Current Medical Issues

REVIEW ARTICLE
Year
: 2018  |  Volume : 16  |  Issue : 4  |  Page : 131--139

Overview of role of nuclear medicine in differentiated thyroid cancers


Saumya Sara Sunny 
 Department of Nuclear Medicine, Christian Medical College, Vellore, Tamil Nadu, India

Correspondence Address:
Saumya Sara Sunny
Department of Nuclear Medicine, Christian Medical College, Vellore - 632 004, Tamil Nadu
India

Abstract

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.



How to cite this article:
Sunny SS. Overview of role of nuclear medicine in differentiated thyroid cancers.Curr Med Issues 2018;16:131-139


How to cite this URL:
Sunny SS. Overview of role of nuclear medicine in differentiated thyroid cancers. Curr Med Issues [serial online] 2018 [cited 2019 Aug 23 ];16:131-139
Available from: http://www.cmijournal.org/text.asp?2018/16/4/131/256315


Full Text

 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 factorFamily 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]{Figure 1}{Table 1}{Figure 2}

Taller than wider lesionPresence of microcalcificationsPresence of central/lateral compartment nodes with loss of fatty hilumSolid component which is hypo/isoechoicIrregular margins

Fine needle aspiration cytology: The Bethesda classification for reporting thyroid cytopathology is shown in [Table 2]Other radiological investigations were as follows:{Table 2}

Chest X-ray and computed tomography (CT) thorax – if lung metastases are suspectedX-rays and magnetic resonance imaging (MRI) – if osseous, brain or spine metastases is suspectedPreoperative 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}{Table 4}

Prognosticate while considering regimens for therapeutic strategies and disease surveillanceRisk-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}

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}

 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}{Figure 5}{Figure 6}

 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 admissionAbsolute contraindications include pregnancy and breast feedingThe fetal thyroid tissue would be destroyed by the radioiodine resulting in cretinismBreastfeeding 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 distanceRadiation exposure to caregiver will not exceed 5 mSv per yearExposure to the public, a child, or a pregnant woman not exceeds 1 mSv (100 mrem) in 1 yearRemain ≥1.8 m (6 feet) away from family members, general public, or caregivers for about 24 h after treatmentAdult caregivers may be closer than 1 m (3 feet) for brief intervals131-I is excretion is maximum during the first 48 h after treatmentPatients should stay well-hydrated (3–4 L of fluid daily) and void frequentlyFemale patients – pregnancy should be delayed 6 months after radioiodine therapyIn men, delay – 3–4 months – recovery of the transient oligospermia.

 Posttherapy Scan



TWBS 2–8 days after treatmentThe 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 achievedIt 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 TWBSThere 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}

 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}

 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}

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1La Vecchia C, Malvezzi M, Bosetti C, Garavello W, Bertuccio P, Levi F, et al. Thyroid cancer mortality and incidence: A global overview. Int J Cancer 2015;136:2187-95.
2Sanabria A, Kowalski LP, Shah JP, Nixon IJ, Angelos P, Williams MD, et al. Growing incidence of thyroid carcinoma in recent years: Factors underlying overdiagnosis. Head Neck 2018;40:855-66.
3Pal T, Vogl FD, Chappuis PO, Tsang R, Brierley J, Renard H, et al. Increased risk for nonmedullary thyroid cancer in the first degree relatives of prevalent cases of nonmedullary thyroid cancer: A hospital-based study. J Clin Endocrinol Metab 2001;86:5307-12.
4Fagin JA, Mitsiades N. Molecular pathology of thyroid cancer: Diagnostic and clinical implications. Best Pract Res Clin Endocrinol Metab 2008;22:955-69.
5Sugitani I, Fujimoto Y, Yamamoto N. Papillary thyroid carcinoma with distant metastases: Survival predictors and the importance of local control. Surgery 2008;143:35-42.
6Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 2016;26:1-33.
7Haugen BR. Initial treatment of differentiated thyroid carcinoma. Rev Endocr Metab Disord 2000;1:139-45.