Unusual Sites of Metastasis of Well-Differentiated Thyroid Cancer: A Systematic Review

Background: Thyroid cancer is one of the most common endocrine malignancies secondary to ovarian cancer. Its incidence has surged swiftly than that of any other malignancy in recent years. Well-differentiated thyroid cancers (WDTC) are relatively common and usually slow-growing tumors with a good prognosis, including three types: Papillary, follicular, and Hürthle cell carcinoma. The first metastatic sites of these types of cancer typically involve lymph nodes, lungs, brain, and bones. Aim: To address the unusual sites of metastasis of well-differentiated thyroid cancer, which were not discussed in the literature before. Methods: The PICOT included adult men and women of 18 years and above, with the primary WDTC metastasized to unusual sites. MEDLINE, CINAHL, Cochrane Library, PubMed, Web of Science, Scopus, NCBI/PUBMED, Google Scholar were systematically screened for English language citations on human studies from 1990 to 2016. Results: The case reports found in literature were summarized in the form of tables including 8 cases of choroid plexus metastases, 22 cases of retropharyngeal node metastases, 5 cases of ovarian metastases, 22 cases of renal metastases, 6 cases of breast metastases, 8 cases of pancreatic metastases, 21 cases of choroid metastases, 10 cases of pituitary metastases, 54 cases of cardiac metastases, and one case of testicular metastases. Conclusion: Rare metastases of WDTC have been reported on distant sites such as kidneys, ovaries, heart, eyes, pancreas, pituitary, and testes. Major cases of uncommon metastases have been reported after several years of diagnosis of WDTC. Careful clinical diagnosis, along with advanced imaging techniques and immune-histopathological assays, can help to diagnose the type of tumor cells in host organs, which is essential for the development of treatment strategies.


Introduction
Thyroid cancer is the second most common endocrine malignancy after ovarian cancer. Well-differentiated thyroid cancers (WDTC) are slow growing that have a good prognosis with proper treatment. It includes three entities, namely, papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), and Hürthle cell carcinoma (HCC) [1]. The common metastasis sites for these types of cancer usually involve lymph nodes with 80% occurrence, lungs (49% ), brain (0.4-1.2%), and bones (25%). In this systematic review, the unusual sites of metastasis of WDTC were addressed, which were not discussed in the literature previously. We reviewed the relevant literature of rare metastases in WDTC according to the methodology, treatment strategies, disease burden, mechanism of metastasis, genetic predisposition/SNPs predisposing to early metastasis, and pharmacotherapeutic strategies aiming at targeting early metastasis [2].

Methodology
The designed PICOT consisted of adult men and women age 18 years and above with primary WDTC metastasized to unusual sites. MEDLINE, CINAHL, Cochrane Library, PubMed, Web of Science, Scopus, NCBI/ PUBMED, Google Scholar were systematically screened for English language citations on human studies from 1990 to 2016. Complete case reports, clinical studies, reviews, and full-text articles were included.
were included in the review. Of the 549 excluded studies, 210 studies were excluded by the title, 305 by reading the abstract, and 34 were excluded after reading the full text ( Figure 1).
A secondary reference was used to state cardiac metastases. Total studies cited were 105 that included 103 original case reports, one secondary reference for cardiac metastases, and one review article. The case reports found in the literature were summarized in the form of tables including eight cases of choroid plexus metastases, 22 cases of Retropharyngeal Node metastases, five cases of ovarian metastases, 22 cases of renal metastases, six cases of breast metastasis, eight cases of pancreatic metastases, 21 cases of choroid metastases, ten cases of pituitary metastases, 54 cases of cardiac metastases, and one case of testicular metastases.

Choroid plexus metastasis
Papillary carcinomas of thyroid origin are well-differentiated tumors, preferably using the lymphatic route for invasion, whereas vascular route for metastases and invasion is uncommon. Distant metastases in the case of PTC are rare and usually involve breasts and lungs, affecting the prognosis negatively [1]. Metastatic invaders use the hematogenous route to choroid plexus. The tumors reported for choroid plexus metastases are renal cell carcinomas and adenocarcinomas of lung [3]. Choroid plexus metastases from thyroid neoplasm especially in case of PTC are very rare. Eight cases of choroid plexus metastases have been reported by 2016. Table 1 sum-

Search strategy
We searched the electronic databases to identify relevant literature using the search terms: 'Papillary thyroid carcinoma', 'follicular thyroid cancer', 'follicular thyroid carcinoma', 'follicular thyroid neoplasm', 'papillary thyroid cancer', 'unusual site of metastasis of well-differentiated thyroid cancer', 'Hürthle cell thyroid cancer', 'distal metastasis of well-differentiated thyroid cancer', 'rare metastasis', 'uncommon metastasis' and 'unusual course of well-differentiated thyroid cancer' Bibliography of relevant papers was also searched. Studies were screened according to pre-defined inclusion and exclusion criteria. Adults with WDTC metastasizing to sites other than lungs, brain, and bones were included. Patients of pediatric age group, undifferentiated thyroid cancer, or well-differentiated types that metastasize to bone, brain, lung, and/or metastasize to rare lymph nodes were excluded from the review. Two investigators independently reviewed the extracted studies, and a third reviewer was consulted for disagreements, if any.

Review process
Our literature search resulted in 654 articles. Two levels of screening were done that resulted in the inclusion of 105 and exclusion of 549 studies. The studies reporting common metastases and reviews of common metastatic sites were excluded. The studies reporting sites with less than 2% frequency of metastases from WDTC, providing a direct reference of original case reports with sufficient data of uncommon metastasis,

Ovarian metastasis
Papillary thyroid carcinomas rarely establish distant metastasis, and the ovarian metastasis is even rarer. Twenty cases have been reported in the literature, and among them, only four cases have been reported with detailed case reports and related information from 1929 to 2016. All the cases were unilateral in metastatic sites with only one exception. According to the seed and soil hypothesis, it is unusual for the follicular cancer cells to establish metastasis in ovaries compared to the papillary cells. The ovarian metastasis is usually reported decades after the primary tumor diagnosis leading to poor prognosis. Solitary ovarian metastasis is even rarer. Case reports of ovarian metastasis extracted from the literature are summarized in Table 3. marizes the case reports reporting choroid plexus metastases from PTC.
PTCs are characterized histopathologically based on the growth pattern, stromal attributes, and cell types. Brain metastases from PTC account for 0.1-5%, with a median survival rate of 12.4 months. Choroid plexus metastases are usually from the neoplasms that depict slow growth patterns, as shown by eight studies summarised in Table 1. However, aggressive variants of PTC are more prone to metastasize in uncommon sites. The seed and soil hypothesis of metastases and biological nature of metastatic invaders seems to play a role in choroid plexus metastases from well-differentiated slow-growing PTC.

Retropharyngeal node (nodes of Rouvière) metastasis
Metastatic invaders prefer the lymphatic route for traveling to the distant sites from thyroid neoplasm. Therefore, lymph node invasion and metastasis are not rare, but metastasis to retropharyngeal node (RPN) is uncommon, with a total number of 94 cases reported. Of these, 31 have been reported in the literature as comprehensive case studies, since 1970 and four of the case reports were for RPN metastases originated from medullary and anaplastic thyroid neoplasms. The and complete immune-histochemistry analysis can be helpful. However, it was neglected in this unique case. Table 5 summarises the case reports of breast metastases in WDTC and related details.

Pancreatic metastasis
Pancreatic cancer is a rare manifestation of thyroid carcinoma, which is often asymptomatic and usually presented as an abdominal ache. Ten cases of pancreatic metastasis from WDTC were found in the literature. However, the data is available for eight cases only, which is mentioned in Table 6. Additionally, the follicular variant of PTC has been reported for pancreatic cancer so far.

Choroid metastasis
Metastasis of WDTC to choroid and orbit does not occur frequently and mostly presented as long-term disease-associated survival and synchronous metastasis

Breast metastasis
The occurrence of breast metastasis for WDTC is 1-2%. However; the solitary metastasis to the breast is very rare with one unusual case of the male patient, while all other cases were of female patients. In male patients, the breast metastasis, a rare occurrence has been diagnosed as invasive ductal carcinoma. To diagnose the cancer type before surgery, careful diagnosis     to various body sites. Choroid metastasis is mostly associated with papillary carcinoma, followed by medullary and follicular carcinomas. Ultrasonography, transillumination, computed tomography (CT), and/or magnetic resonance imaging (MRI) scanning are the main techniques used to diagnose choroid metastasis clinically. A summary of case reports of choroid metastasis from WDTC is described in Table 7.

Pituitary metastasis
Although lung cancer in men and breast cancer in women are associated with pituitary metastasis, yet pituitary metastasis is a rare complication of WDTC. Sufficient information about the use of imaging techniques for pituitary metastasis was not found in the literature. The diagnosis of this type of metastasis is generally delayed because the non-specific systemic symptoms (fatigue, nausea, and weight loss) of underlying malignancy and TSH suppression therapy hide hypopituitarism. Case reports have been summarized in Table 8 from literature reporting pituitary metastasis with WDTC.

Cardiac metastasis
Cardiac metastasis from WDTC with a frequency of 0-2% has been associated with anaplastic thyroid carcinoma (ATC), closely followed by FTC, including HCC, & PTC. In the previous 130 years, 54 cases of WDTC have been reported with cardiac metastasis, which are summarized in Table 9 [104]. Follicular carcinoma, followed by papillary carcinoma, presents the major types for direct tumor invasion involving heart via the venous system.

Testicular metastasis
Testicular metastasis is not a common complication of WDTC, with only a single case report presented in 2014. The invasion of the testis by medullary thyroid cancer has not been reported before or after 2016. A 73-year-old Caucasian man was recommended for uro-   logic surgery due to a nodule in the right testis. Histopathological and immune histopathological examinations revealed that lesions were due to WDTC metastasis [105].

Conclusion
Lungs and lymph nodes are usually overlooked as they are not the common sites of rare metastases. Therefore, major cases of rare metastasis are diagnosed late, which results in poor prognosis. Hence, it is essential to document and review the statistics, including their economic burden from time to time. The relevant data may be used to update guidelines for diagnosis and treatment. The rare metastases have been reported in kidneys, ovaries, eyes, pancreas, pituitary gland, heart, and testes in addition to the most common sites. It is imperative to look for the early clinical signs to rule out the involvement of the above-mentioned systems. Future research may help to predict rare instances of metastases and pave the way for early intervention.

Competing Interests Statement
Author declares no conflict of interest regarding this paper.