In this large-sample study, 409 PTC patients had HTN, the high incidence (14.41%) indicating that more attention should be paid to the outcomes of this population. The tumors in the HTN group tended to be larger and exhibit lymph node metastasis, especially in the male patients aged over 40 years, who were also more liable to have capsule invasion. In terms of the use of antihypertensive agents, diverse therapy (CCB, ACEi/ARB, and CCB + ACEi/ARB) appears to exert little to no effect on the pathological characteristics in PTC patients with HTN.
Our study revealed a positive association between HTN and the tumor size (OR = 1.51, 95% CI: 1.10–2.07) and lymph node metastasis (OR = 1.43, 95% CI: 1.02–1.99) (Fig. 1). These results suggest that HTN could be associated with the invasive features of cancers, which has also been confirmed in a number of prior studies. For instance, Kocher et al. [17] concluded that HTN, as the only component of metabolic syndrome in kidney cancer, is associated with increased tumor size (p = 0.03) and a higher tumor grade (p = 0.04). With regard to gastric cancer, Li et al. [18] found HTN patients to more frequently reach the advanced T stage (p = 0.022) and TNM stage (p = 0.017). A meta-analysis demonstrated HTN was the primary contributor to the risk of prostate cancer and suggested poor oncologic outcomes due to the aggressive tumor features and biochemical recurrence [19].
IR gives rise to high circulating insulin and insulin-like growth factor (IGF) levels, thereby forming a favorable setting for various dysmetabolic conditions that result in a worse prognosis with regard to TC, such as increased TSH levels, rising vascularization, iodine deficiency, and chronic autoimmune thyroiditis. [20] The insulin receptors and IGF receptors have been found to exhibit increased expression in patients with PTC [21]. Evidence has shown a high homeostasis model of IR assessment to be associated with both multifocality and tumor size in patients with PTC [22, 23]. Our study detected that PTC patients with HTN were more likely to have diabetes (13.20% vs 3.01%). It may partly explain the prevalence of advanced features in this population. Another reliable explanation concerns the importance of the RAS in relation to cancer progression, in addition to its role in BP regulation. The reactions of the RAS are regulated by the angiotensin-converting enzymes (ACE and ACE2), which respectively yield Angiotensin II (Ang II), the powerful vasoconstrictor and cell proliferator, and its rival Ang-(1–7). It is worth noting the low level of ACE2 found in larger thyroid tumors and samples generating distant metastases [24]. The Ang II receptor subtype 1 (AT1) has been proven to overexpress in patients with TC as well as to promote the production of vascular endothelial growth factors, which increases tumor angiogenesis [25]. Their binding triggers cell proliferation through the activation of two cellular pathways, mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathway, and also upregulates the expression of ICAM1, adhesion molecule-1, and selectin, which are involved in tumor metastasis and invasion. [10] The tumor size has been found to be reduced following treatments with AT1 antagonists, which supports the role of AT1 in the tumor course [25].
Gender differences in the pathologic features of hypertension in PTC patients showed a better prognosis in these older females (Fig. 2). Estrogen, particularly estradiol (E2), may play a crucial role in these results. E2 regulates the metabolism, mainly via estrogen receptor α (ERα), estrogen receptor β (ERβ), and a small number of membrane-associated receptors (mER) [26]. ERα stimulates the proliferation of tumor cells, while ERβ inhibits their growth and induces apoptosis. The binding of E2 and mER synergistically activates MAPK (BRAF mutation-related) and PI3K signaling pathways (RET/PTC rearrangement-related) [26]. For PTC patients of reproductive age, the level of ERα is higher than that seen in age-matched patients with benign nodules. However, the opposite is true with regard to ERβ expression [27].
In addition, E2 could regulate the volume and activity of most components of the RAS, thereby revealing the RAS to exist in an inhibitory state. For example, E2 activates ACE2 and promotes the protective effects of Ang-(1–7). The expression of AT1 is higher in males than in females, although the opposite is true of AT2 [28]. Previous studies have shown that older age at the onset of menopause is related to an increased risk of PTC [29]. HTN, partly due to the lower E2 levels, could slow down tumor growth in older women with PTC, thereby avoiding the invasive features of cancer. Thus, the interaction between E2 and the RAS potentially leads to gender disparities in terms of the aggressive features of PTC seen in older patients with HTN.
This study further explored the influence of antihypertensive medications on PTC and determined that there was no significant difference in the pathological features of PTC among the group CCB, ACEi/ARB, and CCB + ACEi/ARB (Table 4). Group ACEi/ARB and CCB + ACEi/ARB, however, was made up mostly of older men (age > 40). Therefore, we conducted multivariate analysis and found that patients taking ACEi/ARB were more likely to have bilateral tumors than those taking CCB, while there was no statistically significant difference between CCB and CCB + ACEi group (Table 5). Only a few prior studies have confirmed the role of the calcium ion channels in tumor cell proliferation, cell migration, tissue invasion, and vascularization.[30] Although ACEi/ARB inhibits RAS, we speculate that CCB use may contribute more to limit the aggressiveness of PTC while lowering the BP by blocking the relative channels.
Table 4
Clinicopathological comparison of patients treated with different antihypertensive therapy
Characteristics | CCB | ACEi/ARB | CCB + ACEi/ARB | p |
Sex | | | | < 0.001***† |
Male | 15 (13.64) | 23(54.76) | 29 (69.05) | < 0.001***‡ 0.014*§ |
Female | 95 (86.36) | 19 (45.24) | 13 (30.95) |
Age | | | | 0.33 |
≤ 40 | 2 (1.82) | 2(4.76) | 2 (4.76) | |
> 40 | 108 (98.18) | 40 (95.24) | 40 (95.24) |
Tumor size (cm) | 1.06 ± 0.96 | 0.95 ± 0.57 | 1.06 ± 0.68 | 0.20 |
< 1cm | 70 (63.64) | 25 (59.52) | 20 (47.62) | |
≥ 1cm | 40 (36.36) | 17(40.48) | 22 (52.38) | |
Lymph node metastasis | | | | 0.17 |
No | 78 (70.90) | 28 (66.70) | 23 (54.80) | |
Yes | 32 (29.10) | 14 (33.30) | 19 (45.20) |
AJCC stage | | | | 0.72 |
I | 73 (66.36) | 28 (66.67) | 23 (54.76) | |
II | 33 (33.00) | 13 (30.95) | 17 (40.48) | |
III | 4(3.64) | 1 (2.38) | 2 (4.76) | |
Multifocal tumor | | | | 0.81 |
No | 74 (67.27) | 26 (61.90) | 27 (64.29) | |
Yes | 36 (32.73) | 16 (38.10) | 15 (35.71) |
Capsule invasion | | | | 0.22 |
No | 36 (32.73) | 8 (19.05) | 14 (33.33) | |
Yes | 74 (62.27) | 34 (80.95) | 28 (66.67) |
Bilaterality | | | | 0.34 |
No | 86 (78.18) | 28 (66.67) | 31 (73.81) | |
Yes | 24 (21.82) | 14 (33.33) | 11 (26.19) |
Extrathyroid invasion | | | | 1.00 |
No | 105 (95.45) | 40 (95.24) | 40 (95.24) | |
Yes | 5 (4.55) | 2 (4.76) | 2 (4.76) | |
TSH (µIU/mL) | 2.06 ± 1.23 | 2.32 ± 2.50 | 2.35 ± 1.76 | 0.93 |
†the p value was 0.18 compared ACEi and CCB + ACEi/ARB. |
‡Comparison between group CCB and ACEi/ARB; |
§Comparison between group CCB and CCB + ACEi/ARB; |
Table 5
Effect of different antihypertension therapy on pathological features of PTC
Characteristics | ACEi/ARB | CCB + ACEi/ARB |
Adjusted-OR | p | Adjusted-OR | p |
Tumor size (≥ 1cm) | 1.29 (0.43–3.85) | 0.64 | 2.29 (0.81–6.50) | 0.12 |
Lymph node metastasis | 1.50 (0.49–4.58) | 0.47 | 2.06 (0.72–5.90) | 0.18 |
Multifocal tumor | 1.42 (0.48–4.19) | 0.52 | 0.62 (0.19–1.97) | 0.41 |
Bilaterality | 3.82 (1.13–12.98) | 0.03* | 1.32 (0.34–5.08) | 0.69 |
Capsule invasion | 1.70 (0.51–5.65) | 0.39 | 0.39 (0.14–1.10) | 0.08 |
Extrathyroid invasion | 2.14 (0.17–27.02) | 0.56 | N/A | 1.00 |
AJCC stage | N/A | 1.00 | N/A | 1.00 |
N/A: not applicable |
Although this study was conducted among a large cohort, it is important to recognize that it did have a number of limitations. By design, the patients included in this study were diagnosed with PTC at our center during a three-year period, which meant that their follow-up time was too short to further analyze the impact of HTN on their outcomes. The lack of more HTN-related data, particularly concerning latent factors such as the duration and dosage of antihypertensive drugs and controlled BP values, represents a noticeable limitation of this study, which should be remedied by future studies. The present study was a single-center retrospective study, although the profound implications of the findings justify future multicenter studies.