Early diagnosis of medullary thyroid cancer in case of low serum calcitonin: Role of calcitonin measurement in fine-needle aspiration washout fluid

Background Screening serum calcitonin (sCT) measurement in patients with thyroid nod- ules is still debated. Moreover, sCt cutoffs for medullary thyroid carcino- ma (MTC) are not univocally defined. Also, sensitivity of cytology by fine needle aspiration biopsy (FNAb) has been demonstrated to detect approx- imately half of MTCs. Ct measurement in fine-needle aspiration washout fluid (Ct-FNAb) has high sensitivity and specificity and is helpful in case of non-diagnostic cytology1. Recently, a series oflow sCt MTC has been collected2. Aim The objectives of this retrospective observational study were to define Ct- FNAb levels in subjects with low sCt (below cutoffs diagnostic for MTC) and to evaluate their clinical, ultrasonographic (US), cytological and histo- logical characteristics.Methods We selected subjects with sCt above local normal ranges but below one of the diagnostic cutoff proposed for MTC (26 pg/ml in females and 68 pg/ ml in males), subjected to FNAb with Ct-FNAb measurement and then thy- roidectomized. Results Surprisingly, 50% (8/16) had MTC at histology, 19% cellular C hyperplasia (CCH) and only 31% neither MTC nor CCH. Ct-FNAb was significantly higher in MTC compared to both no MTC no CCH (2001 vs 25.32±55.72 pg/ml; P = 0.013) and to CCH (2001 vs 195.56 ± 286.09 pg/ml; P = 0.008). Even if below the diagnostic cutoff, also sCt was higher in MTC compared to no CCH and no MTC group (19±7 vs 9±4 pg/ml; P=0.019) but was not able to discriminate MTC from CCH. US failed to identify suspicious nod- ules, since MTC differed only for being solid and not haloed. At cytology nearly 90% of MTC lesions were non-diagnostic or, mainly, indeterminate. At histology, 7/8 were low risk micro MTCs. Conclusion HighCt-FNAb despite sCt only slightly elevated suggests: i) early detection of MTC before the onset of high secretion of Ct, ii) a peculiar variant of MTC, able to produce Ct but not to secrete it in bloodstream because of intracellular secretory pathway alteration, iii) possible methodological in- terferences in the dosage of sCt. In conclusion, this study demonstrates the importance of Ct-FNAb to discover early stages of MTC with sCt below diagnostic cutoffs.