Lateralization of Calcitonin Measurements in the Wash-Out Fluid from Thyroid Fine-Needle Aspiration: A Useful Tool for the Diagnosis of C-Cell-Hyperplasia?

Dear Editor:

Cytological analysis of fine-needle aspiration biopsy (FNAB) specimens is not useful in patients with high serum calcitonin (Ct) due to low sensitivity and specificity of FNAB in recognizing medullary thyroid cancer (MTC) (1). Even more so, FNAB cytology is not useful for the diagnosis of C-cell hyperplasia (CCH) (2). Recently, Ct assay in thyroid nodule FNAB wash-out fluid (FNAB-Ct) was noted to be effective in detecting MTC (3), being high in histologically confirmed MTC.

We report a young man with the finding of persistently elevated basal and Pentagastrin (PG)-stimulated serum Ct concentrations. FNAB-Ct of both thyroid lobes performed despite the absence of documented thyroid nodules revealed a significant difference of FNAB-Ct measurements between the two thyroid lobes. This is the first description of histologically confirmed unilateral CCH whose diagnosis was initiated by the finding of values for FNAB-Ct lateralized to one of the thyroid lobes.

A 39-year-old man was referred for evaluation of hypercalcitoninemia. This was noted after resection of a pituitary macroadenoma. His family history was negative for endocrine diseases. Pituitary function was normal and biochemical screening for multiple endocrine neoplasia 1 was negative. Analysis of RET (exons 8,10–15) showed only the frequent G691S polymorphism in exon 11. Thyroid ultrasonography (US) was negative for nodules. Thyroid function tests were normal and tests for antibodies against thyroid antigens were negative.

Ct was assayed by using an ultrasensitive chemiluminescent immunoassay (Liaison CT, DiaSorin, Vercelli, Italy) with a sensitivity of 1 pg/mL, an inter- and intraassay coefficients of variation of 10% and 6%, respectively, and a normal range for men of 0.4–18.9 pg/mL. A standard PG test was performed by sampling blood for serum Ct assay before and 1, 2, 5, and 10 minutes after a intravenously bolus of 0.5 μg/kg PG (Pentagastrin Injection BP NOVA Laboratories Ltd, Leicester, United Kingdom).

Basal and PG-stimulated serum Ct peak were 23.1 and 87.2 pg/mL, respectively (Supplementary Data; available online at www.liebertonline.com/thy), considered borderline for MTC. One year later, the basal and PG-stimulated serum Ct were still elevated (25.1 and 142 pg/mL, respectively; Supplementary Data). Considering the increasing response to Pg, despite the fact that thyroid nodules were still not present on US, a blind FNAB in non-nodular regions of both the right and left lobe of the thyroid was performed after obtaining patient's written informed consent. The FNAB-Ct was higher in the sample from the left lobe (397 pg/mL) than in the sample from the right one (12 pg/mL). The value for the left lobe has been reported to be suggestive of C-cell disease (3). Total thyroidectomy was performed. Histopathology, including immunohistochemistry for Ct, showed CCH (at least three ×100 magnification fields containing >50 cells) with preponderance of cells in the left lobe which had a micronodular (<1 mm) component (Supplementary Data). Three weeks after surgery, basal and PG-stimulated serum Ct levels were normal at 1.4 and 2.6 pg/mL, respectively.

This case suggests, for the first time, that FNAB-Ct might be a reliable tool to identify candidates for CCH, as it is for MTC (3). The histological confirmation of nodular CCH, only in the left lobe, was concordant with the very high value of FNAB-Ct from the same thyroid lobe. Conversely, the poor immunostaining for CCH in the right lobe was consistent with the low FNAB-Ct from that lobe. The independence of FNAB-Ct results for the two lobes is likely enhanced by the absence of C-cells and C-cell diseases in the thyroid isthmus (4). Notably, it appears that asymmetrical CCH is present in about 20% of patients with CCH (5). Histological analysis supported the validity of FNAB-Ct for detecting CCH even when blindly placing the needle directly in non-nodular thyroid.

We hypothesize that FNAB-Ct, performed in non-nodular areas, may be a very useful and reliable tool in the preoperative diagnosis of CCH in patients with elevated serum Ct. More experience is needed to confirm this result. This should come from prospective studies on a suitably large number of subjects.