Thyroglobulin as a Rapid and Cost-Effective Biomarker for Diagnosis of Thyroid Carcinoma Brain Metastasis: A Case Report of a Patient with Metastatic Hurthle Cell Thyroid Carcinoma

Background

Thyroid carcinoma is the most common form of endocrine malignancy [1–3]. Most thyroid carcinomas originate from the thyroid gland’s follicular cells, while papillary thyroid carcinoma (PTC) is the more common type [2–4]. A palpable mass in the thyroid gland, with or without enlarged lymph nodes, is the typical presentation [2,3]. When infiltration of the recurrent laryngeal or branches of the glossopharyngeal nerve is present, additional symptoms such as hoarseness or dysphagia may occur [2]. However, it can also be discovered incidentally during investigations for other conditions [2]. Their etiology involves genetic and environmental factors [2]. In 70% of cases of PTC, there are mutations of the proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B (BRAF) or Rat sarcoma virus (RAS) gene families (HRAS, NRAS, and KRAS), or chromosomal rearrangements of the tyrosine kinase receptor (RET) gene, or found on chromosome 10q11, or neurotrophic tyrosine kinase receptor 1 (NTRK1) gene [4]. Exposure to ionizing radiation, especially during the first 2 decades of life, has emerged as one of the most important predisposing factors for developing thyroid cancer [2,4]. In some cases, long-term multinodular goiter has also been implicated as a pre-disposing factor, as areas with iodine-deficient endemic goiter have a higher incidence of follicular carcinomas [2,4]. The primary method used to diagnose PTC is Fine-Needle Aspiration (FNA) biopsy [2,4,5]. Thyroid function laboratory tests do not provide any helpful information since they are typically normal [2]. Therefore, thyroid ultrasound is the recommended imaging method for localizing thyroid cancer [4,6]. PTCs are characterized by slow growth, with a favorable overall prognosis, but their incidence has increased in recent decades [2–4]. Numerous PTC variants have been reported that have unique molecular profiles and morphologies [2–4]. In addition, specific variants, such as tall cell and oncocytic variants, display resistance to radioactive iodine and exhibit a more severe progression [1–3]. Factors that contribute to a worse prognosis in cases of PTC include the patient’s advanced age, being male, tumor volume, experiencing extra-thyroidal extension, and having specific cancer variants such as the tall, diffuse cell sclerosis variant, solid variant, or follicular variant [2,4]. Metastases of PTCs, when present, usually involve the cervical peripheral lymph nodes, as they have a preference for lymphogenic spread [2,6]. Peripheral lymph node metastasis is relatively common, and according to reports, lymph node metastasis is detected in around 30–80% of patients with PTC during the initial diagnosis; however, this usually does not affect the overall prognosis of the disease [2,6–9]. Nevertheless, metastatic disease is an essential indication for long-term patient follow-up [7–9]. Determining the right course of action for treating PTC relies on the location and severity of the illness during diagnosis [2,3]. Recent recommendations suggest a more cautious approach compared to the past [2,3]. Generally, thyroidectomy is recommended in cases where the biopsy shows malignancy and there are no contraindications [3,4]. Administering radioactive iodine is essential in managing patients with large tumors, metastases, patients over age 45, and those not in the excellent response group postoperatively [2,3]. Chemotherapy is recommended for patients who experience relapse or residual disease after initial treatment [2]. While treatment for PTC generally produces good results, it is essential to note that recurrence rates can reach up to 25% [2,10]. Although distant metastases are not common, they strongly predict an unfavorable prognosis for the patient [11,12]. The lungs and bones are the most frequently affected areas, but the brain is also a possible site of metastasis, albeit rare, with an incidence of about 1% [10–13]. Brain metastases typically occur as a secondary type of metastasis in patients who have already been diagnosed with lung or bone metastases [9,14]. However, distant metastasis to other organs increases the risk of developing metastatic brain disease [14]. The cerebral hemispheres are the most common brain regions affected by metastases [11,15]. However, reported cases of metastases to the pituitary gland and choroid plexus or ventricular system have also been reported [11,15,16]. Although rare, PTC metastasis to the head and neck has been reported [17].

Thyroglobulin (Tg) is a glycoprotein produced by the thyroid gland’s follicular cells [12]. High levels of Tg in the blood of patients who have undergone thyroidectomy may indicate a recurrence of the disease or its spread to other body organs [3,7,18]. Tg levels can also be measured to improve the accuracy of diagnosing metastatic thyroid cancer by examining lymph nodes suspected of being affected [3,7]. In addition, metastatic brain tumors in thyroid cancer patients are tested using a Tg detection stain [19]. Resection of the tumor is an essential aspect of managing metastatic thyroid disease in the brain whenever possible [3]. Patients who cannot undergo surgery may receive conservative treatment using radioisotope therapy and chemotherapeutic agents [3,4]. It is crucial to note that brain tumors often exhibit symptoms only in the later stages of development, potentially resulting in substantial lesion size [20], which poses a severe threat to the patient’s life [20].

Additionally, removing the tumor in an eloquent brain area could adversely affect the patient’s functionality [20]. Ota et al reported the case of a patient who arrived at the hospital after experiencing symptoms of increased intracranial pressure; the tumor was deemed removable, and the medical team acted urgently to provide prompt treatment [21]. Neurosurgeons face challenges when dealing with such cases since they may not be able to intervene effectively [20]. Therefore, patients in such cases usually require conservative treatment [3,4]. It is widely recognized that large cystic metastatic brain tumors can be effectively treated through cyst aspiration and stereo-tactic neurosurgery [22]. Removing the cystic segment without craniotomy during tumor resection lowers the chances of tumor cells spreading due to contamination of the surgery area [23].

We present a case of an 81-year-old male patient who had undergone total thyroidectomy for goiter in the past and presented with metastatic papillary thyroid carcinoma (PTC) to the neck after a gap of 16 years. After two years, the patient developed a solitary cystic brain metastasis. The patient’s lesion was resectable, and a craniotomy was performed to remove the tumor. Nonetheless, the cystic compartment was aspirated during surgery, and a specimen was sent to detect levels of Tg, which were found to be relatively high.

Case Report

We present an 81-year-old white male patient with a medical history of arterial hypertension, chronic obstructive pulmonary disease, and type II diabetes mellitus, who underwent total thyroidectomy 20 years ago to treat goiter. The pathology diagnosis revealed nodular thyroid disease with adenomatoid nodules of the microfollicular-trabecular type and colloid nodules in the thyroid gland. 16 years later, the patient observed a protruding growth on his skin in the sternal notch region. Immediately, a computed tomography (CT) scan of the mediastinum was conducted, revealing a non-uniform 6 cm diameter tumor located in the soft tissue above the suprasternal notch on the medial anterior surface of the left clavicle. This lesion showed low densities and did not absorb contrast in its larger superficial part. However, the internal part exhibited a soft tissue density, showed contrast enhancement, and was diagnosed as a subcutaneous adipose tissue lipoma. The same year, the patient underwent surgical excision of the lesion. Upon investigation of the tissue, it was discovered that a significant amount of cancerous tissue composed of papillary thyroid carcinoma, a pure oncotic variant, had extensively infiltrated the adipose tissue. As part of the staging procedure, the patient underwent a full-body CT scan and a magnetic resonance imaging (MRI) scan of the brain, both negative for metastatic disease. 6 months later, the patient was admitted to our hospital’s Endocrinology Clinic for disease control and staging. After admission, he underwent a chest CT scan, revealing a suspicious micronodule in the left upper lung lobe and pleural thickening in the anterior part of the same lobe. A spirometry test showed severe obstructive lung disease, while a bronchoscopy revealed no malignancy in the bronchial lavage. The patient and his family decided against surgery for a biopsy and instead opted for radioactive iodine 131 (I-131) 120 microCurie (mCi) of radioactive iodine treatment in 2 months later. Post-therapeutic radioactive iodine-131 whole-body scan and single-photon emission computed tomography (SPECT/CT) scan followed, in which multiple foci of iodine fixation were observed in the anatomic location of the thyroid bed as residual tissue, with the expected distribution of the radioisotope in the remaining regions. The patient was discharged, and 6 months later, he had a recurrence of the disease with a large mass of 11 cm in diameter in the same area of the sternal notch and underwent a new surgery and resection of the lesion with the removal of regional lymph nodes. Histological examination revealed metastasis of PTC, a pure oncotic variant. The carcinoma had spread to the outer layer of skin, penetrated the surrounding muscle fibers, and reached the edge, where it was surgically removed. Smaller metastatic foci of the above carcinoma were also recognized in adjacent locations. Furthermore, out of the 4 lymph nodes discovered, 2 indicated the presence of metastatic infiltration from the aforementioned carcinoma. Additionally, a separate meta-static lesion in the perilesional fat was identified. 10 months later, the patient underwent an MRI of the neck. A 5-mm nodular lesion with imaging features matching a lymph node was identified in the postoperative tumor bed. No abnormal cervical lymph nodes were identified. However, a solid paramagnetic uptake subpleural lesion showing molecular diffusion restriction and a broad pleural base on the dorsal surface of the right upper pulmonary lobe, 1.9 mm in diameter, was shown. A SPECT/ CT scan after thyrogen stimulation a year later was negative for secondary metastatic lesions. A repeat chest CT scan the same year showed 3 suspicious pulmonary nodules showing an increase in size compared to the previous one. The patient was then readmitted to the Endocrinology Clinic for staging control and received 200 mCi of I-131 radioisotope. Laboratory control during the last 2 years had shown baseline thyroglobulin values >1 ng/ml with an improvement of values after the second surgery of the formation in the anterior mediastinal wall. The thyroglobulin value increased again at the end of these 2 years to 11 ng/ml with stimulated thyroglobulin at levels above 10 ng/ml in all measurements. The above findings were compatible with persistent biochemical disease [3]. 5 months later, the patient underwent a new chest CT, which showed a pathologically enlarged left axillary lymph node measuring 2 cm centimeters in diameter, 4 nodular lesions in the lung parenchyma: 1 in the right upper lobe (diameter 18 mm), 2 in the left lobe (diameters 14 mm and 6 mm), and 1 in the right lower lobe (diameter 5.7 mm). In addition, this examination revealed thickenings of the pleura and the interstitium. The patient underwent a cervical ultrasound the same day, revealing thyroid tissue measuring 1.08×0.57×0.15 cm in the right common carotid artery. This finding was not present in the previous ultrasound in the previous year. He was readmitted to the Endocrinology Clinic to receive radioisotope 200 mCi. He had a post-treatment full-body SPECT/CT scan, which showed an increased fixation of the radioisotope in the thyroid bed area at the level of the cricothyroid cartilage on the left and in the hyoid bone. Later, an MRI of the brain revealed a single lesion in the right frontal lobe (Figure 1). There were signs of critical mass effect and perilesional edema. The patient was immediately admitted to the Neurosurgery Department of our hospital. On admission to the Neurosurgery Department, the patient showed spastic paraparesis without any other significant findings from the clinical examination. Due to the solitary lesion in a non-eloquent area and signs of mass effect, total resection of the lesion was suggested to the patient, as defined by the standard of care of our department. The tumor was debulked before the resection because of its large size. The expected cystic formation was noticed during the debulking process, which is the suggested technique for tumor resection. Aspiration was performed with a 21-gauge (21-G) needle to gently reduce the tumor’s size and to proceed to full resection of the tumor. Specimens from this colloid-like substance were sent for laboratory examination. High levels of Tg (>300 ng/ml, normal laboratory values for serum specimens are 1.6–55 ng/ml) were found. Cytology revealed malignant cells emerging from a papillary thyroid carcinoma with nuclear pseudo-inclusions. Histological examination of the tumor revealed metastatic infiltration from carcinoma with papillary architecture, consisting of eosinophilic cells with morphological (nuclear pseudo-inclusions) and immunophenotypic (TTF1 +, thyroglobulin +) characteristics compatible with a pure oncocytic variant of papillary thyroid carcinoma (Figures 2, 3). Immediately after the operation, the patient was treated in the Intensive Care Unit (ICU) and transferred to the Department of Neurosurgery. He underwent intensive physiotherapy, was discharged 2 months after the diagnosis of the brain metastasis, and followed up as an outpatient. A few months later, Tg values were significantly decreased.

All measures of Tg levels were conducted on the Alinity i Immunoassay system AI03280 using the Alinity i Thyroglobulin Reagent Kit 09P49, Abbott®. The kit’s microparticles include anti-Tg (mouse, monoclonal)-coated microparticles in MES buffer with protein (bovine) stabilizer. Unfortunately, we had no access to images of the cytology examination or the previous imaging studies.

Discussion

We describe the first measurement of Tg in a cystic compartment of a brain tumor suspected to be a metastatic lesion from PTC via puncture. Early diagnosis of the primary site of metastasis was made possible due to the high Tg values identified within the tumor’s cyst. Moreover, we described a case of an 81-year-old patient with a history of metastatic papillary thyroid carcinoma, a pure oncotic variant with a persistent biochemical disease after initial treatment, who eventually developed brain metastasis. As expected in other cases throughout the literature, brain metastasis was late and secondary to lung metastasis [9,11,13,17,19,21]. However, metastatic lung disease was not proven due to a lack of biopsy. In general, the patient’s history developed following the natural course of the disease [2,5,15,19]. On admission to our department, the patient already exhibited neurological deficits, presenting with paraparesis, so efficient treatment was imperative. Craniotomy and brain tumor removal were suggested to the patient and his relatives. During surgery, fluid from the tumor’s cyst was aspirated and sent to measure Tg levels. The results showed us interestingly high levels of thyroglobulin inside the tumor. However, it is important to consider how this information will be essential for future studies and treatment options. PTCs are rare tumors but are still the most common carcinomas of the endocrine system [1–3]. Although brain metastasis is a rare complication of the disease, it can significantly reduce life expectancy [5,9,19]. Unfortunately, insufficient information is available to establish treatment guidelines for brain metastases of thyroid carcinomas, as they are rare [3,24]. However, based on expert opinions and current guidelines, it is recommended to remove solitary metastases, mainly if they are easily accessible and the patient is in good general health [3,24]. In addition to the patient’s overall health, the location of a solitary brain tumor can also play a significant role in the success of surgical removal [20]. If the tumor is deep within the brain or close to eloquent areas, there is a greater risk for negative functional outcomes after surgery [20]. On the other hand, the effectiveness of stereotactic radiosurgery is well-established nowadays [23–25]. However, stereotactic radiosurgery has a necessary condition concerning the overall volume of the tumor [23–25]. In these cases, attempts could be made to reduce the volume of intracerebral tumors with a cystic compartment to set appropriate limits for performing stereotactic radiosurgery (gamma knife surgery) [23,24]. Aspiration of tumors with cystic compartments has been applied before, with interesting results [23,24]. In our patient, preoperative puncture would not be of use because of the solitary nature of the tumor and its location, making it feasible to remove the metastasis with craniotomy. However, if the patient’s condition or the tumor’s location did not allow major surgery, one could suggest fine-needle aspiration of the tumor’s cyst, which would reduce the size of the tumor and even relieve the patient of symptoms of intracranial hypertension, especially in cases like the one described by Ota et al. [21], whose patient visited the Emergency Department with symptoms of intracranial hypertension due to large metastatic brain lesion. Subsequently, an early diagnosis of the collected fluid would be feasible in a few hours. This would offer the opportunity for early radioisotope therapy and (or) radiosurgery. Despite an extensive literature review, we found no information on directly measuring Tg levels in cystic brain tumors through needle aspiration. Nevertheless, our observation in this case revealed abnormally high Tg levels (>300 ng/ml) in the aspirated fluid. Given that any thyroid carcinoma can synthesize thyroglobulin, we strongly suspect that the elevated thyroglobulin levels in the cystic compartment of the tumor indicated metastatic disease from thyroid carcinoma [7,12]. It is widely recognized that thyroglobulin is a marker for thyroid follicular cells, regardless of whether they are benign or malignant [7,12]. The patient responded well to the treatment, and his post-surgery serum thyroglobulin levels were reduced.

It should be stated that the patient’s pathology examination was conducted before the latest overview of the WHO Classification of Thyroid Neoplasms. Furthermore, despite having undergone a total thyroidectomy in 2002, some residual tissue was still present on the thyroid bed. Therefore, it is essential to note that complete microscopic thyroid gland removal was not achieved.

Conclusions

This report has shown that residual tissue may be present following total thyroidectomy and may be the origin of PTC with metastasis to the brain. While this is uncommon, early detection and treatment of brain metastasis is crucial. Future studies suggest that stereotactic needle aspiration of the cystic compartments in patients with thyroid carcinoma and brain tumors could offer a fast and effective diagnostic tool, ultimately reducing the brain tumor’s size. In addition, this method could enable prompt identification of the tumor’s origin and help treat intracerebral tumors that cannot be surgically removed.