The use of recombinant human thyrotropin (rhTSH) testing in the diagnosis and therapy of differentiated thyroid cancer (DTC) has been adopted over the last two decades as an alternative to the classical thyroid hormone withdrawal avoiding the threat of hypothyroidism. Serum thyroglobulin (Tg) measurement is crucial for monitoring DTC patients over time. Until about a decade ago, optimal sensitivity of Tg assays for the detection of smaller disease foci required Tg measurement after thyrotropin (TSH) stimulation, carried out following thyroid hormone withdrawal or rhTSH administration. In very recent years, significant improvements in assay technology have resulted in highly sensitive Tg (hsTg) assays, sufficiently sensitive to obviate the need for rhTSH stimulation in most DTC patients. The aim of this paper is to review and discuss, via a ‘pros and cons’ approach, the current clinical role of rhTSH to stimulate radioiodine (RAI) uptake for treatment and/or imaging purposes and to increase the clinical sensitivity of Tg measurement for monitoring DTC patients when high-sensitive Tg assays are available.
Luca Giovanella and Leonidas H Duntas
Luca Giovanella, Mauro Imperiali, Frederik A Verburg, and Pierpaolo Trimboli
To assess the diagnostic performance of three high-sensitive assays in a cohort of TgAb-negative and TgAb-positive differentiated thyroid cancer (DTC) patients.
Retrospective study on prospectively selected DTC patients.
Serum samples from 154 DTC patients were obtained 6–12 months after radioiodine ablation and tested by Beckman, Roche, BRAHMS Tg and TgAb assays, respectively. Receiver operating characteristics curves for Tg were plotted using outcome over time as benchmark and assay-specific Tg thresholds were obtained for TgAb-negative and TgAb-positive patients.
The frequency of positive TgAb was 21, 20 and 20% for Beckman, Roche and BRAHMS, respectively. In TgAb-negative patients, clinical sensitivities and specificities of 100% and 85–95%, respectively, were observed across all assays. In TgAb-positive patients, clinical sensitivities and specificities of 80–100% and 92–96%, respectively, were observed using lower thresholds than in patients without TgAb.
Adopting appropriate thresholds, lower than those for TgAb-negative patients, is possible to reliably follow TgAb-positive patients using highly sensitive Tg assays.
Luca Giovanella, Giorgio Treglia, Frederik A Verburg, Massimo Salvatori, and Luca Ceriani
This study was undertaken to evaluate serum cytokeratin 19 fragment (Cyfra 21.1) expressions in patients with advanced thyroid carcinoma and to explore the relationship between serum Cyfra 21.1 and the degree of radioiodine (131I) avidity of thyroid carcinoma cells.
Enrolled were 76 consecutive patients with advanced thyroid carcinoma submitted to high-activity 131I treatment. In each patient, serum thyroglobulin (Tg) and Cyfra 21.1 were measured before 131I administration and compared with the posttreatment whole-body scan results.
Thirty-one (41%) of 76 patients had iodine-avid and 45 (59%) had iodine-refractory diseases respectively. Significantly higher serum Cyfra 21.1, but not Tg, levels were found in patients with 131I-refractory disease compared with patients with iodine-avid disease (P<0.01).
This is the first report describing the potential role of serum Cyfra 21.1 as marker of dedifferentiation and resistance to 131I therapy in patients with advanced thyroid carcinoma.
Lu Zhang, Marco Castellana, Camilla Virili, Anna Crescenzi, Francesco Giorgino, Emanuele Zucca, Luca Ceriani, Franco Cavalli, Luca Giovanella, and Pierpaolo Trimboli
Primary thyroid lymphoma (PTL) is a rare malignancy, and its prognosis depends significantly on its early diagnosis. While fine-needle aspiration (FNA) represents the gold standard to identify differentiated thyroid carcinoma, its reliability for the detection of PTL is still unclear. Here, we conducted a systematic review and meta-analysis to evaluate the diagnostic performance of FNA in PTL.
Research design and methods
A comprehensive literature search of PubMed/MEDLINE and Scopus databases was conducted to retrieve papers reporting histologically proven PTL undergone FNA. The last search was performed in February 2018 without language and time restrictions.
Thirty-two studies describing 593 PTL were included and the pooled FNA sensitivity was 0.48 (95% CI = 0.38–0.58). FNA sensitivity was 0.51 in 20 studies published before 2010 and 0.39 in those published later, 0.50 in six articles with at least 20 cases and 0.44 in nine series enrolled after 2000. This performance was similar in 12 articles including diffuse large B-cell lymphoma (0.54) and those six on marginal zone lymphoma (0.56). Remarkably, FNA sensitivity increased to 0.72 when considering also FNA reports suspicious for PTL reported in 14 articles. Heterogeneity among the series was found. Publication bias was not always detected.
The present meta-analysis demonstrated that FNA has low sensitivity in diagnosing PTL. However, this rate increased when considering also FNA reports suspicious for PTL, which is relevant from a clinical standpoint. This result could support indirectly the use of additional imaging and/or core biopsy when PTL is suspected.
Alexis Vrachimis, Ioannis Iakovou, Evanthia Giannoula, and Luca Giovanella
Most patients with thyroid nodules and thyroid cancer (TC) referred for diagnostic work-up and treatment are not considered at higher risk of infection from SARS-CoV-2 compared to the general population. On the other hand, healthcare resources should be spared to the maximum extent possible during a pandemic. Indeed, while thyroid nodules are very common, only a small percentage are cancerous and, in turn, most thyroid cancers are indolent in nature. Accordingly, diagnostic work-up of thyroid nodules, thyroid surgery for either benign or malignant thyroid nodules and radioiodine treatment for differentiated thyroid cancers may be safely postponed during SARS-CoV-2 pandemic. Appropriate patient counselling, however, is mandatory and red flags should be carefully identified prompting immediate evaluation and treatment as appropriate. For these selected cases diagnostic work-up (e.g. ultrasound, scintigraphy, fine-needle aspiration), surgery and radioiodine therapy may proceed despite the threat of SARS-CoV-2 infection and COVID-19, after an individual risk-benefit analysis.
Marco Castellana, Camilla Virili, Andrea Palermo, Francesco Giorgino, Luca Giovanella, and Pierpaolo Trimboli
Despite the improvements in ultrasound (US) and scintigraphy, 10–20% of patients with primary hyperparathyroidism (PHPT) still have discordant findings. We performed a systematic review and meta-analysis to assess the safety and the diagnostic performance of US-guided PTH washout (FNA-PTH) in patients with PHPT, a suspected parathyroid lesion on US but negative or equivocal scintigraphy.
The review was registered on PROSPERO (CRD42019124249). PubMed, Scopus, CENTRAL and Web of Science were searched until February 2019. Original articles reporting complications and diagnostic performance of FNA-PTH in biochemically and histopathologically diagnosed PHPT were selected. The risk of bias of included studies was assessed through QUADAS-2. Summary operating points were estimated using a random-effects model.
Out of 2573 retrieved papers, nine cohort studies were included in the review. No major procedure-related complications were found. Pooled sensitivity was 95% (95% CI: 91–98; I 2: = 14%) and positive predictive value was 97% (95% CI: 93–100; I 2: = 39%). There were not enough data for specificity and negative predictive value to perform a meta-analysis. However, pooling results of all lesions, they were estimated to be 83 and 73%, respectively.
In patients with biochemically proven PHPT and discordant imaging, FNA-PTH was a safe and accurate procedure. In this specific setting of patients, FNA-PTH could be used as a rule-in test for minimally invasive parathyroidectomy.
Massimo Bongiovanni, William C Faquin, Luca Giovanella, Cosimo Durante, Peter Kopp, and Pierpaolo Trimboli
The second version of The Bethesda System for Reporting Thyroid Cytopathology endorsed the introduction of non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) as a distinct entity with low malignant potential into clinical practice. Consequently, the risk of malignancy (ROM) of cytological diagnoses has changed, but the magnitude of the change remains uncertain. The present systematic review was undertaken to obtain more robust information about the true impact of NIFTP on the ROM among patients undergoing surgery following a fine-needle aspiration cytology (FNAC) diagnosis of suspicious for malignancy (Bethesda V) or malignant (Bethesda VI). As they are managed surgically, these two diagnostic categories are the primary entities that are clinically impacted by the advent of NIFTP.
Systematic review and meta-analysis.
A comprehensive literature search of online databases was performed in November 2018. The search was conducted looking for data of histologically proven NIFTP with preoperative FNAC.
One-hundred fifty-seven articles were identified and nine were included in the study. Overall, there were 13,752 thyroidectomies with a cancer prevalence of 45.7%. When NIFTP was considered non-malignant, the pooled risk difference for ROM was 5.5%. Applying meta-analysis, the pooled prevalence of NIFTP among nodules with FNAC of Bethesda V or Bethesda VI was 14 and 3%, respectively.
This meta-analysis shows that the inclusion of NIFTP leads to a reduction in the ROM for the Bethesda V and Bethesda VI FNAC diagnostic categories by 14 and 3%, respectively. Clinicians should be aware of these data to avoid overtreatment.
Luca Giovanella, Penelope M Clark, Luca Chiovato, Leonidas Duntas, Rossella Elisei, Ulla Feldt-Rasmussen, Laurence Leenhardt, Markus Luster, Camilla Schalin-Jäntti, Matthias Schott, Ettore Seregni, Herald Rimmele, Jan Smit, and Frederik A Verburg
Differentiated thyroid cancer (DTC) is the most common endocrine cancer and its incidence has increased in recent decades. Initial treatment usually consists of total thyroidectomy followed by ablation of thyroid remnants by iodine-131. As thyroid cells are assumed to be the only source of thyroglobulin (Tg) in the human body, circulating Tg serves as a biochemical marker of persistent or recurrent disease in DTC follow-up. Currently, standard follow-up for DTC comprises Tg measurement and neck ultrasound combined, when indicated, with an additional radioiodine scan. Measurement of Tg after stimulation by endogenous or exogenous TSH is recommended by current clinical guidelines to detect occult disease with a maximum sensitivity due to the suboptimal sensitivity of older Tg assays. However, the development of new highly sensitive Tg assays with improved analytical sensitivity and precision at low concentrations now allows detection of very low Tg concentrations reflecting minimal amounts of thyroid tissue without the need for TSH stimulation. Use of these highly sensitive Tg assays has not yet been incorporated into clinical guidelines but they will, we believe, be used by physicians caring for patients with DTC. The aim of this clinical position paper is, therefore, to offer advice on the various aspects and implications of using these highly sensitive Tg assays in the clinical care of patients with DTC.
Marco Castellana, Giorgio Grani, Maija Radzina, Vito Guerra, Luca Giovanella, Maurilio Deandrea, Rose Ngu, Cosimo Durante, and Pierpaolo Trimboli
Several thyroid imaging reporting and data systems (TIRADS) have been proposed to stratify the malignancy risk of thyroid nodule by ultrasound. The TIRADS by the European Thyroid Association, namely EU-TIRADS, was the last one to be published.
We conducted a meta-analysis to assess the prevalence of malignancy in each EU-TIRADS class and the performance of EU-TIRADS class 5 vs 2, 3 and 4 in detecting malignant lesions.
Four databases were searched until December 2019. Original articles reporting the performance of EU-TIRADS and adopting histology as reference standard were included. The number of malignant nodules in each class and the number of nodules classified as true/false positive/negative were extracted. A random-effects model was used for pooling data.
Seven studies were included, evaluating 5672 thyroid nodules. The prevalence of malignancy in each EU-TIRADS class was 0.5% (95% CI: 0.0–1.3), 5.9% (95% CI: 2.6–9.2), 21.4% (95% CI: 11.1–31.7), and 76.1% (95% CI: 63.7–88.5). Sensitivity, specificity, PPV, NPV, LR+, LR− and DOR of EU-TIRADS class 5 were 83.5% (95% CI: 74.5–89.8), 84.3% (95% CI: 66.2–93.7), 76.1% (95% CI: 63.7–88.5), 85.4% (95% CI: 79.1–91.8), 4.9 (95% CI: 2.9–8.2), 0.2 (95% CI: 0.1–0.3), and 24.5 (95% CI: 11.7–51.0), respectively. A further improved performance was found after excluding two studies because of limited sample size and low prevalence of malignancy in class 5.
A limited number of studies generally conducted using a retrospective design was found. Acknowledging this limitation, the performance of EU-TIRADS in stratifying the risk of thyroid nodules was high. Also, EU-TIRADS class 5 showed moderate evidence of detecting malignant lesions.
Alfredo Campennì, Rosaria Maddalena Ruggeri, Massimiliano Siracusa, Giulia Giacoppo, Flavia La Torre, Angiola Saccomanno, Angela Alibrandi, Gianlorenzo Dionigi, Giovanni Tuccari, Sergio Baldari, and Luca Giovanella
The risk of differentiated thyroid cancer (DTC) recurrence is widely evaluated according to the 2015 ATA Risk Stratification System. Topography of malignant nodules has been previously reported as an additional risk factor but is not included in the ATA system. Thus, our study aimed to evaluate the relationship between DTC topography and response to initial therapy.
Patients and methods:
We enrolled 401 low- to intermediate-risk patients with DTC who had undergone thyroidectomy and radioiodine therapy. DTC topography was recorded and compared with the response to therapy as assessed 12 months after the end of therapy.
Overall, 366/401 (91.3%) patients had an excellent response to initial therapy while 22/401 (5.5%) and 13/401 (3.2%) had incomplete biochemical or structural responses, respectively. Incomplete response occurred in 10/36 (27.8%), 5/125 (4.0%), and 4/111 (3.6%) patients whose unifocal malignant nodules were located in the isthmus, right lobe, or left lobe. Incomplete response was also observed in 4/54 (7.4%) and 12/75 (16%) patients carrying multifocal cancers in one or both lobes, respectively. Patients with isthmic cancer more frequently demonstrated incomplete response compared with those who had cancer in other locations (P = 0.00). No significant relationship was found with age, gender, maximum size of malignant nodule, Hashimoto’s thyroiditis, vascular invasion, and extrathyroidal extension (P = 0.78, P = 0.77, P = 0.52, P = 0.19, P = 0.73, and P = 0.26, respectively). The risk of incomplete response was about 65% higher in patients with isthmic lesions compared with other patients (odds ratio = 6.725). A log-rank test demonstrated that disease-free survival (DFS) of patients with isthmic lesions was significantly shorter than that of other patients (P = 0.02).
Our data show that isthmus topography of malignant thyroid nodules is a risk factor for having both persistent disease 12 months after primary treatment and reduced DFS.