis value of CLT was only apparent in patients aged in 35–44 years, so the finer investigation towards age specificity and possible mechanisms should be conducted in the study hindward.
In accordance with previous reports, CLT coexistence was demonstrated much more prevalent in female. We conclude that CLT served as an independent risk factor of some aggressive clinical characteristics, including gross extrathyroidal extension and greater lesion size (> 1 cm) in PTC patients with coexistent CLT of younger age (< 55 years). In the light of authoritative stratification from ATA guideline, PTC patients aged in 35–44 years were estimated more likely to undergo high-risk recurrence.