
==== Front
Medicine (Baltimore)
Medicine (Baltimore)
MD
Medicine
0025-7974
1536-5964
Lippincott Williams & Wilkins Hagerstown, MD

MD-D-24-03006
00033
10.1097/MD.0000000000039602
3
6800
Research Article
Diagnostic Accuracy Study
Risk of malignancy in thyroid nodules with increased 11C-Choline uptake detected incidentally on PET/CT: A diagnostic accuracy study
Frota Lima Livia Maria MD FrotaLima.Livia@mayo.edu
a
Bogsrud Trond Velde MD, PhD TVbog@AOL.com
bc
Gharib Hossein MD Gharib.Hossein@mayo.edu
d
Ryder Mabel MD Ryder.Mabel@mayo.edu
de
Johnson Geoffrey MD, PhD Johnson.Geoffrey@mayo.edu
a
https://orcid.org/0000-0002-9630-576X
Durski Jolanta MD a*
a Department of Radiology, Mayo Clinic, Rochester, MN
b PET Imaging Center, University Hospital of North Norway, Tromso, Norway
c Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital, Aarhus, Denmark
d Division of Endocrinology, Diabetes, Metabolism, & Nutrition, Mayo Clinic, Rochester, MN
e Medical Oncology, Mayo Clinic, Rochester, MN.
* Correspondence: Jolanta Durski, Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA (e-mail: durski.jolanta@mayo.edu).
06 9 2024
06 9 2024
103 36 e3960221 3 2024
16 7 2024
16 8 2024
Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

Purpose:

The purpose was to evaluate the pathological nature of focal thyroid uptake seen in 11C-Choline PET/CT performed for prostate cancer.

Material and methods:

The study was IRB-approved. All 11C-Choline PET/CT exam reports for studies performed between January 01, 2018, and July 30, 2021, in male patients with prostate cancer in our institution were retrospectively reviewed. Exams with “focal thyroid uptake” on their final report were selected. Patients with surgery or ablation in the thyroid prior to the PET/CT, proven parathyroid adenomas or absent thyroid ultrasound were excluded. Repeated PET/CT exams of same patient were excluded. PET images were analyzed visually and semi-quantitatively by measuring the maximum standardized uptake value (SUVmax) of the focal thyroid uptake. Available thyroid ultrasound images, cytology and pathology reports were reviewed. Statistical analyses were performed.

Results:

Out of 10,047 sequential 11C-Choline PET/CT studies, 318 reports included “focal thyroid uptake.” About 128 of these studies were repeat exams and were excluded. Additional 87 patients were excluded, because the uptake was determined to be adjacent, rather than confined to the thyroid gland. Out of the remaining 103 patients, 74 patients had focal thyroid uptake and concurrent thyroid sonographic evaluation. Out of the 74 focal uptakes evaluated with ultrasound, 21 were presumed benign thyroid nodules based on the ultrasound and 53 had further evaluation with biopsy. Sixty three nodules were benign (21 presumed benign on ultrasound and 42 cytology or surgical pathology-proven), 9 nodules were malignant and 2 remained indeterminate. There was no significant difference between the SUVs of the benign and malignant groups (P > .3).

Conclusion:

In this retrospective study of patients with prostate cancer who underwent 11C-Choline PET/CT, we identified a group of patients who underwent thyroid ultrasound for incidental finding of focal 11C-Choline thyroid uptake. Incidence of malignancy in this group was 12%. Therefore, further investigation with ultrasound and possibly ultrasound-guided biopsy may be warranted when a choline avid thyroid nodule is found incidentally on choline PET.

choline
nodules
PET/CT
thyroid
N/ANot ApplicableOPEN-ACCESSTRUE
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pmc1. Introduction

The prevalence of thyroid nodules in the general population is reported to be up to 65%.[1] Thyroid nodules can be incidentally detected on different imaging modalities, such as neck ultrasonography, CT, magnetic resonance imaging or PET/CT. The incidental detection of focal thyroid uptake on FDG PET has been extensively studied, with reported incidence of 2% to 4% with an associated risk of malignancy of about 35%.[2] Incidental focal uptake on Choline PET/CT is less well studied.[3–5] Bertagna et al performed a systematic review to evaluate the prevalence and clinical significance of focal incidental radiolabeled choline uptake in the thyroid gland including 15 articles, including 7 benign and 7 malignant case reports.[5]

Choline is a precursor in the biosynthesis of phosphatidylcholine, a major component of the cellular membrane. It is internalized and metabolized by choline kinase, an enzyme that is overexpressed in certain tumors such as prostate cancer.[3] Multiple studies have shown usefulness of 11C-Choline and 18F-Choline PET imaging for the localization of parathyroid adenomas leading to clinical application in many centers world-wide.[6–12] Physiologic choline activity is seen in the salivary and lacrimal glands, liver, pancreas, and kidneys. Variable physiologic uptake can be seen in the bowel and bone marrow. Low-level uptake is frequently observed in small-volume reactive inguinal, mediastinal, or axillary nodes.[13] The thyroid gland may show diffuse mildly increased uptake on choline PET.[14] However, Ciappuccini et al showed that intense diffuse thyroid uptake on choline PET is associated with auto-immune thyroiditis.[13]

Only a few reports of focal choline uptake in the thyroid gland are found in literature.[3,5,15–17] Albano et al reviewed 368 patients who underwent 18F-choline PET/CT for prostate cancer between 2016 and 2018 with focal thyroid incidental uptake in 9 patients. Out of 9 cases, 5 were reported benign in nature, 1 indeterminate, 2 malignant, and 1 not further evaluated.[3] The purpose of this study was to evaluate the pathological nature of an incidental finding of focal 11C-Choline thyroid uptake on PET/CT to help referring clinicians in further management.

2. Material and methods

This was an IRB-approved retrospective study with the requirement for informed consent waived. The reports of all 11C-Choline PET/CT for staging prostate cancer performed from January 01, 2018, to July 30, 2021, at our tertiary medical center were collected using a Softek Illuminate InSight (Overland Park, KS). Patients with reports describing focal thyroid uptake were selected. Patients’ medical records and images were reviewed by LFL (currently a staff physician at Mayo Clinic, Rochester). Patients were excluded if they had surgery or radioiodine ablation of the thyroid prior to the PET/CT. Patients who proved to have choline uptake adjacent to, rather than in the thyroid gland, on subsequent review of the reports and images or who had had a known parathyroid adenoma, were excluded. Patients who lacked concurrent ultrasound evaluation of the thyroid were excluded. Only the first 11C-Choline PET/CT exam for a given patient was included for review.

PET images were analyzed using Visage Client image software (Visage Imaging Client 7.1.17, Visage Imaging GmbH, Berlin, Germany). Focal thyroid uptake was visually and semi-quantitatively analyzed by measuring the maximum standardized uptake value (SUVmax). Available thyroid ultrasound images were evaluated, including exams performed just prior to the PET/CT, and when possible, associated TI-RADS score, and nodule size were reviewed. Available cytology and pathology reports were reviewed.

2.1. Choline PET/CT imaging protocol

11C-Choline was produced at our on-site PET radiochemistry facility. A CT scout scan was performed to define the body axial range to be imaged. Next, the patient received an intravenous injection of 10 to 20 mCi of 11C-Choline. The patients were imaged per our clinical protocol with 11C-Choline IV injected on the scanner table, followed by CT, then subsequent PET imaging with feet first (Discovery RX, 690, 710 or DMI GE Healthcare). PET imaging initiated approximately 5 minutes after radiotracer injection. Low-dose helical CT images were obtained during shallow breathing for attenuation correction and anatomic correlation (detector row configuration, 16 mm × 0.625 mm; pitch, 1.75; gantry rotation time, 0.5 seconds; slice thickness, 3.75 mm; 140 kVp; and range, 60 to 120 mA with the use of automatic current modulation). PET acquisition was from orbits to the mid-thigh with time-of-flight, 128 × 128 matrices and at a rate of 3 to 4 minutes/bed position depending on body mass index. PET images were reconstructed with a 3-dimensional ordered subsets expectation maximization algorithm (28 subsets, 2 iterations).

2.2. Image analyses

Images were reviewed with Visage Client image software and MIM Software (MIM Software Inc., Cleveland, USA) and a picture archiving and communication system workstation (Centricity; GE Healthcare, Milwaukee, USA). When focal choline thyroid uptake was reported, the focal activity was confirmed to represent conspicuous focal uptake higher than the uptake in the rest of the nearby and contralateral thyroid parenchyma. SUVmax was measured in a spherical region of interest. Medical records were reviewed, including thyroid ultrasound (US) reports and images from scans performed at our institution and elsewhere. For the patients who underwent biopsy/surgery, cytology and pathology results were reviewed.

2.3. Statistical analyses

Patient baseline characteristics were summarized as mean and standard deviation for continuous variables and number (percentage) for ordinal and nominal variables. For continuous variables that showed nonnormality, values were presented instead by mathematical average and standard deviation.

3. Results

Automatic search of 10,047 sequential 11C-Choline PET/CT studies, performed for prostate cancer staging, identified 318 reports with focal thyroid uptake (Fig. 1). One hundred twenty eight of these studies were repeat exams and were excluded. On further review of the reports, images, and clinical information, additional 87 patients were excluded, because the uptake was determined to be adjacent, rather than confined to the thyroid gland, sometimes related to a parathyroid adenoma or uptake in adjacent lymph nodes. Out of the remaining 103 patients, 29 had no further evaluation with ultrasound, predominantly because of the presence of advanced prostate cancer. About 74 patients had focal thyroid uptake and concurrent thyroid sonographic evaluation.

Figure 1. Flowchart of the search strategy for focal thyroid uptake on PET/CT.

Of the 74 patients, 21 evaluated by ultrasound had nodules with benign features on ultrasound and were considered benign or low suspicion for malignancy with no further evaluation recommended as per Thyroid Imaging Reporting & Data System (TI-RADS) proposed by American College of Radiology (ACR).

Of the 74 patients, 53 had nodules with sonographic features that required further evaluation with fine needle aspiration. Out of the 53 biopsied nodules, 39 were benign (Bethesda II), 9 were malignant or suspicious for malignancy (Bethesda V or VI), 1 was a follicular lesion of undetermined significance (FLUS) (Bethesda III) and 4 were suspicious for follicular neoplasm (Bethesda IV).

The 39 cytologically benign nodules had no surgical resection. Two nodules remained indeterminate and were not surgically removed per patients’ decision: 1 oncocytic cell neoplasm (previously reported as Hürthle cell nodule) and 1 FLUS.

Out of the 12 resected nodules, 2 were clearly benign, including 1 follicular hyperplasia and 1 oncocytic cell adenoma (previously known as Hürthle cell adenoma); 1 was found to be a benign follicular adenoma with incidental microscopic adenocarcinoma and 9 nodules were malignant (12%) (Table 1). Out of the malignant nodules, 7 were papillary carcinomas, 1 was MALT lymphoma, and 1 was a squamous cell carcinoma (SCC).

Table 1 Features of biopsy proven malignant thyroid nodules.

Case	Size (cm)	TI-RADS	SUVmax	Final diagnosis	
1	2.5	4	6.2	Malignancy with squamous cell characteristics	
2	2.8	4	5.6	Papillary thyroid carcinoma	
3	0.7	4	3.8	Papillary thyroid carcinoma	
4	1.3	5	4.3	Papillary thyroid carcinoma	
5	1	5	2.6	Papillary thyroid carcinoma	
6	1.2	5	4.3	Papillary thyroid carcinoma	
7	2.6	4	4.2	Papillary thyroid carcinoma	
8	3.5	4	6.7	MALT lymphoma	
9	1.3	5	3.7	Papillary thyroid carcinoma	

The average size of the 74 focal thyroid lesions was 21.3 mm, for the nonmalignant lesions it was 21.6 mm and for the 9 malignant lesions 18.8 mm.

The average SUVmax of the 74 focal thyroid lesions was 4.5 ± 1.7 (SD), for the 42 benign lesions 4.8 ± 1.6, for the 2 indeterminate lesions 5.6 and 10.6, and for the 9 malignant lesions 4.6 ± 1.2. There was no significant difference between the average SUVmax of the benign and malignant groups.

Two of the patients with malignant nodules were found to have metastatic nodes on surgery, including 1 patient with SCC. Primary SCC of the thyroid gland is a rare entity representing <1% of all primary carcinomas of the thyroid gland.[18] This patient underwent fine needle aspiration of the thyroid nodule with overall findings favoring a primary thyroid carcinoma with squamous differentiation. Followed surgical resection confirmed poorly differentiated SCC. Given the exceedingly rare incidence, further exams were performed, which didn’t find any other primary malignancy. Possible metastatic nodes were reported on 11C-Choline PET/CT of this patient with SCC. A second patient with possible metastatic node on 11C-Choline PET/CT had only microscopic involvement of the nodes on pathology.

4. Discussion

Focal choline uptake in the thyroid represented both malignant and benign disease. We found that 12% of 11C-Choline avid nodules, that were further evaluated with ultrasound were malignant. Thyroid US was used to stratify the risk of malignancy for thyroid nodules and had a decisional role for performing fine needle aspiration. The 12% risk of malignancy estimate should be interpreted with caution given only 74 patients with focal uptake on 11C-choline PET/CT were further evaluated with ultrasound. As these were all patients evaluated with 11C-choline PET/CT for metastatic prostate cancer, it is not surprising that 29 patients had no further evaluation with ultrasound. Referring physicians probably chose not to evaluate the thyroid nodules in the presence of advanced prostate cancer. We used 11C-Choline, however, it is reasonable to assume that the clinical significance of an incidental finding of a thyroid nodule with increased uptake of 18F-Choline and 11C-Choline will be the same.

Papillary thyroid carcinoma has been previously shown to be intensely choline avid, even in tumors that were poorly 18F-FDG-avid.[19,20] Our study also demonstrated intense uptake in papillary thyroid malignancy as seen in Figure 2. However, the SUVs were not statistically different from incidental choline avid benign thyroid nodules. No threshold of SUVmax discriminated between benign and malignant lesions. This finding is different from previous report by Ciappuccini et al, which showed that SUV was higher in malignant, than in the benign nodules.[21] However, Ciappuccini used 18F-Choline rather than 11C-Choline and prospectively studied nodules with abnormal cytology. Our population may be too small to show a small difference in SUVmax between the benign and malignant nodules. Another reason may be the partial volume effect, as the smaller malignant nodules in our study had lower SUV values than the larger ones.

Figure 2. A 59-yr-old male with history of prostate cancer, status post prostatectomy and biochemical recurrence (corresponding to patient 7 of Table 1). Focal left thyroid bed uptake (arrow) seen on maximum intensity projection volume-rendered PET data (A) and axial fused PET/CT image (B). Gray-scale ultrasound of the thyroid (C) showed a 26 mm heterogenous hypoechoic nodule in the left lobe of the thyroid with macrocalcifications. Ultrasound-guided fine needle aspiration (D) showed papillary thyroid carcinoma (arrows show needle), which was confirmed after total thyroidectomy. Pathology report showed classic papillary thyroid carcinoma measuring 2.6 × 2.5 × 1.6 cm in mid- to lower-left lobe.

Our data suggests that when an incidental choline avid thyroid nodule is identified on PET, there is a 12% chance the thyroid nodule is malignant, and the intensity of uptake seems not to be a reliable method for differentiating whether it is benign or malignant. One might conclude that a patient with an incidental choline avid thyroid nodule may benefit from an US and possible US-guided fine needle biopsy.

The present study is of importance to clinical practice considering the increasing clinical use of choline PET for parathyroid adenoma localization.[11,12] However, the results of our study of elderly male patients, might not apply to different patient populations, for example young patients and female patients.

A systematic review and meta-analysis of 18 studies performed Treglia et al concluded that radiolabeled choline PET is an excellent diagnostic tool to detect hyperfunctioning parathyroid glands in patients with hyperparathyroidism with sensitivity of 95%.[10]

A retrospective study from our institution published in 2018[7] found a 0.1% (3/2933) frequency of incidental thyroid lesions when searching for possible parathyroid adenomas on a review of almost 3000 patients of 11C-Choline PET/CT. However, the study likely underestimated the incidence of choline avid thyroid nodules because it only included preselected patients with suspected parathyroid adenomas through a review of the electronic medical record and relevant imaging. Thyroid nodules, benign or malignant, should be considered in the differential diagnosis of conspicuous focal choline uptake within or near the thyroid gland, even on studies performed in patients with hyperparathyroidism and possible parathyroid adenomas, given the high incidence of thyroid nodules in the general population.

The clinical value of choline PET to evaluate a thyroid nodule previously identified on US is unclear, and our study did not evaluate this clinical scenario. A recent prospective study in male and female patients showed that 18F-Fluorocholine PET/CT had high sensitivity (90%) and negative-predictive value (96%), but poor specificity (49%) and positive-predictive value (29%) for predicting malignancy in thyroid nodules initially identified on US that had indeterminate cytology prior to choline PET/CT.[21] It is worth noting that our study included only the thyroid nodules which were choline avid. Thus, it is possible that if 1 were to study thyroid nodules initially identified on US and then assess the choline activity in those nodules on PET, at least some, if not most of the nodules would likely show no activity. Therefore, there might be a difference in average SUVmax on choline PET scans between benign and malignant thyroid nodules as shown in other studies.[3]

We acknowledge the limitations of our investigation. First, this study was retrospective and subject to the inherent weaknesses of nonprospective studies. Sensitivity and specificity could not be calculated in this study, because the number of false negative nodules is unknown.

The SUVs on choline PET/CT could vary between exams as it is accepted that the rapid metabolism of choline could result in some variability of SUV. Our investigation represents the experience of a single institution. The data presented here derive from a population of adult men with prostate cancer; therefore, choline PET might need to be further evaluated in younger patients and in women.

5. Conclusion

In this retrospective study of patients with prostate cancer who underwent 11C-Choline PET/CT, we identified a group of patients who underwent thyroid ultrasound for incidental finding of focal 11C-Choline thyroid uptake. Incidence of malignancy in this group was 12%. Therefore, further investigation with ultrasound and possibly ultrasound-guided biopsy may be warranted when a choline avid thyroid nodule is found incidentally on choline PET. It is reasonable to assume that the clinical significance of an incidental finding of a thyroid nodule with increased uptake of 18F-Choline and 11C-Choline will be the same.

Acknowledgments

The authors acknowledge the assistance of Lucy Bahn, PhD, and Sonia Watson, PhD, in editing the manuscript.

Author contributions

Conceptualization: Livia Maria Frota Lima, Trond Velde Bogsrud, Hossein Gharib, Jolanta Durski.

Data curation: Livia Maria Frota Lima.

Formal analysis: Livia Maria Frota Lima, Jolanta Durski.

Investigation: Livia Maria Frota Lima.

Methodology: Livia Maria Frota Lima, Trond Velde Bogsrud, Jolanta Durski.

Project administration: Livia Maria Frota Lima, Jolanta Durski.

Resources: Livia Maria Frota Lima, Jolanta Durski.

Software: Livia Maria Frota Lima.

Supervision: Trond Velde Bogsrud, Hossein Gharib, Mabel Ryder, Geoffrey Johnson, Jolanta Durski.

Validation: Livia Maria Frota Lima.

Visualization: Livia Maria Frota Lima.

Writing – original draft: Livia Maria Frota Lima.

Writing – review & editing: Livia Maria Frota Lima, Trond Velde Bogsrud, Hossein Gharib, Mabel Ryder, Geoffrey Johnson, Jolanta Durski.

Abbreviations:

11C Carbon 11 and 18FFluorine 18

ACR American College of Radiology

CT computed tomography

FDG fludeoxyglucose

FLUS follicular lesion of undetermined significance

IRB Institutional Review Boards

KVp kilovoltage peak

MALT mucosa associated lymphoid tissue

mCi millicurie

MIP maximum intensity projection

PET positron emission tomography

ROI region of interest

SCC squamous cell carcinoma

SD standard deviation

SUVmax maximum standardized uptake value

TI-RADS Thyroid Imaging Reporting & Data System

US ultrasound

The authors have no funding and conflicts of interest to declare.

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

How to cite this article: Frota Lima LM, Bogsrud TV, Gharib H, Ryder M, Johnson G, Durski J. Risk of malignancy in thyroid nodules with increased 11C-Choline uptake detected incidentally on PET/CT: A diagnostic accuracy study. Medicine 2024;103:36(e39602).
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