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Endocrine imaging: what roles do PET and PET/CT play?

Positron emission tomography (PET) is a form of functional imaging and is now widely used to assess metabolism in neoplasia. The most routinely used radiotracer in PET imaging today, 2-[18F] fluoro-2-deoxyglucose (18F-FDG), has a short half-life of 110 minutes. It is known that glucose uptake by cancer cells is increased because of the increased production of glucose transporters that incorporate into the cell membrane. (1) 18F-FDG crosses the cell membrane and is phosphorylated to become FDG-6-phosphate, a compound that is resistant to further metabolic processes. (2) When its kinetic energy is dispersed as a positron, the positron travels a short distance and interacts with an electron. These 2 particles then undergo an annihilation reaction. Their rest mass is converted into two 511-keV photons that are emitted approximately 180 [degrees] apart. If the 2 photons are detected at the same time by a pair of detectors located on opposite sides of the patient, they are considered in coincidence, and the annihilation event can be localized along a straight line joining the coincidence detectors. Mathematical reconstruction methods, corrected for photon attenuation and scatter, can estimate the location and can semiquantify the amount of positron-emitting radionuclides within a patient.

Positron emission tomographic images are acquired almost simultaneously with computed tomographic (CT) images. Fusion of these data sets is accomplished by complex computer algorithms immediately after acquisition. Fused PET/CT imaging continues to advance in the detection of smaller-sized tumors and has established itself as a valuable dual-modality approach that successfully integrates anatomy and physiology for improved efficiency and accuracy in the oncologic and nuclear medicine specialties. (3,4) Fused images provide improved anatomic detail and allow better localization of PET findings. Research with new PET radiotracers continues and will allow functional imaging with PET to advance the fields of nuclear medicine and molecular imaging at unprecedented rates in the upcoming decades.

The role of functional imaging for endocrine abnormalities has increased over the last few decades. Endocrine tumors can be overlooked on conventional anatomic imaging because of a tumor's small size as well as limited or equivocal clinical data. It can also be difficult for conventional imaging to differentiate disease recurrence from post surgical changes. Furthermore, anatomic imaging does not provide information on tumor activity. Endocrine malignancies are uncommon, comprising 1% to 2% of all tumors affecting adults, and 4% to 5% of tumors affecting children. Some endocrine tumors are functional and secrete active substances that trigger physiological symptoms that prompt patient presentation. A smaller fraction of patients with endocrine neoplasms present with symptoms associated with mass effects that are more typically seen in patients with large nonfunctional tumors, which are commonly detected incidentally (ie, the "incidentaloma"). The increasing use of wholebody multidetector CT (MDCT) scans has led to an appreciable rise in the identification of such tumors.

The role of 18F-FDG PET and PET/CT in thyroid disease

Thyroid nodules are extremely common among the adult population, ranging from 4% to 7% within the whole population and a female-to-male ratio of 4:1. (5) The occurrence of malignancy in these nodules is fairly rare; however, correctly categorizing identified nodules is critical for management decisions. Current strategies for characterizing these nodules include nuclear thyroid scintigraphy as well as thyroid ultrasound. Iodine-123 (I-123) scintigraphy allows functional analysis of nodules and classification of "hot" versus "cold" nodules. These terms describe uptake of radiotracer by the nodule and the surrounding thyroid gland. "Hot" nodules, which display high uptake of I-123, are rarely malignant, while "cold" nodules, which display low uptake levels, can be malignant in 5% to 10% of cases. Cold nodules in patients who are younger can carry a malignancy rate of up to 35% to 40%. (6) This test does provide useful data but more commonly leads to further testing to delineate a more accurate diagnosis.



Thyroid carcinomas are classified as either differentiated (ie, papillary or follicular) or undifferentiated (ie, ana plastic), depending on the histologic and cytopathologic findings. Typically, patients with papillary or follicular carcinomas receive iodine-131 (I-131) total body scans in their evaluation. Figure 1 shows a patient who underwent total thyroidectomy for papillary thyroid cancer and was being evaluated for increasing thyro globulin levels after surgery. This patient had a positive I-131 scan, along with an 18F-FDG PET/CT scan that showed increased metabolic activity within the thyroid bed approximately 6 months after surgery.

There have been numerous reports of patients with negative I-131 scans and positive 18F-FDG PET scans, and vice versa. (7-9) This "flip/flop" phenomenon, as it has been termed, was attributable to differentiation of the cancer. Figure 2 shows a patient who underwent an 18F-FDG PET/CT evaluation after a total thyroidectomy for biopsy-proven papillary thyroid cancer. This particular patient was treated with I-131 on 2 separate occasions and on follow-up 2 years later was noticed to have increasing thyroglobulin levels. He had an I-131 scan that was negative and was referred for 18F-FDG PET/CT evaluation for meta static disease. The FDG studies showed a carcinoma.

These and other studies noted that more differentiated cancers are better imaged by I-131, while dedifferentiated thyroid cancers are better imaged by 18F-FDG PET. (7,10) Therefore, the role of 18F-FDG PET/CT is presently applied to those patients who have a negative I-131 scan, a negative chest CT (looking for metastasis), and rising serum thyroglobulin levels following initial thyroidectomy. (9) These patients are thought to have recurrent or metastatic disease that is undetectable by conventional imaging but biochemically apparent because of increasing thyroglobulin measurements. A recent study by Shammas et al (11) reported 18F-FDG PET/CT had a sensitivity of 68.4%, which is slightly lower than previous reported data, for detecting recurrent or metastatic thyroid cancer. However, the Shammas study revealed higher sensitivities for 18F-FDG PET/CT with higher thyroglobulin levels, with a sensitivity approaching 72% when thyroglobulin levels exceed 10 ng/mL. (11) Other recent studies have reported 18FFDG PET (using visual fusion with CT) and dedicated 18F-FDG PET/CT sensitivities for recurrent or metastatic thyroid cancer to be 95% to 100%, although these studies were on smaller patient sample sizes. (12-14)

The advantage of 18F-FDG PET and PET/CT in thyroid cancer imaging can be further verified by reviewing data on patient management affected by 18FFDG PET/CT results. Frilling et al (13) found distant metastases using 18F-FDG PET (with CT comparison) in a number of their thyroid cancer patients who had prior negative I-131 scans, which led to alteration of the initial plan and management in some of their surgical cases. These distant metastases were identified on a 18F-FDG PET staging scan, which led to 3 patients being treated with curative intent using systemic agents instead of surgery for local recurrence. Likewise, Helal et al (14) showed a clinical change in 29 of the 37 patients who were positively identified with recurrent or metastatic disease using 18F-FDG PET. The study by Shammas et al (11) using 18F-FDG PET/CT showed a modification in the treatment of 44% of patients enrolled in the study. Most of these patients went on to have surgery for local recurrence or local metastatic disease in the neck. However, 3 of these patients were correctly diagnosed with distant metastatic disease (2 to the lung and 1 to the mediastinum), which led to nonsurgical intervention and the use of systemic therapy.


The role of 18F-FDG PET/CT in adrenal tumors

Up to 79% of adrenocortical cancers produce some hormone or active agent that may lead to clinical symptoms. (15) Adrenal pheochromocytomas account for approximately 80% of catecho la mine-secreting neoplasms and generally measure 4 to 5 cm at presentation. (16,17) Since functioning adrenocortical tumors can be elucidated using hormonal assays, it is the nonfunctioning tumors that require additional testing and imaging to determine management for optimal patient care.

Imaging of patients with suspected pheochromocytomas usually begins with CT or magnetic resonance imaging (MRI) to assess the tumor. However, the variable appearance of pheochromocytomas on these modalities sometimes makes it quite difficult to establish an accurate diagnosis. These tumors can range from solid to cystic, fatty to necrotic, and homogenous to heterogeneous. Functional imaging provides localization of the tumor to any part of the body, especially extra-adrenal sites or previously postsurgical areas that can have distorted anatomy. (18) Functional imaging with either I-123 metaiodobenzylguanidine (MIBG) scintigraphy or 18F-FDG PET/CT can prove useful for localization, although the anatomic correlation that CT fusion affords PET scanning is superior to that of MIBG alone.


Studies have shown variable uptake of MIBG and 18F-FDG in pheochromocytomas. Some pheochromocytomas fail to accumulate MIBG but are able to accumulate increased 18F-FDG on PET/CT as well as pheochromocytomas that accumulate MIBG without increased metabolic activity seen on 18F-FDG PET/CT. (18-20) A study by Shulkin et al (19) showed that most malignant pheochromocytomas are better visualized with 18F-FDG, while more benign pheo chromocytomas are better detected with MIBG. The patient shown in Figure 3 is a 72-year-old man who under went right adrenalectomy for a pheo chromocytoma that was diagnosed by elevated catecholamines and a positive MIBG scan.

This patient then presented with a left adrenal mass that was positive for MIBG uptake. However, the left adrenal mass showed no increased metabolic activity on 18F-FDG PET/CT. This patient is still undergoing a work-up for suspected left adrenal pheochromocytoma.

A recent study by Timmers et al (20) demonstrated the superiority of 18F-FDG PET/CT in detecting metastatic foci in patients with paragangliomas that have succinate dehydrongenase mutations. These authors concluded that 18F-FDG PET/CT should be the functional imaging study of choice for these types of paragangliomas, since some patients with metastatic lesions had falsely negative MIBG scans. Figure 4 shows a 48-yearold man with elevated catecholamines and metanephrines with uncontrolled hypertension. The patient was evaluated with an MIBG scan that showed increased uptake in his known left paraaortic extra-adrenal paraganglioma as well as another questionable site of second focus of disease. The patient's workup was followed by 18F-FDG PET/CT, which showed hypermetabolic activity within the known paraganglioma as well as 2 additional foci that were lower in the abdomen, consistent with meta static paragangliomas. In this case, 18F-FDG PET/CT was shown to be more accurate in detecting this patient's metastatic paraganglioma sites.



With the increased utilization of whole-body PET/CT scans for diagnosis and clinical staging in oncology, the incidence of unsuspected adrenal gland abnormalities is increasing. It has been reported that up to 1% of patients being evaluated with abdominal CT and as many as 2% to 5% of patients being scanned with contrast-enhanced CT have been found to have adrenal incidentalomas. (21,22) The majority of these incidentalomas are benign and do not produce any biologically active metabolites. Figure 5 shows a patient who underwent 18F-FDG PET/CT for the evaluation of an indeterminate left adrenal mass found on chest CT. Lack of hypermetabolic activity allowed classification as benign incidentaloma, which did not require further invasive procedures.

Other recent studies have also used 18F-FDG PET/CT to help differentiate adrenal masses in oncology patients being evaluated for metastatic disease. A study by Metser et al (23) used a standard uptake value (SUV) of 3.1 for 18F-FDG while attempting to differentiate benign from malignant adenomas in patients referred for adrenal masses thought to be metastatic disease. When using an SUV of 3.1, their study showed a sensitivity of 98.5% and a specificity of 92% when differentiating all adenomas from malignant lesions. During initial staging for non-small-cell lung cancer (NSCLC), the patient in Figure 6 was found to have an adrenal mass on CT. 18F-FDG PET/CT was used to further evaluate this adrenal mass and assist with the final staging and recommendations for treatment. The mass showed hypermetabolic activity on 18F-FDG PET/CT and had an SUV of 12.4. The patient was eventually diagnosed with metastatic NSCLC to the adrenal.

Previous studies have demonstrated a sensitivity of up to 100% with 18F-FDG PET in delineating benign from malignant adrenal lesions. (24-27) A small study by Zettinig et al (28) reported a sensitivity of 100% for 18F-FDG PET in distinguishing benign from malignant lesions in 16 patients. The authors concluded that 18F-FDG is the tracer of choice over 11C-metomidate when attempting classification. Benign aden omas in adrenal glands are not likely to exhibit increased uptake of 18F-FDG, and, therefore, will be negative on 18F-FDG PET/CT imaging.

The physiologic and anatomic correlation provided by 18F-FDG PET/CT can improve the accuracy of diagnosis in these lesions. A larger study by Blake et al (29) analyzed the uptake of 18F-FDG by adrenal lesions and compared it with uptake of 18F-FDG by the liver. This study used an adrenal lesion-liver SUV ratio above 2.68 for diagnosing malignant lesions, which provided a 100% negative predictive value and 100% sensitivity for detecting malignant lesions.

In some of the studies described above, alterations in management were reported for patients correctly diagnosed with malignant lesions by 18F-FDG PET/CT. Another study showed 5 local relapses detected by 18F-FDG PET/CT that led to therapeutic changes in 3 patients, possibly altering patient outcome, that were not described in the article. (30) It is evident that 18F-FDG PET/CT can assist with characterizing benign from malignant adrenal masses that are found incidentally on other imaging modalities. Evidence also supports the use of 18F-FDG PET/CT to assist in classifying benign or malignant adrenal masses found in oncology patients. (23)

The role of PET/CT in pituitary tumors

Pituitary adenomas are common among the population and comprise about 10% to 15% of all diagnosed intracranial tumors as well as up to 20% of tumors seen in the pituitary on radiological examinations. (31,32) The primary treatment of pituitary tumors is resection and long-term monitoring for disease recurrence and metastatic disease. MRI is the current imaging modality used to identify disease recurrence. MRI has been reported to be limited in this area mainly because of the usual postsurgical changes that occur locally following resection. (33,34) With the rate of recurrence for pituitary tumors as high as 50% after surgical excision and the high metabolic rate of these tumors, PET imaging has shown promise for this application. (35) However, there is currently a limited amount of PET/CT data for pituitary tumor imaging.

The most commonly studied PET radiotracer for pituitary imaging is 11C-methionine (MET). Muhr et al (36) perform ed a study of different radiotracers for imaging pituitary adenomas with respect to tumor metabolism, receptor properties, and enzyme content. When comparing tracers in relation to metabolism, they concluded that 11C-methionine was superior to 18F-FDG. Uptake of 18F-FDG in the surrounding brain impaired the ability to visualize and outline the adenomas. The authors ultimately concluded that 11C-methionine PET imaging was highly valuable for detecting recurrence, measuring tumor metabolism, and evaluating treatment of these tumors.

Another recent study by Tang et al (35) compared 11C-methionine PET imaging of recurrent pituitary adenomas with MRI. Although small, this study showed that MET PET found 14 patients with possible residual or local recurrent disease that MRI failed to distinguish from scar tissue. Based on these findings, 9 of these 14 patients went on to have major therapeutic interventions.

The role of PET/CT in parathyroid tumors

Parathyroid tumors are responsible for approximately 85% of all cases of primary hyperparathyroidism (HPT). The vast majority (95%) of these are benign adenomas. (33) Hypercalcemia is the most common clinical manifestation associated with these adenomas.

Limited data are available to support 18F-FDG PET/CT for initial imaging of these tumors, but there are data to suggest its usefulness. A study by Sundin et al (37) looked at 11C-methionine as a radiotracer in imaging patients with HPT. They reported a sensitivity rate of 85% for localization of abnormal parathyroid tissue. CT images were used for anatomical correlation, but these images were not fused.

A more recent study by Beggs et al (38) evaluated imaging patients with negative or equivocal technetium-99m sestamibi (MIBI) scintigraphy. This study reveals an important role for PET in patients for whom parathyroid adenoma is highly suspected but who have negative MIBI scans. The authors reported a sensitivity of 83% and concluded that 11C-methionine PET scanning is valuable for HPT when conventional imaging has failed to locate the adenoma prior to more invasive procedures. The authors recommended scanning to the lower mediastinum to fully evaluate for adenomas.

It should be noted that some studies reported in this section are of PET imaging only and did not have PET/CT fusion, but used side-by-side analysis for anatomical correlation.


The Centers for Medicare and Medicaid Services (CMS) began covering 18F-FDG PET scans in January 1998, and at that time 18F-FDG PET was limited to characterizing single pulmonary nodules and initial staging of NSCLC. Because of professional organizations and clinical data supporting the use of PET and proving its ability to improve patient management and clinical outcomes, changes for reimbursement in PET have continued to evolve. (39) In recent years, the number of indications for 18F-FDG PET and 18F-FDG PET/CT for which CMS provides reimbursement has increased to include diagnosis, staging, and restaging of many types of cancer. Recently, reimbursement for papillary thyroid cancer with negative I-131 total body scans has been approved. With the National Oncology PET Registry (NOPR) implementation, reimbursement is also allowed for imaging of patients who have a type of cancer that is not currently listed in the CMS guidelines as long as all required documentation has been completed. Third-party payers are continuing to improve the reimbursement for 18F-FDG PET and 18F-FDG PET/CT imaging as indicated under the CMS guidelines.


The use of 18F-FDG PET and PET/ CT fusion imaging for the evaluation of endocrine tumors is increasing at a steady pace, with promising data supporting its use in this area of medicine. 18F-FDG PET/CT imaging has led to alterations in staging and improvement in clinical management for patients with positive findings. With the improved anatomic correlation offered by 18F-FDG PET/CT fusion, the accuracy of detecting smaller endocrine tumors will only improve. Although 18F-FDG PET/ CT fusion data is not reported heavily in the literature for all types of endocrine tumors, promising results for imaging with 18F-FDG PET alone should indicate that 18F-FDG PET/CT fusion will only enhance anatomical correlation and lead to the more accurate localization of all tumors described.


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Dr. MacFall recently completed medical school and will begin his Radiology Residency at the Medical University of South Carolina in July 2008. Dr. Gordon is a Professor of Radiology and Nuclear Medicine, and Dr. Davis is a Resident in Nuclear Medicine, Medical University of South Carolina, Charles ton, SC.

Timothy Allan MacFall, MD, Leonie L. Gordon, MD, PhD, and Phillip S. Davis, MD
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Title Annotation:positron emission tomography/computed tomography
Author:MacFall, Timothy Allan; Gordon, Leonie L.; Davis, Phillip S.
Publication:Applied Radiology
Article Type:Clinical report
Geographic Code:1USA
Date:May 1, 2008
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