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 the efficacy of treatment or outcome. Since then, several authors from all over the world have reported their experience of AS in mPTCs. As suggested by current guidelines, AS can be considered as an alternative to immediate surgery to avoid overtreatment in low-risk mPTC and may be the strategy to avoid complications from unnecessary surgery. In the last years, 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, skepticism in patients, families and physicians should be overcome by strong recommendations coming from scientific guidelines. This review analyses the several and different experiences of AS and the potential obstacles in implementing it as a routine approach in mPTC patients.
Eleonora Molinaro, Maria Cristina Campopiano, and Rossella Elisei
Furio Pacini, Stefano Mariotti, Nunzio Formica, Rossella Elisei, Stefano Anelli, Enrico Capotorti, and Aldo Pinchera
Abstract. In the present investigation we studied serum anti-thyroglobulin and anti-thyroid microsomal autoantibodies, measured by hemagglutination technique, in 600 patients with thyroid cancer seen by us from 1975 to 1985 (mean follow-up 46 months). Positive thyroglobulin antibodies and/or microsomal antibodies were found in 138 (23%) patients (23.9% with papillary, 25% with follicular, 16.1% with anaplastic, and 4.1% with medullary thyroid carcinomas). The incidence of positive tests was similar in each decade of life (ranging between 21.9% and 27.9%), whereas in a normal sex-matched population with no evidence of thyroid disease, the frequency of positive tests was very low in young people and increased to 23% in people older than 60. In 64 patients with no evidence of residual or metastasic thyroid tissue after surgery and radioiodine, initially positive antibody titres became negative in 54.6%, decreased in 32.8%, did not change in 3.1%, and increased in 9.3%. On the contrary, antibody titres of patients with persistent disease became undetectable in 8.3%, decreased in 16.6%, remained unchanged in 25%, and increased in 50%. The clinical course of differentiated thyroid cancer was unaffected by the presence of thyroid antibodies and no difference was found in the death rate between antibody-positive and antibody-negative patients (11.5% and 13.6%, respectively). In conclusion, our data indicate that: 1) autoimmune phenomena are not an infrequent finding in thyroid cancer; 2) as in non-malignant thyroid diseases, positive-antibody tests are more frequently observed in females than in males; 3) at variance with normal controls, no age-dependent increase in serum anti-thyroid antibodies was found in thyroid cancer; 4) the presence of metastatic thyroid tissue seems to be necessary to perpetuate the autoantibody synthesis, and 5) anti-thyroid autoantibodies are not a protective or worsening factor in the tumour outcome.
Antonio Matrone, Carla Gambale, Margherita Biagini, Alessandro Prete, Paolo Vitti, and Rossella Elisei
Objective: Recently, several scientific societies designed ultrasound (US) risk stratification systems (RSS) to guide the work-up of thyroid nodules and decide which nodules should undergo fine needle aspiration cytology (FNAC). However, these systems have been developed against papillary thyroid carcinoma, and scanty data on their role in identifying medullary thyroid carcinoma (MTC) are available. The aims of this study are to describe the US features of MTC and evaluate the performance of RSS in identifying MTC.
Methods: We evaluated data of 152 consecutive patients with MTC. We collected the results of the pre-operative neck US of all patients. Ultrasound features of each MTC were evaluated and classified according to the 5 main RSS available.
Results: Median MTC dimension was 1.3 cm. Most of the nodules showed solid composition, hypoechoic pattern, and regular margins. About half of them showed the presence of calcifications, but only a subgroup had microcalcifications. A minority of the nodules showed a “taller than wide” shape. Only 7.9% of all MTC showed the simultaneous presence of at least 4 US features suggestive for malignancy. Ultrasonographic high-risk of malignancy of the MTC included in the 5 RSS, varied from 45.4 to 47.4%, and performing FNAC was suggested in only 48.7-63.8% of all MTC.
Conclusions: In our series neither single nor association of US features are specific for MTC. The 5 main RSS correctly identify less than 50% of MTC and do not suggest of performing FNAC in about half of them with potentially missed or delayed diagnosis.
Furio Pacini, Martin Schlumberger, Henning Dralle, Rossella Elisei, Johannes W A Smit, and Wilmar Wiersinga
Group-author : the European Thyroid Cancer Taskforce
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.
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
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.
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.
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.
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.
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.
To measure the response of serum leptin to exogenous administration of recombinant human TSH (rhTSH) in vivo.
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.
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.
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.
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.
Daniela Pasquali, Luisa Circelli, Antongiulio Faggiano, Massimo Pancione, Andrea Renzullo, Rossella Elisei, Cristina Romei, Giacomo Accardo, Viviana Raffaella Coppola, Maurizio De Palma, Piero Ferolla, Franco Grimaldi, Annamaria Colao, and Vittorio Colantuoni
CDKN1B encodes the cyclin-dependent kinase inhibitor p27Kip1 and is mutated in multiple endocrine neoplasia-like syndromes. CDKN1B also harbors single nucleotide polymorphisms; the T/G transversion at nucleotide 326 (the V109G variant) has been reported to be protective in breast, hereditary prostate, and pancreatic tumors. Association of CDNK1B mutations or polymorphisms with sporadic medullary thyroid carcinoma (MTC) has not been investigated yet.
Objective and design
We screened germline DNA from 84 patients affected by sporadic MTC and 90 healthy age- and gender-matched controls for CDKN1B mutations or polymorphisms by PCR amplification and sequencing of the amplicons. We also tested all germline and 50 tumor tissue DNA for RET proto-oncogene mutations. Computed tomography, ultrasound scans, and serum calcitonin were carried out before surgery and during the follow-up and associated with CDKN1B polymorphism and disease remission.
The T/G transversion at nucleotide 326 was the only DNA variation detected. The overall frequency of the T/G and G/G alleles in combination was 46.4%. This variant (V109G) was correlated with post-operative calcitonin levels in the normal range and biochemical remission. Conversely, the wild-type (T/T) allele was associated with post-operative calcitonin levels above normal and a higher risk to develop clinical recurrence and distant metastases. Somatic RET mutations were significantly associated with a more aggressive behavior especially in wild-type allele-bearing patients.
Collectively, in sporadic MTC, the CDKN1B V109G polymorphism correlates with a more favorable disease progression than the wild-type allele and might be considered a new promising prognostic marker.
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
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).
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.
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.
Cristina Romei, Stefano Mariotti, Laura Fugazzola, Augusto Taccaliti, Furio Pacini, Giuseppe Opocher, Caterina Mian, Maurizio Castellano, Ettore degli Uberti, Isabella Ceccherini, Nadia Cremonini, Ettore Seregni, Fabio Orlandi, Piero Ferolla, Efisio Puxeddu, Francesco Giorgino, Annamaria Colao, Paola Loli, Fabio Bondi, Barbara Cosci, Valeria Bottici, Antonello Cappai, Giovanni Pinna, Luca Persani, Verga Uberta, Marco Boscaro, Maria Grazia Castagna, Carlo Cappelli, Maria Chiara Zatelli, Antongiulio Faggiano, Giuseppe Francia, Maria Luisa Brandi, Alberto Falchetti, Aldo Pinchera, Rossella Elisei, and The ItaMEN network
Multiple endocrine neoplasia type 2 (MEN 2) is a genetic disease characterized by medullary thyroid carcinoma (MTC) associated (MEN 2A and 2B) or not familial MTC (FMTC) with other endocrine neoplasia due to germline RET gene mutations. The prevalence of these rare genetic diseases and their corresponding RET mutations are unknown due to the small size of the study population.
We collected data on germline RET mutations of 250 families with hereditary MTC followed in 20 different Italian centres.
Results and conclusions
The most frequent RET amino acid substitution was Val804Met (19.6%) followed by Cys634Arg (13.6%). A total of 40 different germline RET mutations were present. Six families (2.4%) were negative for germline RET mutations. The comparison of the prevalence of RET germline mutations in the present study with those published by other European studies showed a higher prevalence of Val804Met and Ser891Ala mutations and a lower prevalence of Leu790Phe and Tyr791Phe (P<0.0001). A statistically significant higher prevalence of mutations affecting non-cysteine codons was also found (P<0.0001).
Furthermore, the phenotype data collection showed an unexpected higher prevalence of FMTC (57.6%) with respect to other MEN 2 syndromes (34% MEN 2A and 6.8% of MEN 2B). In conclusion, we observed a statistically significant different pattern of RET mutations in Italian MEN 2 families with respect to other European studies and a higher prevalence of FMTC phenotype. The different ethnic origins of the patients and the particular attention given to analysing apparently sporadic MTC for RET germline mutations may explain these findings.