This study included 20 patients (17 women, 3 men; mean age, 61.1±11.6 years) who had thyroid nodules with isolated macrocalcifications and underwent neck CT or chest CT (Fig. 1). Thyroid nodules with isolated macrocalcifications were defined as isolated calcified nodules with complete posterior acoustic shadowing in which no solid component was obviously identified within the nodules on US (Figs. 2-4). The enrolled patients were selected from 82 patients with isolated macrocalcifications detected by US at two institutions. Forty-four patients with isolated macrocalcifications were found in the cohort data (dataset 1, n=4,081) of patients with thyroid nodules at one institution; details about this cohort have previously been published [6]. Thirty-eight patients with isolated macrocalcifications were found in the cohort data (dataset 2, n=3,061) of patients with thyroid nodules in whom fine-needle aspiration (FNA) or core needle biopsy (CNB) was performed from January 2011 to June 2018 at another institution. In dataset 1, nodules with isolated macrocalcifications were retrospectively determined by reviewing the thyroid US of 408 patients for which the word "macrocalcification" was used in the radiology report of thyroid US [6]. In dataset 2, nodules with isolated macrocalcifications were retrospectively determined by reviewing the US of all patients. Among the 82 patients with isolated macrocalcifications detected by US at the two institutions, 62 patients who did not undergo neck or chest CT were excluded from this study (Fig. 1).

FNA or CNB was routinely performed for large (≥1 cm) isolated macrocalcifications and was selectively performed for small (<1 cm) isolated macrocalcifications if the previous FNA results were inconclusive, to evaluate the contralateral lobe for thyroid lobectomy, in patients suspected of having lymph node metastasis, and by the request of the referring physician. The final diagnoses of malignant tumors were made by surgery or based on malignant findings on FNA or CNB, and final diagnoses of benign nodules were determined by surgery or based on benign findings on FNA or CNB.

High-resolution US examinations were performed using a 10- to 12-MHz linear-array transducer (AplioXG, Toshiba, Otawarashi, Japan) and 5- to 12-MHz linear-array transducers (iU22 or EPIQ7, Philips Medical Systems, Bothell, WA, USA). Neck CT scans were obtained in 11 patients and chest CT scans in nine patients. For CT examinations, 64-channel multidetector CT scanners were used. Unenhanced neck CT was performed to evaluate the calcified mass before biopsy in seven patients, and both unenhanced and contrast-enhanced neck CT was performed as part of the preoperative evaluation in four patients diagnosed with thyroid cancer. Unenhanced chest CT was obtained in four patients and contrast-enhanced chest CT in five patients for the evaluation of lung lesions. The neck CT scans were reconstructed into axial images with scan parameters of 2- to 4-mm slice thickness, 512×512 matrix, and a 22- to 25-cm field of view (FOV). The chest CT scans were reconstructed into axial images with scan parameters of a 2.5- to 5-mm slice thickness, a 512×512 matrix, and a 33- to 43-cm FOV. The unenhanced neck and chest CT scans were reviewed to evaluate isolated macrocalcifications in 15 patients, and enhanced chest CT scans were reviewed in five patients.

US-guided FNA was performed in the conventional manner using a 21- to 23-gauge needle and at least two samples were obtained from each nodule [15]. Direct smears or liquid-based cytology was used for the preparation of FNA specimens. The specimen was smeared on a slide and immediately fixed in 95% ethanol using the direct smear method. In the liquid-based cytology method, the specimens were prepared using the ThinPrep 2000 processor (Hologic Co., Marlborough, MA, USA).

US-guided CNB was performed using a free-hand technique and a disposable 18-gauge, double-action spring-activated needle (1.1-cm excursion, TSK Acecut, Create Medic, Yokohama, Japan) as described previously [6,16]. Each specimen was immediately fixed in 10% neutral buffered formalin solution and stained in the standard manner for a histopathologic examination. The interpretation of FNA or CNB was based on the Bethesda system for reporting thyroid cytopathology [17] and the six categories of a CNB pathology reporting system [18]. After the patients underwent biopsy, we immediately compressed the biopsy site, and the patients were observed as they performed manual self-compression of the biopsy site for 20-30 minutes.

US were retrospectively reviewed by an experienced radiologist (D.G.N.) with 21 years of experience in performing thyroid US and interventional procedures. A reviewer who had no previous knowledge of the FNA results or final diagnoses determined the presence of isolated macrocalcifications from the database of patients’ US. The CT features of the included nodules with isolated macrocalcifications were retrospectively evaluated by two radiologists (D.G.N. and W.P.) through consensus in a blind fashion. The CT features of the isolated macrocalcifications were categorized into central and rim calcifications. A central calcification was defined as a calcified nodule with an intranodular macrocalcification located in its center. Central calcifications were further subcategorized as either complete calcifications (compact entire calcifications) or partial calcifications (coarse partial calcification with an obvious non-calcified soft tissue component within the calcified nodule). A rim (peripheral) calcification was defined as a calcified nodule with complete or incomplete curvilinear rim calcification. The CT features of central isolated macrocalcifications were evaluated on axial CT scans with a wide window width (1,500 Hounsfield units) to assess the internal architecture of the calcified nodules.

We assessed the nodule size and frequency of nondiagnostic FNA results and malignant tumors according to the CT features of isolated macrocalcifications. The Mann-Whitney U test was used to compare the mean nodule size and the Fisher exact test was used to compare the nondiagnostic FNA rate between complete and partial central calcifications. Statistical analyses were performed using SPSS for Windows version 24.0 (IBM Corp., Armonk, NY, USA). A significant difference was defined as a P-value of <0.05.

CT scans were obtained in 20 of the 82 patients with isolated macrocalcifications (24.4%). The size of the 20 nodules ranged from 6 to 20 mm (mean size, 12.3±3.4 mm). Among the 20 nodules with isolated macrocalcifications, both FNA and CNB were performed simultaneously in nine (45.0%), FNA alone in 10 (50.0%), and CNB alone in one (5.0%) in the initial biopsy procedure. The initial FNA results of the 19 nodules were nondiagnostic (n=9, 47.4%), benign (n=6, 31.6%), atypia of undetermined significance/follicular lesion of undetermined significance (n=2, 10.5%), suspicious for malignancy (n=1, 5.3%), and malignant (n=1, 5.3%). The initial CNB results of the 10 nodules were nondiagnostic (n=1, 10.0%), benign (n=4, 40.0%), indeterminate (n=4, 40.0%), and malignant (n=1, 10%). Final diagnoses were obtained in 12 of the 20 nodules (60.0%), and eight nodules showed inconclusive FNA or CNB results. Malignant tumors were found in four of the 20 nodules (20.0%), of which three were conventional papillary thyroid carcinomas (PTC) and one was found to be invasive encapsulated follicular variant PTC.

CT Features of Isolated Macrocalcifications

Central calcifications were found on the CT of 19 of the 20 nodules (90.0%) with isolated macrocalcifications, and rim calcifications were found in two (10.0%) (Table 1). Among the 18 nodules with central calcifications, complete calcifications were found in six nodules (Fig. 1) and partial calcifications in 12 nodules (Fig. 2). The two nodules with rim calcifications showed incomplete rim calcifications, and no complete rim calcifications were observed (Fig. 3).

In the 18 nodules with central isolated macrocalcifications, the mean size of nodules belonging to the partial calcification subtype was larger than that of nodules belonging to the complete calcification subtype, but this difference was statistically insignificant (P=0.098) (Table 2). Nondiagnostic FNA results were found in nine of the 19 nodules that underwent FNA (47.4%). The nondiagnostic rate was similar in central calcifications (47.1%) and rim calcifications (50%), and there was no significant difference in the nondiagnostic rate between complete and partial central calcifications (P=0.620) (Table 2). Malignant tumors were only found in four of the 18 nodules with a central isolated macrocalcification (22.2%). There was no significant difference in the frequency of malignant tumors between complete and partial central calcifications (P=0.999).