Thyroid Autoimmunity and Thyroid Cancer – The Pathogenic Connection: A 2018 Update

Abstract

The association between thyroid cancer and thyroid autoimmunity has long been suggested, but remains to be elucidated for several decades. Here the data on this issue are updated by summarizing relevant papers published between 2012 and early 2018. Although numerous papers demonstrated the significant increase in the prevalence of thyroid autoimmunity (positive intrathyroidal lymphocyte infiltration and/or anti-thyroglobulin/thyroid peroxidase antibodies) in patients with thyroid cancers as compared to those with benign nodules, and also the significant increase in the prevalence of papillary thyroid cancer (PTC) in patients with thyroid autoimmunity as compared to those without, there are some crucial biases that should be taken into account for their interpretation. However, a difference in the incidence of thyroid autoimmunity in patients with PTCs and those with other types of thyroid cancers appears to support the significant association of two conditions. Thyroid autoimmunity is, at least partly, likely to be elicited against antigens shared by normal and cancerous thyroid tissues, thereby inducing autoimmunity. At the same time, elevated TSH levels (even within the normal reference ranges), which often accompany Hashimoto’s patients are a risk factor for thyroid cancer. However, it is still unclear whether or not the co-existence of thyroid autoimmunity impacts on cancer characteristics and prognosis. This issue needs to be further investigated with large-scale prospective studies.

Key words

papillary thyroid cancer - TSH - benign nodule - bias

Introduction

Thyroid cancer and Hashimoto’s thyroiditis/chronic thyroiditis are both very common and their prevalence has been increasing worldwide during the last several decades. Association between thyroid cancer, particularly papillary thyroid carcinoma (PTC), and thyroid autoimmunity (intrathyroidal lymphocyte infiltration and/or anti-thyroid antibodies) has long been suggested. The first paper reporting the possible association of these two conditions was published more than 60 years ago [1], and numerous papers were thereafter published to investigate their association.

The data published until 2011 were summarized in several review articles. For example, one performed meta-analysis of 38 eligible studies published between 1957 and 2011 and showed, using >10 000 histologically confirmed thyroid cancer surgical samples, that intrathyroidal lymphocyte infiltration [observed in 23.2% (ranged from 5 to 85) of PTCs] was more frequently observed in PTCs than in other types of thyroid cancers and benign nodules, and PTCs with co-existing lymphocyte infiltration were significantly related to females, multifocal involvement, the absence of extrathyroidal extension, less lymph node metastasis and long recurrence-free survival, confirming the significant association of PTC with pathologically proven Hashimoto’s thyroiditis and the favorable clinicopathological characteristics of PTC patients with Hashimoto’ thyroiditis as compared to those without thyroiditis [2]. Another study divided the data from 19 articles into two groups – fine needle aspiration cytology (FNAC) group and archival thyroidectomy specimen group, and demonstrated the significant linkage between thyroid cancer and Hashimoto’s thyroiditis in the latter, but not the former, groups. Thus the average prevalence rate of PTC in Hashimoto’s patients was 1.2% (ranged from 0 to 2.95) in ~18 000 FNA specimens versus 27.6% (ranged from 9.5 to 36.7) in ~10 000 surgical samples [3]. These results strongly suggest that the higher prevalence of co-occurrence of thyroid cancer and thyroid autoimmunity in the studies with thyroid surgical specimens may be attributed to a bias due to patient selection for thyroidectomy. However, there is also a concern about lower diagnostic accuracy of FNAC than pathological examination of surgical specimens [3]. Indeed, it has been reported that 10 to 30% cytology is actually indeterminate in FNAC [4] [5]. The differences in diagnostic criteria, patient backgrounds, etc. also contributed to these wide variations. Overall, the coexistence of these two conditions ranged from 0 to 85% [2] [6] [7].

This review summarizes and updates the data on the association of these two conditions reported after the publications of the two review articles mentioned above. First, the association was analyzed by two different ways – (i) incidence of thyroid autoimmunity in patients with thyroid cancer versus those with benign nodules and (ii) incidence of thyroid cancer in patients with thyroid autoimmunity versus those without. The former was further analyzed with two different categories – surgical specimens and FNAC as in the review mentioned above [3]. Then cause-effect relationship between these two conditions and the impacts on their co-occurrence on cancer characteristics were summarized. The readers can also refer to other recently published reviews [6] [8] [9].

Association of thyroid autoimmunity with thyroid cancer

In the reports studying the relationship between thyroid autoimmunity and thyroid cancer, the presence of thyroid autoimmunity has been judged by the presence in sera of autoantibodies against thyroid autoantigens [thyroglobulin (Tg) and thyroid peroxidase (TPO)] and/or histopathological evidence of intrathyroidal lymphocyte infiltration. In some studies, only diffuse lymphocyte infiltration was defined as Hashimoto’s thyroiditis/chronic thyroiditis, but lymphocyte infiltration just surrounding the malignant tumor was not [10] [11] [12], while both were considered as thyroid autoimmunity [13] or the details were not specified in other reports. Although a limited, focal lymphocyte infiltration may just represent the immune response to tumor antigens, the presence of anti-thyroid autoantibodies and/or any type of lymphocyte infiltration was defined as thyroid autoimmunity in this review. This is because immune response to thyroid tumor is a critical issue in this review and also it is difficult to distinguish tumor-associated lymphocyte infiltration from background lymphocytic thyroiditis, irrespective of diffuse or focal [6]. To the best of my knowledge, there is no study comparing the incidence of PTC between patients with diffuse lymphocyte infiltration and those with focal infiltration. Thyroid nodules were, needless to say, diagnosed pathologically with surgical specimens or with FNAC (as benign or suspicious/malignant in the case of the latter).

Incidence of thyroid autoimmunity in patients with thyroid cancer versus those with benign nodules

In the following sections, the data obtained with surgical samples and FNAC are separately summarized.

Studies with surgical specimens

Similar to the studies published until 2011 (see above), numerous retrospective studies using surgical specimens reported the higher prevalence of lymphocyte infiltration and/or anti-thyroid autoantibodies (anti-Tg and/or anti-TPO) in patients with PTCs as compared to those with other types of thyroid cancers or benign goiters/nodules [10] [11] [13] [14] [15] [16] [17] [18] [19] [20] [21] ([Table 1]). The majority of Hashimoto’s patients have anti-Tg and/or anti-TPO antibodies, and the minority of healthy subjects have these antibodies without intrathyroidal lymphocyte infiltration. Of interest, the incidence of anti-thyroid antibodies was also higher in thyroid cancers than benign nodules in such sero-positive but non-Hashimoto’s patients [14]. Anti-Tg antibodies seem to be a better marker than anti-TPO antibodies [15] [16]. It is also reported that scattered lymphocyte infiltration is more frequent in benign nodules than PTCs [17].

Table 1 Comparison of the prevalence of thyroid autoimmunity between PTCs and benign nodules in surgical specimens.

First author [ref.]	Prevalence of thyroid autoimmunitya [%, (number of patients/number of samples)]		p
	in PTCs	in benign nodules
Campos [20]	26.8 (11/41)	6.6 (13/198)	0.0058
Ye [10]	18.4 (188/1024)	6.4 (66/1028)	<0.001
Boi [13]	40.0 (38/95)b	26.0 (25/96)b	0.04
	2.9 (1/35)	36.5 (19/52)	<0.001
Lun [14]	18.8 (127/676)	7.2 (129/1802)	<0.01
	27.2 (140/514)c	15.4 (232/1510)c
	15.4 (79/513)d	8.1 (122/1507)d
Zhang [11]	40.7 (44/144)	12.7 (64/503)	<0.001
Giagouta [12]	32.0 (441/1380)	29.1 (240/824)	0.61 i
Azizi [15]	20.6 (48/233)e	10.2 (182/1790)e	<0.0001
	31.3 (73/233)f	26.7 (478/1790)f	0.13
Wu [16]	16.2 (87/537)e	10.4 (166/1595)e	0.000
	5.2 (28/537)f	3.4 (54/1595)f	0.06
Vasileiadis [18]	33.2 (129/389)	26.2 (117/447)	0.027
	32.4 (11/34)b	24.2 (22/91)b	0.356
	38.2 (13/34)b,e	19.8 (18/91)b,e	0.033
Cho [21]	70.1 (180/257)f	25.3 (65/257)f	<0.001
Qin [19]	23.6 (56/237)e	12.6 (177/1401)e	<0.001
	12.7 (30/237)f	7.6 (106/1401)f	0.009
de Alcantara-Jones [23]	27.3 (9/33)	31.3 (5/16)	0.8
Veit [17]	47.8 (32/67)	3.0 (3/100)g	<0.001
		27.0 (27/100)h	<0.01
	34.0 (23/67)f	5.0 (3/60)f	<0.001
Selek [22]	29.8 (172/577)	30.7 (90/293)	0.34
	17.0 (98/577)e	14.0 (41/293)e	0.31
	25.1 (145/577)f	28.3 (83/293)f	0.36

^a Judged by histology of the surgical specimens, if not specified; ^b The tumors with indeterminate cytology were selected. Pathological diagnosis was done following surgery; ^c,d Judged by anti-Tg antibodies and anti-TPO antibodies, respectively, after removing patients with histologically proven Hashimoto’s thyroiditis; ^e,f Judged by anti-Tg antibodies and anti-TPO antibodies, respectively; ^g In focal to diffuse dense lymphocyte infiltration with germinal centers; ^h In focal to diffuse dense lymphocyte infiltration with germinal centers and also scant scattered lymphocyte infiltration; ⁱ p>0.05 is depicted in italic.

Similar analyses were done in patients who had thyroid tumors with indeterminate cytology in FNAC which were later confirmed to be cancers by surgery. One paper found the similar results with lymphocyte infiltration as a diagnostic indicator for thyroid autoimmunity [18], and the other did also so with anti-Tg antibodies, but not with lymphocyte infiltration [13].

In contrast, there are some contradictory data; Selek et al. and de Alcantara-Jones et al. [12] [22] [23] reported no difference in the prevalence of lymphocyte infiltration or anti-thyroid antibodies between thyroid cancer group and benign tumor group.

PTC patients with thyroid autoimmunity were in general younger and occasionally predominant in females, and had smaller tumor sizes and more micro-calcification than those with benign nodules ([Table 2]). Serum concentrations of TSH were largely higher (even in the normal range) and in some reports T₃ was lower. Other indicatives for the presence of thyroiditis (e. g., hypoechogenicity in ultrasonography) may also be helpful to detect the presence of thyroid autoimmunity.

Table 2 Comparison of clinical and biochemical markers for PTCs versus benign nodules in surgical specimens.

First author [ref.]	Age	Sex	T3/T4	TSH	Lymphocyte infiltration	TgAb	TPOAb	Others
Ye [10]	younger	M<F	→a	↑b	↑	↑	↑	micro-calcification ↑
Boi [13]	younger	N.A.d	N.A.	↑	N.A.	↑	↑
Lun [14]	younger	→	↑c (fT3)	↑	↑	↑	↑
Azizi [15]	younger	→	N.A.	↑	N.A.	↑	→
Wu [16]	younger	→	↓ (fT3)	↑	N.A.	↑	→
Vasileiadis [18]	→	→	N.A.	↑	↑	↑	N.A.	tumor sizes ↓
Qin [19]	younger	→	N.A.	↑	N.A.	↑	↑	tumor sizes ↓
Selek [22]	younger	M<F	N.A.	N.A.	→	→	→

^a,b,c No change, an increase and a decrease, respectively; ^d Not assessed.

In these analyses, although the reasons for surgery were not always specified clearly, some papers described the reasons that thyroidectomy was done in general because of suspicion of malignancy for thyroid nodules under diagnostic procedures such as palpation, FNAC and ultrasonography and, in some cases, because of cosmetic reasons or recurrence of Graves’ hyperthyroidism [10] [15] [18]. Selection bias for thyroidectomy is always a critical issue in this type of analysis. It is possible that increased attention to the thyroid gland may facilitate frequent diagnosis of thyroid cancers in Hashimoto’s patients [24]. Thus, thyroid nodules may be found at the earlier stage in Hashimoto’s patients than non-Hashimoto’s patients, because the former group takes often medical follow up for their thyroid autoimmunity/dysfunction. Therefore, if Hashimoto’s patients have PTCs more frequently than non-Hashimoto’ patients, the prevalence of thyroid autoimmunity may be higher in PTC group than non-PTC group. This association was only observed in PTC, but not in other types of cancer – follicular thyroid cancer (FTC) or medullary thyroid cancer (MTC) [9] [17] [25].

Studies with FNAC

Like the studies published until 2011, Castagna et al. [26] reported no difference in the incidence of thyroid autoimmunity (judged by the presence/absence of anti-thyroid antibodies) between thyroid nodules of benign cytology and suspicious/malignant cytology ([Table 3]). Thus, the presence of thyroid autoimmunity did not affect the diagnostic accuracy. Of interest, in this study, some patients (14.3%, 358/2504) with suspicious nodules (Thy4/5), indeterminate nodules (Thy3) or large nodular goiters underwent surgery; the prevalence of cancer at final histology was significantly higher in patients with nodular autoimmune thyroiditis than those with other nodular diseases (nodular Graves and nodular goiter with/without anti-thyroid antibodies), because the proportion of suspicious nodules was significantly higher in the former than in the latter (60.7% vs. 21.5 to 30.0%). However, the significantly higher incidence of thyroid autoimmunity (including both Hashimoto’s thyroiditis and Graves’ disease) in suspicious/malignant cytology can be calculated in another recent study on FNAC [27]. On an individual basis, Graves’ disease and anti-Tg antibodies, not Hashimoto’ thyroiditis, are risk factors for suspicious/malignant cytology. The significant difference was also reported in FNAC, in which, however, histologically proven patients were pre-selected for analysis [13]. In both papers, TSH is an independent risk factor for PTC.

Table 3 Comparison of the prevalence of thyroid autoimmunity between benign and suspicious/malignant cytology.

First author [ref.]	Prevalence of thyroid autoimmunity[%, (number of patients/number of samples)]		p
	Suspicious/malignant cytology	Benign cytology
Boi [13]	49.2 (93/189)a	30.0 (560/1864)a	<0.001
Castagna [26]	10.7 (13/121)b	13.0 (279/2148)b	0.5 e
	15.7 (19/121)c	16.9 (363/2148)c	0.80
Hadjisavva [27]	52.1 (25/48)d	35.6 (162/455)d	0.025

^a,b,c Judged by lymphocyte infiltration, anti-Tg antibodies and anti-TPO antibodies, respectively; ^d Judged by combination of history, clinical, and ultrasonographic examination and anti-thyroid antibodies; ^e p>0.05 is depicted in italic.

Overall, only a few papers studied the association between thyroid cancer and thyroid autoimmunity in FNAC specimens since 2012. The results reported by Castagna et al. clearly showed a crucial bias between FNAC and surgery. Surgery is in general performed when thyroid nodules are suspicious for malignancy. Suspicious/malignant cytology was indeed more frequent in patients with nodular autoimmune thyroiditis than those with other nodular diseases [26] and in nodules in patients with Hashimoto’ disease/Graves’ disease than those without autoimmune thyroid disease [12.8% (25/196) vs. 6.9% (23/332)] [27]. On the other hand, the possibility of low sensitivity of FNAC for diagnosis of Hashimoto’s thyroiditis and/or thyroid cancer cannot be completely excluded. Especially, follicular and Hürthle cell neoplasms cannot be accurately diagnosed by FNAC [3].

Incidence of thyroid cancer in patients with thyroid autoimmunity versus those without

Analysis was also done from a different perspective, that is, the incidence of PTC was compared between patients with/without thyroid autoimmunity ([Table 4]). The significant increases of PTC prevalence were demonstrated in patients with thyroid autoimmunity (judged by the presence of either lymphocyte infiltration or anti-thyroid antibodies) as compared to those without thyroid autoimmunity in all [6] [18] [28] [29] [30] but one [12] of the reports. In most of these studies, when thyroid autoimmunity was diagnosed – prior to or simultaneously with diagnosis of cancer – was unclear. In one retrospective but longitudinal study conducted by Cho et al. in Taiwan, ~1500 newly diagnosed Hashimoto’s patients (and ~6000 non-Hashimoto controls) were monitored to determine the incidence of developing cancer, which found 1.7-fold higher for thyroid cancer in Hashimoto’s patients than controls (1.58 vs. 0.14 per 1000 person-years). In addition, Hashimoto’s patients of older ages were at higher risk of developing thyroid cancers, particularly in the first 3 years after diagnosis of Hashimoto’s disease. It is clear that diagnosis of Hashimoto’s thyroiditis was made before that of thyroid cancer in this study, indicating a causative role for thyroid autoimmunity in thyroid cancer development [30]. In another study with ~900 Hashimoto’ cases operated in Johns Hopkins hospital, the most commonly associated condition was reported to be PTCs (followed by medullary thyroid cancers and Hürthle cell carcinomas) [31].

Table 4 Comparison of the prevalence of PTCs between patients with/without thyroid autoimmunity.

First author [ref.]	Prevalence of PTC [%, (number of patients/number of samples)]		p
Lymphocyte infiltration/ anti-thyroid antibodies	+	–
Boi [13]	60.3 (38/63)a	44.5 (57/128)a	0.04
	66.0 (66/100)b	52.7 (106/201)b	0.03
Konturek [28]	23.5 (106/452)a	7.5 (530/7093)a	<0.001
Zhang [29]	29.4 (247/839)a	19.4 (1488/7685)a	<0.05
Giagouta [12]	64.8 (441/681)	939/1523	0.16 d
Chen [30]	1.58c, 0.9 (14/1521)a	0.14c, 0.08 (5/6084)a	<0.001
Vasileiadis [18]	57. 9 (128/221)b	42.3 (261/615)b	<0.001
Graves’ disease	+	–
Boutzios [32]	33.7 (61/181)	5.7 (509/9007)	0.01
Medas [34]	20.6 (87/423)	34.3 (822/1576)	<0.01
Yeh [35]	1.23 (210/17 033)	1.02 (347/34 066)	<0.05

^a,b Judged by lymphocyte infiltration and anti-thyroid antibodies, respectively; ^c The incidence rates (per 1000 person-years); ^d p>0.05 is depicted in italic.

The prevalence of PTC was also higher in Graves’ disease than non-Graves’ thyroid diseases in operated subjects [32] [33] [34] [35].

Some critical biases also exist in the above mentioned studies. In the report by Chen et al., because of retrospective nature of this study, it is highly possible that there is a non-negligible bias that Hashimoto’ patients took more intense follow-up than control subjects as mentioned above, thereby resulting in earlier finding of thyroid cancer. Also the reasons for thyroidectomy in Hashimoto’s patients are not only cancer suspicion but also huge goiter, which likely increases a chance to find occult, subclinical micro-carcinomas.

Similar studies were done in indeterminate cytology patients [5] [6] [18]. However, the data are inconsistent as shown in [Table 5]. Thus, the prevalence of PTC was higher in thyroid autoimmunity-negative group in one study [13], and lower in other studies [5] [18].

Table 5 Comparison of the prevalence of PTC in indeterminate cytology with/without thyroid autoimmunity.

First author [ref.]	Prevalence of PTC [%, (number of patients/number of samples)]		p
	Thyroid autoimmunity-positive	Thyroid autoimmunity-negative
Boi [13]	5.0 (1/20)a	50.7 (34/67)a	<0.001
Vasileiadis [18]	33.3 (13/31)a	25.0 (23/92)a	0.3 c
	40.6 (13/31)b	22.3 (21/94)b	0.033
Karatzas [5]	49.2 (30/61)a	23.7 (31/133)a	<0.001

^a,b Thyroid autoimmunity positivity/negativity was judged by lymphocyte infiltration and anti-Tg antibodies, respectively; ^c p>0.05 is depicted in italic.

Cause-Effect Relationship

Several possible pathomechanisms for the association of thyroid cancer and thyroid autoimmunity were proposed [8]; (i) immunity is elicited towards pre-existing tumor cells leading to specific autoimmunity (tumor defense-induced autoimmunity), (ii) pre-existing autoimmunity leads to malignancy due to inflammation (inflammation-induced carcinoma), and also (iii) two diseases co-occur by common causes.

Immunity is elicited towards pre-existing tumor cells leading to specific autoimmunity

Cancers can elicit immune response by secreting several molecules such as cytokines and chemokines, which attract inflammatory/immune cells into tumor sites [6]. Immune system also recognizes tumor antigens, and induces anti-tumor immune response. Therefore, following successful surgical resection of cancer, immune response would theoretically weaken. Several reports show that this is the case [17] [36] [37] [38]. Among 23 patients in whom TPO antibody titers could be monitored after surgery and radiotherapy, the titers decreased in all patients with an exception who kept high titers and experienced recurrence [17]. Similarly, anti-Tg antibody titers gradually decreased in the majority (84%, 42 out of 50) of thyroid cancer patients who attained remission after treatment and became completely negative [36]. Durante et al. also found that early post-treatment normalization of anti-Tg antibody titers was negatively associated with a persistent/recurrent disease rate [37]. However, these data rather indicate that declines in anti-thyroid antibody titers means complete ablation of the thyroid glands, because decreases of anti-TSH receptor antibodies are well known phenomena in Graves’ disease following successful ablation of the thyroid glands by subtotal/total thyroidectomy or radiotherapy [39] [40]. However, the fact that rising/de novo appearance of anti-Tg antibodies suggest disease recurrence [41] means induction of anti-Tg antibodies by reaction of immune system to tumor antigens.

Some papers discussed about this issue from a point of epitope repertoire. Fiore et al. summarized their data on Tg epitopes to anti-Tg antibodies, showing that the epitopes on Tg molecules to anti-Tg antibodies are more diverse in Hashimoto’ patients with PTC than those without PTC, which suggests that two different autoimmune mechanisms may be involved in lymphocyte infiltration in PTC; one is typical of AITD and the other is typical of immune reaction to PTC [42]. Lupoli et al. also reported the qualitative difference in Tg epitopes between differentiated thyroid cancers with and without recurrent disease. Thus the former recognizes the immune-dominant Tg epitope clusters (I, III, and IV), while the latter non-specific, non-immune-dominant Tg epitopes [43]. These data clearly demonstrate that generation of autoantibodies in thyroid cancer patients is very likely to be reactive against cancers. Thus, anti-thyroid antibodies may be an indication for a more active immune system [44].

It remains unclear why immune reaction can be elicited against PTC but not other types of thyroid cancers.

Pre-existing autoimmunity leads to malignancy due to inflammation (inflammation-induced carcinoma)

Thyroid autoimmunity sometimes leads to hypothyroidism with elevated serum TSH. It has long been well known that the risk of thyroid cancer increases with increasing concentrations of serum TSH levels, even within normal ranges [42]. Indeed many papers quoted above reported that both thyroid autoimmunity and TSH are independent risk factors for malignancy in thyroid nodules [10] [13] [14] [15] [16] [18] [19] [21] [22].

Furthermore, the inflammatory response may create a favorable setting for malignant transformation by causing DNA damage through reactive oxygen species formation [3], as well known for other cancers. However, there is no direct evidence to support this idea in thyroid cancer.

Clear causal relationship is found between Hashimoto’ thyroiditis and primary thyroid lymphoma [45] [46]. Thus, it is reported that the prevalence of Hashimoto’s thyroiditis in patients with primary thyroid lymphoma is almost 100%, lymphoma develops after 3 to 18 year-Hashimoto’s history, and the risk of Hashimoto’ patients to develop primary thyroid lymphoma is 40 to 80 times greater than that of the general population.

Two diseases co-occur by common causes

Benvenga et al. published a review paper regarding environmental factors such as air pollution and endocrine-disrupting chemicals as a common cause for thyroid autoimmunity and thyroid cancer [47], but this concept has not yet fully substantiated.

Is Thyroid Autoimmunity Beneficial for or Harmful Against Thyroid Cancer?

Thyroid cancer patients with thyroid autoimmunity were generally younger with female dominance, had smaller tumors, less distant metastasis, and favorable TNM stages than those without ([Table 6]). However, the data on extrathyroidal invasion, lymph node metastasis and prognosis were inconsistent. Some reports showed less extrathyroidal invasion [12] [22] [29] [48] [49] [50], but others more [7] [19] [51] in PTCs with thyroid autoimmunity. Similarly, some showed less lymph node metastasis [12] [29] [36] [48] [51] [52], but others more [16] [18] [28] [53] [54].

Table 6 Analysis of characteristics for PTCs co-occurrence with thyroid autoimmunity versus PTCs without thyroid autoimmunity.

First author [ref.]	Markers	Age	Sex (male)	Tumor size	Invasion	Lymph node metastasis	Distant metastasis	TNM	Prognosis
Thyroid autoimmunity (lymphocyte infiltration and/or positive anti-thyroid antibodies)
Yoon [48]	LIa	younger	↓	↓	↓	↓	N.A.	N.A.	N.A.
Jeong [49]	LI	younger	↓	↓	↓	→	N.A.	→	↑
Ye [10]	LI	→	↓	→	→	→	→	→	N.A.
Lun [14]	ATAbb	younger	↓	↓	N.A.	→	N.A.	↓	N.A.
Zhang [11]	LI	→	↓	→	N.A.	→	N.A.	→	N.A.
Wu [16]	ATAb	→	↓	↑	N.A.	↑	N.A.	N.A.	N.A.
Vasileiadis [18]	LI	→	→	→	→	↑	N.A.	N.A.	N.A.
Giagouta [12]	LI	younger	→	↓	↓	↓	↓	↓	N.A.
Durante [37]	TgAb	→	→	↓	↑	→	→	N.A.	↓
Qin [19]	TPOAb	younger	→	→	→	→	N.A.	→	N.A.
	TgAb	→	↓	→	↑	→	N.A.	→	N.A.
Konturek [28]	TPOAb	N.A.	N.A.	↓	N.A.	↑	N.A.	N.A.	N.A.
Dvorkin [36]	LI or ATAb	→	↓	↓	→	↓	→	N.A.	↑
Zhang [29]	LI	younger	↓	↓	↓	↓ (lateral LN)	N.A.	↓	N.A.
Hacihamdioglu [24]	LI or ATAb	older	↓	↓	→	→	→	N.A.	→
Iliadou [7]	LI	→	→	→	↑	→	→		→
Girardi [50]	LI	→	↓	↓	→	→	→	↓	N.A.
Zhu [51]	LI	→	↓	→	↑	↓ (central LN)	N.A.	N.A.	N.A.
Shen [53]	ATAb	younger	↓	→	N.A.	↑	↓	→	N.A.
Ieni [52]	LI	younger	↓	↓	N.A.	↓	N.A.	↓	N.A.
Selek [22]	LI, ATAb	→	↓	↓	↓	→	↓	↓	N.A.
Jo [54]	TgAb		→	↓	→	→	↑	N.A.	N.A.
Graves’ disease
Pellegriti [55]	THc, 131I- uptake	→	→	→	N.A.	→	→	→	↓
Medas [34]	TH	→	→	→	→	↑	N.A.	N.D.	↓

N.A.: Not assessed; N.D.: Not determined; ^a Lymphcote infiltration; ^b Anti-thyroid antibodies; ^c Thyroid hormones.

Regarding distant metastasis, Shen et al. reported more cervical lymph node metastasis but less distant metastasis in anti-Tg-antibody positive group [53], suggesting that the positive anti-Tg antibody status could be a risk factor for metastatic cervical lymph nodes but a protective factor for distant metastasis. Jo et al. also concluded that positive anti-Tg antibodies, even without anti-TPO antibodies nor lymphocyte infiltration, are associated with worse primary tumor characteristics (higher rates of lymphatic invasion and lymph node metastasis) but rarely show poor prognosis [54]. They speculated that this might be attributed to more aggressive treatment of these patients.

Jeong et al. and Dvorkin et al. showed better prognosis, but Durante and his colleagues had worse prognosis in thyroid cancer patients with thyroid autoimmunity than those without [36] [37] [49]. Pellegriti et al. and Medas et al. found poorer prognosis in thyroid cancer patients complicated with Graves’ disease than those not complicated [34] [55]. This is likely due to the presence of thyroid stimulating antibodies, a mimic of thyroid growth stimulator TSH, in Graves’s sera. Indeed a higher local lymph node metastasis rate was also noted in one of the latter papers [34]. Incidental micro-PTC patients with Graves’ disease are younger than those with euthyroid goiter, suggesting an increased risk for micro-PTC in Graves’ patients [56].

The data implying a protective effect of anti-TPO antibodies on thyroid cancer progression are reported; progression to TNM stage 4 only in patients with thyroid cancers and no anti-TPO antibodies (4/67, 6%) [17], and a higher relative risk for thyroid cancers in Hashimoto’s patients with low-negative anti-TPO antibodies as compared to those with positive TPO antibodies [57]. Anti-TPO antibodies may exert their anti-cancer effect by complement-mediated cell death and/or antibody-dependent cell-mediated cytotoxicity [13].

Whether infiltrative lymphocytes are beneficial (anti-tumorigenic or protective) or harmful (pro-tumorigenic) in thyroid cancer patients may depend on their phenotypes. The presence of lymphocyte infiltration, such as T cells, B cells, macrophages, Th17 cells, NK cells, CD83⁺ mature and activated dendritic cells (DCs) is related with a better prognosis in patients with differentiated thyroid cancer, while infiltration of programmed death-1⁺ T cells, CD25⁺ regulatory T cells [58], plasmacytoid DCs [59] and double-negative T cells [60] and macrophages with M2 phenotype [61] seem to be a marker for poor prognosis. CD25⁺ regulatory T cells are well known to negatively regulate immune response and their frequency increases with PTC aggressiveness, and conversion of naïve T cells to regulatory T cells is facilitated by plasmacytoid DCs [8]. Thus, it can be mentioned that immune response plays a protective role in some patients, but, promotes cancer development and progression in other patients, explaining the inconsistent data on the influence of thyroid autoimmunity on cancer characteristics and progression.

Relationship between Hashimoto’s disease and RET-PTC chromosome translocation in PTC has long been discussed [6] [62]. PTC with BRAF^V600E, another important driver mutation in PTC, has been well known to be more aggressive than PTC without the mutation [63] [64]. In contrast to RET-PTC which is frequently associated with Hashimoto’s thyroiditis, several studies show that the presence of BRAF^V600E is negatively associated with lymphocyte infiltration, and is protective for aggressiveness of PTC [62] [65] [66] [67].

Discussion

Here this review has summarized papers, which studied the relationship between thyroid autoimmunity and thyroid cancer, especially PTC, published between 2012 and early 2018. The association between these two conditions, analyzed in two different ways – (i) the prevalence of thyroid autoimmunity in thyroid cancer versus benign nodules and (ii) the prevalence of thyroid cancer in patients with thyroid autoimmunity versus those without, summarized in the sections II, was largely significant when analyzed with surgical specimens, but not always so with FNAC samples. There are numerous biases that should be taken into account when interpret all these data. Main biases include, on the one hand, selection of patients for thyroidectomy in surgical specimens and, on the other hand, lower diagnostic accuracy of FNAC. However, the significance in an increase of the prevalence of thyroid autoimmunity in PTC as compared to other types of thyroid cancer is likely meaningful. Resnde de Paiva et al. recently published a systematic review regarding the association between thyroid cancer and Hashimoto’s thyroiditis with 36 studies published between 1955 and 2016 [9]. Although the data obtained with surgery and FNAC were mixed up, they found the statistically significant association between two conditions in PTC, not in FTC or MTC. There seems to be no, or if any only a little, bias for selection of patients for thyroidectomy of PTC or other types of thyroid cancer.

Given the significant association between thyroid autoimmunity and thyroid cancer, rising/appearance of anti-thyroid antibodies after cancer recurrence and differences in epitope repertoire of anti-Tg antibodies between Hashimoto’s patients and PTC patients support “tumor defense-induced autoimmunity” theory (see, section III). By contrast, it is clear that Hashimoto’ disease is the precedent pathology in primary thyroid lymphoma. Regarding “inflammation-induced carcinoma” theory, no definitive data exist to support this theory, although elevated serum TSH levels (even within the normal reference ranges), which are often observed in Hashimoto’s patients are a well-known risk factor for thyroid cancer,.

The data summarized in section IV indicate that thyroid autoimmunity does not appear to substantially affect the characteristics and prognosis of thyroid cancer, or its effect may be dependent on types of lymphocytes infiltrated into the thyroid gland. Although the data are so variable, the presence of thyroid autoimmunity tends to confer favorable characteristics such as smaller tumors, less distant metastasis and lower TNM stages, but not less extrathyroidal invasion or lymph node metastasis, or better prognosis, to PTCs.

In conclusion, I would like to conclude that the association between thyroid autoimmunity and PTC appear to be significant (from the data on section II), and immune response is likely elicited towards tumor antigens in PTC patients, which are shared with normal thyroid tissues thereby inducing specific thyroid autoimmunity (section III). However, there is no definitive data showing how the co-existence of thyroid autoimmunity impacts on cancer characteristics and prognosis (section IV). To draw a definitive conclusion, prospective and long-term follow-up studies with a large number of normal subjects and Hashimoto’ patients are definitely necessary.

Conflict of Interest

The authors declare that they have no conflict of interest.

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