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| REVIEW ARTICLE |
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| Year : 2018 | Volume
: 16
| Issue : 4 | Page : 131-139 |
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Overview of role of nuclear medicine in differentiated thyroid cancers
Saumya Sara Sunny
Department of Nuclear Medicine, Christian Medical College, Vellore, Tamil Nadu, India
| Date of Web Publication | 16-Apr-2019 |
Correspondence Address:
Saumya Sara Sunny
Department of Nuclear Medicine, Christian Medical College, Vellore - 632 004, Tamil Nadu
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/cmi.cmi_47_18
There has been a rising trend in the incidence of differentiated thyroid cancers. Diagnostic and therapeutic modalities using Radioiodine are employed in these conditions. This article aims to provide an overview of the types, staging, evaluation, treatment and follow up of thyroid cancers with focus on the nuclear medicine techniques.
Keywords: Anaplastic cancer, follicular cancer, papillary cancer
How to cite this article:
Sunny SS. Overview of role of nuclear medicine in differentiated thyroid cancers. Curr Med Issues 2018;16:131-9 |
| Introduction | |  |
Thyroid cancers can be broadly divided into three main categories:
- Papillary cancer – 85%
- Follicular cancer – 12%
- Anaplastic (undifferentiated) cancer – <3%.
Other malignancies of the thyroid include medullary thyroid cancer (MTC), either familial or isolated familial MTC or part of the multiple endocrine neoplasia type 2 (MEN2) syndrome and primary thyroid lymphoma. The common malignancies that produce metastases to the thyroid include breast, colon, renal cancer, and melanoma.
| Incidence | | |
In the recent past, there has been an increase in cases diagnosed. The age- and gender-adjusted incidence of thyroid cancer has seen a rising trend in all ethnicities.[1] The female-to-male ratio of papillary thyroid cancer (PTC) is approximately 2.5:1, with most of the female preponderance occurring during the fourth and fifth decades of life.
The increased incidence was earlier attributed to the use of head-and-neck external beam radiation in childhood. However, some studies suggest that the rise in incidence may be primarily due to an improved detection of very small lesions of by neck ultrasonography and fine-needle aspiration cytology.[2]
| Risk Factors | | |
- Certain malignancies and benign conditions of the head and neck respond to radiation therapy. Such exposure of the thyroid during childhood is a known environmental risk factor
- Family history – Conditions such as Carney complex, familial polyposis, Werner syndrome, MEN2, or Cowden syndrome increase the risk of malignancy in a thyroid nodule. In one study, it was found that in relatives of thyroid cancer patients, there was a 10-fold increased risk of cancers in the thyroid.[3]
| Pathogenesis | | |
The initiation and progression of differentiated thyroid cancers may be dependent on mutations in the genes encoding for the proteins in the mitogen-activated protein kinase pathway. The importance of this pathway is emphasized by the finding of exclusive, nonoverlapping activation mutations in NTRK1, RET/PTC, RAS, or BRAF in nearly 70% of differentiated thyroid cancers.[4]
| Clinical Features | | |
Thyroid cancer typically presents as a painless thyroid nodule. Most of them are incidentally detected. A history of rapid increase in size, firm-to-hard consistency, presence of central or lateral compartment nodes, and fixation of the nodule to surrounding tissues may be suggestive of a malignancy. Recent onset hoarseness or vocal cord paralysis, dyspnea, or dysphagia depending on the extent of involvement/compression of adjacent structures may occur. Follicular variant of thyroid cancer may present primarily with bone pain or fractures secondary to metastases.
| Investigations | | |
- Ultrasonography neck: The suspicious lesions are reported based on the TIRADS criteria [Figure 1]. The following features [Table 1] increase the chance of malignancy [Figure 2]
 | Table 1: Sonographic patterns, estimated risk of malignancy, and fine-needle aspiration guidelines for thyroid nodules (American Thyroid Association guidelines 2015)
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 | Figure 2: The American Thyroid Association nodule sonographic pattern and risk of malignancy (American Thyroid Association guidelines 2015).
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- Taller than wider lesion
- Presence of microcalcifications
- Presence of central/lateral compartment nodes with loss of fatty hilum
- Solid component which is hypo/isoechoic
- Irregular margins
- Fine needle aspiration cytology: The Bethesda classification for reporting thyroid cytopathology is shown in [Table 2]
- Other radiological investigations were as follows:
- Chest X-ray and computed tomography (CT) thorax – if lung metastases are suspected
- X-rays and magnetic resonance imaging (MRI) – if osseous, brain or spine metastases is suspected
- Preoperative voice assessment.
| Staging | | |
AJCC 8th edition of the tumor, node, and metastasis staging of thyroid carcinomas
The main purpose of post-operative staging for thyroid cancer [Table 3] and [Table 4] is essential to: | Table 3: Differentiated thyroid malignancy; Tumor node metastasis definitions AJCC 8th edition
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- Prognosticate while considering regimens for therapeutic strategies and disease surveillance
- Risk-stratify patients for communication among health-care givers and research purposes and tracking by cancer registries.
| Stage of Thyroid Cancers | | |
Locoregional or distant metastases
The most common site is the regional lymph nodes which are noted in 50%–70% of all cases. Distant metastases account for <5% of the cases of which lungs and bones are the most common. Brain metastases are also noted. Other visceral metastases are very rare.[5]
| Treatment | | |
Guidelines
The American Thyroid Association (ATA) published evidence-based guidelines in 2015 for the staging and management of differentiated thyroid cancer [Table 5]. In addition, guidelines have been published by the National Comprehensive Cancer Network and a European consensus group.[6] | Table 5: American Thyroid Association risk stratification (dynamic staging)
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The basic goals of initial therapy for patients with differentiated thyroid carcinoma (DTC) are to reduce the risk of persistent disease, determine the risk of surgical complication, improve disease-specific and overall survival, reduce associated morbidity, and accurately stage the disease and risk stratify while reducing treatment-related morbidity and avoiding unnecessary therapy.[7]
| Surgical Management | | |
Surgery is the primary mode of treatment. The operative approach depends primarily on the extent of the disease (e.g., size of the primary tumor, presence of extrathyroidal extension, or lymph node metastases), the patient's age, and the presence of comorbid conditions.
Total thyroidectomy is the recommended approach along with central compartment or lateral neck dissection depending on the extent of involvement.
Common postoperative complications were as follows: hypocalcemia secondary to hypoparathyroidism and laryngeal nerve damage.
| Postoperative Thyroxine Supplementation | | |
After total thyroidectomy, the presence of persistent disease and risk for recurrence should be assessed for determining the need for additional treatment, in particular, radioiodine therapy.
After thyroid surgery, all patients require suppressive doses of LT4/levothyroxine (usually 1.6–2 mcg/kg/day). It can be started postoperatively to replace normal hormone production and to suppress regrowth of tumor cells.
The ATA 2015 guidelines suggest the following: for patients with high-risk thyroid cancer patients, initial thyroid-stimulating hormone (TSH) suppression to below 0.1 mU/L is recommended; for intermediate-risk, TSH suppression to 0.1–0.5 mU/L is recommended; and for low risk, 0.5–2 mU/L is recommended.
| Postoperative Evaluation | | |
To assess the postoperative disease status accurately, two main modalities are currently in use to ascertain the same are thyroid whole-body radioiodine scintigraphy (TWBS) and stimulated serum thyroglobulin (sTg). This is carried out approximately 4–6 weeks after thyroidectomy.
Stimulated serum thyroglobulin
It is employed as an optimal tumor marker. In routine practice, patients are advised low-iodine diet and advised to stop T4 tablets for a period of 4 weeks to achieve adequate TSH stimulation (target TSH >30 mU/L). This is to ensure that disease burden is not falsely suppressed due to lack of adequate TSH stimulation.
Another option available is to inject recombinant TSH injection 0.9-mg intramuscularly following which the TWBS and sTg are measured within 24 h. However, in view of the high cost, it is not routinely practiced.
Thyroid whole-body radioiodine scintigraphy
Radioactive I-131 enters the cells that express sodium-iodide symporters, and by the property of gamma emission (energy of 606 KeV), planar images are obtained by gamma camera imaging.
The routine practice includes an oral administration of dose of 74MBq of iodine-131, following which planar whole-body anterior and posterior views and spot views of the neck were acquired after 48 h [Figure 3]. | Figure 3: Normal thyroid whole-body radioiodine scintigraphy showing physiological uptake in the salivary glands, stomach wall, bowel, and bladder (Case of a 40/F, posttotal thyroidectomy and radioactive iodine-131 ablation on follow-up, serum thyroglobulin – <0.1 ng/ml) (Image courtesy: Department of Nuclear Medicine, Christian Medical College, Vellore).
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| Decision on Radioactive Iodine Ablation | | |
The combination of sTg and TWBS gives a good estimate of the tumor burden and the dose for the radioactive iodine (RAI) ablation (RAIA) varies from center to center.
The ATA guidelines recommend 150 mCi for metastases to the lymph nodes, 200 mCi for pulmonary metastases, and 250 mCi for osseous metastases [Figure 4], [Figure 5], [Figure 6].[6] | Figure 4: Thyroid whole-body radioiodine scintigraphy showing residual tumor in the thyroid bed (41/F with follicular variant of papillary thyroid cancer, biopsy P T2N1aMx, posttotal thyroidectomy on follow-up, serum thyroglobulin – 72.4 ng/ml) Image courtesy: Department of Nuclear Medicine, Christian Medical College, Vellore).
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 | Figure 5: Thyroid whole-body radioiodine scintigraphy showing multiple osseous lesions. (54/F with poorly differentiated thyroid carcinoma, P T4 N0 M1, postthyroidectomy, serum thyroglobulin – 78330 ng/ml) (Image courtesy: Department of Nuclear Medicine, Christian Medical College, Vellore).
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 | Figure 6: Thyroid whole-body radioiodine scintigraphy showing bilateral pulmonary metastases (34/F with classical variant of thyroid carcinoma, P T2 N1b M1, postthyroidectomy and iodine ablation, serum thyroglobulin – 4485 ng/ml) (Image courtesy: Department of Nuclear Medicine, Christian Medical College, Vellore).
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| Decision-Making Based on the American Thyroid Association Risk | | |
In our institution, 100 mCi of radioactive I-131 is given to all patients. However, in patients with low risk disease - young (age < 55) patients, favourable histology, completely resected disease, no extrathyroidal extension, no nodes/distant metastases, low disease burden (as corroborated by sTg and TWBS) – the dose is reduced to 50 mCi. All other patients receive 100 mCi of radioactive I-131. However, ATA guidelines state that RAI remnant ablation is not routinely recommended after thyroidectomy for ATA low-risk DTC patients.[6] Consideration of specific features of the individual patient that could modulate recurrence risk, disease follow-up implications, and patient preferences is relevant to RAI decision-making.
| Radioactive Iodine Ablation | | |
- The oral administration of the high-dose therapy requires inpatient admission
- Absolute contraindications include pregnancy and breast feeding
- The fetal thyroid tissue would be destroyed by the radioiodine resulting in cretinism
- Breastfeeding should be stopped at least 6–8 weeks prior to RAIA.
| Acute Side Effects | | |
Sialadenitis and neck edema are commonly reported a few days after the therapy. This can be prevented by frequent use of sialogogues such as sour candies/lemon pieces to prevent stasis of radioactive iodine within the salivary glands. Pain or edema can be managed with nonsteroidal anti-inflammatory drugs.
| Long-Term Effects | | |
Loss of taste sensation and dryness of mouth are common if sialogogues are not adequately used. Transient oligospermia can be present. The risk of secondary malignancies such as leukemia (from recent studies) is negligible and comparable to the risk in the general public.
| Discharge and Instructions | | |
- Exposure rate at time of discharge <50 μSv/h at 1-m distance
- Radiation exposure to caregiver will not exceed 5 mSv per year
- Exposure to the public, a child, or a pregnant woman not exceeds 1 mSv (100 mrem) in 1 year
- Remain ≥1.8 m (6 feet) away from family members, general public, or caregivers for about 24 h after treatment
- Adult caregivers may be closer than 1 m (3 feet) for brief intervals
- 131-I is excretion is maximum during the first 48 h after treatment
- Patients should stay well-hydrated (3–4 L of fluid daily) and void frequently
- Female patients – pregnancy should be delayed 6 months after radioiodine therapy
- In men, delay – 3–4 months – recovery of the transient oligospermia.
| Posttherapy Scan | | |
- TWBS 2–8 days after treatment
- The post-treatment scan reveals new sites of uptake in about 10% of patients. This significantly alters the patient's prognosis.
| Follow-Up | | |
Lifelong follow-up is recommended for DTC as local recurrences are said to occur even up to 15 years after the initial diagnosis. The long-term management of these patients often remains a challenge. The differences in patient and tumor characteristics, risk of recurrence, and locoregional and distant metastases have contributed to the difficulty in framing a definitive protocol.
They are required to follow-up every 6–8 months after the initial RAI with sTg and TWBS to assess the clinical, biochemical, and structural response. If lymph nodal recurrence is strongly suspected and TWBS does not pick up disease, an ultrasonography of the neck can be performed for reviewing the size and morphology of the metastatic nodes.
| Decision on Repeat Radioactive Iodine | | |
- Repeat RAI is not recommended when a patient is disease free, i.e., clinically with no evidence of disease, negative TWBS, and negligible sTg or when a stable status has been achieved
- It is recommended in cases with large disease burden, Tg <10 ng/ml with local/distant disease on follow-up.
- Empirical RAI of 100 mCi I-131 is given in the setting of elevated sTg but negative TWBS
- There is no upper limit to the number of RAI that given be given to the patient, as long as disease is picked up on TWBS and there is biochemical response.
| When to Stop Radioactive Iodine | | |
Once the disease dedifferentiates, it becomes iodine refractory. In this setting, sTg continues to rise and TWBS is negative. This condition is termed as thyroglobulin-elevated negative iodine scan. F18-fluorodeoxyglucose positron emission tomography/CT scan in these patients will show the disease burden accurately [Figure 7]. These patients will not benefit from more RAI and have to be offered other systemic therapy such as tyrosine kinase inhibitors (TKIs). | Figure 7: 64/F with papillary thyroid cancer, pT2N1M1 with lung metastases, thyroid whole-body radioiodine scintigraphy is negative (seen on the four images on the left), but fluorodeoxyglucose positron emission tomography-computed tomography shows lung lesions (colour image on the right). (Image courtesy: Department of Nuclear Medicine, Christian Medical College, Vellore).
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| Other Systemic Therapy | | |
Most commonly used class of drugs is the TKIs. The most common used TKI is sorafenib. Other options include sunitinib and lenvatinib. TKI therapy should be considered in RAI-refractory DTC patients with symptomatic, rapidly progressive, metastatic disease [Table 6]. | Table 6: Factors to review when considering kinase inhibitor therapy (American Thyroid Association guidelines 2015)
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| Role of External Beam Radiation Therapy | | |
There is no role for routine adjuvant external beam radiation therapy (EBRT) to the neck in patients with DTC following complete surgical removal of the thyroid tumor. Adjuvant EBRT may be considered in cases with gross extrathyroidal extension and residual gross disease. It can also be considered in patients requiring frequent neck re-operations for locoregionally recurrent disease.
| Prognosis | | |
The prognosis of DTC is generally good. This is primarily dependent on the biologic behavior of the tumor cells and on the timely appropriate treatment which includes total thyroidectomy and ablation by radioiodine-131. However, in approximately, 30% of patients, at 30 years of follow-up, have recurrence of disease. It is thus of utmost importance to evaluate the prognostic factors and identify high-risk patients [Table 7]. Age >55 years, male gender, increased vascular invasion and extrathyroidal extension of the tumor, histological tall cells and columnar cells, and presence of lymph nodal or distant metastases are all considered as risk factors that can lead to poor prognosis. | Table 7: Clinical implications of response to therapy reclassification in patients with differentiated thyroid cancer treated with total thyroidectomy and radioiodine remnant ablation (American Thyroid Association guidelines 2015)
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Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]
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