Comparative study of single-center patients with thyroid metastases from colorectal cancer and previously reported cases in the literature

Thyroid metastasis of malignant tumors is observed in 1.9–9.5% of histologically examined autopsy cases [1], with thyroid metastases from non-thyroid malignancies remaining a rare occurrence in clinical practice, comprising only 1.4–3% of all thyroid neoplasms [2]. Studies from the USA and UK, including 15 cases of metastatic thyroid tumors, found that the kidney was the most common primary source of thyroid metastasis, while only one case showed thyroid metastasis from CRC [17]. Between January 2005 and December 2015, there were only four cases of thyroid metastasis from CRC in our center (Table 1), and we also collected relevant cases by a literature search using PubMed, which identified 17 patients with detailed information available (Table 2).

Willis [18] hypothesized that there were two possible reasons for why metastasis to the thyroid gland is so uncommon. One is a mechanical explanation, namely that the thyroid gland is an organ that receives an extremely abundant supply of arterial blood. This rapid blood flow rate prevents tumor cells from remaining fixed in the thyroid gland. The second is a chemical explanation, i.e., that the high oxygen saturation and high iodine content in the thyroid gland tissue may prevent the growth of tumor cells [18]. In fact, thyroid diseases that lead to reduced blood flow or low iodine levels, such as Hashimoto’s thyroiditis, have been suggested as potential risk factors for the development of thyroid metastases. However, in the reported patients with thyroid metastases from CRC, we found that the majority of patients were euthyroid and that the early symptoms and signs tended to be subtle. The clinical features, such as an enlarging neck mass, dyspnea, and dysphagia, appear during the course of disease progression. Three out of four patients (75%) in our center were diagnosed on detailed routine follow-up examination, as compared to only three out of the previously reported 17 cases. This may be related to our relatively regular follow-up schedule, indicating its contribution to the early detection and diagnosis of thyroid metastases from CRC in our clinical work.

In contrast to the much greater preponderance of primary thyroid tumors in women compared to that in men, the picture regarding thyroid metastases from CRC is less clear. Furthermore, a number of studies have reported that patients with thyroid metastasis from colon cancer tend to be older than 60 years [1, 3, 5, 19‐22]. This may be related to the fact that most primary CRC patients are older at diagnosis or that older patients are more prone to organic or functional thyroid disorders, which may increase the risk of thyroid metastases from CRC. Herein, in the identified 21 patients, the female-to-male ratio was 1:1.2, and the median age of the 21 patients was 59 years. Among them, the median ages of our patients and previously reported cases were 44.5 years (range, 36–54 years) and 66 years (range, 28–82 years), respectively.

For patients with thyroid metastases from CRC, the primary tumor is mainly located in the distal colon or rectum. According to our statistics, 71.4% of the primary tumors (15/21 cases) were distributed throughout the distal colon or rectum (75% [3/4 cases] in our center and 70.5% [12/17 cases] in the previously reported cases in Table 2). Thyroid metastases from CRC usually occur in patients with advanced CRC and often occur concomitant with, or appear after, other metastases [23]. Herein, we found that all four patients treated in our center showed combined pulmonary and other organ metastases, including liver, ovarian, and adrenal gland metastases. In the previously reported patients [1, 3‐16] (Table 2), 76.5% (13/17), 23.5% (4/17), and 23.5% (4/17) showed concomitant pulmonary, liver, and other organ metastases except to the lungs and liver, respectively.

The diagnosis of thyroid metastasis is frequently delayed because the early symptoms and signs are subtle, and symptomatic thyroid dysfunction is rare. The time from CRC diagnosis to thyroid metastasis varies. Some tumors are metachronous while others are synchronous. In the present study, the median time from the primary CRC diagnosis to thyroid metastasis was 28 months in all patients (26 months in our center and 35 months in the previously reported cases in Table 2). Hematogenous spread is the most important pathway for metastasis [1], because, in many cases, thyroid metastasis is accompanied by liver and, especially, lung metastases [1, 5, 6, 8, 9, 14]. Furthermore, as described above, 81.0% of all patients (17/21) showed concomitant lung metastasis. Among them, all four patients in our center showed lung metastasis, and 75% (3/4) developed thyroid metastasis after lung metastasis. In the previously reported cases [1, 3‐10, 13, 14], the corresponding proportions were 76.5% (13/17) and 76.9% (10/13) of patients, respectively. Therefore, CRC can be considered to metastasize to the thyroid gland mainly via the hematogenous pathway, i.e., CRC spreads to the thyroid gland through the portal vein, vena cava, and pulmonary vein [2‐7]. However, it has also been proposed that the special physiology and pathology of the vertebral venous system enable such tumors to bypass the portal vein, pulmonary vein, and vena cava and to be transferred directly to the thyroid or any part of the body, without entering the thoracic and abdominal cavity [24]. As summarized in Table 2, a patient had no other organ metastasis except for thyroid metastasis, while another three of the previously reported patients and one patient treated in our center developed thyroid metastasis before lung metastasis; these findings support the existence of a vertebral venous system for metastatic spread.

The most common clinical features of thyroid metastases from CRC include an enlarging neck mass, dyspnea, dysphagia, dry cough, hoarse voice, and wheezing, among others. One patient treated in our center had an enlarging neck mass at the time of presentation, while neck masses were found in the other three patients on detailed routine follow-up examination. As seen in Table 2, there were seven (41.2%), five (29.4%), and three (17.6%) cases with an enlarging neck mass, dyspnea, and dysphagia, respectively, out of the previously reported cases, and only three patients (17.6%) were found on routine follow-up examination. The cases in our center were euthyroid, and the early symptoms and signs were subtle when they were diagnosed. This finding may be related to our regular and detailed follow-up and indicates its contribution to both the early detection and diagnosis of thyroid metastases from CRC in our clinical work and, potentially, to the reduced prevalence of acute symptoms such as dyspnea and dysphagia.

In many studies from overseas, most patients were reportedly asymptomatic early in the disease course [1, 3, 16], and some patients with thyroid metastases from CRC showed no clinical features until death, which may be the reason for why the proportion of histologically diagnosed autopsy cases is higher than that of cases diagnosed in clinical practice [2, 5, 15]. Currently, the routine follow-up examinations of patients with CRC include only thoracic, abdominal, and pelvic examinations, and not neck evaluations, which may lead to misdiagnosis or delayed diagnosis of thyroid metastasis. A previous clinical study found that 10 to 15% of patients with colorectal cancer would have lung metastases [25]. According to our statistics, there are 13,000 patients with colorectal cancer treated in our center between January 2005 and December 2015, of which 1560 patients undergo lung metastasis, which accounting for 12%. All four cases of thyroid metastases from CRC treated in our center showed combined pulmonary metastases, accounting for 0.26%. For the patients with thyroid metastases of CRC, the proportion of combined pulmonary metastases is quite high. In our study, 81.0% of all patients (17/21) showed concomitant lung metastasis. Therefore, the presurgical evaluation and postoperative follow-up should include the thyroid, especially in high-risk patients with CRC lung metastases and/or a history of thyroid nodules. The diagnosis of thyroid metastases from CRC should be made by a combination of history taking, thyroid function tests, and imaging studies. If required, fine needle aspiration biopsy and pathological examination for suspicious patients, along with immunohistochemical analyses, should be performed to confirm the diagnosis.

As mentioned above, thyroid metastasis from CRC is a manifestation of advanced CRC. Patients with advanced CRC generally undergo comprehensive treatment with chemotherapy. Furthermore, for patients with thyroid metastases from CRC, aggressive surgical treatment can help avoid the appearance of crises such as dyspnea and dysphagia, and may thus result in a better prognosis and quality of life of the patients [4, 5, 23]. The chemotherapy regimens used include combination chemotherapy with XELOX, mFOLFOX6, or FOLFIRI [1, 4, 5]. Accordingly, for patients suitable for targeted therapy, combination chemotherapies including bevacizumab or cetuximab should be considered [6].

Thyroid metastases from CRC are associated with a poor prognosis and high mortality. Except for the patient described in case 4 herein, who died 5 months after the diagnosis of thyroid metastasis from CRC, the other patients are currently alive, with the longest follow-up being 27 months. The median survival time after thyroid metastasis during 3 years of follow-up of the previously reported 17 patients was 12 months (Table 2). A number of studies, as well as our present study, have shown that the majority of patients with thyroid metastases from CRC usually have concomitant metastases in other organs and a poor prognosis [1, 7, 12, 13]. Hence, it is obvious that thyroid metastases represent a CRC end-stage manifestation. The prognosis of patients with thyroid metastases from CRC are related to many factors, including the grade of malignancy of the primary lesion, the presence of other metastases, and whether the metastases are timely diagnosed and a radical treatment strategy is employed for the thyroid lesions [1, 26‐28]. A shorter mean survival in patients who were treated non-surgically (25 months), as compared to in patients who underwent thyroidectomy alone or thyroidectomy with adjuvant therapy (34 months), was reported in one series [24]. However, according to our analysis, the overall survival in patients treated non-surgically (8/21) and patients who underwent thyroidectomy alone or thyroidectomy with adjuvant therapy (13/21) did not significantly differ (p = 0.388). In addition, we found that the overall survival of patients whose other metastases were treated with radical surgery was superior to those undergoing palliative treatment (p = 0.022). These results indicate that while there is no significant relationship between thyroidectomy and overall survival, radical treatment of the other metastases influences the survival of the patients. Aggressive surgical treatment can moreover help avoid the appearance of crises such as dyspnea and dysphagia and thus enhance the patients’ quality of life.