Papillary thyroid carcinoma and primary aldosteronism: A new syndrome or a mere association?

Abstract

Primary aldosteronism (PA) is a common disorder, and the condition is underdiagnosed; the prevalence could reach one-third in patients with hypertension, and thyroid carcinoma is the second most common cancer, with papillary thyroid carcinoma (PTC) accounting for 90% of cases. Lymph node metastasis is common in PTC. However, pressure symptoms, including invasion of major local veins and the vagus nerve, are extremely rare. The association between primary hyperaldosteronism and PTC is rare. The interaction between genetic and environmental factors could explain the association. Whether the coexistence of PTC and PA influences the prognosis of PTC is to be explained. The association between PTC and PA with contralateral metastasis, vagus nerve involvement, and invasion to the internal jugular vein is extremely rare. We conducted a comprehensive literature search for relevant articles addressing the possible association of PA and PTC, and we found only 17 cases reported in the literature. The majority were women (10:6 with one study not reporting the gender), the ages ranged from 48 years to 77 years, and perioperative diagnosis was possible in 8 cases. Physicians might need to screen patients with PTC and local invasion for PA.

Key Words: Papillary thyroid carcinoma; Primary aldosteronism; Contralateral metastasis; Vagus nerve; Internal jugular vein; Invasion

Core Tip: Papillary thyroid carcinoma (PTC) and primary aldosteronism are common endocrine disorders. However, their coexistence in the same patient is rare. Local invasion of PTC, including invasion of major local veins and vagus nerve, is extremely rare. This manuscript reviewed the available literature regarding the possible association of PTC and primary aldosteronism and discussed the extremely rare contralateral metastasis and local invasion of PTC to the vagus nerve and internal jugular vein. Our manuscript gave a broader insight into the coexistence of two common endocrine disorders and discussed the risk factors for their association.

INTRODUCTION

Primary aldosteronism (PA) is a common disorder with a prevalence of 9.4% worldwide; males, low-middle income countries, and South-East Asian are more commonly affected[1]. The prevalence of PA in hypertensive patients might be 3-fold the detected rate because of the autonomous aldosterone production in a significant proportion of patients with primary hypertension that is not suppressible with dietary sodium loading[2]. Importantly, patients with PA had higher rates of coronary artery disease, stroke, and atrial fibrillation compared to essential hypertension[1]. Furthermore, PA is associated with diabetes, metabolic syndrome, and left ventricular hypertrophy[3]. There are two main causes: Conn’s adenoma (70%) and bilateral adrenal hyperplasia (30%). Despite the association with target organ damage, the screening for PA is low, resulting in a high rate of morbidity and mortality[4]. PA is associated with psychopathology, sleep quality, and impaired quality of life, all of which improved following treatment[5]. PA is a common cause of high blood pressure with a broad spectrum from subtle to florid hypertension. It could present with a single focus, multiple foci, or diffuse. The disease is associated with renal damage and high mortality.

Despite the above, only 2% of high-risk patients are screened and do not receive the appropriate therapy[6]. The discovery of somatic mutations responsible for aldosterone production in aldosterone-producing adenomas and possibly for bilateral or idiopathic hyperaldosteronism, and germline mutations in familial PA, substantially improved the understanding of PA[2]. Previous recommendations for the diagnosis of PA are limited by a lack of details for use in clinical practice. In addition, different laboratories used different cut-off values for plasma renin activity, and adrenal venous sampling is not uniform (sequential/simultaneous, with cosyntropin or not)[7,8]. Moreover, many physicians are not adherent to the recommendations of holding the antihypertensive medications for 4 weeks before testing and screening of 50%-100% of patients with hypertension[9].

Screening is recommended for patients with hypokalemia, resistant/persistent hypertension, age ≤ 40 years, history of PA in the first-degree relatives, hypertension with (target organ damage, concurrent adrenal incidentaloma, obstructive sleep apnea, unexplained atrial fibrillation, anxiety, and other psychosomatic pathology[10]. There is an increasing concern about the association of PA with various malignancies. Lang et al[11] reported that 35.5% of patients with PA are diagnosed with malignancy at any time; some of them had more than one malignancy. The high cancer rate in PA could be explained by oxidative stress, upregulation of the renin-angiotensin system, and high aldosterone levels[12-14]. The prevalence of malignancy was 9.6% in patients with PA compared to 6% in their counterparts without the disease. Maciel et al[15] reported higher renal cell carcinoma, colon cancer, breast cancer, and other neuroendocrine malignancies in patients with PA and papillary thyroid carcinoma (PTC) compared to their counterparts without PTC. However, literature about the association of PA with PTC is scarce. Maciel et al[15] in their recent case-control study found a prevalence of 29.20%, 95% confidence interval: 21.9%-37% in patients with PTC compared to 20.44%, 95% confidence interval: 14.22%-28.35% in control subjects without PTC. Importantly, the prevalence of stage 11 and 111 hypertension was higher in patients without PTC, 73% vs 23%. Therefore, screening for PA should not be restricted to those with resistant hypertension. Patients with PTC and PA are younger, with less multifocality, with similar risk stratification, recurrence, and tumor-node-metastasis-based stage. The authors suggested the association of PA and PTC as a new recommendation for PA screening because of their findings, and they controlled for age, gender, and body mass index. Furthermore, they conducted all the confirmatory tests for PA. Nakamura et al[16] conducted a study in Japan and reported a prevalence of 18.5% of PA in patients with PTC. The authors recommend screening for PA in patients with PTC because the signs and symptoms are usually mild, and serum aldosterone levels are mildly elevated. Importantly, the screening for PA in PTC is cost-effective and is highly needed for the early introduction of treatment and prevention of its serious consequences.

Thyroid carcinoma is the second most common cancer and the first endocrine tumor, accounting for 3% of all cancers. In the year 2022, there were 821173 new cases and 47485 deaths, with a significant impact on the patients’ physical health and quality of life. PTC accounts for 90% of cases of thyroid cancer and is a malignant tumor with the highest growth rate worldwide (incidence is rising by 6% annually). Lymph node metastasis is common. However, pressure symptoms, including invasion of major local veins and vagus nerve, are extremely rare[17-19]. The carcinoma is usually confined to the thyroid, with microscopic extra-thyroid involvement observed in one third. However, gross local invasion is extremely rare (5%), and the direct involvement of adjacent vessels is observed in < 1% of cases and is associated with poor outcomes[20,21]. The risk factors of thrombus formation are a hypercoagulable state, hypothyroidism, and circulating tumor cells from the involved lymph nodes[22-24].

What is known and the existing gaps in the literature. What is already known: PA is a common disorder and is associated with many comorbidities. However, screening is suboptimal with increasing morbidity and mortality. What is unknown: The association between PA and malignancy, including thyroid carcinoma, was reported in previous studies, but the association with PTC is scarce.

ARARE ASSOCIATION BETWEEN PA AND PTC WITH CONTRALATERAL LYMPH NODES INVASION

We read with great interest the Li et al[23] manuscript, which reported a rare case of PTC associated with primary hyperaldosteronism and complicated by complete invasion of the vagus nerve and the internal jugular vein. The patient underwent a laparoscopic right adrenal tumor resection, which revealed a benign tumor. Total thyroidectomy with lymph node dissection was performed after the blood pressure and hypokalemia were normalized. The left recurrent laryngeal nerve was anastomosed to the vagus nerve with left internal jugular vein resection and ligation. The patient received radioactive iodine (I-131) treatment and thyroid-stimulating hormone suppression therapy postoperatively, and follow-up showed persistence of left vocal cord paralysis with significant improvement in the voice quality (timbre) and pitch. Li et al[23] reported an extremely rare case of vocal cord paralysis discovered to be vagus nerve paralysis during surgery. The author conducted anastomosis of the vagus to the recurrent laryngeal nerve in a novel approach. In addition, the authors reported PTC with contralateral metastasis in similarity to Osborne et al[25], Ding et al[26], Yuan et al[27], and Yoon et al[28]. The contralateral metastasis is most likely due to Skip metastasis because the tumor was in the upper pole of the thyroid, age > 45 years, and the tumor was a small tumor size (< 1 cm), which are risks for skip metastasis. The incidence of skip metastases ranged from 1.6% to 21.8%. Other explanations for contralateral lymph nodes involvement are ectopic primary thyroid tumor and the simultaneous occurrence of two lesions of PTC, where one lesion is not located within the thyroid gland[29]. Microscopic vascular invasion involving the internal jugular vein is very rare in PTC[26]. We reviewed PubMed and Google Scholar and found 17 previous studies[30-45] as shown in Table 1. Female dominance was obvious (10:6, with one study not reporting the gender), the ages ranged from 48 years to 77 years, and perioperative diagnosis was possible in 8 cases. The diagnosis of choice for suspected internal jugular vein involvement is ultrasound[35], computed tomography, magnetic resonance imaging[46], and fine needle aspiration[47].

Table 1 presents case reports on the possible association between papillary thyroid carcinoma and internal jugular vein invasion.

Ref.	Age	Gender	Time of diagnosis	Method of diagnosis	Outcome
Onaran et al[30], 1998	48	Female	Preoperative	Doppler US	Not reported
Ingle et al[31], 2004	Not reported	Not reported	Not reported	Not reported	SVC syndrome
Agrawal et al[32], 2009	48	Male	Postoperative	Enhanced CT	Not reported
Fotis et al[33], 2009	49	Female	Intraoperative	Not reported	SVC syndrome
Mugunthan et al[34], 2010	51	Female	Postoperative	Enhanced CT	Not reported
Kobayashi et al[35], 2011	69	Female	Preoperative	Duppler US	Not reported
Kobayashi et al[35], 2011	77	Male	Preoperative	Duppler US	Not reported
Babu et al[36], 2012	68	Female	Preoperative	Enhanced CT	Not reported
Ataiekhorasgani et al[37], 2014	75	Female	Preoperative	Enhanced CT	Not reported
Al-Jarrah et al[38], 2014	62	Female	Intraoperative	Not reported	Not reported
Dikici et al[39], 2015	52	Female	Postoperative	Not reported	Not reported
Jain et al[40], 2019	44	Female	Postoperative	Not reported	Not reported
Rampelly et al[41], 2022	50	Male	Preoperative	Doppler US, CT	Not reported
Sezer et al[42], 2021	63	Male	Postoperative	Neck MRI	Not reported
Liu et al[43], 2023	61	Female	Preoperative	Doppler US, CT	Lung metastasis
Im et al[44], 2023	53	Female	Preoperative	Doppler US, CT	Pulmonary metastasis
Adnan et al[45], 2025	56	Male	Preoperative	Doppler US, CT	Pulmonary metastasis

Doppler US: Doppler ultrasound; CT: Computed tomography; SVC syndrome: Superior vena cava syndrome; MRI: Magnetic resonance imaging.

The association of PA and PTC could be explained by circadian misalignment because mice lacking cryptochrome Cry 1 and Cry 2 genes (core clock genes) had salt-sensitive hypertension, which is similar to idiopathic hyperaldosteronism in humans[48-51]. Another plausible explanation is the insulin resistance, which was suggested to have a significant role in the development of differentiated thyroid carcinoma, and insulin-like growth factor and insulin receptor expression were reported in PTC[52,53]. Further explanations might be that aldosterone worsens the course of autoimmune thyroiditis, which was shown to be associated with PTC[53]. On the other hand, high aldosterone levels alone cannot explain the development of PA because other conditions, including renovascular hypertension, Gitelman’s syndrome, and Bartter’s syndrome, are not associated with PA[11,54-56].

CONCLUSION

We discussed a rare association between PTC and PA in a patient who presented with contralateral lymph nodes involvement, internal jugular invasion, and vagus nerve involvement. The associations could be explained by skip metastasis, ectopic thyroid, and the occurrence of two lesions. Genetic and environmental factors display insulin resistance, autoimmune system disruption, and the remote influence of high aldosterone on the other endocrine system could explain the associations. A high suspicion rate and imaging (Doppler ultrasound and/or contrast-enhanced computed tomography) for patients with pressure symptoms is mandatory for the diagnosis and subsequent management.

ACKNOWLEDGEMENTS

We want to acknowledge Mohanad Osman (Medical student in the Faculty of Medicine, Prince Fahd Bin Sultan University, Tabuk, Saudi Arabia for the assistance with the table and core tip recording.