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Laboratory and Clinic of Experimental Medicine and Endocrinology (A.V.d.B., R.B.), Departments of Nuclear Medicine (A.M., T.D.P., L.M.), Pathology (M.D., B.V.D.), and Head and Neck Surgery (P.D.), Universitaire Ziekenhuizen Gasthuisberg, B-3000 Leuven, Belgium
Address all correspondence and requests for reprints to: R. Bouillon, Laboratory for Experimental Medicine and Endocrinology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. E-mail: . roger.bouillon{at}med.kuleuven.ac.be
Abstract
Fluorodeoxyglucose (FDG) whole body positron emission tomography (PET) scan is increasingly used in the diagnostic work-up or follow-up of patients. In these conditions, positive PET scans with unexpected hot spots within the thyroid region could be defined as thyroid FDG-PET incidentaloma (in analogy with unexpected sonographic thyroid nodules).
We describe eight consecutive patients referred to the endocrine department because of thyroid "hot spots," incidentally detected by whole body FDG-PET scan (September 1999 to March 2001). Using ultrasound, fine needle aspiration cytology (FNAC), and histology reports, we tried to identify the pathology underlying thyroid FDG-PET incidentaloma. FNAC showed an indication for surgery in all patients. Surgery has been performed in 7 patients. Malignancy was correctly identified in five patients: two medullary thyroid carcinomas, one with lymph node invasion, and three papillary thyroid carcinomas with invasion through the thyroid capsule in two of the PTC cases. In two patients with a positive FDG-PET scan, FNAC pointed to follicular neoplasms, and final histology reports showed follicular adenoma. In the remaining patient, FNAC revealed a follicular lesion, but surgery has not yet been performed.
In conclusion, a small series of consecutive thyroid FDG-PET incidentaloma cases is presented and suggests a high rate of clinically relevant malignancies.
THYROID INCIDENTALOMAS ARE discovered in several ways. Usually they are detected in the course of an imaging study [ultrasound (US) or computerized tomography (CT)] for suspected nonthyroid diseases. US studies report a nodule prevalence ranging from 19–46% in the general population. The risk of carcinoma in impalpable thyroid nodules ranges from 1.5–10% (1).
Fluorodeoxyglucose (FDG) positron emission tomography (PET) differs from conventional imaging techniques (CT,US) that rely on morphologic alterations for tumor detection. It is indeed a functional imaging technique that relies on in vivo visualization of lesional glucose metabolism (2). Malignant and inflammatory lesions exhibit increased rates of glycolysis and glucose uptake (3). In thyroidology, the clinical value of FDG-PET is established in the follow-up, and localization of recurrences in a subgroup of thyroid cancers [i.e. papillary and follicular thyroid cancer recurrences with elevated thyroglobulin levels and negative radioiodine whole body scan (4, 5), and metastatic medullary thyroid cancer (6)]. However, there is no established role of FDG-PET in the diagnosis of highly prevalent cold thyroid nodules. To discriminate frequent benign from rare malignant lesions, the preferred approach now is fine needle aspiration cytology (FNAC).
FDG-PET is increasingly used in the diagnostic work-up and in the follow-up of patients in medicine and oncology departments. In the course of a whole body FDG-PET for a nonthyroid malignancy or a paraneoplastic phenomenon, a scan with an unexpected hot spot within the thyroid region is occasionally found. We would define this phenomenon as a thyroid FDG-PET incidentaloma.
This communication describes the first series of eight consecutive thyroid FDG-PET incidentaloma cases, referred to our department for FNAC and advice.
Subjects and Methods
Subject A
A 51-yr-old male was referred to a gastro-enterologist because of an elevated carcinoembryonic antigen (CEA) value of 12.4 µg/liter (normal value < 3 µg/liter). Clinical examination, CT scan of the abdomen, gastroscopy, and ileocoloscopy were negative. A FDG-PET scan revealed a hot spot at the right side in the thyroid region. A subsequent calcitonin value was elevated at 158 ng/liter (normal value <10 ng/liter). Thyroid US showed a hypoechoic nodule in the right lobe. Ultrasound guided FNAC suggested a medullary thyroid carcinoma (MTC). An evaluation to exclude pheochromocytoma (urinary catecholamin excretion and adrenal US) was negative. Total thyroidectomy and bilateral selective lymph node dissection revealed a gray 1-cm diameter lesion in the right upper pole. This tumor consisted of sheets of large polygonal cells with eosinophilic cytoplasm separated by fibrous stroma. Positive immunostaining for CEA and calcitonin confirmed the diagnosis of MTC. Lymph nodes were free of metastasis. At postsurgery evaluation 3 months later, serum CEA and calcitonin were normal.
Subject B
A 71-yr-old female returned to her gastro-enterologist for postsurgical evaluation 3 months after a presumed curative resection of a pT2N0 M0 colonic carcinoma. The hemoglobin value had returned to normal. The CEA value, however, remained elevated (56.8 µg/liter compared with the preoperative value of 42.7 µg/liter). A CT scan of the abdomen revealed no local recurrence nor liver metastasis. A FDG-PET scan showed a cervical hot spot corresponding to the right lower thyroid lobe (Fig. 1
, A and B). An elevated calcitonin 853 ng/liter (normal < 10 ng/liter), the US image of a hypoechoic nodule (20 mm) in the right thyroid lobe and the result of FNAC (immunocytochemistry for CEA and calcitonin was positive) supported the suspicion of MTC. A preoperative evaluation for pheochromocytoma was negative: adrenals were normal on the previously performed CT scan, and the excretion of urinary catecholamines was normal. A total thyroidectomy and bilateral selective lymph node dissection revealed a gray tumor measuring 22 mm in diameter in the right lobe. It consisted of large polygonal cells separated by fibrovascular septa. Congo Red stain showed amyloid deposits in these septa. Tumor cells stained positive for chromogranin and calcitonin confirming the diagnosis of MTC. One lymph node in the area of the right recurrent nerve contained an MTC metastasis. Additional radiotherapy (50 Gy) of the neck was therefore performed. Thereafter, CEA had normalized (1 µg/liter) and calcitonin remained slightly elevated at 13 ng/liter.
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A 53-yr-old female presented to the rheumatology department for investigation of anemia. A mixed connective tissue disease was previously suspected. A normochromic anemia with a hemoglobin value of 80 g/liter was unexplained. Bone marrow aspiration and biopsy showed weak erythropoiesis and a preponderance of myeloid precursors. These non pathognomonic alterations pointed to the possibility of a thymoma or a paraneoplastic phenomenon. A CT scan of the thorax showed a well demarcated mass in the left anterior mediastinum corresponding to a thymoma or lymph nodes. An FDG-PET scan showed two hot spots, one corresponding to the left anterior mediastinal mass and a second one corresponding to the right thyroid lobe. Thyroid US showed an irregular hypoechoic nodule in the right thyroid lobe and FNAC of this nodule suggested a papillary thyroid carcinoma. A combined surgical procedure for resection of the thoracic and cervical tumors was performed. After sternotomy, a large mass (35 mm diameter) was identified behind the left clavicle and first rib, invading the pleura and the left lung. Resection of this mass was followed by a total thyroidectomy and cervical lymph node dissection. The mediastinal mass consisted of a large lymph node containing an undifferentiated tumor with multiple psammoma bodies on one side and on the other side foci of squamous differentiation. The diagnosis of a thyroid papillary carcinoma with invasion of the thyroid capsule and a cervical lymph node was confirmed; the mediastinal tumor remained a diagnostic problem, a dedifferentiated metastasis of the thyroid carcinoma was most likely. Accordingly, post 131I therapeutic scans showed uptake in the thyroid bed and in the left mediastinum. At the last CT scan of the chest there was progression of tumor in the mediastinum.
Subject D
A 52-yr-old women presented to the hematology department for a follow-up visit. Morbus Hodgkin had been diagnosed (nodular sclerosing type, stage II B with iliacal and inguinal lymph nodes). After six cycles of chemotherapy (Adriamycin, Bleomycin, Velbe, Dacarbazin scheme), she remained in complete remission. However, 11 months after the initial diagnosis she complained of joint pain, especially at the left hip and a FDG-PET scan with special attention to this region was ordered. It was negative except for diffuse thyroidal uptake. Thyroiditis or invasion by the lymphoma were suggested as the possible causes of the thyroidal uptake. On clinical examination, bilateral thyroid nodularity was noted and confirmed by US. FNAC of the right and left nodules showed very cellular aspirates containing cell groups and a few follicles. A few mitoses were seen. A few atypical cells had an irregular elongated nucleus, colloid was absent. A small number of small and larger lymphoid cells were seen. The cytological diagnosis was follicular neoplasia and a total thyroidectomy was performed to exclude follicular carcinoma. The histologic diagnosis was follicular adenoma with Hashimoto thyroiditis.
Subject E
A 57-yr-old woman presented at the rheumatology department because of anemia, joint pains, and myalgia. She had declined invasive procedures, and steroids had been prescribed for a resumed polymyalgia rheumatica, but upon tapering the steroids the clinical picture deteriorated with a toxic anemia (hemoglobin value of 70 g/liter) and weight loss. Bone marrow aspiration and biopsy were inconclusive. An FDG-PET scan was ordered to find the primary site of inflammation or to detect an undefined primary tumor. The FDG-PET scan showed enhanced bone marrow uptake and a left cervical hot spot. FNAC of an hypoechoic nodule in the left thyroid lobe suggested papillary carcinoma.
Total thyroidectomy was performed. The diagnosis of a PTC was confirmed. Although small (13 mm diameter), there was invasion through the thyroid capsule in the strap muscles. Anemia persisted, and a second bone marrow aspiration and biopsy pointed to the second problem: multiple myeloma.
Subject F
A 63-yr-old women presented to the oncology department complaining of low back pain in December 1999. Her past medical history consisted of a right mastectomy in 1988 and left breast carcinoma excision and adjunctive irradiation in 1996. Spinal MRI images suggested metastatic lesions to the sacrum and the eighth dorsal vertebra. In the absence of evidence of other metastatic lesions, an FDG-PET scan was performed to confirm the MRI findings. It showed a sacral lesion and an unexpected right anterior cervical lesion. The patient was referred for FNAC of an hypoechoic nodule in the right thyroid lobe containing some microcalcifications. FNAC was poorly cellular and showed sheets of enlarged follicular cells with large eccentric nuclei. Intranuclear pseudoinclusions were seen in some of the cells. A small amount of colloid was present. Cell margins were accentuated. The diagnosis of papillary carcinoma was put forward. Total thyroidectomy was performed and final histology has been debated. Atypia, intranuclear pseudoinclusions, and nuclear grooves were present in some cells but were less pronounced compared with the nuclear atypia in the cytology specimen. Negative immunohistochemistry for thyroid peroxidase and positive immunostaining for HBME1 reinforced the final diagnosis of a PTC.
Subject G
A 56-yr-old man was referred to the pneumology department because of small peripheral lung nodules on chest x-ray detected in the course of preoperative screenings for a hernia. A FDG-PET scan was ordered to search for an unknown primary tumor or other metastatic lesions. A hot spot in the right lung top or anterior mediastinum was identified. A thoracoscopic lung biopsy of the peripheral nodules was performed and showed mixed dust fibrosis. The attention was then drawn to the thyroid lesion and the patient was referred for FNAC of an unpalpable retroclavicular nodule in the inferior right thyroid lobe. Cytology revealed sheets and groups of Hürthle cells with a large amount of cytoplasm, enlarged nuclei, and anisokaryosis. Colloid was abundantly present. The diagnosis of follicular neoplasm, probably Hürthle cell adenoma, was made. In face of this Hürthle cell tumor, surgery was planned and confirmed the diagnosis of an Hürthle cell adenoma.
Subject H
An 80-yr-old man was referred for investigation of a large necrotic, suggestive of a liver metastasis. Ten years earlier, in 1991 a left upper lung lobectomy was performed for a squamous cell carcinoma. A FDG-PET scan showed a hot spot in the liver and a second one in the right anterior cervical region. FNAC of a hypoechoic nodule in the right thyroid lobe was performed: cell groups as well as some rosettes were present. The nuclei of the follicular cells were slightly enlarged. A small amount of colloid was present, as well as multinucleated giant cells and calcifications. It was classified as a follicular neoplasm, probably follicular adenoma. A liver biopsy showed a large cell undifferentiated carcinoma. Immunostaining was positive for keratine and negative for thyroglobulin. The histology specimen of the lung carcinoma resected in 1991 was revised and diagnosed as a well differentiated squamous cell carcinoma. The liver mass was considered as a possible metastasis of the lung tumor. The thyroid lesion is left untreated.
FDG-PET method
The PET imaging was performed with a CTI-Siemens HR+ scanner (Knoxville, TN) with an axial field of view of 15 cm, and a spatial resolution of 6 mm. All patients fasted during 6 h preceding the tracer administration. Sixty minutes after the iv injection of 6.5 megabecquerels/kg 18F-FDG (to a maximum of 555 megabecquerels), a whole-body emission scan was performed. The raw imaging data were reconstructed in a 128 x 128 matrix with use of an in-house iterative reconstruction algorithm without attenuation correction.
Discussion
We describe eight consecutive cases of thyroid FDG-PET incidentaloma. Ultrasound examination and FNAC were obtained in all, at this stage surgery and histology have been performed in seven of them. Our study suggests a high malignancy rate in thyroid PET-incidentaloma. Malignancy was correctly identified in five of seven patients in whom histology is obtained: two cases of MTC (subject A and B) and three cases of PTC (patient C, E, and F) caused focally increased FDG-uptake in the thyroid region. In patient D, a lymphoma patient, the positive PET scan with bilateral and diffuse FDG uptake and bilateral suspicious FNAC were, however, due to thyroiditis accompanying follicular adenoma. Diffuse thyroidal FDG uptake has indeed been described in a cancer screening study in Japan in 0.4% of male and 8.9% of female subjects. In the 36 subjects with diffuse thyroidal FDG uptake in that study, it was attributed to chronic thyroiditis. Indeed, it was proven by pathology in 2 subjects; in the others, clinical follow-up showed stable thyroid size and in the majority antithyroid antibodies were positive (7). Chronic thyroiditis is probably the most frequent benign cause of diffuse thyroidal FDG-uptake, although it can also be observed in Graves’ disease (8). Autonomous adenoma can cause focal uptake in circumscript hypermetabolic areas (9). In patient G, focal FDG-PET uptake was caused by a Hürthle cell adenoma; in patient H, FNAC suggested a follicular neoplasm, but surgery has not been performed due to the patients poor general condition.
Besides a high malignancy rate, the present study also suggests a high rate of clinically significant malignancies; in other words, malignancies with an expected clinically relevant malignant biological behavior within the life span of the patient. Of the MTC cases, there was lymph node invasion in one (subject B) of two. Of the three PTC cases there was invasion of the thyroid capsule in two of them. Moreover, mediastinal lymph node invasion containing undifferentiated tumor, probably dedifferentiated thyroid carcinoma was present in case C, and there was invasion of the strap muscles in subject E.
We explain the high rate of thyroid malignancy and the high rate of clinically significant malignancies in thyroid PET-incidentaloma in two ways. The most obvious explanation is the FDG-PET principle in itself. FDG-PET preferably picks up malignant lesions because of the increased rates of glycolysis and glucose uptake. One of the glucose transport proteins, GLUT 1 has been found to be expressed at high levels in a variety of cancers. By immunostaining, GLUT 1 expression was frequently detectable in differentiated and anaplastic thyroid carcinoma, but not in benign nodules or normal thyroid (10). GLUT1 mRNA levels were increased in 1 of 24 adenomas and in 8 of 43 thyroid carcinomas studied by Lazar et al. (11). Second, the patient population in whom FDG-PET was performed was a group of patients with a paraneoplastic phenomenon or another problem that made one or another malignancy highly probable. As a consequence a high pretest probability for carcinoma was present in this study population.
This element of clinically relevant malignant behavior was not considered in previous reports on thyroid FDG-PET incidentaloma; a recent report by Davis et al. considers five cases of occult PTC identified by FDG-PET; however, data on tumor diameter, thyroid capsule, or lymph nodes are not available (12). Other previous studies were largely limited to isolated case reports: Stokkel et al. report the detection of a 5-mm diameter papillary thyroid carcinoma in a patient with a lip tumor (13); Wiesner et al. (14) reported the detection of an FDG-PET positive Hürthle cell tumor of the thyroid during staging procedures in a patient with malignant melanoma. The tumor was considered benign as no growth was observed over a 12-month time period, and pathological confirmation was not obtained. Ramos et al. (15) reported four oncology patients with incidental FDG uptake due to a suspected (n = 2) or confirmed (n = 2: one Hürthle cell carcinoma and one PTC) second primary tumor in the thyroid.
Two limitations of our study should be considered. First, we did not perform a quantitative analysis to calculate dose uptake ratios, neither did we perform semiquantitative studies taking into account correction for background activity [standardized uptake value (SUV)]. Pilot studies evaluating the usefulness of these measurements in differentiating benign from malignant thyroid tumors showed significantly higher dose uptake ratio and SUV values in the malignant tumors compared with benign tumors (16, 17). However, in the series by Sasaki, some recurrences/metastases of papillary carcinomas and one follicular carcinoma recurrence had a relatively low SUV and there was overlap with the follicular adenoma range. The authors concluded that high FDG uptake in a thyroid tumor suggested malignancy even though low levels could not completely rule out malignancy (17). Second, at this stage, histology is not obtained in one patient with a follicular lesion.
In conclusion, whereas US thyroid incidentaloma usually represent benign or occult malignant lesions, thyroid PET-incidentaloma detect mainly malignancies with an expected clinical relevance rather than occult carcinoma.
Prospective FDG-PET studies including quantitative or semiquantitative uptake parameters are necessary to evaluate the true prevalence and clinical relevance of malignancies in this new category of thyroid incidentaloma.
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We thank B. Caillou of the Institut Gustave Roussy (Villejuif, France) for the review of the final slides and the immunohistochemistry of Subject F. We gratefully acknowledge the contributions of the referring physicians M. T’Seyen, J. L. Coolens, E. Van Cutsem, R. Westhovens, G. Verhoef, R. Paridaens, D. Blockmans, K. Nackaerts. We thank C. Dignef and D. Vandyck for the excellent secretarial assistance.
Footnotes
Abbreviations: CEA, Carcinoembryonic antigen; CT, computerized tomography; FDG, fluorodeoxyglucose; FNAC, fine needle aspiration cytology; MTC, medullary thyroid carcinoma; PET, positron emission tomography; SUV, standardized uptake value; US, ultrasound.
Received August 2, 2001.
Accepted December 26, 2001.
References
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|
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 |
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|
|
|
|
 |
|
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