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Eleonora Molinaro, Maria Cristina Campopiano, and Rossella Elisei

In the last decades, the incidence of thyroid cancer (TC) has more than doubled, but the disease-specific mortality rate was stable. To date 30-40% of all TC is represented by papillary microcarcinomas (mPTC), an indolent tumor, that probably remained undiagnosed before routine ultrasound use.

In 1993, Miyauchi was the first who hypothesized a conservative approach for low-risk mPTC and introduced the concept of active surveillance (AS) in its clinical management. The progression rate of mPTC during AS was low and delaying surgery did not impact on the efficacy of treatment or outcome. Since then, several authors from all over the world have reported their experience on AS in mPTCs.

As suggested by current guidelines, AS can be considered as an alternative to immediate surgery to avoid over-treatment in low-risk mPTC and may be the strategy to avoid complications from unnecessary surgery. In the last years, the AS inclusion criteria have been extended to both bigger tumors and to younger/healthier patients. The adoption of AS should take into consideration not only tumor characteristics, but also patient psychological profiles and medical team expertise.

Its safety and efficacy have been demonstrated in long-term outcome studies and in other types of tumors, however, scepticism in patients, families and physicians should be overcome by strong recommendations coming from scientific guidelines.

This review analyses the several and different experiences on AS and the potential obstacles in implementing it as a routine approach in mPTC patients.

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Maria Annateresa Provenzale, Emilio Fiore, Clara Ugolini, Liborio Torregrossa, Riccardo Morganti, Eleonora Molinaro, Paolo Miccoli, Fulvio Basolo, and Paolo Vitti

Objective

Papillary thyroid microcarcinomas (microPTC) may be ’incidental’ (Inc-microPTC), occasionally found at histology after surgery for benign disease or ‘non-incidental’ (Non-Inc-microPTC), diagnosed on clinical grounds. It is unclear whether these different microPTC reflect the same disease. The aim of the study was to compare Inc-microPTC and Non-Inc-microPTC for clinical and histological features as well as for serum TSH, a known factor involved in PTC development.

Design

We evaluated histology and serum TSH levels of consecutive patients submitted to thyroidectomy for goiter with compressive symptoms or for cytological diagnosis suspicious/indicative of PTC.

Methods

In total, 665 consecutive patients (259 with a single thyroid nodule, SN and 406 with a multinodular gland, MN) were included in the study. According to histology, patients were classified as: benign nodular goiter (Benign, n=291); Inc-microPTC (n=92); Non-Inc-microPTC (n=67) and PTC≥1cm (macroPTC, n=215).

Results

Inc-microPTC were significantly more frequent in MN than in SN (66/406, 16.2% vs 26/259, 10.0%, P=0.02). Patients with Inc-microPTC compared with Non-Inc-microPTC were older (mean age±s.d. 53.3±13.2 years vs 44.9±14.8 years, P=0.0002), had a smaller tumor size (median 4mm vs 9mm, P<0.0001), a higher frequency of multifocality (70/92, 76.1% vs 35/67, 52.2% P=0.001) and lower levels of TSH (median 0.6mIU/L, IR: 0.4–1.0mIU/L vs value 1. mIU/L, IR: 0.6–1.4mIU/L vs P=0.0001).

Conclusion

Incidental and non-incidental papillary thyroid microcarcinomas appear to be two different entities.

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Patrizia Agretti, Eleonora Ferrarini, Teresa Rago, Antonio Candelieri, Giuseppina De Marco, Antonio Dimida, Filippo Niccolai, Angelo Molinaro, Giancarlo Di Coscio, Aldo Pinchera, Paolo Vitti, and Massimo Tonacchera

Objective

MicroRNAs (miRNAs) are small endogenous noncoding RNAs that pair with target messengers regulating gene expression. Changes in miRNA levels occur in thyroid cancer. Fine-needle aspiration (FNA) with cytological evaluation is the most reliable tool for malignancy prediction in thyroid nodules, but cytological diagnosis remains undetermined for 20% of nodules.

Design

In this study, we evaluated the expression of seven miRNAs in benign nodules, papillary thyroid carcinomas (PTCs), and undetermined nodules at FNA.

Methods

The prospective study included 141 samples obtained by FNA of thyroid nodules from 138 patients. miRNA expression was evaluated by quantitative RT-PCR and statistical analysis of data was performed. Genetic analysis of codon 600 of BRAF gene was also performed.

Results

Using data mining techniques, we obtained a criterion to classify a nodule as benign or malignant on the basis of miRNA expression. The decision model based on the expression of miR-146b, miR-155, and miR-221 was valid for 86/88 nodules with determined cytology (97.73%), and adopting cross-validation techniques we obtained a reliability of 78.41%. The prediction was valid for 31/53 undetermined nodules with 16 false-positive and six false-negative predictions. The mutated form V600E of BRAF gene was demonstrated in 19/43 PTCs and in 1/53 undetermined nodules.

Conclusions

The expression profiles of three miRNAs allowed us to distinguish benign from PTC starting from FNA. When the assay was applied to discriminate thyroid nodules with undetermined cytology, a low sensitivity and specificity despite the low number of false-negative predictions was obtained, limiting the practical interest of the method.

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Rossella Elisei, Loredana Lorusso, Paolo Piaggi, Liborio Torregrossa, Giovanni Pellegrini, Eleonora Molinaro, Laura Agate, Valeria Bottici, Fabiana Pani, Andrea Cacciato Insilla, Francesca Casella, Raffaele Ciampi, Ilaria Tognetti, Gabriele Materazzi, Fulvio Basolo, and Cristina Romei

Background

Medullary thyroid cancer (MTC) is capable of secreting several proteins, such as calcitonin (Ct), carcinoembryonic antigen (CEA), chromogranin and others. Recently, we observed an aggressive MTC with high levels of serum carbohydrate antigen 19.9 (Ca 19.9) and a rapid evolution to death.

Objective

The aim of this study was to evaluate whether high levels of serum Ca 19.9 could be a prognostic factor of death in patients with advanced MTC.

Patients and methods

We measured Ca 19.9, CEA and Ct in 100 advanced structural recurrent/persistent MTC patients and in 100 cured or biochemically affected MTC patients. Clinical and pathological data were also collected.

Results

Sixteen percent of the patients with advanced MTC had high levels of Ca 19.9. The group with abnormal Ca 19.9 levels had significantly higher levels of CEA and Ct compared with the group with normal values of Ca 19.9 (P<0.0001 for both Ct and CEA). At variance, all 100 patients in the MTC control group showed normal levels of Ca 19.9. Moreover, among the advanced cases, the Ca 19.9-positive group showed a higher mortality rate than the group with normal levels. A logistic regression analysis demonstrated that an elevated level of Ca 19.9 is a predictor of mortality (OR=3.78, P=0.04), independent from Ct doubling time.

Conclusions

These results demonstrated that an elevated value of serum Ca 19.9 appears to be a predictive factor of poor prognosis in advanced MTC patients and identifies those cases with a higher risk of mortality in the short term.

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Ferruccio Santini, Giulia Galli, Margherita Maffei, Paola Fierabracci, Caterina Pelosini, Alessandro Marsili, Monica Giannetti, Maria Grazia Castagna, Serenella Checchi, Eleonora Molinaro, Paolo Piaggi, Furio Pacini, Rossella Elisei, Paolo Vitti, and Aldo Pinchera

TSH-receptor (TSHR) has been found in a variety of cell types, including preadipocytes and adipocytes. In vitro, TSH-mediated preadipocyte and adipocyte responses include proliferation, differentiation, survival, and lipolysis.

Objective

To measure the response of serum leptin to exogenous administration of recombinant human TSH (rhTSH) in vivo.

Patients

One hundred patients with differentiated thyroid cancer already treated by total thyroidectomy and 131I remnant ablation were enrolled. Mean (±s.e.m.) body mass index (BMI) was 26.9±0.6 kg/m2.

Methods

Patients received a standard dose of rhTSH for measurement of thyroglobulin in the follow-up of their disease. Blood samples were taken for the assay of TSH and leptin before the first administration of rhTSH (time 0), and 24 h (time 1), 48 h (time 2), 72 h (time 3), and 96 h (time 4) after the first administration of rhTSH.

Results

Significant mean serum leptin increments, with respect to basal value, were 16, 13, 18, and 11% at times 1, 2, 3, and 4 respectively. Significant positive correlations of leptin–area under the curve with respect to basal leptin levels (r=0.43; P<0.0001) and BMI (r=0.32; P<0.005) were observed.

Conclusions

Acute rhTSH administration in hypothyroid subjects under l-thyroxine therapy produces a rise in serum leptin. This increase is proportional to the adipose mass suggesting that a functioning TSHR is expressed on the surface of adipocytes. The role that TSHR activation in adipocytes might play in physiological and pathological conditions remains a matter of investigation.

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Maria Cristina Campopiano, Debora Podestà, Francesca Bianchi, Carlotta Giani, Laura Agate, Valeria Bottici, Virginia Cappagli, Loredana Lorusso, Antonio Matrone, Luciana Puleo, Laura Valerio, David Viola, Paolo Piaggi, Rossella Elisei, and Eleonora Molinaro

Objective:

At present, recombinant TSH cannot be used for the treatment of metastatic differentiated thyroid cancer patients. The aim of this study was to evaluate if the type of TSH stimulation, recombinant or endogenous, had an impact on the outcome of these patients.

Design and methods:

We compared the outcome of two propensity score-matched groups of metastatic patients, stimulated by either only recombinant TSH (n = 43) or only endogenous TSH (n = 34).

Results:

As expected from the matching procedure, the clinical–pathological features and the cumulative 131-I activities administered to the two groups were very similar. After 4 years of follow-up, 4% of patients were cured, 3% had biochemical disease and 93% had structural disease. However, 91% of patients obtained a clinical benefit from this therapy in terms of stabilization of the disease or complete remission or partial response. When considering the two groups separately, we did not find any difference in their outcome. When considering the response to 131-I therapy of the single type of metastases, 8% of lymph node metastases and 8% of lung metastases disappeared but none of the bone metastases. The response to 131-I therapy of the single type of metastases was similar when we looked at the two groups separately.

Conclusions:

This study shows (i) an overall clinical benefit of the 131-I therapy, since the majority of patients remained affected but with a stable disease, and (ii) that the preparation with either recombinant or endogenous TSH has no impact on the 131-I therapy efficacy and the outcome of our two groups of patients.