Once the diagnosis of PHPT has been established, the detection and localization of the abnormal glands become top priority. Due to the characteristics of embryonic development, the position of the parathyroid gland varies between patients, and the relationship between of the parathyroid gland with the recurrent laryngeal nerve and inferior thyroid artery is complicated. [9] Parathyroid nodules often need to be differentiated from thyroid nodules, surrounding soft tissues, and posterior cervical lymph nodes. Tc-99m MIBI SPECT/CT is the initial diagnostic choice, as it shows both cervical and mediastinal lesions, with high positive predictive value more than 80%. [10, 11] In principle, 99mTc-MIBI is absorbed by the hyperfunctioning parathyroid tissue, as well as the normal thyroid tissue, and its clearance from thyroid tissue is faster than that of the parathyroid gland. After obtaining early and delayed images, the hyperfunctioning parathyroid tissue can be analyzed by comparing the changes of the two images. Although the reported sensitivity of Tc-99m MIBI SPECT/CT is high, it is not sufficient for preoperative localization of parathyroid adenomas when used alone.
The detection rate of abnormal parathyroid by US was significantly higher than 99mTc MIBI SPECT/CT (93.0% vs. 63.0%) in this study. In comparison, the sensitivity and accuracy of US in locating parathyroid nodules in 97 cases of PHPT were significantly higher than those of Tc-99m MIBI SPECT/CT (93.0% vs. 63.0% and 88.0% vs. 63.0%). There were 37 false negatives in Tc-99m MIBI SPECT/CT and the pathologies were parathyroid adenomas, hyperplasia, and parathyroid cysts, respectively. False negatives in Tc-99m MIBI SPECT/CT is mainly associated with smaller adenomas. In a recent study, Jones et al. [12] showed that Tc-99m MIBI SPECT/CT had a sensitivity of 93% for adenomas > 500 mg, yet the sensitivity was significantly reduced (51%) for adenomas < 500 mg. In this study, the maximum diameter of abnormal nodules less than 1cm was 16 cases, accounting for 16.7% in total 120 nodules. On the other hand, parathyroid hyperplasia often involves multiple glands, which is small for a single gland, so it is difficult to detect with Tc-99m MIBI SPECT/CT. The cell composition of abnormal parathyroid nodules has also been identified as a factor affecting the accuracy of Tc-99m MIBI SPECT/CT. In 122 cases of parathyroid adenoma, Tc-99m MIBI SPECT/CT found false negatives in 26 (38%) of 68 adenomas formed predominantly of chief cells, while false negatives were also detected in two (9.0%) of 23 adenomas formed predominantly by oxyphil cells and in eight (25.8%) of 31 mixed adenomas. [13]These results suggest that the histological characteristics of parathyroid adenoma influence the imaging results of Tc-99m MIBI SPECT/CT. Although MIBI uptake is not related directly to PTH production and secretion, it is a marker of cell metabolism (mitochondrial uptake), then it is expected glands responsible for higher PTH levels are more likely to be detected by SPECT/CT. Other factors may also affect the detection of abnormal parathyroid lesions, including serum calcium levels and the cystic degeneration of nodules.
Another important confounding factor affecting the diagnostic value of Tc-99m MIBI SPECT/CT is concomitant thyroid nodules, which is known to be more frequent in PHPT patients than in general population. Particularly, some thyroid nodules exhibit intense MIBI uptake early with no tendency to wash-out or delayed wash-out, then mimicking parathyroid adenomas. In this study, three cases were false positives for Tc-99m MIBI SPECT/CT, of which the pathologies were nodular goiter, follicular adenoma and normal parathyroid gland. Since Tc-99m MIBI SPECT/CT is a non-specific tumor imaging agent, it also accumulates in thyroid cancer and thyroid adenomas.
In this study, we also identified that residual parathyroid sign and polar vascular sign are characteristic US manifestations of parathyroid adenomas and this study proposes for the first time that the appearance of these two signs are closely related to the size of nodules. The parathyroid gland is mainly composed of a large number of chief cells, along with some eosinophils and cell-matrix proteins. The chief cells are closely arranged, while the cytoplasm and matrix are rich in adipose cells. Hence, US demonstrates homogeneous hyperechoic parenchyma. [14]Residual parathyroid signs are presented with a hyperechoic rim or cap around some parathyroid hypoechoic abnormalities on US imaging, which has been confirmed by histopathologic results (Fig. 1). Only a few scholars have reported this manifestation of US. [15]The sensitivity of this sign in the diagnosis of parathyroid nodules is 63.6%, and it is highly sensitive to parathyroid adenomas with a maximum diameter of ≤ 1.55 cm. However, it is difficult to find residual normal glands when the tumor is large, which may be caused by smaller residual normal gland tissue and compression. Some pathologists have also proposed that the residual normal parathyroid tissue is a reliable standard for parathyroid adenoma, but it can only be seen in 50–60% of cases. [16, 17] This is similar to the results of this study, and the diagnosis of parathyroid adenoma cannot be ruled out when there is no residual normal parathyroid tissue. In this study, three cases of functional parathyroid cysts presented with residual parathyroid signs detected by US but not by Tc-99m MIBI SPECT/CT. Parathyroid cysts are rare and usually occur in the neck of the lower parathyroid gland with high levels of PTH. However, most scholars believe that parathyroid cysts represent degenerative adenomas. [18, 19] In fact, some of these cases in the current study presented with hyperparathyroidism.
Approximately 95% of adenomas occur in the neck and usually obtain their blood supply from branches of the inferior thyroid artery. The normal parathyroid gland has no visible flow signal on color and power Doppler due to thin nutrient vessels or slow velocity. Parathyroid adenomas are hypervascular and suspended by a vascular pedicle consisting of an extrathyroidal feeding artery enveloped in fat. The polar vascular sign is defined as the presence of an enlarged vascular pedicle around the nodule, which originates from the inferior or superior thyroid arteries (Fig. 2). The superior or inferior thyroid artery that terminates at the parathyroid adenoma is thicker than the contralateral artery at a similar position. Tn this study, the sensitivity of this sign in the diagnosis of parathyroid nodules is 79.0% for parathyroid adenomas with maximum diameter > 1.35 cm. To our current knowledge, some scholars have reported polar vascular sign in but not associated this manifestation of US with the size of abnormal lesions. Previously, Lane et al. [20] used US to reveal extrathyroidal feeding arteries in the detection of abnormal parathyroid glands, but there were few cases, no tracking of the whole source of the supply vessels, and no connection between this sign and the size of the nodules mentioned. Only the weight of the resected nodules was measured after the operation, but the weight included the nodules and the surrounding normal parathyroid glands, limiting the accuracy. Lastly, some of the postoperative tissues were broken and could not be weighed precisely. In another study, [21] similar findings from 4D CT with polar vascularity were found. However, it is difficult to fully display the whole feeding vessel and their origin. Compared with traditional CT, the ionizing radiation of 4D CT is much higher, and the vascular reconstruction is time-consuming.
We found PTC in ten (10.3%) of the 97 PHPT cases, and 9 out of 10 cases (90%) were PTMC and did not involve any lymph node or distant metastases. The association between thyroid disease and PHPT was first described more than 70 years ago. [22] Several reports have described an increased incidence risk of cancer in patients with PHPT. [23, 24].Some scholars have found that PHPT is mainly accompanied by non-medullary carcinomas, especially PTMC. [25] Some studies[26] have uncovered several susceptible factors of PTC in PHPT, such as the tumor-promoting effects of PTH, the goitrogenic effect, and increased mitotic activity induced by hypercalcemia and neck irradiation. However, it remains controversial whether PTC is related to PHPT because PTMC is also detected in up to one-third of thyroid gland autopsies of persons deceased from other reasons. [27] Some experts considered the evolution of PTMC is usually indolent and their radical therapy did not contribute to a decrease of mortality, therefore recommend conservative therapy and follow-up in these cases ,[28] while others argued despiting the small size and accidental discovery, the incidence of lymph node metastasis in patients with PTMC ranges from 4–65%, with a loco-regional recurrence rate of up to 20% .[29, 30] Therefore, thyroidectomy could be recommended. We are inclined to the latter point of view, especially for the PTMC close to the capsule or the dorsal recurrent laryngeal nerve and those with lymph node metastasis. Moreover, the secondary operation will be more complicated, so thyroid ultrasound examination should be performed before parathyroidectomy, and concomitant thyroidectomy should be performed at the same time as PTMC was found.
There were twelve cases of ectopic parathyroid nodules in this group. For which the display rate of Tc-99m MIBI SPECT/CT was better than that of US(66.6%vs50.0%). However, neither of the imaging modalities identified one case located in the posterior pharyngeal wall that was resected by intraoperative PTH monitoring. Tc-99m MIBI SPECT/CT is superior to US in the preoperative display of ectopic parathyroid nodules, especially those of ectopic locations like the retrotracheal region, retrosternal region, upper mediastinal, and intrathymic regions.
FNA is a feasible option for preoperative localization of nodules that cannot be identified by Tc-99m MIBI SPECT/CT or US. US-guided FNA of the suspected lesion with subsequent PTH measurement in the washout was first applied in the 1980s, [31] with a sensitivity of 70–100% and specificity of 75–100% for parathyroid adenomas.[32] Other scholars believe that FNA has the risk of implantation metastasis along the biopsy tract, which is theoretically possible. However, the true incidence of this complication is controversial. In a study of 81 parathyroid samples, there were no cases of parathyroid tumor metastasis induced by FNA during a follow-up period of 5.8 years. [33] Another pitfall of parathyroid biopsy is atypical features, such as capsule infiltration, cellular pleomorphism, fibrous band, and increased proliferation index after the parathyroid biopsy. These histological changes are similar to atypical adenomas or parathyroid carcinomas and may also mislead pathologists. [34]
This study has a few limitations. First, it is a retrospective study. Secondly, the diagnosis was made by experts in different departments, which may affect the statistical results. Lastly, a small number of negative cases resulted in a low specificity, which may lead to a certain deviation in the results.