Abstract
Introduction
Incidental uptake within or adjacent to the thyroid gland is occasionally observed on somatostatin receptor-targeted PET imaging in patients with neuroendocrine neoplasms (NENs). The reported prevalence and clinical relevance of such findings are not well established.
Materials and methods
We reviewed PET scan reports for all patients undergoing [68Ga]Ga-DOTA-TOC PET/CT or [64Cu]Cu-DOTA-TATE PET/CT in our department from 2018 to 2022. Scans reporting incidental uptake within or adjacent to the thyroid gland were reviewed post hoc to extract semi-quantitative scores of tracer uptake for the incidental lesions. We further extracted data from electronic patient charts, including cytology and histology.
Results
A total of 3692 PET scans were performed on 1808 unique patients. Incidental abnormal thyroid uptake was reported in 42 of the 1808 patients, with thyroid malignancy identified in five of these 42 patients. Two patients had medullary thyroid cancers, two had neuroendocrine tumor metastases, and one had a renal clear cell carcinoma metastasis. Focal uptake in close relation to the thyroid gland, suggestive of parathyroid adenoma, was reported in another 13 of the 1808 patients, with biochemical hyperparathyroidism found in six of these 13 patients.
Conclusion
In patients undergoing somatostatin receptor-targeted PET scans for evaluation of NENs, the prevalence of reported abnormal uptake within or adjacent to the thyroid gland was low. However, the rates of thyroid malignancy and parathyroid adenomas were substantial. Prospective studies are needed to determine the optimal diagnostic and therapeutic strategies for these incidental findings.
Introduction
Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms with predominant neuroendocrine differentiation most frequently found in the gastrointestinal tract, pancreas, and lungs (1, 2, 3). NENs share the expression of general neuroendocrine tumor markers such as chromogranin A and synaptophysin, and they usually show high expression of somatostatin receptors (SSTRs) (3, 4). The SSTR expression on NENs can be visualized with PET imaging using radioactive isotopes (e.g. 68Ga and 64Cu) bound to a chelating agent (DOTA) and coupled with somatostatin analogues (e.g. TOC and TATE). In our department, we use two SSTR-targeted tracers, [68Ga]Ga-DOTA-TOC and [64Cu]Cu-DOTA-TATE, for PET imaging of NENs. They are comparable tracers with similar patient-based sensitivity, although [64Cu]Cu-DOTA-TATE appears to have a better lesion detection rate than [68Ga]Ga-DOTA-TOC in patients with NENs (1).
Many tissues, including endocrine organs, exhibit physiological SSTR expression, leading to tracer uptake. The pituitary gland and the adrenal glands usually display very high uptake, whereas the thyroid gland exhibits varying degrees of diffuse uptake. Occasionally, increased focal tracer uptake is observed in the thyroid gland. Previous studies suggest that such focal uptake can represent differentiated thyroid cancer (originating from the follicular epithelium of the thyroid) and medullary thyroid carcinoma (MTC) (originating in the neuroendocrine parafollicular cells of the thyroid) (5, 6, 7, 8). Patients with multiple endocrine neoplasia type 2A (MEN2A) or 2B (MEN2B) are predisposed to medullary thyroid cancer (9, 10). When these patients undergo SSTR imaging for known/suspected pheochromocytoma, focal thyroid tracer uptake is suggestive of medullary thyroid cancer. However, in the context of SSTR imaging in patients with NENs, limited studies are available. Further investigation is needed to clarify the extent to which focal or heterogeneous thyroid SSTR tracer uptake represents thyroid malignancy (6, 11, 12).
In addition to focal SSTR tracer within the thyroid gland, focal SSTR-tracer uptake can also occur in close proximity to the thyroid. This thyroid-adjacent focal tracer uptake may indicate NEN lymph node metastasis or a parathyroid adenoma. Parathyroid adenomas express SSTR, and cases of parathyroid adenomas identified on SSTR-tracer PET imaging have been reported (10, 13, 14, 15). However, no previous studies have systematically examined how focal SSTR-tracer uptake adjacent to the thyroid gland relates to parathyroid adenomas.
The primary aim of this retrospective study was to evaluate the prevalence of reported abnormal SSTR-tracer uptake in the thyroid gland and to evaluate the cancer risk. The secondary aim was to evaluate the prevalence of reported focal uptake in close relation to the thyroid gland and, further, to assess how frequently such uptake represents NEN metastases or parathyroid adenomas that need further diagnostic workup.
Materials and methods
PET tracers
The two PET tracers [68Ga]Ga-DOTA-TOC and [64Cu]Cu-DOTA-TATE were used for imaging NENs. The tracers consist of a positron-emitting radioisotope (68Ga or 64Cu) complexed to the chelating agent DOTA and coupled to a somatostatin analogue (TOC or TATE, respectively). Five subtypes of the somatostatin receptor have been identified (SSTR1–SSTR5) (16). Mainly SSTR2 is expressed in NENs, and to a lesser degree SSTR1 and SSTR5, while SSTR3 and SSTR4 are only occasionally expressed in NENs (17, 18). DOTA-TOC has binding affinity mainly for SSTR2 and SSTR5, and DOTA-TATE mainly binds to SSTR2 with a high binding affinity (1).
Patients
Patients with diagnosed or suspected NENs are referred to the Department of Clinical Physiology and Nuclear Medicine (Copenhagen University Hospital—Rigshospitalet) from the Eastern part of Denmark with approximately 2.7 million inhabitants. We extracted SSTR-tracer PET scan descriptions for all patients undergoing [68Ga]Ga-DOTA-TOC PET/CT or [64Cu]Cu-DOTA-TATE PET/CT in our department from January 2018 to December 2022. Next, a search algorithm identified scans that included variations of the search term ‘thyroid’ or ‘parathyroid’ in the scan reports. These reports were then individually reviewed. Scans reporting focal uptake (only one lesion with increased uptake) or heterogeneous uptake (varying degrees of increased tracer uptake and/or two or more foci with increased uptake) within the thyroid gland (suspected thyroid adenoma/carcinoma/metastasis) were included in the study. Furthermore, scans reporting focal uptake in relation to the thyroid gland (suspected parathyroid adenoma) were included.
Characterization of abnormal uptake
As this was a retrospective study, no formal definition of incidental uptake was applied. No patients were scanned due to suspicion of thyroid or parathyroid disease; therefore, all abnormal findings in or adjacent to the thyroid gland were considered unexpected. The assessment of whether uptake within or adjacent to the thyroid gland was abnormal (i.e. above or different from physiological uptake) and possibly clinically important was made by the expert nuclear medicine physicians who reviewed and reported the PET scans. All included scans were reviewed post hoc to extract Krenning scores and maximum standardized uptake values (SUVmax) in order to characterize the incidental lesions (19, 20). The Krenning score is a semi-quantitative estimate of the degree of SSTR uptake (0: no uptake; 1: very low uptake; 2: uptake less than or equal to that of the liver; 3: uptake greater than the liver; and 4: uptake greater than that of the spleen) (19). For processes with heterogeneous uptake, the Krenning score was based on the focus/area with the highest uptake. The SUVmax is a (semi-)quantitative measure of tissue uptake (20).
PET imaging
The patients received a standard dose of either 150 MBq [68Ga]Ga-DOTATOC or 200 MBq [64Cu]Cu-DOTA-TATE administered intravenously, and the PET/CT acquisition started after 45 min or 60 min, respectively. The PET/CT acquisitions were performed on Siemens Biograph TruePoint mCT 64 or Siemens Biograph Vision 600 scanners (Siemens, Erlangen, Germany). Prior to the PET acquisition, patients underwent a diagnostic CT scan with intravenous iodine-containing contrast, unless CT contrast was contraindicated. The PET scans were recorded in 3D list mode for 3 min per bed position, and the scans covered the area from the skull base to the middle of the thighs. The images were reconstructed using a 3D-ordered subset expectation maximization algorithm with correction for the measured point spread function using the vendor-supplied TrueX algorithm (Siemens). All images were corrected for randoms, scatter, attenuation (CT-based), and filtered with a 3D Gaussian 2-mm filter.
Chart review
Electronic patient charts of patients with reported focal or heterogeneous thyroid uptake of SSTR tracer were reviewed. We extracted data regarding levels of thyroid hormones at the time of the scan; reports of thyroid disease; whether follow-up due to the thyroid uptake was performed; results of thyroid scintigraphy, ultrasound examination, and fine needle aspiration biopsy (FNAB); and histology description of the surgical specimen. Similarly, we made chart reviews in patients with focal uptake in relation to the thyroid. Here, we extracted data on levels of parathyroid hormone (PTH), ionized calcium, and vitamin D; reports of suspected or confirmed hyperparathyroidism; urine analyses and genetic analyses (to rule out or confirm familial hypocalciuric hypercalcemia); history of hyperparathyroidism; results of parathyroid scintigraphy; and histology description of the surgical specimen.
Ethical considerations
This retrospective study was performed as a quality assurance study, and it was approved by the local research committee (project number 543_22) at the Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital—Rigshospitalet. The study was conducted according to the principles of the Declaration of Helsinki.
Results
A total of 3692 SSTR-targeted PET scans were performed, with some patients undergoing repeat PET scans. Twenty-five percent (n = 910) of the scans used the [68Ga]Ga-DOTA-TOC tracer, and 75% (n = 2782) used the [64Cu]Cu-DOTA-TATE tracer. The number of unique patients who underwent PET scans was 1808.
Abnormal SSTR-tracer uptake in the thyroid gland
Abnormally increased thyroid uptake was noted in 42 of the 1808 patients (2.3%), with focal thyroid uptake in 27 patients and heterogeneous uptake in 15 patients (Table 1). Thyroid-specific follow-up imaging was performed in 11 of 27 (41%) patients with focal thyroid uptake and in five of 15 patients (33%) with heterogeneous uptake.
Characteristics of patients with abnormally increased SSTR tracer uptake in the thyroid gland (n = 42; 2.3% of the total patient sample).
| Focal uptake (n = 27) | Heterogeneous uptake (n = 15) | |
|---|---|---|
| Female, n (%) | 16 (59) | 9 (60) |
| Age in years, median (range) | 67 (24–83) | 68 (26–86) |
| SSTR tracer applied, n (%) | ||
| [64Cu]Cu-DOTA-TATE | 12 (45) | 10 (67) |
| [68Ga]Ga-DOTA-TOC | 6 (22) | 3 (20) |
| [64Cu]Cu-DOTA-TATE and [68Ga]Ga-DOTA-TOCa | 9 (33) | 2 (13) |
| Follow-up recommended in PET report, n (%) | 9 (33) | 2 (13) |
| Follow-up imaging performed, n (%) | 11 (41) | 5 (33) |
| Type of follow-up imaging, n (%) | ||
| Ultrasound and scintigraphy | 6 (22) | 3 (20) |
| Scintigraphy alone | 1 (4) | – |
| Ultrasound alone | 4 (15) | 2 (13) |
| Cytology and/or histology, n (%) | 7 (26) | 5 (33) |
aPatients having scans with both tracers at different time points.
Information regarding the thyroid lesions for the 12 patients that underwent cytological and/or histological evaluation is shown in Table 2. Needle biopsy was performed in 11 of the 42 patients with abnormal (focal or heterogeneous) thyroid uptake. Three of these demonstrated follicular neoplasia, all of which underwent hemithyroidectomy with the histological diagnosis of follicular adenoma. Two cases of MTC were diagnosed, one of them in a patient with known MEN2. Three of the cases represented metastasis to the thyroid gland (two from NEN and one from a renal clear cell carcinoma). One additional focus (not included in Table 2) was suspected to be a thyroid NEN metastasis, but this process was not biopsied due to widespread disseminated disease. However, the focal uptake disappeared following peptide receptor radionuclide therapy, supporting that it probably was a NEN metastasis. The overall verified malignancy rate in patients with focal thyroid uptake was three out of 27 (11%). The verified malignancy rate in patients with heterogeneous thyroid uptake was two out of 15 (13%). For the 27 patients with focal and the 15 patients with heterogeneous thyroid uptake, the mean Krenning scores were 2.8 and 2.5, respectively. Eleven patients were scanned with both tracers. However, four of these were treated with surgery or radionuclide therapy between the [68Ga]Ga-DOTA-TOC and [64Cu]Cu-DOTA-TATE scans, and hence, the thyroid lesions were only visible on the [68Ga]Ga-DOTA-TOC scans. For the remaining seven patients, five lesions were visualized with both tracers (similar uptake levels), one lesion was seen only with [68Ga]Ga-DOTA-TOC, and one only with [64Cu]Cu-DOTA-TATE. Benign processes had Krenning scores in the range of 2–4, while malignant lesions ranged 3–4. The SUVmax is also given for each process in Table 2. Benign processes ranged from 5.8 to 27.0, while malignant ones ranged from 12.2 to 19.8.
Data on the thyroid processes with abnormal SSTR-tracer uptake for patients that underwent cytological or histological evaluation (n = 12).
| Primary condition | SSTR-tracer uptake | Krenning scorea | SUVmax | Thyroid scintigraphy | Cytology | Histology |
|---|---|---|---|---|---|---|
| Suspected NET | Heterogeneous | 2 | 14.2 | Isofunctioning nodule | Benign cells | – |
| Paraganglioma | Heterogeneous | 2 | 12.5 | Hypofunctioning nodule | Inconclusive | Adenoma |
| Pheochromo-cytoma | Focal | 4 | 14.5 | – | Follicular goiter | – |
| Intestinal NET | Focal | 2 | 5.8 | – | Benign cells | – |
| Lung carcinoid | Focal | 2 | 9.5 | Hypofunctioning nodule | Follicular neoplasia | Oncocytoma |
| Intestinal NET | Focal | 4 | 27.0 | – | Follicular neoplasia | Follicular adenoma |
| Pancreatic NET | Heterogeneous | 3 | 18.1 | Hypofunctioning nodule | Follicular neoplasia | Follicular adenoma |
| MEN2 | Focal | 3 | 12.2 | – | – | MTC |
| Suspected NET | Heterogeneous | 3 | 19.8 | – | Malignant cells | MTC |
| Intestinal NET | Focal | 4 | 15.1 | Hypofunctioning nodule | NET metastasis | NET metastasis |
| Lung carcinoid | Focal | 3 | 14.8 | Hypofunctioning nodule | Inconclusive | NET metastasis |
| Pancreatic NET | Heterogeneous | 3 | 17.1 | Hypofunctioning nodule | Renal clear cell carcinoma metastasisb | Renal clear cell carcinoma metastasisb |
MTC, medullary thyroid carcinoma; NET, neuroendocrine tumor; SUVmax, maximum standardized uptake value.
aIn cases with heterogeneous uptake, the Krenning score is based on the lesion/area with the highest SSTR-tracer uptake. bRelapse of renal clear cell carcinoma (left-sided nephrectomy 9 years earlier).
Examples of physiological thyroid SSTR-tracer uptake, as well as cases with focally and heterogeneously increased uptake in the thyroid gland, are shown in Fig. 1.
Examples of SSTR-tracer uptake in the thyroid gland on maximum intensity projections (MIP; left column) and fused axial PET/CT images (right column). A and B demonstrate increased diffuse uptake in both lobes of the thyroid gland, which is a normal physiological variant. C and D show increased focal uptake in the left thyroid lobe (follicular adenoma, marked by a white arrow). E and F show increased focal uptake in the right thyroid lobe (NEN metastasis, marked by a white arrow). G and H show heterogeneously increased uptake in the right thyroid lobe (medullary thyroid carcinoma, marked by a white arrow).
Citation: Endocrine Connections 13, 12; 10.1530/EC-24-0419
Focal SSTR-tracer uptake adjacent to the thyroid gland suggestive of parathyroid adenoma
Focal uptake of SSTR tracer in close relation to the thyroid gland, suggestive of a parathyroid adenoma, was reported in 13 (0.7%) patients (Table 3). The mean Krenning score for the 13 detected lesions was 2.1. Three cases were detected with [64Cu]Cu-DOTA-TATE and four cases were detected with [68Ga]Ga-DOTA-TOC, while the remaining six cases were visualized with both tracers (scans performed at different time points). The SSTR-tracer uptake was similar (same level Krenning score) in four of the cases visualized with both tracers, and in two cases, the [64Cu]Cu-DOTA-TATE uptake was higher than the [68Ga]Ga-DOTA-TOC uptake (Krenning score one level higher). Parathyroid-specific follow-up with blood samples was performed on 12 patients, of whom five had classical primary hyperparathyroidism (PHPT) (elevated PTH and elevated ionized calcium) and one had normocalcemic PHPT. No cases of normal PTH and elevated calcium levels were identified. The Krenning scores for the six cases with PHPT were 1, 1, 2, 2, 3, and 3. Of the five patients with classical PHPT, all had the diagnosis of MEN1. Two of them underwent parathyroidectomy, both with confirmed parathyroid adenoma according to the histology description. The remaining three patients with MEN1 and PHPT had previously undergone a total of seven parathyroidectomies with the removal of a total of 8 parathyroid glands. According to the histology descriptions, three glands had nodular hyperplasia and the remaining five were categorized as adenomas. The patient with normocalcemic PHPT had a lung carcinoid tumor as the primary diagnosis. This patient did not undergo surgery. An example of focal SSTR-tracer uptake in a parathyroid adenoma is shown in Fig. 2.
Focal SSTR-tracer uptake in a parathyroid adenoma on a maximal intensity projection (MIP) (A) and fused axial PET/CT image (B). In the fused PET/CT image, the parathyroid adenoma is seen posterior to the left thyroid lobe in close proximity to the esophagus (marked by a white arrow).
Citation: Endocrine Connections 13, 12; 10.1530/EC-24-0419
Characteristics of patients with focal SSTR-tracer adjacent to the thyroid gland suspicious for parathyroid adenoma or hyperplasia (n = 13).
| Tracer uptake suspicious for parathyroid adenoma (n = 13) | |
|---|---|
| Female, n (%) | 9 (69) |
| Age in years, median (range) | 59 (19–83) |
| SSTR-tracer applied, n (%) | |
| Only [64Cu]Cu-DOTA-TATE | 3 (23) |
| Only [68Ga]Ga-DOTA-TOC | 4 (31) |
| [64Cu]Cu-DOTA-TATE and [68Ga]Ga-DOTA-TOCa | 6 (46) |
| Primary condition, n (%) | |
| Intestinal NEN | 3 (23) |
| Lung NEN | 1 (8) |
| Pancreatic NEN (not MEN1) | 2 (15) |
| MEN1b with pancreatic NEN | 5 (38) |
| MEN1b without pancreatic NEN | 1 (8) |
| SDHA mutation@ | 1 (8) |
| Parathyroid-specific follow-up, n (%) | |
| Scintigraphy and blood samples | 5 (38) |
| Blood samples alone | 7 (54) |
| No follow-up | 1 (8) |
| Biochemical hyperparathyroidism, n (%) | |
| Elevated PTH and elevated ionized calcium | 5 (38) |
| Elevated PTH, ionized calcium within normal range | 1 (8) |
| PTH and ionized calcium within normal range | 6 (46) |
| Normal PTH and elevated ionized calcium | 0 (0) |
| No blood samples | 1 (8) |
| Parathyroid adenoma identified on scintigraphy, n (%) | |
| Yes | 4 (31) |
| No | 1 (8) |
| Scintigraphy not performed | 8 (61) |
aPatients having scans with both tracers at different time points. bHigh risk of hyperparathyroidism, @SDHA (succinate dehydrogenase type A) mutations lead to increased susceptibility for pheochromocytoma and paraganglioma.
Parathyroid scintigraphy was performed in five patients as a dual-isotope (99mTc-Sestamibi and 123I) scintigraphy with digital subtraction, including subtraction SPECT/CT. In four patients, the parathyroid scintigraphy positively identified a parathyroid adenoma coinciding with the corresponding SSTR PET focus. In one PET/CT description, the CT scan identified a process in close relation to the lower pole of the left thyroid lobe without [64Cu]Cu-DOTA-TATE uptake. This PET-negative process is not included in Table 3, but the patient underwent parathyroid scintigraphy that identified a possible adenoma at the same location, and the diagnosis was confirmed with the subsequent parathyroidectomy.
Discussion
In this retrospective study, 3692 PET scan reports by expert nuclear medicine physicians were screened for abnormally high SSTR-tracer uptake in relation to the thyroid gland. Two cases of MTC and three cases of thyroid metastasis were detected due to thyroid-related abnormal PET findings. The overall malignancy rate in patients with abnormally high uptake in the thyroid gland was thus five out of 42 (12%). However, only 12 patients underwent cytological and/or histological evaluation, and in this subgroup, the malignancy rate was five out of 12 (42%). Six cases of hyperparathyroidism were detected, yielding a rate six out of 13 (46%) for hyperparathyroidism in the group with abnormal SSTR-tracer uptake adjacent to the thyroid gland.
A recent systematic review of incidental findings on SSTR-tracer PET imaging analyzed 21 studies that comprised a total of 2906 study subjects. Incidental findings were reported in 6% of the study subjects. The most frequent location of these incidentalomas was the thyroid gland (n = 65; 49% of all incidental findings). Twenty-five of the patients with reported thyroid uptake had focal uptake, which was due to thyroid malignancy in five cases (four cases of papillary carcinoma and one case of medullary carcinoma) (6). This corresponds to a malignancy rate of 8% in patients with abnormal focal thyroid uptake. A retrospective study, not included in the above-mentioned systematic review, analyzed 1968 sequential patients that underwent [68Ga]Ga-DOTA-TATE PET imaging. Focal thyroid uptake was reported in 85 patients, and further evaluation demonstrated six cases of MTC and two cases of follicular neoplasia. The rate of MTC was thus 7% in patients with focal uptake (5).
In our present retrospective study, thyroid-specific follow-up was performed in less than half of the patients with reported abnormal thyroid SSTR-tracer uptake. The low follow-up rate can most likely be attributed to the clinical condition of the patients (extent of primary disease, prognosis, etc.) and the uncertainty regarding the significance of abnormal thyroid uptake. The true malignancy rate could thus be underestimated. The low follow-up rate is comparable to that of a study investigating the significance of focal thyroid uptake on [18F]F-fluorodeoxyglucose PET scans, where approximately half of the patients underwent further thyroid-specific follow-up. The malignancy rate in that study was 8%, which is also comparable to our present study (21).
It has previously been shown that both MTC and differentiated thyroid cancer can exhibit increased SSTR-tracer uptake (6, 22). Studies comparing PET imaging of MTC using SSTR-tracers and F-DOPA (an established tracer for MTC imaging) show comparable results, although F-DOPA PET is favored (23, 24). Some advocate that DOTA-TATE PET scans can be used for staging and follow-up of patients with MTC (7, 8, 25). With this in mind, abnormally increased thyroid uptake, particularly in patients with known MEN2 strongly associated with MTC, should be investigated further (26). Initially with blood samples (calcitonin measurements in particular), and in cases with elevated calcitonin levels, proceed to surgery (with or without ultrasound and cytological evaluation) (27). In Denmark, surgery is always recommended in patients with MEN2 when calcitonin levels rise above the normal reference value regardless of ultrasound findings and cytology (26, 28).
In one case, a metastasis in the thyroid gland originating from a renal clear cell carcinoma was identified. This patient had 9 years earlier been curatively treated with a left-sided nephrectomy. The fine needle biopsy was compatible with a renal clear cell carcinoma metastasis, and the patient underwent a right-sided hemithyroidectomy that confirmed the diagnosis and possibly cured the patient. Metastatic renal clear cell carcinomas have previously been reported to be SSTR-tracer avid, and there is even a case report with such a metastasis in the thyroid gland (29, 30). When unexpected SSTR-tracer uptake is seen in a patient previously treated for renal clear cell carcinoma, it is thus important to consider relapse of this disease rather than just assume NEN disease.
Parathyroid adenomas, the most frequent cause of PHPT, are known to express the SSTR on their cell surface, unlike non-neoplastic parathyroid tissue (14). Focal uptake of SSTR-tracer adjacent to the thyroid gland is, therefore, suspicious for parathyroid adenoma. In our present study, five cases of classical PHPT were reported, corresponding to 38% of the 13 cases with uptake adjacent to the thyroid gland. Additionally, one case of normocalcemic PHPT was identified. This is also a clinically relevant finding, as this condition may warrant medical or surgical treatment (31). Accordingly, uptake adjacent to the thyroid gland should be followed by blood samples (PTH, ionized calcium, vitamin D) to screen for PHPT (32, 33).
Traditionally, parathyroid disease in MEN1 has been classified as multiglandular hyperplasia or nodular hyperplasia. However, the histological distinction of nodular hyperplasia from adenoma (i.e. neoplastic proliferation) is arbitrary, and multiple small adenomas may be present (34, 35). In our present study, focal uptake adjacent to the thyroid gland was associated with parathyroid adenomas in patients with MEN1, in line with previous reports (10, 36). These findings have clinical consequences in relation to the planning of parathyroid surgery. The recommended surgical treatment for primary hyperparathyroidism in MEN1 is subtotal parathyroidectomy (37). When a patient with hyperparathyroidism and MEN1 is treated with subtotal parathyroidectomy, the surgeon will firstly remove the adenomas/most hyperplastic glands as visualized by an imaging modality (e.g. parathyroid scintigraphy, ultrasound, PET, etc.) and preserve half of the parathyroid gland that appears least pathological.
One parathyroid adenoma without DOTA-TATE uptake was identified on the CT scan and later visualized as a possible adenoma on the parathyroid scintigraphy. Histological examination of the surgical specimen confirmed that it was, in fact, a parathyroid adenoma. Occasionally, the diagnostic CT scan (especially when performed with CT contrast) is a better modality to find parathyroid adenomas than SSTR-PET and parathyroid scintigraphy. Therefore, if the parathyroid scintigraphy does not identify an adenoma in patients with MEN and hyperparathyroidism, it may be beneficial to look thoroughly at the latest CT scan. Indeed, it has previously been shown that routine CT scans (performed for reasons other than suspected parathyroid disease) can positively identify parathyroid adenomas (38). In our present study, parathyroid-specific follow-up was performed in 12 out of 13 patients, which is a high percentage. In the study by Bunch et al., the recommended blood testing was only performed in 13 of 39 patients. Nevertheless, three and four of the tested patients had PHPT and secondary hyperparathyroidism, respectively. Thus, similar to our study, a substantial percentage of the patients were diagnosed with PHPT (38).
A head-to-head comparison study conducted in our department demonstrated that the patient-based sensitivity for detecting NENs was the same for [68Ga]Ga-DOTA-TOC and [64Cu]Cu-DOTA-TATE (1). However, the two tracers have different affinity profiles for the SSTRs and, hence, may have different sensitivity for detecting thyroid and parathyroid pathology. In this retrospective study, relatively more lesions were detected with [68Ga]Ga-DOTA-TOC than [64Cu]Cu-DOTA-TATE. Nonetheless, similar levels of SSTR-tracer uptake were demonstrated in most patients scanned with both tracers.
Strengths of this study include a thorough follow-up of a rather large sample of all consecutive [68Ga]Ga-DOTA-TOC and [64Cu]Cu-DOTA-TATE PET scans at our department. The electronic patient chart system at our hospital contains data from multiple national registries, including diagnoses, blood samples, imaging results, and pathology. The patients and their clinical course are, therefore, well characterized. However, the usual caveats of retrospective studies still apply, including a lack of systematic thyroid- and parathyroid-specific follow-up in patients with abnormal SSTR-tracer uptake within or adjacent to the thyroid gland, respectively. The true rates of thyroid malignancy and parathyroid adenomas in these patients are likely underestimated. Additionally, only scan reports rather than the scan images were screened. The true rate of uptake in relation to the thyroid gland may, therefore, be higher than reported here. However, all cases with thyroid malignancy had Krenning scores of 3 or 4. We find it unlikely that lesions with Krenning scores of 3 and 4 were not reported. However, lesions with Krenning score 2 are likely underreported in the present study, while lesions with Krenning score 1 typically will be evaluated as not clinically relevant. More systematic and prospectively conducted studies of the relationship between SSTR-uptake and thyroid and parathyroid diseases are needed to guide future clinical practice.
Conclusions
In patients undergoing SSTR-tracer PET scans for evaluation of NENs, the prevalence of reported abnormal uptake within or adjacent to the thyroid gland was low (2.3% and 0.7 %, respectively) in the present study. The malignancy rate was five out of 42 (12%) in cases with abnormally increased thyroid uptake, in line with previous studies, and it was as high as five out of 12 (42%) in the subgroup with cytological and/or histological evaluation. Focal as well as heterogeneous thyroid uptake can represent thyroid pathology, including benign thyroid adenomas, MTC, and NEN metastases. Other studies have demonstrated that cancers derived from the follicular epithelium can also be SSTR-tracer positive. Additionally, focal uptake of SSTR tracer near the thyroid gland often represents parathyroid adenomas. In the present study, six out of 13 cases (46%) with uptake adjacent to the thyroid gland had biochemical hyperparathyroidism. Unless the clinical condition of the patient speaks against it, reported abnormal SSTR uptake within or adjacent to the thyroid gland should be investigated with further diagnostic work-up as it may have clinical consequences. Future studies, preferentially prospective, are needed to clarify the true magnitude and significance of abnormal thyroid and parathyroid uptake in SSTR-targeted PET imaging.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
Data availability statement
Research data are not shared due to privacy constraints.
Author contribution statement
SS: Conceptualization; data curation; validation; visualization; writing – original draft. CHH: Conceptualization; writing – review and editing. AKR: Conceptualization; writing – review and editing. PSO: Conceptualization; supervision; writing – review and editing. PKC: Conceptualization; supervision; validation; visualization; writing – review and editing.
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