11 C-Choline PET/CT in the Management of Primary Hyperparathyroidism

Primary hyperparathyroidism (PHPT) is a relative common medical problem caused by the inappropriate secretion of parathyroid hormone (PTH) by one or more parathyroid glands. The diagnosis is established by serum calcium and PTH levels and once the diagnosis is established imaging studies help localize the hyperfunctioning adenoma in preparation for curative surgery. Until now, the imaging studies most commonly utilized in PHPT are ultrasonography and 99m Tc-Sesta-methoxyisobutylisonitrile (MIBI) parathyroid scintigraphy. However, these studies often fail to localize the adenoma and inappropriately delay patient referral to a potentially curative surgery. We present the case of a 64-year-old female with symptomatic PHPT who had 3 negative 99m Tc-Sestamibi Scans over a period of 5 years who eventually had a PET/CT with 11 C-Choline that identified a right lower parathyroid adenoma. She underwent a right lower parathyroidectomy and had a successful outcome. We present a review the current imaging techniques used in the management of PHPT including 99m Tc-Sesta-MIBI scintigraphy and its limitations and novel use of PET/CT with 11 C-Choline and 18 F-Choline in this disease and emphasize the fact that, according to current guidelines, failure to localize the adenoma should not delay referral for curative surgery.


Introduction
We present the case of a 64-year-old female with a personal history of melanoma in situ. At age 56 a screening bone scan identified osteoporosis. Laboratory studies showed a PTH level of 75.5 pg/ml (nl 7.5 -53.3 pg/mL) inappropriately high for a serum calcium of 9.7 mg/dl (nl 8.4 -10.2). Her 25-OH D Vitamin levels were normal at 37 ng/ml (nl 30 -100), and 24 hr urine calcium was normal 334.4 mg/24 hs (nl > 200). She was referred to an endocrinologist who established the diagnosis of PHPT. A cervical US identified slightly enlarged parathyroid glands (6 mm) at the right superior and right inferior locations, nevertheless a 99m Tc-Sestamibi scan failed to identify an adenoma. She was not referred for surgery.
Over the course of the following 4 years she underwent multiple laboratory studies confirming the diagnosis of PHPT. Her PTH levels gradually rose from 75.4 to 98.7 to 105.6 to 164.0 to 187.3 mg/dl. During this time frame she received treatment with calcium, tibolone, vitamin D supplements, and underwent 2 additional 99m Tc-Sestamibi scans that failed to identify a parathyroid adenoma. Clinically, she developed fatigue, difficult concentration, gastritis, and abdominal pain that was labeled as irritable bowel syndrome. The osteoporosis progressed according to image evaluation. She was finally referred for a surgical consultation.
Laboratory studies again confirmed the PHPT diagnosis. By this time both, the patient and her endocrinologist, were convinced that a localization study was required prior to an operation. Based on recent reports, a PET/CT with 11 C-Choline was performed. Images were obtained 23 and 38 minutes after the IV injection of 11 C-Choline (740 MBq). This imaging study identified a right inferior parathyroid adenoma ( Figure 1 and Figure 2). Surgical exploration was recommended.
Using the radio-guided technique, similar to that described by Norman et al. [1], the patient was injected IV 5 mCi 99m Tc-labeled Sesta-MIBI one hour prior to the surgical procedure. The patient underwent a radio-guided, minimally invasive cervical exploration through a 2 cm incision. All 4 parathyroid glands were identified. The right lower gland was found to be enlarged and was completely excised.  Using the gamma probe, this enlarged gland was proven to be hyperactive compatible with a parathyroid adenoma. Using intraoperative PTH levels we confirmed an adequate decrease in the PTH levels, fulfilling the Miami Criteria for cervical exploration for PHPT and confirming the removal of the adenoma causing her PHPT [2]. Her recovery was uneventful, and the patient was discharged to home the following day. The pathology report confirmed a benign parathyroid 12 mm adenoma. At a 6-month follow-up the patient is completely asymptomatic. Her fatigue and abdominal pain have resolved and her calcium, vitamin D, and PTH levels have returned to normal levels. Informed consent was obtained from the patient for this case report.

Discussion
Primary hyperparathyroidism (PHPT) is defined as hypercalcemia or widely fluctuating serum calcium levels caused by the inappropriate secretion of parathyroid hormone (PTH) by one or more parathyroid glands [ [14].
Nowadays most patients present with subtle symptoms such as fatigue, general malaise, decreased concentration, decreased ability to learn new things, heartburn, arthralgias, myalgias or bone pain [19] [20] [21] [22]. In the past, nephrolithiasis was reported in approximately 40% -80% of patients, but now occurs only in 20% -25% of the cases [23] [24]. Int. J. Otolaryngology and Head & Neck Surgery The diagnosis of PHPT is established by laboratory studies, regardless of the imaging findings [25] [26]. The diagnosis is established by PTH levels that are inappropriately elevated to the patient's serum calcium level. Other adjuncts to confirm the diagnosis include serum calcium, phosphorus (chloride-to-phosphate ratio > 33), and serum 25 OH Vitamin D levels (usually normal or low). In addition, measurement of 24-hour urinary calcium excretion helps exclude familial benign hypocalciuric hypercalcemia as the cause for hypercalcemia [1] [27] [28] [29].
The current management of PHPT consists of surgical excision of the abnormal parathyroid glands as it is the only permanent and curative treatment for the disease. There is growing consensus that surgery is appropriate in the vast majority of patients including those with asymptomatic disease because it is the only definitive therapy and is the only treatment that can prevent the long-term consequences of having the disease [30] [31]. According to American Association of Endocrine Surgeons Guidelines, parathyroidectomy is indicated for all symptomatic patients, and should be considered for most asymptomatic patients as it is more cost-effective than observation or pharmacologic therapy [32]. Surgical exploration for PHPT by an experienced surgical team is associated with a very high cure rate (> 95%) [11]. The operation corrects the symptoms and can have very positive long-term effects in the health of patients preventing morbidity associated with the disease such as osteoporosis, nephrolithiasis, renal failure, cardiovascular disease, and even some malignancies.

Imaging Modalities
Once the diagnosis of PHPT has been established via laboratory studies, imaging evaluation helps localize the hyperfunctioning parathyroid gland and thus assists in surgical planning. Parathyroid localization studies are not used to confirm the diagnosis of PHPT, but rather to aid in the surgical management of the disease [33]. Nearly a third of patients with PHPT are not being referred to a surgeon because the endocrinologist has not been able to localize the parathyroid adenoma on a scan [34]. A negative 99m Tc-Sesta-MIBI scintigraphy delays the referral for definitive management of patients with PHPT by an average of 2.7 years [35].
Until now, in our institution, as well as in many institutions worldwide, the imaging study most commonly used to localize the hyperfunctioning parathyroid gland(s) has been the 99m Tc-Sesta-MIBI scintigraphy preferably in combination with hybrid imaging with SPECT/CT (single photon emission computed tomography/computed tomography). This study relies on the fact that both, thyroid and parathyroid tissue demonstrate radionuclide uptake. 99m Tc-Sesta-MIBI washes out of thyroid tissue earlier, leaving only parathyroid tissue that demonstrates activity 2 -4 hours after injection [36] [37] [38]. MIBI imaging has the advantage over ultrasound in that it is able to identify ectopic parathyroid adenomas. However, the 99m Tc-Sesta-MIBI is negative in more than 35% of patients M. R. Alvarez et al. with proven PHPT. In some series, the 99m Tc-Sesta-MIBI scintigraphy was negative 65% -81% of PHPT patients [11] [39]. This high false negative rate of the 99m Tc-Sestamibi scan has prompted the search for other localization imaging techniques for patients with PHPT. Ultrasonography (US) is one of the modalities that is being used more frequently to localize abnormal parathyroid glands [40]. It is simple, safe, fast, non-invasive, low-cost, not associated with body irradiation, and widely available [4] [41] [42] [43]. In addition, ultrasonography offers the advantage of depicting potential concomitant thyroid disease which is present in approximately 40% of patients with parathyroid disease [44]. Studies of physician-performed ultrasounds show accuracy rates that compare favorably with the accuracy of traditional radiology departments in the vicinity of 75% to 80% [45] [46] [47].
On US, adenomas appear as well-defined hypoechoic lesions with potential cystic or necrotic areas [4] [42]. Neck ultrasound's sensitivity for localizing parathyroid adenoma varies from 57% to 89%. When compared side-by-side to 99m Tc-Sesta-MIBI scintigraphy in patients with overt PHPT, the sensitivity of US was of 90% compared to 70% for 99m Tc-Sesta-MIBI scan [43]. However, in patients with normocalcemic PHPT the sensitivity for both studies decreases to 50% and 40% respectively [26].
Computed tomography scanning (CT) has also been used by some centers to help localize abnormal parathyroid glands. Classic CT scanning has a very low sensitivity, but CT scanning with dynamic contrast images (4D-CT) have shown promising results, with accuracy rates of approximately 88% [48] [49].
Contrast enhanced MRI is a non-invasive, non-radiating imaging technique that can be used when radiation is contraindicated. MRI does not usually play a significant role in PHPT imaging. The sensitivity of MRI is in the range of 80% and is associated with a greater financial cost compared to other imaging modalities such as US. MRI is contraindicated patients with renal failure when gadolinium contrast is necessary and is also contraindicated patients with pacemakers Thus, PET/CT with 18 F-Fluorocholine has the ability to detect not only parathyroid adenomas measuring less than 1cm, but also carcinomas, multiple adenomas, and even gland hyperplasia in patients with secondary hyperparathyroidism. The tracer 18 F-Fluorocholine (5 to 10 mCi) is usually injected intravenously and the scan is acquired after 5 -15 minutes. 18  When compared to 99m Tc-Sesta-MIBI imaging, PET/CT with 18 F-Fluorocholine has shown improved spatial resolution allowing for detection of smaller lesions.
In contrast to what occurs with 99m Tc-Sesta-MIBI, PET/CT with 18 F-Fluorocholine has proven to be able to detect hyperfunctioning parathyroid adenomas in normocalcemic PHTP as in overt PHPT [55]. In addition, because of the rapid biokinetics of choline, it is associated with a shorter study protocol. 18 F-Fluorocholine has added advantage of being widely available in many nuclear medicine departments due to its original use for prostate cancer [26] [52]. 18

F-Fluorocholine
PET/CT is reported to have a sensitivity of 92% and specificity of 100%, in contrast to 49% and 100% for Sesta-MIBI SPECT/CT, 46% and 100% for 99m Tc-Sestamibi/pertechnetate subtraction imaging (with planar images), and 44% and 100% for (99m)Tc-, (99 m) and 99m Tc-Sestamibi dual-phase imaging, respectively. In addition, the acquisition time also compares favorably for 18 F-Fluorocholine PET/CT compared to other nuclear medicine modalities (5 -15 minutes vs. 60 -64 minutes post-injection) [56]. For all these reasons, many authors consider that PET/CT with 18 F-Fluorocholine should now be considered as the new first line imaging technique for patients the PHPT [26]. It offers a sensitive, fast, easy-toperform imagining modality that is especially useful in the early stages of the disease when the abnormal parathyroid glands are still small and for those cases where ultrasonography, 99m Tc-Sesta-MIBI scintigraphy with planar or SPECT/CT images could not detect the location of the adenoma [52]. In a comparative study of 34 patients with PHPT by Bossert et al.; 99m Tc-Sestamibi detected only 15% of abnormal parathyroid glands, US detected 68%, and 18 F-Fluorocholine PET/CT detected 71% [26].
In addition to 18 F-Fluorocholine, there are other radiotracers which have been studied for the detection of adenomas using the PET/CT technology in patients with PHPT. Such tracers include 11 C-Choline, 11 C-Methionine, 18 F-Fluorodeoxyglucose, and 18 F-FET [53].
Similar to 18 F-Fluorocholine, 11 C-Choline is a precursor of phosphatidylcholine, a phospholipid component of the cellular membrane that is avidly taken up by hyperfunctioning parathyroid cells as well as certain neoplastic cells. In a prospective study of 40 patients, the utility of 11 C-Choline PET/CT was compared to that of 99m Tc-Sesta-MIBI imaging. Patients were injected 10 -20 mCi (370 -740 MBq) of 11 C-Choline and a CT was obtained followed by a PET acquisition initiated approximately 5 minutes after injection. The 11 C-Choline PET/CT was positive in 37 of 40 patients. In 29 of 40 cases, 11 C-Choline PET/CT and 99m Tc-Sesta-MIBI were concordant, but 11 C-Choline PET/CT findings were clearer in 9 of these 29 studies [5]. Authors concluded that 11 C-Choline PET/CT is imaging that combines both functional and anatomical information and is a promising tool for parathyroid adenoma localization with the advantages of superior accuracy, quicker and easier acquisition, and better image quality when compared to 99m Tc-Sesta-MIBI scanning [5]. 11  and those patients who may not be able to undergo MRI [57]. 11 C-Choline has a short physical half-life (20.4 minutes) and this fact combined with low-dose CT results in much less radiation exposure than other conventional nuclear techniques and 4D CT [57]. It is worth noting, however, that the short half-life of 11 C-Choline has also largely limited its use due to the small number of institutions located near a cyclotron production facility. Some European centers use 18 F-Fluorocholine instead of 11 C-Choline, which alleviates this issue; however, 18 F-Fluorocholine is not FDA approved in the United States, and 11 C-Choline is approved for restaging recurrent prostate cancer and is thus more readily available [51]. This is precisely the reason why we decided to use 11 C-Choline and not 18 F-Fluorocholineas the radiotracer for the PET/CT in this patient.
Another tracer that has been successfully used in PHPT is 11 [54]. Similar to 11 C-Choline, 11 C-Methionin also has a short half-life (20 min), which limits its use. Authors of this meta-analysis conclude that 11 C-MethioninPET/CT may be considered a reliable second-line imaging modality in PHPT, but that 18 F-Fluorocholine PET may be associated with a slightly higher accuracy [54]. Martinez-Rodriguez et al. and Rosiek et al. also consider 11 C-Methionin PET/CT to be a helpful strong secondline imaging study to be used when planning for parathyroidectomy. Authors in both of these publications emphasize the usefulness of 11 C-Methionine specially in patients in whom their first line imaging techniques of either cervical ultrasonography and/or 99m Tc-Sesta-MIBI have failed to localize the adenoma [36] [58].
The case presented illustrates the utility of the novel 11 C-Choline PET/CT over the traditional Sesta-MIBI scintigraphy for localizing the hyperfunctioning parathyroid adenoma in PHPT. Using the appropriate radiotracers, PET/CT provides better spatial resolution and shorter time acquisition when compared to the traditional 99m Tc-Sesta-MIBI imaging in patients with PHPT. This higher resolution allows the detection of even the smallest of pathological glands and reduces the duration of the surgery, thus potentially decreasing healthcare costs [36] [58] [59] [60]. The earlier use of this novel imaging modality would have led this patient more promptly to curative surgery.

Conclusion
Several imaging studies are now available to localize parathyroid adenomas in PHPT. When selecting an imaging study for this purpose, several factors need to be taken into consideration. These factors include availability, cost, institutional experience with the specific technique, as well as sensitivity, specificity, positive Int. J. Otolaryngology and Head & Neck Surgery predictive value of each imaging modality. Based on the data gathered in this review, we conclude that in patients with PHPT, a PET/CT with 18 F-Fluorocholine or 11 C-Choline could now be used as a first-line imaging study to localize parathyroid adenomas and should definitely be performed when other imaging studies such as US or 99m Tc-Sesta-MIBI scintigraphy have failed to localize the adenoma.
As the current case exemplifies, performing a PET/CT earlier in the disease course may lead to more promptly to curative surgery.