That’s not Metastatic Thyroid Cancer: Patterns of Non-malignant Radioiodine Uptake

Radioactive iodine (RAI) has played a key role in the identifi cation and treatment of the most common types of thyroid cancer since its inception in 1936, with the fi rst recorded treatment of hyperthyroidism in 1941 [1]. Use of iodine-131 (I 131) for treatment of thyroid cancer was soon to follow with the fi rst demonstrated uptake from thyroid adenocarcinoma by Seidlin in 1943 [2]. In the years that followed, these fi rst experiences allowed RAI to become a critical radiopharmaceutical in the treatment and surveillance of papillary and follicular thyroid carcinoma.


Introduction
Radioactive iodine (RAI) has played a key role in the identifi cation and treatment of the most common types of thyroid cancer since its inception in 1936, with the fi rst recorded treatment of hyperthyroidism in 1941 [1]. Use of iodine-131 (I 131) for treatment of thyroid cancer was soon to follow with the fi rst demonstrated uptake from thyroid adenocarcinoma by Seidlin in 1943 [2]. In the years that followed, these fi rst experiences allowed RAI to become a critical radiopharmaceutical in the treatment and surveillance of papillary and follicular thyroid carcinoma.
RAI is produced in a nuclear reactor by the neutron bombardment of Tellurium 127 and has a half-life of 8.02 days. Once ingested, nowadays usually in pill form, about 90% of the dosed RAI is rapidly absorbed and secreted into the extracellular iodine pool [3]. Part of this absorbed RAI is renally excreted, but given the usually high TSH expression in thyroid carcinomas and its effect to increase the expression of the sodium-iodine symporter (NIS), much is taken up into by follicular cells into tissue by the NIS receptors. Once trapped in the follicular cell, it rapidly undergoes organifi cation. Organifi cation is defi ned as oxidation and eventual binding of the RAI to tyrosine residues on thyroglobulin [4,5]. During this process and for substantial time after, RAI undergoes Beta decay and with consequent damage of the surrounding tissue. RAI predominantly decays by Beta emission to xenon-133, with a gamma emission of 364 keV [3]. Importantly, when I-131 decays, 10% of this decay is expressed as gamma rays, which can be detected by standard gamma cameras thereby allowing for surveillance of disease response and localization of potential metastatic lesions.
Whole body scintigraphy is used in patients with differentiated thyroid carcinomas, for assessment after treatment with RAI, and may also be used for localization of metastatic disease in patients with increase in thyroglobulin levels. However, it is by no means a perfect method. Whereas I-131 is a sensitive marker for the detection of thyroid cancer, it is not specifi c to thyroid tissue. Physiologic uptake is commonly observed in the salivary glands, thymus, and GI tissue. Thyroid tissue, either residual cells in the thyroidectomy bed or in ectopic location will also have increased RAI uptake [6]. This is commonly seen and well understood. However, RAI uptake has been observed in several other circumstances, which can make the surveillance and treatment of metastatic thyroid cancers extremely diffi cult. Infl ammation, contamination, and importantly metabolism are all conditions in which RAI uptake has been observed [7][8][9][10]. It becomes diffi cult and extraordinarily important in the treatment of patients with metastatic thyroid cancers to be able to determine whether the uptake seen on whole body scintigraphy is representative of metastatic disease or not. Therefore, precise interpretation by a trained radiologist or nuclear medicine physician is critical in optimally managing this high-risk disease.
Based on that, we have highlighted a series of cases which illustrate unique examples of thyroid uptake which would appear to represent metastatic thyroid disease, but in fact do not. This was correlated with the mechanism of localization to further aid understanding and clinical recall. By presenting these cases that illustrate rare, but important instances, in which metastatic disease can be mistaken for other types of uptake, our goal is to prevent patient worry, misdiagnosis, and potential unnecessary treatments.

Abstract
Radioactive Iodine (RAI) has been an integral part of the identifi cation, surveillance, and treatment of the most common types of metastatic thyroid carcinoma since its fi rst use in 1941. However, false positive uptake of RAI on whole body scintigraphy scans in tissues other than in metastatic disease is frequently observed. This article presents a case series of relatively uncommon situations of RAI uptake which could be mistaken for malignant uptake. Cases were divided into categories based on uptake mechanism: metabolic, physiologic, infl ammatory, and contamination. http://doi.org/10.17352/2455-8702.000033

Materials and Methods
Clinical cases were retrieved in a retrospective manner from the nuclear medicine database and cases were reviewed and selected. From this extensive dataset, cases which illustrated unique examples of non-malignant and/or non-thyroidal uptake on I-131 whole body scintigraphy scans were thoroughly reviewed. Protected patient information was systematically removed from all images. The uptake on these cases were categorized as metabolic, physiologic, infl ammation and contamination. After case selection, a review of the literature was performed to elucidate different physiological mechanisms of iodine localization and to correlate imaging fi ndings.

Case 1: Metabolic uptake of RAI
Hepatic uptake seen on thyroid scintigraphy was originally thought to be secondary to residual metastatic thyroid cells.
Later studies were not able to show its correlation with serum thyroglobulin or distant metastatic disease [3]. Currently, RAI uptake in the liver is attributed to the metabolism of thyroglobulin from either residual normal and/or malignant thyroid cells. There is also evidence for normal hepatic uptake Examples of infl ammatory disease that can have RAI uptake are illustrated in fi gures 6 -8.

Discussion
I-131 has good sensitivity for the detection of thyroid tissue and is an important lifesaving theranostic agent that can detect and treat thyroid cancer. As detailed above, given that there are other causes of uptake including physiological, metabolic, infl ammatory and contamination, RAI is not specifi c to metastatic thyroid cancer. It is important to recognize the causes and distribution of non-malignant uptake to decrease the number of false positive studies, resulting in a specifi city of over 90% as reported on literature [11,12].
The ultimate goal is to improve patient care through more comprehensive radiographic understanding of these       Focal uptake in the mediastinum correlated to a soft tissue nodule suspicious for metastasis (yellow arrow). Subtle activity in the midabomen (red arrow) is also seen. SPECT-CT images (B) shows that the accumulation in the mid-abdomen correlated to radiotracer accumulation in irregular soft tissue surrounding the inferior vena cava and aorta in the abdomen, corresponding to previously known retroperitoneal fi brosis (red arrow). There is heterogeneous diffuse low-level radiotracer uptake throughout the bilateral lungs (red arrows). (C) Coronal chest CT image show bilateral areas of central bronchiectasis, with diffuse airway wall thickening and mucoid impactation (red arrows), consistent with expect changes of cystic fi brosis. (D) coronal SPECT-CT image shows that the uptake seen in the whole body images corresponds to these areas of infl ammatory changes in the lungs (red arrows), with no suspicious abnormalities to suggest metastatic disease.  There is expected activity in the thyroid bed (black arrow) and area of uptake lateral to the face on the left, which corresponded to hair uptake (red arrow), bilateral hands (yellow arrow) avnd perineum (blue arrow), consistent with contaminant.