Low risk of malignancy related to prostate-specific membrane antigen-PET/CT-positive thyroid incidentalomas

Prostate cancer (PCa) is the most diagnosed malignancy among men in Northern Europe, with age-standardised incidence rates exceeding 100 per 100,000 in Denmark, Sweden and Norway [1].

Prostate-specific membrane antigen (PSMA) PET/CT is widely used for staging and management of PCa, particularly in higher-risk disease and in biochemical recurrence, improving diagnosis and treatment decisions [2]. As its use expands, incidental PSMA uptake unrelated to PCa is occasionally recognised, including thyroid incidentalomas of uncertain clinical relevance.

Currently, no national Danish clinical guideline addresses the management of PSMA-PET/CT-positive thyroid incidentalomas. The national guideline on thyroid cancer from the Danish Head and Neck Cancer Group (DAHANCA) was recently updated [3]. Although this guideline does not cover PSMA-PET/CT-positive incidentalomas, it provides thorough recommendations on the management of PET-positive incidentalomas encountered by the ¹⁸F-fluorodeoxyglucose (FDG) tracer. According to the guideline, focal FDG-PET/CT-positive thyroid incidentalomas should be referred for evaluation in a fast-track cancer pathway due to the risk of malignancy. A systematic review of FDG-PET-positive incidentalomas reported a malignancy rate of 34.8% [4], whereas a prospective Danish cohort study demonstrated a malignancy rate of 24% in focal FDG-positive thyroid lesions [5].

Although data are conflicting and evidence is limited, early data on PSMA-PET/CT-positive thyroid incidentalomas suggest malignancy rates comparable to those of FDG-PET-positive thyroid incidentalomas [6]. Accordingly, most ear, nose and throat (ENT) departments refer patients with focal PSMA-PET/CT-positive thyroid incidentalomas for fast-track workup. Diffuse PSMA uptake, in contrast, is generally associated with inflammatory rather than malignant changes [7], and a 2022 systematic review and meta-analysis found no malignant cases among patients with diffuse uptake [8].

However, the malignancy risk of focal PSMA-PET/CT-positive thyroid incidentalomas remains unclear, and it is uncertain whether fast-track referral is justified. Thus, the aim of this study was to assess the incidence of focal PSMA-PET/CT-positive thyroid incidentalomas and their associated malignancy risk in an unselected cohort of patients undergoing PSMA-PET/CT for suspected PCa and to evaluate the need for fast-track workup.

Methods

Study design and population

This retrospective cohort study evaluated all PSMA-PET/CTs performed at the Department of Nuclear Medicine, Gødstrup Hospital, from 1 January 2019 to 31 December 2023. Only patients with PSMA uptake in the thyroid gland were further reviewed. The inclusion criterion was patients with focal PSMA uptake in the thyroid gland. Patients with diffuse (non-focal) uptake or patients without subsequent ENT referral were excluded. Indications for PSMA-PET/CT were either initial staging of newly diagnosed men with intermediate or high-risk PCa or biochemical recurrence after curatively intended treatment. During the study period, the tracer was changed from ⁶⁸Ga to ¹⁸F.

Prostate-specific membrane antigen-PET/CT evaluation

Initial assessment of thyroid PSMA uptake pattern and intensity was based on the interpreting nuclear medicine physicians’ report. Uptake was classified as focal or diffuse, and then as mild, moderate or intense, based on subjective assessment without predefined criteria. A CT correlate was also noted.
PSMA uptake patterns were routinely re-evaluated at the weekly PCa multidisciplinary team meetings and further reviewed by an experienced head and neck surgeon if needed. Cases of focal uptake later reclassified as non-focal were excluded.

Ear, nose and throat evaluation

Patients referred for ENT evaluation were assessed according to the national DAHANCA protocol for focal FDG-PET/CT–positive thyroid nodules. The workup included a full ENT examination with flexible endoscopy of the upper airways, blood tests including thyroid-stimulating hormone (TSH), T3, T4, thyroid peroxidase antibodies (TPO), calcitonin, calcium++, cervical ultrasonography, fine-needle aspiration (FNA) and/or thyroid scintigraphy when indicated.

Thus, FNA was performed for nodules ≥ 10 mm, except when a thyroid scintigraphy was indicated. Scintigraphy was reserved for solitary nodules with suppressed TSH (< 0.3 mU/l) and no red flag features such as rapid growth, suspected metastases, impaired vocal cord mobility or EU Thyroid Imaging Reporting and Data System (TIRADS) 5 classification [9]. If scintigraphy demonstrated a hypofunctioning nodule, FNA was performed. Cytology was evaluated according to the Bethesda System by thyroid cytopathologists [10].

If FNA revealed a malignant or suspicious cytology (Bethesda III–VI), a hemithyroidectomy was recommended. Nodules with benign cytology (Bethesda II) were followed. Non-diagnostic cytology led to repeat FNA, whereas persistent non-diagnostic results triggered recommendation of hemithyroidectomy. Surgery was also indicated for suspicious EU-TIRADS features, considerable growth (> 3 mm in diameter) or new concerning symptoms during follow-up. Patients without these findings were discharged with a benign outcome.

Data collection & analysis

Electronic medical records were reviewed for demographics, imaging, referral data, PCa characteristics, laboratory results, pathology reports and follow-up duration. The incidence of PSMA thyroid incidentalomas was determined, patient pathways were mapped and malignancy risk was assessed based on histopathology and clinical outcomes.

This study was conducted as a quality study and was approved by the Hospital Board of Directors.

Statistics

Data are presented as number/percentages and mean/standard deviation or median/range according to the criteria for normal distribution. The 95% CI for the malignancy rate was calculated using the Wilson score interval.

Trial registration: not relevant.

Results

Patient characteristics

In total, 1,477 PSMA-PET/CT scans were performed in 1,376 patients during the five-year study period. Thyroid PSMA uptake was present in 80 scans (5.4%), showing a diffuse uptake in 38 (2.6%) and a focal uptake in 42 (2.8%). Forty male patients were included in the study. See Figure 1.

Baseline characteristics, including age, indication for PSMA PET/CTs, tracer use and PCa classification, are shown in Table 1.

Prostate-specific membrane antigen-PET/CT & ear, nose and throat workup

The PSMA thyroid uptake pattern was predominantly a single focal lesion (92.5%), with moderate-to-intense uptake in 92.5% of cases, as shown in Table 2.

Ultrasound was performed in all 40 patients. An ultrasonographic correlate was found in 34 patients (85%), whereas a convincing CT correlate was present only in 18 patients (45%). Twenty-one patients (52.5%) had suspicious ultrasonographic features defined as EU-TIRADS 4 or 5. FNA was performed in 29 patients, raising suspicion (Bethesda III-VI) in six patients (15%). Nine patients (22.5%) underwent diagnostic hemithyroidectomy, and malignancy was confirmed in one patient (2.5%).

FNA was not performed in the remaining 11 patients due to absence of visible nodule identified on ultrasound at the initial ENT assessment (three cases), nodule size < 10 mm without suspicious features (four cases), multinodular goiter without a dominant lesion (one case), intrathoracical lesion and thus inaccessible for FNA (two cases) or scintigraphy revealing a “hot” area corresponding to subclinical hyperthyroidism (one case).

Diagnostic hemithyroidectomy was performed mainly due to these findings: four (44%) with FNA results consistent with Bethesda IV, one (11%) with an intrathoracic nodule inaccessible for FNA, two (22%) with growth of a nodule with previously benign cytology, one (11%) with repeat non-diagnostic FNA results and one (11%) with malignant cytology (Bethesda VI). 

In ten patients, neither FNA nor histological analysis was performed.

Follow-up

Follow-up was defined as the interval from the PSMA PET/CT to discharge from the ENT department, either after 1) benign findings (n = 26), 2) diagnostic hemithyroidectomy (n = 9), 3) death (n = 2) or 4) patients lost to follow-up (n = 2). This adds up to 39 patients.

One additional patient (Bethesda II) is still under observation, with 523 days of ongoing follow-up.

Of the two patients who died, one (Bethesda I) died from sepsis 106 days after the scan with no signs of thyroid cancer. The second patient (Bethesda II) died from disseminated PCa after 281 days.

Both patients who were lost to follow-up had Bethesda II cytology and were asymptomatic.

Among patients who did not undergo surgery, follow-up duration varied widely. Three patients without an ultrasonographic correlate were discharged after the initial ENT evaluation without further follow-up; none had a convincing CT correlate. Four patients with an ultrasound nodule measuring < 1 cm, without suspicious features, and not undergoing FNA were followed for a median of 340 days and were subsequently discharged as having benign findings. The nodules resolved completely in two patients and remained stable in size in the other two.

The patients with Bethesda II cytology had a median follow-up of 349 days before discharge. Two patients underwent hemithyroidectomy due to growth/compressive symptoms. Patients with Bethesda I cytology who did not undergo hemithyroidectomy had a median follow-up period of 454 days; one of six patients with Bethesda I underwent hemithyroidectomy. One patient with Bethesda IV cytology declined hemithyroidectomy and was followed for 1,713 days before discharge, whereas the remaining four Bethesda IV patients underwent hemithyroidectomy.

Two patients had intrathoracic adenomas; one declined hemithyroidectomy and was followed for 1,061 days before discharge; the other underwent hemithyroidectomy.

Rate of malignancy

The rate of malignancy in this cohort was 1/40 (2.5%; 95% CI: 0.04-12.9%). The single malignant case was histologically confirmed as papillary thyroid carcinoma (PTC). The focal PSMA-PET/CT uptake is shown in Figure 2. Additional information regarding the malignant case is provided in Supplementary table S1.

Discussion

In our cohort, the incidence of focal thyroid uptake on PSMA PET/CT was 2.8%, consistent with a 2025 systematic review and meta-analysis reporting 0.5-6.2% across seven studies [11].

With 40 patients, our study represents the second-largest cohort reported to date, second only to Piek et al. (43 patients) [12], whereas most other studies included only 6-7 patients [13-17].

A major strength of our study is the near-complete case inclusion. We reviewed all PSMA PET/CTs over five years and included 40 of 42 patients with focal uptake, supporting a reliable malignancy risk estimate.

Unlike many previous studies that used variable assessments and follow-up, all patients underwent a uniform diagnostic workup.

We observed a malignancy rate of 2.5% among focal PSMA-positive thyroid incidentalomas. This is slightly lower than the 7% reported by Piek et al. [12] and notably lower than the 11% reported by Koçar et al. [18]. The latter study relied partly on cytology for malignancy classification. Two of their four malignant cases were diagnosed solely on FNA with Bethesda VI cytology. While Bethesda VI carries a malignancy risk of 95.7%, it is not absolute, and reliance on cytology alone may inflate malignancy estimates [19].

Malignancy risks vary substantially across small cohorts. Two cohorts of six patients each reported no malignant cases [14, 17], whereas others reported rates of 28.5% and 16.6% [15, 16]. Another study reporting a malignancy rate of 16.6% based solely on cytology similarly raises concerns about overestimation [13].

This study has several limitations. Its retrospective single-centre design may introduce information bias and limit generalisability. In addition, not all cases had histopathological verification. The small cohort size (n = 40) reduces statistical power and limits the ability to draw firm conclusions regarding malignancy risk. Finally, benign FNA findings may miss small malignant lesions due to sampling error or microcarcinomas.

Nevertheless, our study included nine hemithyroidectomies – the highest number of surgically validated cases reported in this context – supplemented by long-term clinical follow-up. While recognising that neither cytology nor follow-up alone can exclude malignancy with complete certainty, this combined approach provides a robust assessment of clinically significant malignancy.

Altogether, our data suggest that the clinically significant malignancy risk is likely at the lower end of the range reported across previous studies.

The only malignancy identified in our cohort was PTC, which is consistent with findings from prior studies in which PTC was the predominant histological subtype. PTC generally carries an excellent prognosis, with five-year relative survival for nonlocalised disease improving from 83.5% in 2000-2004 to 92.3% in 2010-2015 [20].

All patients had PCa, either with unfavourable intermediate- or high-risk disease or with biochemical recurrence after curatively intended treatment. Despite this, all were referred through a fast-track cancer pathway, with a median time of three days to the initial ENT consultation.

Given the low malignancy risk observed, the typically favourable prognosis of PTC and the competing treatment priorities in patients with advanced PCa, our findings highlight a considerable risk of overtreatment.

Patients with focal PSMA uptake in thyroid incidentalomas should not routinely be referred to fast-track cancer pathway in the abscence of additional suspicion of thyroid malignancy. Instead, priority should be given to PCa management. However, national studies are needed to confirm the safety and generalisability of this approach.

Conclusions

Focal PSMA uptake in thyroid incidentalomas is uncommon and carries a low risk of clinically relevant malignancy. Patients should not routinely be referred to a fast-track cancer pathway, and priority should be given to PCa management to avoid unnecessary interventions.