Fine‐needle aspiration of parathyroid adenomas: Indications as a diagnostic approach

Abstract Background We aimed to determine the indication of fine‐needle aspiration (FNA) for parathyroid adenoma (PA)‐suspected nodules and the cytological features of PA, and to discuss the ancillary techniques for diagnostic confirmation. Method Clinical, cytological, and histological examinations of 15 PA patients (4.0% of all PA resected patients) were conducted through FNA on 16 nodules. We also examined the cytological preparations of 10 follicular neoplasms (FNs) and 10 poorly differentiated thyroid carcinomas (PDTCs). Results FNA was performed to detect PA in nine (56.3%) nodules. The remaining seven (43.8%) nodules underwent FNA for lesions considered as thyroid nodules or lymph nodes. The levels of parathyroid hormone (PTH) in the aspiration needle washout fluid were observably high, except for that from one nodule with unsatisfactory FNA. Cytologically, the incidences of wedge pattern (86.7%) and salt and pepper chromatin (86.7%) in PAs were significantly higher than in FNs and PDTCs. In contrast, the appearance of colloid globules and nuclear grooves was less frequent than that of FNs and PDTCs. GATA‐3 expression was intense in all PAs that immunocytochemistry were performed. Histologically, capsular invasion and/or laceration, tumor seeding, granulation tissue, and fibrosis were observed. Conclusions When PA localization is unusual or inconclusive despite extensive imaging, FNA may be performed. We asserted that wedge pattern, salt and pepper chromatin, and the absence of colloid globules and nuclear grooves are diagnostic cytological indicators of PA rather than of FN or PDTC. We recommend PTH measurements using needle washout fluid for PA‐suspected nodules, and immunocytochemistry with the GATA‐3 antibody for cytologically PA‐suspected nodules.

cellularity. We also examined the preparations of 10 FNs (8 adenomas and 2 carcinomas) and 10 poorly differentiated thyroid carcinomas (PDTCs) that were aspirated during the same period. Table 1 shows the definitions of the main cytological findings used in this study.
Immunocytochemical examination was performed using the following We determined the statistical significance of data using Fisher's exact probability test. P value <.05 was considered to be statistically significant.

| Clinical findings
The median age of the patients was 61 years (range 41-71 years). The female-to-male ratio was 12:3. Serum calcium levels were measured prior to thyroid FNA in all cases, and ranged from 9.7 to 12.8 mg/dL (median: 10.8). In 12 patients (80%), the serum calcium levels were higher than normal values. The levels of i-PTH ranged from 76 to 1537 pg/mL (median: 149 pg/mL) and were elevated in all samples.
Based on the UE reports, seven (43.8%) and six (37.5%) nodules were considered to be intrathyroid and extrathyroid lesions, respectively. The location of the remaining three nodules was not determined to be intrathyroidal or extrathyroidal. Out of the 16 nodules, 8 (50.0%), 7 (43.8%), and 1 (6.3%) were suspected to be PA, thyroid nodules, and lymph nodes, respectively.

| FNA
FNA was performed to determine the location of PA in nine (56.3%) nodules collected from patients with primary hyperparathyroidism. In

| Arrangements
Tissue fragments composed of tumor cells and stromal components were observed in 60%, 50%, and 60% of PAs, FNs, and PDTCs, respectively. Trabecular arrangement was frequently detected in all tumors. Triangular cell clusters with one sharp corner (wedge pattern) ( Figure 1) were observed in 86.7% of PAs, and the incidence was significantly higher than that of FNs (P < .001) and PDTCs (P < .01). Insular and cribriform patterns were observed in PAs (80.0%, 53.3%) and PDTCs (50.0%, 80.0%), while it was not observed in any of the FNs.
While all FNs displayed a microfollicular pattern, the incidence of the pattern was low in PAs (26.7%, P < .01). Naked cells were more frequently detected in PAs (73.3%) than in PDTCs (30.0%) (P < .05).

| Tumor cells
Oxyphilic cytoplasm was observed in 53.3% of PAs, while intracytoplasmic fat vacuoles were not detected in all cases of PA. The nuclei in PAs were predominantly rounded in shape and did not exhibit multinucleation or the presence of nuclear grooves or prominent nucleoli. The incidence of salt and pepper chromatin pattern ( Figure 2) was significantly higher in PAs (86.7%) than in FNs (0%, P < .001) or PDTCs (20.0%, P < .01).

| PTH assay
The levels of parathyroid hormone (PTH) were measured in the aspiration needle washout fluid from 10 out of 16 PA nodules (62.5%). The levels of i-PTH and highly sensitive PTH (HS-PTH) were measured in two and seven nodules, respectively. In the remaining nodule, both parameters were measured. i-PTH and HS-PTH levels ranged from 355 pg/mL to 5000 pg/mL and from 211 pg/mL to 2 700 000 pg/mL, respectively. The levels were observably higher than the normal ranges in serum (i-PTH: 15-70 pg/mL, HS-PTH: 74-273 pg/mL), except for that in one nodule in which FNA was deemed unsatisfactory.

| Pathological findings
Dimashkieh et al described FNA as a useful diagnostic tool for PA. 13,14 We opined that FNA should be avoided in the preoperative diagnosis for PA to the maximum extent possible. FNA has been performed on only 4.0% of PA resected patients at our institution.
Although the frequency appears remarkably low, this could not be Fortunately, clinical complications such as hematoma, parathyromatosis, and recurrence were not observed in the cases studied here. The primary purpose of FNA for PA-suspected nodules is the measurement of PTH levels in the needle washout fluid. Therefore, in such cases, we ensured that the needle was not moved considerably during the aspiration. This might have helped reduce the risk of complications. In resected preparations, capsular invasion, capsular laceration, tumor seeding, granulation, and fibrosis were observed. These findings may be attributed to FNA. 16,17 When we histologically examine PAs with a history of FNA, it is necessary to consider its effect.
Knezevic-Obad et al reported that the inadequate rate of parathyroid FNA (40%) was significantly higher than that of thyroid nodules (12%), owing to the depth of location and intensive blood circulation. 13 However, as the inadequate rate in the current study was 6.3%, the inadequacy of parathyroid FNA was not proved.
According to the previous reports, the diagnostic accuracy of FNA in PAs ranged from 72% to 80%. 1,5 Heo et al reported that the accuracy of FNA for PA-suspected nodules (86.7%) was considerably higher than that for unsuspected nodules (50.0%). 1 Clearly, the cytological diagnosis of PA was influenced by clinical information. Similarly, in our study, the accuracy for PA-suspected nodules tended to be higher than that for unsuspected nodules. However, the difference was not statistically significant. To avoid references to misleading clinical information, we recommend observing the cytological preparations before referring to clinical information, as we practiced.
In this study, wedge, insular, and cribriform patterns and salt and pepper chromatin were more frequently observed in PAs than in FNs.
In contrast, colloid globules and nuclear grooves were less frequent in PAs. Compared to PDTCs, wedge pattern, naked cells, predominant round nuclei, and salt and pepper chromatin were more frequent in PAs, whereas colloid globules, multinucleation, and nuclear grooves were less frequent. Therefore, the cell arrangements of PAs were similar to those of PDTCs, whereas the nuclear observations of PAs were similar to those of FNs. In conclusion, wedge pattern, salt and pepper chromatin, and the absence of colloid globules and nuclear grooves are better diagnostic indicators of PA than of FN or PDTC. Among the findings, the wedge pattern is a novel indicator proposed by us.
When the localization of PA-suspected nodules is unusual or inconclusive despite extensive imaging, FNA may be indicated. In such cases, measurement of PTH levels in the needle washout fluid is particularly effective and the sensitivities (87.0%-93.6%) and specificities