The role of ¹⁸F-FCH PET/CT in patients with uremic hyperparathyroidism compared with ^99mTc-sestaMIBI SPECT/CT and ultrasonography

Uremic hyperparathyroidism (uHPT) is a common complication of end-stage chronic kidney disease (CKD), including secondary hyperparathyroidism (SHPT) and tertiary hyperparathyroidism (THPT) [1]. In CKD progression, both hyperphosphatemia and 1,25-dihydroxy vitamin D deficiency cause hypocalcemia and stimulate parathyroid hormone (PTH) secretion from the parathyroid gland, called SHPT [2]. SHPT patients remain in a stage of HPT 1 year after receiving a kidney transplantation, called THPT [3, 4]. Hypertrophic parathyroid glands of these patients develop into hyperplasia or adenoma that is not affected by serum levels of calcium and autonomously secrete excessive PTH [3, 4]. With the increasing prevalence of chronic diseases such as diabetes and hypertension, the overall incidence of CKD continues to rise. In addition, the incidence of uHPT is increasing, which seriously affects the prognosis of CKD patients [1].

For patients with uHPT, surgical management leads to superior survival and biochemical cure rates, as well as more favorable cost profiles compared to medical treatment [1, 5]. The indications for parathyroidectomy (PTX) in THPT are quite broad, including hypercalcemia, nephrocalcinosis, severe pruritus, low bone mineral density, and symptomatic hypercalcemia [6]. The 2017 Kidney Disease Improving Global Outcomes (KDIGO) guideline suggests that persistent parathyroid hormone (PTH) elevations over ninefold the upper limit of normal should be considered an indication for surgical management [7]. However, considering the poor physical condition of the uremic population, it is important for the surgeon to obtain information about parathyroid glands by imaging prior to PTX [1, 8]. Accurate preoperative gland localization can help surgeons rapidly identify the parathyroid gland during an operation and reduce the operative time. In addition, early detection of ectopic glands may help reduce the risk of recurrence by resection [1].

Routine preoperative gland localization imaging for PTX includes parathyroid scintigraphy with ^99mTc-sestaMIBI and ultrasonography (US) of the neck [9, 10]. However, no conventional imaging method shows great superiority at present. ¹⁸F-fluorocholine (FCH) PET, a common imaging modality used for prostate cancer, can be used to localize hyper-functioning parathyroid glands [11], and many studies have indicated that it has high diagnostic efficiency for primary hyperparathyroidism (PHPT) [9, 12‐14]; nevertheless, no clinical study has only evaluated the diagnostic value of ¹⁸F -FCH PET for uHPT. In this study, the diagnostic performance of preoperative gland localization of ¹⁸F -FCH PET/CT for uHPT was investigated compared to ^99mTc-sestaMIBI SPECT/CT and US.

In this study, we prospectively evaluated the performance of ¹⁸F-FCH PET/CT imaging in uHPT patients. The crucial findings of the study are summarized as following. First, ¹⁸F-FCH PET/CT imaging has high sensitivity, specificity, accuracy, and PPV for hyper-functioning parathyroid gland localization. The lesion-based sensitivity and accuracy of ¹⁸F-FCH PET/CT were significantly higher than those of ^99mTc-sestaMIBI SPECT/CT and US. Second, ¹⁸F-FCH PET/CT is superior to US in identifying intrathyroidal parathyroid hyperplasia. Third, no significant associations were observed between PET parameters and laboratory parameters in SHPT.

After a clinical study [11] in 2014 showed that parathyroid adenoma in patients with prostate cancer were observed in ¹⁸F-FCH PET imaging, some studies [9, 17‐19] were published suggesting that ¹⁸F-FCH PET could be used not only for hyper-functioning gland localization but also showed high sensitivity in patients with PHPT compared to conventional imaging methods, reaching as high as 92–96% in per-lesion analyses. PHPT is mostly caused by a solitary parathyroid adenoma [20], and SHPT and THPT patients often present with multiple parathyroid hyperplasia of varying sizes [1, 4, 20]. A previous study [21] reported a strong positive correlation between SUVmax and preoperative PTH levels in PHPT patients. However, the PTH levels of uHPT were generally much higher than those of PHPT. So, the excellent diagnostic efficacy of ¹⁸F-FCH PET cannot be extrapolated easily to uHPT patients. Our study is the first study which focuses only on uHPT. Because most lesions were visualized in both early and late images, we did not analyze the diagnostic performance of the two phases separately.

Our results indicate a sensitivity of 84.13% (per-lesion analyses) for ¹⁸F-FCH PET/CT for the detection of hyper-functioning parathyroid glands in patients with uHPT, slightly below that of PHPT as reported in previous studies [9, 17‐19]. This may be because uHPT patients often present with multiple glandular disorders, and some smaller lesions had no obvious tracer uptake [22]. Although some studies have reported greater uptake of FCH in parathyroid adenomas than in hyperplastic lesions for PHPT patients [18, 23], it remains unclear whether the lower sensitivity of ¹⁸F-FCH PET/CT for uHPT than PHPT is attributable to pathological features. Overall, in our study, ¹⁸F-FCH PET had a higher sensitivity and accuracy compared to ^99mTc-sestaMIBI SPECT/CT and US in uHPT patients.

Alharbi et al. [21] reported a strong positive correlation between SUVmax and preoperative PTH levels and between adenoma background ratio (ABR) and preoperative PTH levels. Nevertheless, we did not observe a significant association between PET parameters and preoperative laboratory parameters in 16 SHPT patients. This difference between studies may be due to the fact that PTH levels of SHPT patients were generally higher than those of PHPT patients included in the previous study (mean PTH level 2191.93 ± 840.85 pg/mL vs. 122.4 ± 49.9 pg/mL).

In our study, ¹⁸F-FCH PET/CT showed superior diagnostic performance compared to ^99mTc-sestaMIBI SPECT/CT in detecting hyperparathyroidism. In ¹⁸F-FCH PET/CT true-positive findings, some lesions were not detected by MIBI, which may be associated with the small gland size. Previous studies have investigated lesions closely associated with thyroid location and/or patients with adenoma with abnormal washout patterns, who had undergone thyroid surgery, or with multiglandular disorder syndrome (MGDS), which may have resulted in the reduced sensitivity of ^99mTc-sestaMIBI [24]. Furthermore, compared to ^99mTc-sestaMIBI SPECT/CT, ¹⁸F-FCH PET/CT has significant technical advantages such as higher spatial resolution, shorter imaging time, and lower radiation exposure [12, 25, 26].

For PHPT patients, the sensitivity of US for detecting enlarged parathyroid glands ranges from 70 to 100% in experienced hands [27]. Nevertheless, in the presence of multinodular goiter and multiple parathyroid lesions, the sensitivity decreases from 47 to 84% in unskilled hands [27]. Patients with uHPT often have multiple lesions, which in turn decreases the sensitivity of US. Intrathyroidal parathyroid adenomas are easily missed by US. A previous study [28] showed that a hyperechoic line is produced by the strong reflection of US in the layer where the parathyroid gland is histologically separated from thyroid tissue, which represents the very thin capsules of both the parathyroid and thyroid glands. Although a hyperechoic line is the main sign of intrathyroidal parathyroid adenoma, it is difficult to identify and is often ignored by operators [28]. In this study, ¹⁸F-FCH PET correctly located three instances of intrathyroidal parathyroid hyperplasia, which were misdiagnosed as thyroid nodules by US, and the SUVmax of intrathyroidal hyperplasia was higher than that of other parathyroids in the same patient. ¹⁸F-FCH PET is a functional imaging modality that helps to distinguish parathyroid glands from thyroid nodules, although benign and malignant thyroid nodules may manifest regional ¹⁸F-FCH uptake [29‐32]. ¹⁸F-FCH PET is still superior to US in this respect if we comprehensively analyze the PTH, SUVmax, and tracer uptake of other parathyroid glands. In addition, combined with the high spatial resolution of PET/CT, it is conducive for the visualization of parathyroid glands.

Although ¹⁸F-FCH PET is highly sensitive to hyper-functioning parathyroid glands, false-positive and false-negative results should be considered. One meta-analysis [33] showed that decreased volumes of individual glands and pathological characteristics, such as a low number of functional adenomatoid cells or oxyphilic cells, may result in false-negative results in ¹⁸F-FCH PET. Calabria et al. [34] showed that enlarged lymph nodes, thymoma, adrenal adenoma, meningioma, sarcoidosis, colon cancer, bladder cancer, and multiple myeloma may manifest with abnormal FCH uptake. Therefore, when identifying lesions with abnormal FCH uptake, we should explore the anatomical site to distinguish it from enlarged lymph nodes and thymoma to reduce false-positive results and identify small lesions. More importantly, we should pay attention to distinguishing thyroid nodules and intrathyroidal parathyroids and study the detailed morphological and metabolic differences in future work.

¹⁸F-FCH PET/CT was more sensitive and accurate for uHPT than ^99mTc-sestaMIBI SPECT/CT and US and had better preoperative diagnostic efficacy, particularly for lesions diagnosed as thyroid nodules by US.