Prognostic significance of FDG PET/CT on the follow-up of patients of differentiated thyroid carcinoma with negative I131 whole-body scan and elevated thyroglobulin levels.

To the Editor: Avery interesting article has been recently published on Clinical Nuclear Medicine about the prognostic significance of FDG PET/CT on the follow-up of patients with differentiated thyroid carcinoma with negative 131I scan and elevated thyroglobulin (Tg) levels. The authors evaluated 105 patients with negative I whole-body scan with high Tg levels; all patients underwent F-FDG PET/CT, and the results were also analyzed in comparison to Tg levels. PET/CT was positive in 75 patients (69 true-positive and 6 false-positive results) and negative in 30 (20 true-negative and 10 false-negative results), thus reaching 87% sensitivity, 77% specificity, 92% positive predictive value, 66% negative predictive value, and 75% accuracy. The authors also reported that PET/CT accuracy dramatically increase when Tg levels are greater than 38.2 ng/mL with thyroid-stimulating hormone (TSH) stimulation greater than 1.9 ng/mL under TSH suppression, thus reaching 93%. One of the most interesting findings is the fact that patients with a negative F-FDG PET/CT examination and Tg values that can be ‘‘suppressed’’ by hormone therapy are reported to have a more favorable prognosis regarding mortality and risk of recurrence, and this aspect seems to be unrelated to Tg levels in ‘‘off-therapy. ’’ Although the importance of Tg values for prognosis has been extensively evaluated, this appears to be the first time that this aspect is demonstrated to have a prognostic significance for recurrent thyroid carcinoma. This could underline another important mechanism in dedifferentiation, which could be a part of a more complex series of molecular changes involved in the loss of capability of I uptake. Up to now, several mechanisms have been discovered in the dedifferentiation process. The so-called flip-flop phenomenon, defined as the inverse relationship between 131I and 18F-FDG uptake in thyroid carcinoma, due to high GLUT-1 (glucose transporter type 1) gene expression associated with a decrease in energy-dependent transport mediated by the Na/I-symporter, has been recently hypothesized to be also related to PTEN (phosphatase and tensin homolog) expression, which might affect the surface expression of GLUT-1. Besides this well-known phenomenon, a second metabolic change has been suspected by another recent study by RosenbaumKrumme et al, corroborated by the fact that also thyroid incidentalomas, which are for the most part benign lesions or carcinomas in a very early stage, often show high FDG uptake. Now, this article seems to demonstrate that the modifications in the mechanisms of feedback of Tg secretion could be another important parameter in the process of dedifferentiation; in fact, patients whose Tg secretion is not inhibited by hormone therapy have a worse prognosis, strictly related with a higher grade of dedifferentiation. Many molecular chaperones and folding enzymes, such as BiP, GRP94, calnexin, protein disulfide isomerase, endoplasmic reticulum protein 72 (ERp72), and more recently ERp29, have been shown to associate simultaneously and/or sequentially with Tg in the course of its maturation, thus forming large heterocomplexes in the endothelium reticulum of thyrocytes. Anyway, their role also in modifying Tg secretion and their interrelation with other factors is still under active investigation. In particular, ERp29 has been recently studied in the Tg secretion as well as in carcinogenesis, and there is an evidence of high ERp29 levels in tumors of various origins and under the conditions of genotoxic stress, such as ionizing radiation; moreover, there is the evidence p53 is strictly correlated on the effect of antineoplastic drugs on ERp29, thus suggesting that a modification in p53, as it often happens during dedifferentiation, can affect in many ways Tg secretion and feedback. More recently, also ghrelin, a 28-aminoacid peptide mainly secreted by the stomach and that both stimulates pituitary growth hormone secretion and modulates food intake and energy metabolism in mammals, has been demonstrated to have a stimulatory effect on TSH-induced expression of the tissue-specific key genes involved in the synthesis of Tg. Taken together with the findings of Vural et al, these data suggest that understanding the physiopathologic mechanisms and metabolic ways of determining differences in radiopharmaceutical uptake and correlating these findings with microscopic and clinical patterns are indispensable to precisely clarify the real meaning of FDG hypermetabolism or hypometabolism and its prognostic value, the possible use of Tg values for prognostic purposes, and possible targets for an adequate and satisfactory therapy.