18F-FDG PET/CT concurrent with first radioiodine post-therapeutic scan in high risk differentiated thyroid cancer: a useful tool or just an expensive diversion?

BACKGROUND: Aim of the present study was to evaluate the clinical impact of fluorine-18F-fluorodeoxyglucose PET/CT (18F-FDG-PET/CT) concurrent with post-therapeutic whole-body radioiodine scan (TxWBS) after first radioiodine (RAI) treatment in patients with high-risk differentiated thyroid carcinoma (DTC). METHODS: This was a retrospective, single-center study including 39 patients with DTC (22 females, 17 males, median age 54; IQR: 35-60 years, 87% papillary thyroid cancer, 13% follicular thyroid cancer). All patients underwent 18F-FDG-PET/CT and RAI treatment, both performed off L-T4 about 3 months after total thyroidectomy. TxWBS was obtained 3 days afterwards using planar technique and SPECT/CT of neck and thorax regions. Semiquantitative analysis was performed on positive 18F-FDG-PET/CT scans to assess SUVmax, SUVratio, MTV and TLG values in target lesions (hottest 18F-FDG-positive lesion present in each patient). Receiver operating characteristics (ROC) curve analysis was obtained to establish a cut-off point for SUVmax able to predict the presence of RAI nonavid lesions. Univariate and multivariate analyses were executed to find out predictive factors for abnormal 18F-FDG-PET/CT imaging. RESULTS: In 11 (28%) patients 18F-FDG-PET/CT and TxWBS were both negative and in 9 (23%) both positive, showing loco-regional or distant metastases. In 14 patients (36%) 18F-FDG-PET/CT showed more lesions than TxWBS, while in 5 (13%) patients more lesions were present at TxWBS than 18F-FDG-PET/CT. Overall, 23 patients (59%) showed 18F-FDG avid lesions and 18F-FDG-PET/TC changed the management in 14 (36%), including the choice to perform RAI therapy with higher activities than expected, lymph-node dissection for loco-regional metastases, direct therapy for solitary bone metastases. Through ROC curve analysis, a value superior to 7.25 of SUVmax was able to predict the presence of RAI non-avid lesion at TxWBS. Serum stimulated thyroglobulin and extranodal invasion resulted to be risk factors for abnormal 18F-FDG-PET/CT imaging. However, only extranodal invasion turned out to be an independent risk factor for abnormal 18F-FDG-PET/CT. CONCLUSIONS: The present study demonstrated the clinical value of RAI-concurrent 18F-FDG-PET/CT in patients with high-risk DTC. However, some questions remain open, including the pretherapeutic thyroglobulin level to use as indication to 18F-FDG-PET/CT and the predictive value of 18F-FDG-PET/CT semiquantitative parameters.

Changes in Radiosensitivity to Gamma-Rays of Lymphocytes from Hyperthyroid Patients Treated with I-131.

This study investigated the peripheral blood lymphocytes (PBL) response to a dose of γ-rays in patients treated with radioiodine (I-131) for hyperthyroidism vs. healthy controls, to gain information about the individual lymphocytes' radio-sensitivity. Blood samples were taken from 18 patients and 10 healthy donors. Phosphorylated histone variant H2AX (γ-H2AX) and micronuclei (MN) induction were used to determine the change in PBL radio-sensitivity and the correlations between the two types of damage. The two assays showed large inter-individual variability in PBL background damage and in radio-sensitivity (patients vs. healthy donors). In particular, they showed an increased radio-sensitivity in 36% and 33% of patients, decrease in 36% and 44%, respectively. There was a scarce correlation between the two assays and no dependence on age or gender. A significant association was found between high radio-sensitivity conditions and induced hypothyroidism. PBL radio-sensitivity in the patient group was not significantly affected by treatment with I-131, whereas there were significant changes inter-individually. The association found between clinical response and PBL radio-sensitivity suggests that the latter could be used in view of the development of personalized treatments.

Side effects of theragnostic agents currently employed in clinical practice.

Nuclear medicine plays an increasingly important role in several neoplasms management through a theragnostic approach by which targeted molecular imaging and radiotherapy are obtained with the use of radionuclide pairs with similar characteristics. In some cases, nuclear theragnostic use a pair of agents with identical chemical and biological characteristics while in others are employed theragnostic molecules which are not chemically or biologically identical but show similar biodistribution (so-called "twins in spirit" radiopharmaceuticals). This strategy was developed for the first time over 75 years ago, when iodine-131 was used for diagnostic imaging, confirmation of target expression and radionuclide therapy of thyroid cancer. Other theragnostic approaches were subsequently introduced with significant clinical results and some of them are currently considered standard treatment for different cancers. However, as any other therapy, also nuclear theragnostic treatment carries the potential risk of early deterministic and late stochastic off-target adverse effects, generally minimal and easily managed. This article reviews the reported side effects and risks of the main radiopharmaceuticals used for nuclear theragnostic in oncology for the treatment of thyroid cancer, neuroendocrine neoplasms, adrenergic tumors, metastatic prostate cancer, and liver tumors. Selecting appropriate patients using a multidisciplinary approach, meticulous pretreatment planning and knowledge of methods permit to decrease the incidence of these potential side effects.

Radiation dose in nuclear medicine: the hybrid imaging.

Hybrid imaging procedures such as single-photon emission computed tomography/computed tomography (SPECT/CT) and positron emission tomography/computed tomography (PET/CT) showed a rapid diffusion in recent years because of their high sensitivity, specificity, and accuracy, due to a more accurate localization and definition of scintigraphic findings. However, hybrid systems inevitably lead to an increase in patient radiation exposure because of the added CT component. Effective doses due to the radiopharmaceuticals can be estimated by multiplying the administered activities by the effective dose coefficients, while for the CT component the dose-length product can be multiplied by a conversion coefficient k. However, the effective dose value is subject to a high degree of uncertainty and must be interpreted as a broad, generic estimate of biologic risk. Although the effective dose can be used to estimate and compare the risk of radiation exposure across multiple imaging techniques, clinicians should be aware that it represents a generic evaluation of the risk derived from a given procedure to a generic model of the human body. It cannot be applied to a single individual and should not be used for epidemiologic studies or the estimation of population risks due to the inherent uncertainties and oversimplifications involved. Practical ways to reduce radiation dose to patients eligible for hybrid imaging involve adjustments to both the planning phase and throughout the execution of the study. These methods include individual justification of radiation exposure, radiopharmaceutical choice, adherence to diagnostic reference levels (DLR), patient hydration and bladder voiding, adoption of new technical devices (sensitive detectors or collimators) with new reconstruction algorithms, and implementation of appropriate CT protocols and exposure parameters.

The role of positron emission tomography and positron emission tomography/computed tomography in thyroid tumours: an overview.

Positron emission tomography (PET) and PET/computed tomography (PET/CT) with different tracers have been increasingly used in patients with thyroid tumours. The aim of this article is to perform an overview based on literature data about the usefulness of PET imaging in this setting. The role of Fluorine-18-Fluorodeoxyglucose (FDG) PET and PET/CT in differentiated thyroid carcinoma (DTC) is well established, particularly in patients presenting with elevated serum thyroglobulin levels and negative radioiodine whole-body scan. Iodine-124 PET and PET/CT may serve a role in staging DTC and obtaining lesional dosimetry for a better and more rationale planning of treatment with Iodine-131. FDG-PET and PET/CT are useful in the post-thyroidectomy staging of high-risk patients with less differentiated histological subtypes. PET and PET/CT with different tracers seem to be useful methods in localizing the source of elevated calcitonin levels in patients with recurrent medullary thyroid carcinoma. Incorporation of FDG-PET or PET/CT into the initial workup of patients with indeterminate thyroid nodules at fine needle aspiration biopsy deserves further investigation. FDG-PET report should suggest further evaluation when focal thyroid incidentalomas are described because these findings are associated with a significant risk of cancer.

Italian Guidelines for the Management of Non-Functioning Benign and Locally Symptomatic Thyroid Nodules.

AIM: This guideline (GL) is aimed at providing a reference for the management of non-functioning, benign thyroid nodules causing local symptoms in adults outside of pregnancy. METHODS: This GL has been developed following the methods described in the Manual of the National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology (AME) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence and only those classified as "critical" were considered in the formulation of recommendations. RESULTS: The present GL contains recommendations about the respective roles of surgery and minimally invasive treatments for the management of benign symptomatic thyroid nodules. We suggest hemithyroidectomy plus isthmectomy as the first-choice surgical treatment, provided that clinically significant disease is not present in the contralateral thyroid lobe. Total thyroidectomy should be considered for patients with clinically significant disease in the contralateral thyroid lobe. We suggest considering thermo-ablation as an alternative option to surgery for patients with a symptomatic, solid, benign, single, or dominant thyroid nodule. These recommendations apply to outpatients, either in primary care or when referred to specialists. CONCLUSION: The present GL is directed to endocrinologists, surgeons, and interventional radiologists working in hospitals, in territorial services, or private practice, general practitioners, and patients. The available data suggest that the implementation of this GL recommendations will result in the progressive reduction of surgical procedures for benign thyroid nodular disease, with a decreased number of admissions to surgical departments for non-malignant conditions and more rapid access to patients with thyroid cancer. Importantly, a reduction of indirect costs due to long-term replacement therapy and the management of surgical complications may also be speculated.

Papillary thyroid microcarcinoma: extrathyroidal extension, lymph node metastases, and risk factors for recurrence in a high prevalence of goiter area.

BACKGROUND: Although papillary thyroid microcarcinoma (PTMC) is diagnosed with increasing frequency, the best therapeutic option and follow-up protocol have not been established yet, especially in the case of incidental diagnosis. We reviewed our series of patients with PTMC to determine risk factors for recurrence in an area where there is a high prevalence of goiter. METHODS: The medical records of all patients who underwent thyroidectomy with a final pathology report of PTMC between October 2002 and June 2007 were reviewed. PTMC was defined as a papillary thyroid carcinoma 10 mm or less in diameter. Follow-up evaluation was obtained by outpatient consultation and/or telephone interview. RESULTS: In a series of 2,220 patients who underwent thyroidectomy for a thyroid carcinoma, 933 had a PTMC. Diagnosis was incidental in 704 patients (75.5%). Upon multivariate analysis, tumor size, nonincidental diagnosis, and neck node metastases at diagnosis were independent risk factors for extracapsular spread (ECS), while ECS, multifocal disease, and number of removed lymph nodes were independent risk factors for lymph node metastases at diagnosis. Follow-up evaluation was completed in 287 patients, 9 (3.1%) of whom experienced recurrence. The number of removed and metastasized nodes at first operation and the length of the follow-up were independent risk factors for recurrent disease. CONCLUSIONS: Incidental diagnosis of PTMC is frequent in a high prevalence of goiter area. PTMC shows a variable degree of aggressiveness. Management protocols should be based on patient- and tumor-related prognostic factors, as for larger tumors.

A case of metastatic struma ovarii treated with 131I therapy: focus on preservation of fertility and selected review of the literature.

Struma ovarii is a rare monodermal ovarian teratoma composed predominantly of mature thyroid tissue. We describe herein the case of a 22-year-old woman who underwent a right salpingo-oophorectomy for struma ovarii at the age of 12 years, who was admitted 8 years later with signs and symptoms of a left pelvic tumor. Laparoscopy detected a left ovarian endometriotic cyst and multiple nodules on the pelvic peritoneum, right lateral abdominal wall, diaphragm, vesical plica and liver. The diagnosis was abdominal and pelvic widespread dissemination of recurrent struma ovarii, with features consistent with the follicular variant of papillary thyroid carcinoma. The patient was treated with a combination of conservative surgery and two 131I administrations (cumulative activity of 350 mCi after dosimetric evaluation). Because of the high degree of hormonogenesis shown by the metastases, the first administration was performed following use of recombinant human (rh) thyroid-stimulating hormone (TSH) to reach adequate TSH levels. To avoid the 'stunning effect' and to obtain high-quality scintigraphy, a whole-body scan was performed with 123I after rh-TSH and before the 131I therapy. We also discuss the potential role and the possible benefit of using gonadotropin-releasing hormone analogs and ovarian tissue cryopreservation to preserve fertility in women treated with 131I for pelvic metastases from malignant struma ovarii.

Accumulation of 131I in Esophageal Diverticulum Diagnosed by SPECT/CT.

A 72-year-old man underwent total thyroidectomy and radioiodine remnant ablation for papillary thyroid cancer in 2016. The posttherapy whole-body scan showed uptake in the neck, classified as residual thyroid tissue. Two years later, the patient came to our observation to perform a second radioiodine therapy for high levels of thyroglobulin. The planar posttherapy scan showed a focal radioiodine area in the neck. SPECT/CT diagnosed a voluminous esophageal diverticulum located in the upper third of the esophagus. A CT performed to discover the source of thyroglobulin excluded locoregional or distant metastases and confirmed the presence of a Zenker diverticulum.

Radio-guided surgery of differentiated thyroid cancer using (131)I or 99mTc-Sestamibi.

The classical therapeutic approach to patients with differentiated thyroid cancer (DTC) is based on total or near-total thyroidectomy, followed by (131)I treatment and thyroid-stimulating hormone suppressive therapy. This approach allows complete cure in many patients, especially when the tumour is diagnosed at an early stage; it also allows long-term survival in patients with locoregional recurrences or distant metastases if they can be treated with (131)I. In contrast, when metastatic DTC deposits lose their ability to trap (131)I (non-functioning metastases), a worse prognosis is expected. Nevertheless, in patients with locoregional non-functioning recurrences, an early diagnosis and prompt surgical extirpation can lead to a favourable prognosis. In these cases, radical surgery is needed. This can be achieved with radio-guided surgery using a hand-held gamma probe and a tumour-seeking radiotracer to detect, intraoperatively, the smallest metastatic lesions. In this paper, we discuss the two principal techniques proposed in the literature for radio-guided surgery of non-functioning DTC metastatic recurrences, the first using high doses of (131)I and the second using low doses of 99mTc-Sestamibi.

Treatment of local and regional recurrences of differentiated thyroid cancer by radio-guided surgery with iodine-131.

UNLABELLED: BACKGROUND/MATERIAL AND METHODS: The aim of this study was to assess the reliability of radioiodine ((131)I) and a gamma probe for radio-guided surgery (RGS) to detect and radically dissect lymph node recurrence (LNR) in 15 patients with differentiated thyroid cancer (DTC). The major inclusion criterion was the presence of a radioiodine-positive LNR after previous total thyroidectomy and at least two ineffective (131)I treatments. The protocol was designed as follows: Day 0--all patients were hospitalized and received 3.7 GBq of (131) I while clinically hypothyroid. Day 3--pre-surgery whole-body scan with a therapeutic (131)I dose (TxWBS) was acquired. Day 5--neck surgery using a gamma probe (Navigator GPS, AutoSuture, Italy), recording the absolute counts and the lesion/background (L/B) counts ratio was performed. Day 7--post-surgery TxWBS was performed using the remaining radioactivity. RESULTS AND CONCLUSIONS: This protocol permitted us to identify neoplastic foci with high sensitivity and specificity, enabling us to remove lymph node metastases resistant to radioiodine therapy in a single session. The protocol also allowed detection of some additional tumoural foci in sclerotic areas or behind vascular structures that were not seen at the pre-surgery TxWBS evaluation.

Posterior mediastinal hyperfunctioning insular thyroid carcinoma.

A case is presented of a posterior mediastinal mass arising in a 57-year-old woman with severe compressive cervical symptoms and hyperthyroidism. Computed tomography showed intrathoracic thyroid tissue that displaced the trachea towards the front and the right and invaded the posterior mediastinum. Pathological examination showed features of a poorly differentiated (insular) thyroid carcinoma. To the best of our knowledge, this is the first reported case of a posterior mediastinal insular thyroid carcinoma with thyroid hyperfunction.

Imaging in endocrinology: 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in differentiated thyroid carcinoma: clinical indications and controversies in diagnosis and follow-up.

In recent years, 2-[(18)F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) has emerged as an important tool for the postoperative management of patients with differentiated thyroid cancer (DTC) and it is widely used in selected clinical situations. The most valuable role that FDG-PET/CT plays in clinical practice is that it can be used to obtain prognostic information in patients with increasing thyroglobulin (Tg) levels and negative (131)I whole-body scan post-thyroidectomy and radioiodine (RAI) ablation. FDG-PET/CT may also have a potential role in the initial staging and follow-up of high-risk patients with aggressive histological subtypes, in the identification of patients who are at the highest risk of disease-specific mortality, in the management of patients with RAI-refractory disease, in clinical trials of novel targeted therapies in patients with advanced metastatic disease, and in the evaluation of thyroid nodules with indeterminate fine-needle aspiration for cytology. However, several controversies remain to be resolved, namely: the cutoff value of Tg in the selection of DTC patients for FDG-PET/CT, whether FDG-PET/CT scanning should be performed under thyrotropin stimulation or suppression, and the clinical significance of thyroid FDG-PET/CT incidentalomas. The aim of the present article is to provide an overview of the data about the molecular basis for, clinical indications of, and controversies related to the use of FDG-PET/CT in patients with DTC.

Papillary thyroid microcarcinoma: proposal of treatment based on histological prognostic factors evaluation.

BACKGROUND: Papillary thyroid cancer accounts for approximately 80% of thyroid tumors and its incidence has increased over the past decades. Papillary thyroid microcarcinomas (PMCs), defined by the World Health Organization as less than 1.0 cm in size, are identified with greater frequency. The majority of patients with PMCs follows a benign clinical course, however a subgroup of these carcinomas is as aggressive as bigger tumors. Risk factors related with poor outcome have not been defined and the optimal treatment has not been proved. The authors investigated histologic prognostic factors predicting high risk patients considered for more aggressive treatment and propose reviewed therapeutic guidelines based on analysis of histopathologic features which determined the recurrence rate. STUDY DESIGN: One hundred forty nine patients with PMC who underwent surgery were retrospectively analyzed. Clinical and histopathologic parameters potentially predicting patient outcome and recurrent disease were statistically investigated, after a minimum follow-up of 5 years. RESULTS: After a median follow-up of 5.4 years 28 of 149 patients experienced recurrent disease. All of them were reoperated on and newly treated with radioiodine administration. The multivariate statistical analysis identified extrathyroidal invasion (Odds Ratio, OR, 58.54; P=0.013), the solid pattern (OR,25.77; P>0.001), the tumor multifocality (OR, 15.80; P= 0.005), and the absence of tumor capsule (OR, 9.74; P=0.015) as significant and indipendent risk factors for the appearance of PMCs recurrences. Of note, none of the PMC "incidentally" discovered at histopathological examination alone experienced recurrent disease during follow-up. CONCLUSIONS: Although most PMC have favourable long-term prognosis, some patients (19% in our series) presented aggressive clinical course strongly correlated with some histopathologic features (extrathyroidal invasion, tumor multifocality, solid pattern and absence of capsule) who need to be investigated and for whom a radical therapeutic approach is recommended based on total thyroidectomy and regional lymphadenectomy followed by radioiodine administration.