MIBI uptake lesion is used to be considered blindly as hyperparathyroidism since there is a lack of evidence for the role of differential diagnosis of parathyroid 99mTc-MIBI SPECT/CT. For 201 patients with MIBI uptake lesion on parathyroid 99mTc-MIBI SPECT/CT, approximately two-thirds of them were confirmed as PHPT, while one-third of them were non-PHPT. This study demonstrated that parathyroid 99mTc-MIBI SPECT/CT combined with serum Ca and serum PTH has potential qualitative diagnostic value for differentiating MIBI uptake lesion, which failed to be valued in the previous studies.
MIBI sensitivity is influenced by several factors. The study by Erbil Y et al  found that both adenoma weight and oxyphil cell content were significantly correlate with MIBI uptake. Especially adenoma weight > 600 mg, it is the most significant factor in obtaining MIBI uptake. MIBI deficiency glands are smaller than MIBI uptake glands. High oxyphil cell content (> 20%) is the an independent factor in obtaining MIBI uptake despite adenoma weight. The abundant intra-cytoplasmic mitochondria probably account for intense MIBI uptake by thyroid adenoma . Furthermore, the cell cycle may play a role in imaging, where parathyroid cells are more likely to be in a G0 or non-growth phase while autonomous parathyroid tissues such as adenomas tend to be in a growth phase (G2 + S), which is common in SHPT . Moreover, 99mTc-MIBI scintigraphy is also related to preoperative serum Ca and serum PTH . At last, autoimmune thyroid disease (AITD) is an important influential factor for MIBI uptake and may impede parathyroid lesion detection .
The first step for the management of MIBI uptake lesion on the parathyroid 99mTc-MIBI SPECT/CT is to determine the origin of the lesion. By univariate analyses, gender, both serum Ca and serum PTH, the diameter of the shortest axis of the lesion, density, border of lesion were significant factors for differentiating PHPT from non-PHPT. PHPT is classically associated with an elevated level of total serum Ca and of serum PTH. However, in some patients, serum PTH level may be normal but inappropriate to hypercalcemia [1, 14]. In this study, we found similar findings by multivariate analyses, only serum Ca was independent factor for differentiating PHPT from non-PHPT. Lavryk OA et al  performed the extensive analysis of 1753 patients with PHPT, demonstrating 97% of them with either elevation of serum Ca or serum PTH, 20% with only elevation of serum PTH, and 6% with only elevation of serum Ca and 3% with both serum Ca and serum PTH within the reference range. Minimally elevated preoperative serum PTH levels can influence the management of PHPT . However, in our study, the higher serum Ca is, the more PHPT likely to be (Table 1). The serum Ca, which is measured before receiving any treatments exerts relatively favorable value in differentiating PHPT from non-PHPT with the cut-off value of 2.6 mmol/L, yielding AUC of 0.931, sensitivity of 85.7%, specificity of 89.2%. The diameter of the shortest axis of the lesion is another independent factor for differentiating PHPT from non-PHPT. The diameter of shortest axis of non-PHPT is more likely larger than that of PHPT, with cut-off value of 20.4 mm, yielding AUC of 0.728, sensitivity of 62.2%, specificity of 87.1%.
SPECT/CT provides incremental value of the location of lesions [3, 17]. Definite location of the lesion would assist the ascertain nature of PHPT or non-PHPT. Most of the PHPT lesions locate behind the thyroid or below the thyroid, which can be clearly shown on the sagittal reconstruction on CT, while lesions from the thyroid are located in the thyroid.
The second question for the management of MIBI uptake lesion on the parathyroid 99mTc-MIBI SPECT/CT is to determine the specific nature of PHPT or non-PHPT based on the radiological performance of 99mTc-MIBI SPECT/CT combined with serum Ca and serum PTH. Parathyroid adenoma, parathyroid hyperplasia, parathyroid cancer are the main causes of the PHPT. Serum Ca, serum PTH, and border of lesion are significant factors for the differential diagnosis among them. Our study is in line with previous studies that the median serum PTH in parathyroid cancer is commonly much higher than serum PTH in other causes of PHPT, which would be 5 to 10 times higher than the upper limit of the norm . The median serum Ca in parathyroid adenoma was lower than those in parathyroid cancer and parathyroid hyperplasia. Not surprisingly, lesion of parathyroid cancers shows unclear border indicating infiltration of adjacent tissues.
In present study, the thyroid disease, such as thyroid nodular goiter, thyroid papillary cancer and thyroid adenoma greatly accounted for false positive results. Some features of non-PHPT still partially overlap with those of PHPT while some features on the 99mTc-MIBI SPECT/CT is specifically for the non-PHPT, such as radiation reduction of the lesion and radioactive uptake time. Totally, in 21 patients, lesions with radiation reduction were confirmed as thyroid goiter nodular while in three patients, MIBI uptake lesions, which were visible only in the early phase were confirmed as thyroid papillary cancer. Based on our results, it is difficult to distinguish which phase is better for diagnosis of MIBI uptake lesion. However, according to Xue J et al  early scan of 99mTc-MIBI SPECT/CT was much better than delayed scan. The diameter of the shortest axis of lesion and border of lesion play an important role in the determination of different types of non-PHPT. According to our results, larger lesions with clear border tend to be thyroid adenoma, which is full of eosinophilic cells. The border of lesion and relationship with surrounding tissues are efficiently in the distinction of malignancy lesions from benign ones. Thyroid papillary cancer commonly shows unclear rim and unevenly infiltrating the normal thyroid tissues around the lesion. On contrast, benign tumors, especially thyroid adenoma usually demonstrate clear border even if the diameter of the shortest axis of lesion is large.
We are fully aware that our study has several limitations: First, inherent limitations of a retrospective analysis and relatively small patient population of the parathyroid cancer, parathyroid hyperplasia, thyroid papillary cancer, thyroid adenoma could have affected the study results. In addition, 99mTc-MIBI SPECT/CT characteristics were partially used to determine only single MIBI uptake lesion which was confirmed as PHPT. Multiple MIBI uptake lesions, ectopic thyroid lesion, ectopic parathyroid lesion and SPTH were excluded in our study. Furthermore, patients in our study refer to only six pathological types (parathyroid cancer, parathyroid hyperplasia, parathyroid hyperplasia, thyroid papillary cancer, thyroid adenoma, thyroid nodular goiter), some other diseases that may demonstrate MIBI uptake have not studied, which remains an area to explore for future studies.