World J Oncol

World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access

Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc

Journal website https://www.wjon.org

Review

Volume 15, Number 1, February 2024, pages 14-27

Autoimmune Thyroid Disease and Differentiated Thyroid Carcinoma: A Review of the Mechanisms That Explain an Intriguing and Exciting Relationship

Figure 2. Histopathological findings in a total thyroidectomy specimen from an individual with GBD and PTC. On the upper left side (blue circle), thyroid follicles of different sizes are observed, lined by predominantly cuboidal follicular cells, with little colloid inside, pale pink in color and slightly scalloped (characteristic of GBD). In the central part (yellow circle), lighter thyroid cells are observed, with ground glass nuclei, which form microfollicles or are loose, invading the stroma, with mild fibrosis partially delimiting the lesion (corresponding to PTC); there is little interstitial lymphocytic infiltrate which predominates on the right side of the image (× 40, stained with hematoxylin and eosin). GBD: Graves-Basedow disease; PTC: papillary thyroid carcinoma.

Figure 3. Molecular mechanisms most frequently associated between GBD and DTC. GBD: Graves-Basedow disease; DTC: differentiated thyroid carcinoma; TRAb: thyroid receptor antibody.

Figure 4. Molecular mechanisms most frequently associated between HT and DTC. HT: Hashimoto’s thyroiditis; DTC: differentiated thyroid carcinoma; TSH: thyrotropin.

Figure 5. Histopathological findings in a total thyroidectomy specimen from an individual with HT and PTC. Histopathological section of total thyroidectomy in a patient with HT and PTC, showing an intense lymphocytic infiltrate that forms lymphoid follicles of different sizes. In the midst of this infiltrate some thyroid follicles (predominantly small) with colloid inside have been trapped. In the blue circle, neoplastic thyroid cells are observed, with a ground-glass-shaped nucleus, with scant cytoplasm, arranged in a disorganized pattern and without a capsule, corresponding to PTC (× 10, stained with hematoxylin and eosin). HT: Hashimoto’s thyroiditis; PTC: papillary thyroid carcinoma.

**Table 1.** Risk of DTC According to Different Definitions of Hyperthyroidism (Including Graves-Basedow Disease)
Causes of hyperthyroidism	Measure of association (SIR) and risk of DTC	95% CI
^aMeta-analysis. ^bStudies that found significant results. CI: confidence interval; DTC: differentiated thyroid carcinoma; HR: hazard ratio; SIR: standardized incidence ratio.
Unspecified toxic nodular goitre	0.46	0.12 - 1.82
	1.17	0.42 - 3.21
	0.09^b	0.03 - 0.3^b
	0.65	0.19 - 2.22
Toxic uninodular goitre	0.38	0.08 - 1.91
	2.93	0.34 - 25.15
	5.85	0.6 - 57
	0.74	0.1 - 5.66
	0.65	0.19 - 2.21
	2.71	0.15 - 49.54
	1.26	0.44 - 3.57
	0.23	0.05 - 1.16
	0.62	0.06 - 6.07
	1.3	0.52 - 3.29
Toxic multinodular goitre	0.35	0.06 - 1.91
	1.7	0.4 - 7.2
	0.96	0.12 - 7.55
	1.23	0.21 - 7.04
	0.74	0.28 - 1.95
	1.4	0.15 - 13.44
	1.67	0.62 - 4.51
	3.25	0.44 - 23.9
	0.94	0.1 - 8.56
	1.66	0.69 - 3.97
Toxic nodules	3.94 (overall)^b	2.57 - 5.77^b
	4.87 (men)	0.59 - 17.6
	3.88 (women)^b	2.48 - 5.77^b
TSH levels below the normal range	2.65 (overall)^b	1.27 - 5.52^b
	1.07 (men)	0.25 - 4.62
	3.74 (women)^b	1.53 - 9.19^b
Graves-Basedow disease^a	1.0	0.68 - 1.46
Graves-Basedow disease^a	0.89	0.63 - 1.26
Graves-Basedow disease^a	5.3^b	2.4 - 11.6^b
Graves-Basedow disease	2.67	1.00 - 7.18
Graves-Basedow disease	3.77 (overall)^b	2.94 - 4.75^b
	5.84 (men)^b	2.52 - 11.5^b
	3.61 (women)^b	2.77 - 4.61^b
Graves-Basedow disease	HR: 2.98 (men)^b	1.08 - 8.19^b
	HR: 1.60 (women)^b	1.11 - 2.31^b
Hyperthyroidism (global)	HR: 6.80^b	3.584 - 12.91^b

Table 1. Risk of DTC According to Different Definitions of Hyperthyroidism (Including Graves-Basedow Disease)

Causes of hyperthyroidism

Measure of association (SIR) and risk of DTC

95% CI

^aMeta-analysis. ^bStudies that found significant results. CI: confidence interval; DTC: differentiated thyroid carcinoma; HR: hazard ratio; SIR: standardized incidence ratio.

Unspecified toxic nodular goitre

0.46

0.12 - 1.82

1.17

0.42 - 3.21

0.09^b

0.03 - 0.3^b

0.65

0.19 - 2.22

Toxic uninodular goitre

0.38

0.08 - 1.91

2.93

0.34 - 25.15

5.85

0.6 - 57

0.74

0.1 - 5.66

0.65

0.19 - 2.21

2.71

0.15 - 49.54

1.26

0.44 - 3.57

0.23

0.05 - 1.16

0.62

0.06 - 6.07

1.3

0.52 - 3.29

Toxic multinodular goitre

0.35

0.06 - 1.91

1.7

0.4 - 7.2

0.96

0.12 - 7.55

1.23

0.21 - 7.04

0.74

0.28 - 1.95

1.4

0.15 - 13.44

1.67

0.62 - 4.51

3.25

0.44 - 23.9

0.94

0.1 - 8.56

1.66

0.69 - 3.97

Toxic nodules

3.94 (overall)^b

2.57 - 5.77^b

4.87 (men)

0.59 - 17.6

3.88 (women)^b

2.48 - 5.77^b

TSH levels below the normal range

2.65 (overall)^b

1.27 - 5.52^b

1.07 (men)

0.25 - 4.62

3.74 (women)^b

1.53 - 9.19^b

Graves-Basedow disease^a

1.0

0.68 - 1.46

Graves-Basedow disease^a

0.89

0.63 - 1.26

Graves-Basedow disease^a

5.3^b

2.4 - 11.6^b

Graves-Basedow disease

2.67

1.00 - 7.18

Graves-Basedow disease

3.77 (overall)^b

2.94 - 4.75^b

5.84 (men)^b

2.52 - 11.5^b

3.61 (women)^b

2.77 - 4.61^b

Graves-Basedow disease

HR: 2.98 (men)^b

1.08 - 8.19^b

HR: 1.60 (women)^b

1.11 - 2.31^b

Hyperthyroidism (global)

HR: 6.80^b

3.584 - 12.91^b

**Table 2.** Risk of DTC in Patients With HT
Causes of hypothyroidism	Measures of association (SIR) and risk of DTC	95% CI
^aMeta-analysis. ^bStudies that found significant results. CI: confidence interval; CLT: chronic lymphocytic thyroiditis; DTC: differentiated thyroid carcinoma; FTC: follicular thyroid carcinoma; PTC: papillary thyroid carcinoma; SIR: standardized incidence ratio; HT: Hashimoto’s thyroiditis.
Studies in patients with Hashimoto’s thyroiditis	1.93^b	1.6 - 2.34^b
	2.24^b	1.22 - 4.11^b
	4.16^b	2.87 - 6.04^b
	3.02^b	1.94 - 4.69^b
	1.64^b	1.38 - 1.95^b
	1.34	0.96 - 1.85
	1.56	0.68 - 3.58
	1.80^b	1.53 - 2.11^b
	0.99	0.65 - 1.50
	1.57^b	1.38 - 1.78^b
	2.33	0.92 - 5.92
	1.39^b	1.26 - 1.52^b
	2.52	0.36 - 17.81
	1.58^b	1.45 - 1.71^b
	0.40	0.09 - 1.70
	1.44	0.97 - 2.13
	1.16	0.74 - 1.82
	11.8^b	4.24 - 33.1^b
	2.76^{a, b}	1.95 - 3.92^b
	1.49^{a, b}	1.42 - 1.57^b
	1.65 (for PTC)^b and 0.73 (for FTC)^a	1.04 - 2.61^b and 0.41 - 1.27 (respectively)
	1.83^{a, b} (for CLT (+) vs. CLT (-))	1.51 - 2.21^b

Table 2. Risk of DTC in Patients With HT

Causes of hypothyroidism

Measures of association (SIR) and risk of DTC

95% CI

^aMeta-analysis. ^bStudies that found significant results. CI: confidence interval; CLT: chronic lymphocytic thyroiditis; DTC: differentiated thyroid carcinoma; FTC: follicular thyroid carcinoma; PTC: papillary thyroid carcinoma; SIR: standardized incidence ratio; HT: Hashimoto’s thyroiditis.

Studies in patients with Hashimoto’s thyroiditis

1.93^b

1.6 - 2.34^b

2.24^b

1.22 - 4.11^b

4.16^b

2.87 - 6.04^b

3.02^b

1.94 - 4.69^b

1.64^b

1.38 - 1.95^b

1.34

0.96 - 1.85

1.56

0.68 - 3.58

1.80^b

1.53 - 2.11^b

0.99

0.65 - 1.50

1.57^b

1.38 - 1.78^b

2.33

0.92 - 5.92

1.39^b

1.26 - 1.52^b

2.52

0.36 - 17.81

1.58^b

1.45 - 1.71^b

0.40

0.09 - 1.70

1.44

0.97 - 2.13

1.16

0.74 - 1.82

11.8^b

4.24 - 33.1^b

2.76^{a, b}

1.95 - 3.92^b

1.49^{a, b}

1.42 - 1.57^b

1.65 (for PTC)^b and 0.73 (for FTC)^a

1.04 - 2.61^b and 0.41 - 1.27 (respectively)

1.83^{a, b} (for CLT (+) vs. CLT (-))

1.51 - 2.21^b

**Table 3.** Summary of Genetic Alterations in HT and TC
Genetic alterations	Outcomes in AITD and DTC
HT: Hashimoto’s thyroiditis; TC: thyroid cancer; AITD: autoimmune thyroid disease; DTC: differentiated thyroid carcinoma; PTC: papillary thyroid carcinoma.
RET/PTC rearrangements	In experimental models in mice, designed to express RET/PTC, they more frequently develop thyroid hyperplasia, solid tumor variants of PTC and metastatic cancer and findings of chronic thyroiditis. In individuals who were exposed to radiation in the Chernobyl disaster and who had a diagnosis of HT, they more frequently developed RET/PTC-induced PTC. Between 3-60% of patients with PTC and around 90% of individuals with HT have this genetic alteration.
p63 protein	It is commonly expressed in PTC and in HT.
BRAFV600E	BRAFV600E mutation is less frequent in individuals where HT coexists with PTC.
PI3K/Akt pathway	Elevated expression of PI3K/Akt in individuals with HT and DTC.

Table 3. Summary of Genetic Alterations in HT and TC

Genetic alterations

Outcomes in AITD and DTC

HT: Hashimoto’s thyroiditis; TC: thyroid cancer; AITD: autoimmune thyroid disease; DTC: differentiated thyroid carcinoma; PTC: papillary thyroid carcinoma.

RET/PTC rearrangements

In experimental models in mice, designed to express RET/PTC, they more frequently develop thyroid hyperplasia, solid tumor variants of PTC and metastatic cancer and findings of chronic thyroiditis. In individuals who were exposed to radiation in the Chernobyl disaster and who had a diagnosis of HT, they more frequently developed RET/PTC-induced PTC. Between 3-60% of patients with PTC and around 90% of individuals with HT have this genetic alteration.

p63 protein

It is commonly expressed in PTC and in HT.

BRAFV600E

BRAFV600E mutation is less frequent in individuals where HT coexists with PTC.

PI3K/Akt pathway

Elevated expression of PI3K/Akt in individuals with HT and DTC.