Differential Diagnostic Value of Parathyroid 99mTc-MIBI SPECT/CT in MIBI Uptake Lesion

Background: To investigate the role of parathyroid technetium-99m-hexakis2-methoxy-2-methylpropylisonitrile ( 99m Tc-MIBI) single photon emission computed tomography/ computed tomography (SPECT/CT) combined with the serum calcium (Ca) and serum parathyroid hormone (PTH) in the differential diagnosis of MIBI uptake lesion. Methods: 201 patients with MIBI uptake lesion on parathyroid 99m Tc-MIBI SPECT/CT from January 2015 to July 2019 were enrolled in this study. All patients who underwent surgical resection were classied into two groups: primary hyperparathyroidism (PHPT) and non-PHPT in terms of the pathological ndings. Radiological performance of 99m Tc-MIBI SPECT/CT, serum Ca and serum PTH were comparable between the two groups. Results: 201 patients (135 females; median age, 53.0 years; age range, 29 – 79 years) were included. Pathological ndings were as follows: PHPT was in 126 (62.7%) patients, including parathyroid adenoma in 106 patients, parathyroid cancer in 12 patients and parathyroid hyperplasia in 8 patients, while non-PHPT were in 75 (37.3%) patients, including thyroid adenoma in 14 patients, thyroid papillary cancer in 15 patients and thyroid nodular goiter in 46 patients. In the following multivariable logistic regression analysis, serum Ca and diameter of the shortest axis of the lesion were the independent factors for differentiating PHPT from non-PHPT. In receiver operating characteristic (ROC) analyses, the cut-off value of serum Ca differentiating PHPT from non-PHPT was 2.6 mmol/L, yielding the area under the ROC curve (AUC) of 0.931, sensitivity of 85.7%, specicity of 89.2%; the cut-off value of diameter of the shortest axis of the lesion was 20.4mm, yielding AUC of 0.728, sensitivity of 62.2%, specicity of 87.1%. Conclusion: Parathyroid 99m Tc-MIBI SPECT/CT combined with serum Ca and serum PTH

However, the role of parathyroid 99m Tc-MIBI SPECT/CT in the qualitative diagnosis of MIBI uptake lesion remains indeterminate due to tracer accumulation of 99m Tc-MIBI is nonspeci c. Normal parathyroid glands are not visible on 99m Tc-MIBI SPECT/CT, but hyper-functioning glands usually show increased radiopharmaceutical uptake.
Unfortunately, many diseases not from parathyroid, show MIBI uptake, and cause false positive results. Diseases from thyroid such as thyroid nodular goiter, thyroid papillary cancer, thyroid follicular adenoma (oncocytic variant), and metastatic thyroid cancer were the main contributors for the false positive results [4]. Additionally, lymph nodes, branchial cleft remnants, and enlarged thymus acts with a cystic morphology also account for false positive results [5][6][7]. Currently, if there exists a suspicion of PHPT, parathyroid 99m Tc-MIBI SPECT/CT would be performed for the location of hyper-functioning parathyroid lesion [8], and for the suspected PHPT, surgery would be carried out [9].
To date, it seems that determination of the nature of false positive lesion before the operation is out of duty of parathyroid 99m Tc-MIBI SPECT/CT, as this examination alone or combined use of serum Ca and serum PTH has not been used as a qualitative diagnosis of MIBI uptake lesion to provide abundant information of nature of the lesion. Actually, parathyroid 99m Tc-MIBI imaging followed by CT may provide many additional characteristics those were not valued in the past. We, therefore, conducted this study to evaluate the differential diagnostic role of parathyroid 99m Tc-MIBI SPECT/CT combined with serum Ca and serum PTH for the MIBI uptake lesion.

Patients
We conducted a retrospective review of consecutive patients with MIBI uptake lesion on preoperative parathyroid 99m Tc-MIBI SPECT/CT who subsequently underwent an operation and con rmed by pathological ndings at our institution from January 2015 to July 2019. Serum Ca and serum PTH were performed in all patients before any treatments and after operation. Exclusion criteria were patients as follows: patients who were suspected with secondary hyperparathyroidism (SHPT); patients with multiple MIBI uptake lesions or ectopic parathyroid or ectopic thyroid; patients who had the history of parathyroid or thyroid surgery.
All patients provided informed written consent, which was ethically approved by the First Hospital of Jilin University research ethics committee. 99m Tc-MIBI SPECT/CT The dual-phase 99m Tc-MIBI examination consisted of an early phase SPECT and a delayed-phase SPECT/CT, which was obtained using dual-head SPECT/CT (GE Discovery NM/CT670). All patients were injected intravenously with 925 1110 MBq of 99m Tc-MIBI. Early phase SPECT images were obtained after 10 minutes and delayed-phase SPECT/CT images were acquired after 150 minutes with full views of the neck and thorax. Lowenergy high-resolution collimators were used for image acquisition and images were acquired in a 128 × 128 matrix, with a 20% window centered around the voltage of 140 kV. A low-dose CT was registered immediately after SPECT without moving the patient for attenuation correction of SPECT images. CT slices (10 mm thick) were acquired in a 256 × 256 matrix, with 2.5 mA, 140 kV. Reconstruction was performed by the Ordered Subsets Expectation Maximization technique (OSEM). The images were inherently registered to Xeleris workstation software (GE Medical Systems).

Image Interpretation
Two nuclear physicians who were unaware of the histopathological results interpreted all parathyroid 99m Tc-MIBI SPECT/CT ndings by consensus. For visual analysis, a distinct focus of increased or separate MIBI uptake in the neck was considered positive for a PHPT on scintigraphy.
The continuous variables with non-normal distribution are presented as median (range). The categorical variables are reported as number (percentage). Comparisons of continuous variables between the two groups were performed with Mann-Whitney U-test and Kruskal-Wallis H-test were used in multiple groups. Categorical variables were compared by Pearson chi-square or Fisher's exact test as appropriate. Signi cant variables identi ed by univariate analyses were included in the subsequent multivariate logistic regression analysis. The optimum cut-off value of potential factors of differentiating PHPT from non-PHPT was calculated using receiver operating characteristic (ROC) curves. The area under the ROC curve (AUC) was calculated and used to compare the diagnostic value of these factors. Statistical analyses were performed using SPSS software (v. 24.0). All pvalues were two-sided and p < 0.05 was considered statistically signi cant in all analyses.

Patient Characteristics
A total of 243 patients with MIBI uptake lesion on parathyroid 99m Tc-MIBI SPECT/CT who underwent surgery were enrolled at the beginning. After exclusion of 46 patients (25 patients who were suspected with SHPT; 12 patients with multiple MIBI uptake lesions or ectopic parathyroid or ectopic thyroid; 5 patients who had the history of parathyroid or thyroid surgery), 201 patients (66 males, 135 females; median age, 53.0; age range, 29-79 years) were eligible for this study.
In terms of pathological ndings, all enrolled subjects were classi ed into two groups: PHPT and non-PHPT. In detail, PHPT was in 126 (62.7%) patients, including parathyroid adenoma in 106 patients, parathyroid cancer in 12 patients, and parathyroid hyperplasia in 8 patients, while non-PHPT were in 75 (37.3%) patients, including thyroid adenoma in 14 patients, thyroid papillary cancer in 15 patients, and thyroid nodular goiter in 46 patients.

Factors For Differentiating Phpt From Non-phpt
Upon analyzing the association of potential factors for differentiating PHPT from non-PHPT, a total of seven factors including age, gender, serum Ca, serum PTH, diameter of the shortest axis of the lesion, density, border of lesion was associated with differentiating PHPT from non-PHPT by univariate analysis.
In the following multivariable logistic regression analysis, serum Ca and diameter of the shortest axis of lesion were the independent factors for differentiating PHPT from non-PHPT (Table 1). In ROC analyses, the cut-off value of serum Ca was 2.6 mmol/L, yielding AUC of 0.931, sensitivity of 85.7%, speci city of 89.2%; the cut-off value of the diameter of the shortest axis of lesion was 20.4 mm, yielding AUC of 0.728, sensitivity of 62.2%, speci city of 87.1%.  Fig. 1-3.  Yes 0 (0%) 0 (0%) 0 (0%) 4 (28.6%) 0 (0%) 6 (13.0%) In non-PHPT, gender, radioactive uptake time, radiation reduction of the lesion, the diameter of the shortest axis of lesion were associated with the speci c pathology (thyroid adenoma, thyroid papillary cancer, thyroid nodular goiter) ( Table 2). Lesion of thyroid nodular goiter was more likely to show radiation reduction in the center of the lesion than those in thyroid adenoma and thyroid papillary cancer (both p < 0.05, Z=-3.581, Z=-3.686). The median diameter of the shortest axis of lesion in thyroid papillary cancer was shorter than those of thyroid Discussion 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 99m Tc-MIBI SPECT/CT. For 201 patients with MIBI uptake lesion on parathyroid 99m Tc-MIBI SPECT/CT, approximately two-thirds of them were con rmed as PHPT, while one-third of them were non-PHPT. This study demonstrated that parathyroid 99m Tc-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 in uenced by several factors. The study by Erbil Y et al [10] found that both adenoma weight and oxyphil cell content were signi cantly correlate with MIBI uptake. Especially adenoma weight > 600 mg, it is the most signi cant factor in obtaining MIBI uptake. MIBI de ciency 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 [11]. 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 [12]. Moreover, 99m Tc-MIBI scintigraphy is also related to preoperative serum Ca and serum PTH [13]. At last, autoimmune thyroid disease (AITD) is an important in uential factor for MIBI uptake and may impede parathyroid lesion detection [4].
The rst step for the management of MIBI uptake lesion on the parathyroid 99m Tc-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 signi cant 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 ndings by multivariate analyses, only serum Ca was independent factor for differentiating PHPT from non-PHPT. Lavryk OA et al [15] 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 in uence the management of PHPT [16]. 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 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 [18]. 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 in ltration 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 99m Tc-MIBI SPECT/CT is speci cally for the non-PHPT, such as radiation reduction of the lesion and radioactive uptake time. Totally, in 21 patients, lesions with radiation reduction were con rmed as thyroid goiter nodular while in three patients, MIBI uptake lesions, which were visible only in the early phase were con rmed as thyroid papillary cancer. Based on our results, it is di cult to distinguish which phase is better for diagnosis of MIBI uptake lesion. However, according to Xue J et al [19] early 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, 99m Tc-MIBI SPECT/CT characteristics were partially used to determine only single MIBI uptake lesion which was con rmed 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.   A 66-year-old female patient of parathyroid cancer with serum Ca 3.45mmol/L and serum PTH 1312.5pg/ml. Parathyroid 99mTc-MIBI SPECT/CT showed MIBI, which was behind the thyroid in ltrating to surrounding thyroid tissue.

Figure 3
A 64-year-old male patient of parathyroid hyperplasia with serum Ca 3.26mmol/L and serum PTH 324.8pg/ml.
Parathyroid 99mTc-MIBI SPECT/CT showed MIBI uptake lesion, which was located below the thyroid possessing low density and clear border.

Figure 4
A 37-year-old female patient of thyroid adenoma with serum Ca 2.25mmol/L and serum PTH 37.5pg/ml.
Parathyroid 99mTc-MIBI SPECT/CT showed MIBI uptake lesion, which was located in the thyroid. Figure 5