Comparison of 68Ga PET/CT to Other Imaging Studies in Medullary Thyroid Cancer: Superiority in Detecting Bone Metastases

Comparison of 68Ga PET/CT to Other Imaging Studies in Medullary Thyroid Cancer: Superiority in... Abstract Context Persistent disease after surgery is common in medullary thyroid cancer (MTC), requiring lifelong radiological surveillance. Staging workup includes imaging of neck, chest, abdomen, and bones. A study integrating all sites would be ideal. Despite the established use of gallium-68 (68Ga) positron emission tomography (PET)/CT with somatostatin analogues in most neuroendocrine tumors, its efficacy is controversial in MTC. Objective Evaluate the efficacy of 68Ga PET/CT in detecting MTC lesions and evaluate tumor expression of somatostatin receptors (SSTRs) associated with 68Ga PET/CT findings. Methods Prospective study evaluating 30 patients with MTC [group 1 (n = 16), biochemical disease; group 2 (n = 14), metastatic disease]. Patients underwent 68Ga PET/CT, bone scan, CT and ultrasound of the neck, CT of the chest, CT/MRI of the abdomen, and MRI of the spine. 68Ga PET/CT findings were analyzed by disease site as positive or negative and as concordant or discordant with conventional studies. Sensitivity and specificity were calculated using pathological or cytological analysis or unequivocal identification by standard imaging studies. Immunohistochemical analysis of SSTRs was compared with 68Ga PET/CT findings. Results In both groups, 68Ga PET/CT was inferior to currently used imaging studies except for bone scan. In group 2, 68Ga PET/CT sensitivities were 56%, 57%, and 9% for detecting neck lymph nodes, lung metastases, and liver metastases, respectively, and 100% for bone metastases, superior to the bone scan (44%). Expression of SSTRs, observed in 44% of tumors, was not associated with 68Ga-DOTATATE uptake. Conclusions 68Ga PET/CT does not provide optimal whole-body imaging as a single procedure in patients with MTC. However, it is highly sensitive in detecting bone lesions and could be a substitute for a bone scan and MRI. Medullary thyroid cancer (MTC) is a rare neuroendocrine tumor that arises from the parafollicular cells of the thyroid and secretes calcitonin (Ctn) and carcinoembryonic antigen (CEA), which are used as tumor markers. MTC occurs either as a sporadic form or, in 20% to 30% of the cases, as part of an autosomal dominant inherited syndrome called multiple endocrine neoplasia, which is caused by a germline mutation of the rearranged during transfection (RET) proto-oncogene. A substantial percentage (38% to 90%) of patients remains with persistent disease after surgical treatment and will need lifelong radiological surveillance in addition to Ctn and CEA measurements (1–3). Several studies have indicated the best imaging modalities for the radiological surveillance of these patients. With the knowledge that MTC metastatic sites involve cervical lymph nodes (LNs), lung, mediastinal LNs, liver, and bone, the currently recommended studies include neck ultrasound, contrast-enhanced neck and chest CT, three-phase contrast-enhanced multidetector abdominal CT, or contrast-enhanced MRI of the abdomen and spine and bone scan (2, 4, 5). As metastatic disease frequently involves multiple organs, a single whole-body imaging technique in MTC would be ideal for time saving and comfort of patients. High-resolution positron emission tomography (PET)/CT with deoxy-glucose radiolabeled with fluorine-18 (18F-FDG PET/CT) is useful for tumors with aggressive behavior and high glucose consumption. The studies investigating the role of 18F-FDG PET/CT in neuroendocrine tumors have demonstrated high sensitivity only with high-grade tumors, correlating with a worse prognosis (6). However, most neuroendocrine tumors have an indolent behavior (7–9), and other radiolabeled peptides may be more sensitive. For example, 6-fluoro-(18F)-L-3,4-dihydroxyphenylalanine (18F-DOPA) PET has been shown to be superior to 18F-FDG PET/CT in MTC lesions and is probably the most sensitive PET technique in patients with MTC (10–13). New promising gallium-68 (68Ga) radiolabeled somatostatin analogue peptides (DOTATATE, DOTATOC, and DOTANOC) in PET/CT imaging have improved the detection and localization of neuroendocrine tumors. Based on the knowledge that MTC is a neuroendocrine tumor that expresses somatostatin receptors (SSTRs), few studies, mostly case series, have evaluated the role of 68Ga-DOTATATE PET/CT (68Ga PET/CT) in MTC (13–18) with variable results, showing 68Ga PET/CT sensitivity between 33% and 100%, with variability likely related to the production and half-life of 68Ga. We conducted a prospective study aimed at the evaluation of the sensitivity and specificity of 68Ga PET/CT in detecting metastatic MTC lesions identified by the best recommended conventional imaging modalities in different sites. The secondary objective was to analyze the immunoexpression of the SSTRs and Ki-67 in available MTC tumors and compare these findings with detection by 68Ga PET/CT. Patients and Methods Imaging studies Thirty patients with MTC and elevated Ctn were prospectively included between May 2013 and January 2016 at the Instituto do Câncer do Estado de São Paulo, Brazil. The study was approved by the local research ethics committee. Informed consent was obtained from all patients before imaging. The patients were classified in two groups: group 1 included patients with biochemical disease (Ctn >10 pg/mL with no evidence of disease by previous imaging studies), and group 2 included patients with previously known metastatic disease. Patients were evaluated by imaging studies that included 68Ga PET/CT, bone scan, ultrasound of the neck, contrast-enhanced CT of the neck and chest, and three-phase CT or MRI of the abdomen. MRI of spine and/or long bones was performed in case of bone uptake by bone scan or 68Ga PET/CT. An immunochemiluminescence assay (Immulite 2000; Siemens Diagnostics, Malvern, PA) measured Ctn (normal range <5 pg/mL for females and <8.4 pg/mL for males) and CEA (normal range <5 ng/mL). PET/CT studies were obtained after intravenous injection of 185 MBq radiolabeled 68Ga-DOTATATE in an automated system (Modular LabPharmTracer; Eckert-Ziegler, Berlin, Germany) with 68Ga eluate from a 68Ga generator (Obninsk, Kaluga Oblast, Russia) and complexation with DOTATATE (piCHEM, Graz, Styria, Austria). PET images were acquired on a Discovery 690 PET/CT scanner (GE Healthcare, Waukesha, WI) using three-dimensional time-of-flight mode, with 2 minutes per bed position with 15 cm per bed along 3 cm of overlap between beds with the patients lying supine on the scanner bed with the arms along the body. Acquisition matrix was 192 × 192 pixels with an in-slice pixel size of 3.27 mm and a transaxial slice thickness of 3.27 mm, correcting images for attenuation, scatter, random radiation decays, dead time, and decay. A three-dimensional ordered-subset expectation maximization iterative reconstruction algorithm was used to reconstruct images, using two iterations and 28 subsets as reconstruction settings. CT protocol used an automatic exposure control, a 10- to 400-mAs range, 120 kVp, a 0.5-second rotation time, and 1.37 pitch. Images had an axial slice thickness of 3.27 mm and a resolution of 512 × 512 pixels. A semiquantitative analysis was performed by the median of maximum standardized uptake (SUV max) obtained by manually placing a volume of interest over the whole abnormal lesion, avoiding undesired adjacent areas. In each patient, all scans were taken within a median of 31 (4 to 111) days. 68Ga PET/CT findings were classified as positive or negative on visual interpretation by blinded board-certified nuclear medicine physicians and as concordant or discordant with the conventional imaging studies. Two radiologists (R.M.C.F. and E.F.) and two nuclear physicians (G.C.F. and C.A.B.) who were unaware of clinical data and each other’s results independently evaluated the imaging findings. The interobserver variation was 7.3% and 4.6% for nuclear medicine and radiology, respectively. After a consensus, the interobserver agreement was 0.98 for nuclear medicine and 0.99 for radiology. The 68Ga PET/CT and conventional images results were analyzed by comparing the same lesions on a per-organ and per-patient basis, and an analysis of influence of additional information provided by 68Ga PET/CT on the patient’s management was evaluated. Immunohistochemistry A total of 98 paraffin-embedded samples were obtained from the department of pathology of the Instituto do Câncer do Estado de São Paulo and Hospital das Clínicas da Faculdade Medicina da Universidade de São Paulo. All cases were reviewed prior to further analysis regarding the state of conservation and quality and quantity of the material; diagnostic review and morphological classification were performed according to the classification of the World Health Organization (19, 20). Representative samples of tumors of the primary site and/or metastatic sites for LNs and/or visceral organs and bone were selected. Exclusion criteria for the immunohistochemical and molecular analysis were lack of biologic samples recovered from the file and insufficient tumor. Paraffin sections of 3 μm thickness were deparaffinized in xylol and ethanol in decreasing degrees to hydration. Antigen retrieval was performed in 0.01 M sodium citrate buffer (pH 6.0) in a stainless steel pressure cooker. After antigen retrieval, endogenous peroxidase blocking was performed with 6% hydrogen peroxide. Slides were washed in tap and distilled water and PBS. Histological sections were incubated overnight at 4°C with SSTR2 (rabbit monoclonal, UMB1 clone, product code ab134152, titration 1:400; Abcam), SSTR3 (rabbit polyclonal, product code ab28680, titration 1:500; Abcam), SSTR5 (rabbit polyclonal, product code ab28618, titration 1:1000; Abcam), and Ki-67 (MIB-1 clone, product code M7240, titration 1:500 in PBS containing 1% bovine serum albumin; DAKO, Glostrup, Denmark). Antigen-antibody binding was amplified with Post Primary Block (NovoLink Max Polymer Detection System RE7140-K, Newcastle upon Tyne, UK). Slides were washed between steps with PBS three times for 5 minutes each. Sections were developed with diaminobenzidine substrate (D5637; Sigma, St. Louis, MO) and counterstained with Harris’s hematoxylin. Nuclear and/or cytoplasmic golden brown was considered positive. Positive controls consisted of a specimen from pancreas (SSTR2 and SSTR5), brain (SSTR3), and tonsil (Ki-67). Negative control was performed by omission of the antibody, based on protocols validated by the literature and the product label (21–24). A board-certified pathologist (R.S.) examined all stained slides according to criteria defined by the Clinical and Laboratory Standards Institute (25): score 0 (cases that did not express the marker in question were considered negative in any cell of interest), score 1 (weak positive/borderline cases showed weak staining in <10% of the cells of interest), score 2 (cases with moderate to strong staining between 10% and 50% of the cells of interest were considered positive), and score 3 (cases with moderate to strong staining were considered positive in >50% of the cells of interest). The immunohistochemical evaluation for the Ki-67 marker was performed quantitatively by counting the absolute number of neoplastic cells with nuclear expression, selecting the areas with the highest expression (hot spots), and the result was expressed as a percentage by the ratio of the number of positive cells and the total number of cells evaluated. At least 2000 cells per sample or 50 large-scale fields were evaluated (26, 27). Statistical analysis Descriptive statistics were calculated for categorical (frequencies and percentages) and continuous variables (mean, median, and minimum and maximum values). The definition of a true-positive lesion and analysis of sensitivity and specificity in each site were based on (1) cytological or pathological analysis or by unequivocal identification by established gold-standard imaging studies defined as neck ultrasound and CT for neck lesions, (2) chest CT with contrast for pulmonary nodules and mediastinal LNs, (3) three-phase contrast-enhanced CT or MRI abdomen for liver lesions, and (4) MRI for bone lesions (MRI of spine or from specific sites identified by bone scan or by 68Ga PET/CT), which are considered reference standards (2). Radiological follow-up indicating progression of a lesion was also used to confirm a true-positive lesion. For ethical and practical reasons, not every lesion interpreted as positive underwent a biopsy. Wilcoxon test, logistic regression, and receiver operating characteristic curves were performed to analyze the association between SUV max of LNs and positivity for metastatic disease, using the software JMP version 11 (SAS Institute, Inc., Cary, NC). Results From a total of 30 patients, 16 were classified as having biochemical disease (group 1) and 14 with established metastatic disease (group 2) prior to entering the study. Table 1 demonstrates demographic and clinical data. In group 1, there were 14 women and 2 men with a median age of 52 years (range, 24 to 78 years), median Ctn level was 133 pg/mL (range, 11 to 1162 pg/mL), and median CEA level was 4.85 ng/mL (range, 0.6 to 140 ng/mL) with a median duration of disease of 11 years (range, 1 to 31 years). In group 2, there were 3 women and 11 men with a median age of 44 years (range, 19 to 72 years), median Ctn was 8323 pg/mL (range, 564 to 101,083 pg/mL), median CEA was 245 ng/mL (range, 9.4 to 3287 ng/mL), and median duration of disease was 7 years (range, 0.25 to 19 years). Except for one patient in group 2, all patients underwent total thyroidectomy with LN dissection; in addition, patients from group 2 underwent other treatments, including external beam radiotherapy to the neck and bone and systemic treatment with conventional chemotherapy and/or tyrosine kinase inhibitors. Table 1. Clinical Characteristics Characteristic Occult MTC (n = 16) Metastatic MTC (n = 14) Age, median (range), y 52 (24–78) 44 (19–72) Sex, n (%)  Female 14 (87.5) 3 (21.4)  Male 2 (12.5) 11 (78.5) Hereditary MTC, n (%) 7 (43.7) 7 (50) RET mutationsa Cys634Thyr (2), Val804Met, Cys611Trp, Cys634Arg (2), Cys620Arg Cys634Thyr/Y791F (2), Cys609Thyr, Val804Met, Met918T (3) Time from diagnosis, median (range), y 11 (1–31) 7 (0.25–19) Time of metastatic disease, median (range), y — 3 (0.25–10) Ctn, median (range), pg/mL 133 (12–1162) 8323 (564–101,083) DT Ctn, median (range), mo — 23 (1.86–106) CEA, median (range), ng/mL 4.85 (0.6–140) 245 (9.4–3287) DT CEA, median (range), mo — 29 (7–167) Characteristic Occult MTC (n = 16) Metastatic MTC (n = 14) Age, median (range), y 52 (24–78) 44 (19–72) Sex, n (%)  Female 14 (87.5) 3 (21.4)  Male 2 (12.5) 11 (78.5) Hereditary MTC, n (%) 7 (43.7) 7 (50) RET mutationsa Cys634Thyr (2), Val804Met, Cys611Trp, Cys634Arg (2), Cys620Arg Cys634Thyr/Y791F (2), Cys609Thyr, Val804Met, Met918T (3) Time from diagnosis, median (range), y 11 (1–31) 7 (0.25–19) Time of metastatic disease, median (range), y — 3 (0.25–10) Ctn, median (range), pg/mL 133 (12–1162) 8323 (564–101,083) DT Ctn, median (range), mo — 23 (1.86–106) CEA, median (range), ng/mL 4.85 (0.6–140) 245 (9.4–3287) DT CEA, median (range), mo — 29 (7–167) Abbreviation: DT, doubling time. a Numbers in parentheses indicate the number of patients with the RET mutation. View Large Table 1. Clinical Characteristics Characteristic Occult MTC (n = 16) Metastatic MTC (n = 14) Age, median (range), y 52 (24–78) 44 (19–72) Sex, n (%)  Female 14 (87.5) 3 (21.4)  Male 2 (12.5) 11 (78.5) Hereditary MTC, n (%) 7 (43.7) 7 (50) RET mutationsa Cys634Thyr (2), Val804Met, Cys611Trp, Cys634Arg (2), Cys620Arg Cys634Thyr/Y791F (2), Cys609Thyr, Val804Met, Met918T (3) Time from diagnosis, median (range), y 11 (1–31) 7 (0.25–19) Time of metastatic disease, median (range), y — 3 (0.25–10) Ctn, median (range), pg/mL 133 (12–1162) 8323 (564–101,083) DT Ctn, median (range), mo — 23 (1.86–106) CEA, median (range), ng/mL 4.85 (0.6–140) 245 (9.4–3287) DT CEA, median (range), mo — 29 (7–167) Characteristic Occult MTC (n = 16) Metastatic MTC (n = 14) Age, median (range), y 52 (24–78) 44 (19–72) Sex, n (%)  Female 14 (87.5) 3 (21.4)  Male 2 (12.5) 11 (78.5) Hereditary MTC, n (%) 7 (43.7) 7 (50) RET mutationsa Cys634Thyr (2), Val804Met, Cys611Trp, Cys634Arg (2), Cys620Arg Cys634Thyr/Y791F (2), Cys609Thyr, Val804Met, Met918T (3) Time from diagnosis, median (range), y 11 (1–31) 7 (0.25–19) Time of metastatic disease, median (range), y — 3 (0.25–10) Ctn, median (range), pg/mL 133 (12–1162) 8323 (564–101,083) DT Ctn, median (range), mo — 23 (1.86–106) CEA, median (range), ng/mL 4.85 (0.6–140) 245 (9.4–3287) DT CEA, median (range), mo — 29 (7–167) Abbreviation: DT, doubling time. a Numbers in parentheses indicate the number of patients with the RET mutation. View Large All patients were evaluated by imaging studies, including 68Ga PET/CT, neck ultrasound, neck and chest CT, three-phase abdominal CT or MRI, and bone scan. MRI of the spine and of a specific site was done to confirm metastatic disease based on bone scan and 68Ga PET/CT findings. Analysis of imaging studies was performed according to site of disease, and 68Ga PET/CT findings were compared with the gold or reference standard methods for each site. In group 1 (n = 16), ultrasound identified suspicious cervical LNs in eight patients and 68Ga PET/CT in three patients (also detected by ultrasound). All of these patients underwent fine-needle aspiration biopsy (FNAB), and cytology confirmed MTC in six patients with LNs detected by ultrasound and in three patients with LNs detected by 68Ga PET/CT. Therefore, the rate of detection of neck disease in this group of patients, initially defined as having biochemical disease, was 37.5% with ultrasound and 18.7% with 68Ga PET/CT. Considering the association of ultrasound and FNAB as the gold standard, the sensitivity of 68Ga PET/CT in detecting neck disease was 50% and specificity was 100% in group 1 patients. In this same group, two patients were found to have distant metastatic disease, one patient had a hilar LN detected by chest CT and 68Ga PET/CT, and another patient had a bone lesion (right humerus) identified by MRI and 68Ga PET/CT. In bone scan, this lesion was considered indeterminate. In addition, three patients had uptake in bone, two with bone scan and one with 68Ga PET/CT, that was not confirmed by MRI and considered false-positive results. Table 2 demonstrates all the imaging findings for each patient from group 2. In this group (n = 14), ultrasound detected suspicious cervical LNs in 10 patients and 68Ga PET/CT in 6 patients. The cytology confirmed MTC in 9 of 10 patients (ultrasound) and in 5 of 6 patients (68Ga PET/CT). The detection rate of metastatic LNs was 64.3% for ultrasound and 35.7% for 68Ga PET/CT. The sensitivity of 68Ga PET/CT in detecting neck disease in this group of patients was 56.6%, and specificity was 80% (Fig. 1). Table 2. Findings of Ga68-DOTATATE PET/CT and Conventional Studies in Patients With Metastatic MTC (Group 2) Patient No. Ctn (pg/mL) CEA (ng/mL) Ga68 PET/CT Neck Ultrasound CT Chest CT/MRI Abdomen Bone Scan MRI Bone Altered Plan 1 8683 248 Liver + − Liver − + Yes Bone FNAB − 2 895 65 Pancreas − − Liver − − No Endoscopic ultrasound W FNA − 3 2763 152 Neck LN − − Liver − ND No FNAB − 4 12,376 242 Neck LN + MD LN Liver + + No MD LN FNAB + Bone 5 4652 340 Neck LN + MD LN lung − − + Yes MD LN FNAB + Bone 6 50,948 3287 Bone + − Liver − + Yes FNAB + 7 4359 22.5 − + Lung Liver − ND No FNAB + 8a 7962 618 Thyroid 6.5-cm thyroid nodule Lung Liver − + Yes Adrenal Adrenal Bone 9 31,092 1939 MD LN + MD LN lung Liver + + No Lung FNAB + Bone 10 101,083 2203 Bone − − Spleen − + Yes Liver 11 14,256 188 MD LN + MD LN − − ND No Lung FNAB + Lung 12 59,979 650 Neck LN + MD LN Pancreas + + No MD LN FNAB + Lung Liver Lung Kidney Bone 13 795 16 Neck LN + MD LN Pancreas + + No MD LN FNAB + Lung Kidney Lung Liver Bone 14 564 9.4 Neck LN + − − − ND No FNAB + Patient No. Ctn (pg/mL) CEA (ng/mL) Ga68 PET/CT Neck Ultrasound CT Chest CT/MRI Abdomen Bone Scan MRI Bone Altered Plan 1 8683 248 Liver + − Liver − + Yes Bone FNAB − 2 895 65 Pancreas − − Liver − − No Endoscopic ultrasound W FNA − 3 2763 152 Neck LN − − Liver − ND No FNAB − 4 12,376 242 Neck LN + MD LN Liver + + No MD LN FNAB + Bone 5 4652 340 Neck LN + MD LN lung − − + Yes MD LN FNAB + Bone 6 50,948 3287 Bone + − Liver − + Yes FNAB + 7 4359 22.5 − + Lung Liver − ND No FNAB + 8a 7962 618 Thyroid 6.5-cm thyroid nodule Lung Liver − + Yes Adrenal Adrenal Bone 9 31,092 1939 MD LN + MD LN lung Liver + + No Lung FNAB + Bone 10 101,083 2203 Bone − − Spleen − + Yes Liver 11 14,256 188 MD LN + MD LN − − ND No Lung FNAB + Lung 12 59,979 650 Neck LN + MD LN Pancreas + + No MD LN FNAB + Lung Liver Lung Kidney Bone 13 795 16 Neck LN + MD LN Pancreas + + No MD LN FNAB + Lung Kidney Lung Liver Bone 14 564 9.4 Neck LN + − − − ND No FNAB + Altered plan: detection of a new metastatic site of disease, resulting in modification in follow-up interval, examinations, or treatment. Abbreviations: −, negative; + positive; MD, mediastinal; ND, not done; W FNA, with fine needle aspiration. a Patient included at diagnosis of medullary thyroid carcinoma. View Large Table 2. Findings of Ga68-DOTATATE PET/CT and Conventional Studies in Patients With Metastatic MTC (Group 2) Patient No. Ctn (pg/mL) CEA (ng/mL) Ga68 PET/CT Neck Ultrasound CT Chest CT/MRI Abdomen Bone Scan MRI Bone Altered Plan 1 8683 248 Liver + − Liver − + Yes Bone FNAB − 2 895 65 Pancreas − − Liver − − No Endoscopic ultrasound W FNA − 3 2763 152 Neck LN − − Liver − ND No FNAB − 4 12,376 242 Neck LN + MD LN Liver + + No MD LN FNAB + Bone 5 4652 340 Neck LN + MD LN lung − − + Yes MD LN FNAB + Bone 6 50,948 3287 Bone + − Liver − + Yes FNAB + 7 4359 22.5 − + Lung Liver − ND No FNAB + 8a 7962 618 Thyroid 6.5-cm thyroid nodule Lung Liver − + Yes Adrenal Adrenal Bone 9 31,092 1939 MD LN + MD LN lung Liver + + No Lung FNAB + Bone 10 101,083 2203 Bone − − Spleen − + Yes Liver 11 14,256 188 MD LN + MD LN − − ND No Lung FNAB + Lung 12 59,979 650 Neck LN + MD LN Pancreas + + No MD LN FNAB + Lung Liver Lung Kidney Bone 13 795 16 Neck LN + MD LN Pancreas + + No MD LN FNAB + Lung Kidney Lung Liver Bone 14 564 9.4 Neck LN + − − − ND No FNAB + Patient No. Ctn (pg/mL) CEA (ng/mL) Ga68 PET/CT Neck Ultrasound CT Chest CT/MRI Abdomen Bone Scan MRI Bone Altered Plan 1 8683 248 Liver + − Liver − + Yes Bone FNAB − 2 895 65 Pancreas − − Liver − − No Endoscopic ultrasound W FNA − 3 2763 152 Neck LN − − Liver − ND No FNAB − 4 12,376 242 Neck LN + MD LN Liver + + No MD LN FNAB + Bone 5 4652 340 Neck LN + MD LN lung − − + Yes MD LN FNAB + Bone 6 50,948 3287 Bone + − Liver − + Yes FNAB + 7 4359 22.5 − + Lung Liver − ND No FNAB + 8a 7962 618 Thyroid 6.5-cm thyroid nodule Lung Liver − + Yes Adrenal Adrenal Bone 9 31,092 1939 MD LN + MD LN lung Liver + + No Lung FNAB + Bone 10 101,083 2203 Bone − − Spleen − + Yes Liver 11 14,256 188 MD LN + MD LN − − ND No Lung FNAB + Lung 12 59,979 650 Neck LN + MD LN Pancreas + + No MD LN FNAB + Lung Liver Lung Kidney Bone 13 795 16 Neck LN + MD LN Pancreas + + No MD LN FNAB + Lung Kidney Lung Liver Bone 14 564 9.4 Neck LN + − − − ND No FNAB + Altered plan: detection of a new metastatic site of disease, resulting in modification in follow-up interval, examinations, or treatment. Abbreviations: −, negative; + positive; MD, mediastinal; ND, not done; W FNA, with fine needle aspiration. a Patient included at diagnosis of medullary thyroid carcinoma. View Large Figure 1. View largeDownload slide (a) Patient with LNs in 68Ga PET/CT (arrows) and ultrasound, in which fine-needle aspiration biopsy confirmed disease. (b) A true-positive result for 68Ga PET/CT. (c) Patient with positive 68Ga PET/CT (arrow) and negative ultrasound. (d) A false-positive result for 68Ga PET/CT. (e) Patient with negative 68Ga PET/CT and positive neck ultrasound (f) and FNAB; a false-negative 68Ga PET/CT result. Figure 1. View largeDownload slide (a) Patient with LNs in 68Ga PET/CT (arrows) and ultrasound, in which fine-needle aspiration biopsy confirmed disease. (b) A true-positive result for 68Ga PET/CT. (c) Patient with positive 68Ga PET/CT (arrow) and negative ultrasound. (d) A false-positive result for 68Ga PET/CT. (e) Patient with negative 68Ga PET/CT and positive neck ultrasound (f) and FNAB; a false-negative 68Ga PET/CT result. Analysis of liver lesions by three-phase contrast-enhanced CT or MRI of the abdomen and 68Ga PET/CT demonstrated disease in 11 of 14 patients by abdominal CT or MRI and in only 1 patient by 68Ga PET/CT. No false-positive lesions were identified by 68Ga PET/CT (Fig. 2). Analysis of lung lesions in this group of patients also revealed superiority of CT; seven patients had disease detected by chest CT and four patients by 68Ga PET/CT. Further analysis of these findings revealed that the size of the lesions may influence the 68Ga-DOTATATE uptake; all false-negative cases (true lesions in CT with no 68Ga-DOTATATE uptake) were in nodules <1 cm (Fig. 3). Detection of mediastinal LNs was similar by both 68Ga PET/CT and chest CT (6 of 14 patients). Regarding bone metastases, bone scan identified lesions in 4 of 14 patients and 68Ga PET/CT in 9 of 14 patients. All of these lesions were confirmed by MRI, and there were no lesions detected only by MRI (Fig. 4). In summary, in group 2, 68Ga PET/CT sensitivity was 56% to detect cervical metastases, 9% for liver metastasis, and 57% for lung metastasis. However, 68Ga PET/CT sensitivity was superior to bone scan in detecting bone lesions. Figure 2. View largeDownload slide Images demonstrate a variable pattern of 68Ga-DOTATATE uptake in hepatic lesions. (a, b) A lesion in CT [arrow in (a)] with mild uptake [arrow in (b)] presenting as a true positive. (c, d) A lesion in CT (c) without uptake shown by the arrow (d) presenting as a false negative. (e, f) A normal liver with normal radiopharmaceutical uptake, a true negative. No false-positive liver images of 68Ga-DOTATATE PET/CT were found in this study. Figure 2. View largeDownload slide Images demonstrate a variable pattern of 68Ga-DOTATATE uptake in hepatic lesions. (a, b) A lesion in CT [arrow in (a)] with mild uptake [arrow in (b)] presenting as a true positive. (c, d) A lesion in CT (c) without uptake shown by the arrow (d) presenting as a false negative. (e, f) A normal liver with normal radiopharmaceutical uptake, a true negative. No false-positive liver images of 68Ga-DOTATATE PET/CT were found in this study. Figure 3. View largeDownload slide Images demonstrate lung nodules with 68Ga-DOTATATE uptake: (a, b) a true-positive result and lung nodules in CT [arrows in (a)] with 68Ga-DOTATATE uptake [arrows in (b)]; (c, d) a micronodule in CT [arrow in (c)] with no 68Ga-DOTATATE uptake (d); a false-negative result. Note in images (a) and (b) that the larger nodules in the left lung present mild uptake, whereas the smaller nodule in the right lung presents a faint uptake. Figure 3. View largeDownload slide Images demonstrate lung nodules with 68Ga-DOTATATE uptake: (a, b) a true-positive result and lung nodules in CT [arrows in (a)] with 68Ga-DOTATATE uptake [arrows in (b)]; (c, d) a micronodule in CT [arrow in (c)] with no 68Ga-DOTATATE uptake (d); a false-negative result. Note in images (a) and (b) that the larger nodules in the left lung present mild uptake, whereas the smaller nodule in the right lung presents a faint uptake. Figure 4. View largeDownload slide Images demonstrate a positive bone lesion in the second left rib detected by both (a) bone scan and (b–d) 68Ga-DOTATATE PET/CT. Arrows indicate the same lesion in bone scan (a) and in 68Ga-DOTATATE PET/CT (b–d). In another patient, a positive bone lesion in the lumbar spine detected by (f–h) 68Ga-DOTATATE PET/CT but not seen in the (e) bone scan. Figure 4. View largeDownload slide Images demonstrate a positive bone lesion in the second left rib detected by both (a) bone scan and (b–d) 68Ga-DOTATATE PET/CT. Arrows indicate the same lesion in bone scan (a) and in 68Ga-DOTATATE PET/CT (b–d). In another patient, a positive bone lesion in the lumbar spine detected by (f–h) 68Ga-DOTATATE PET/CT but not seen in the (e) bone scan. Table 3 demonstrates the sensitivity and specificity of 68Ga PET/CT for each site of disease for the entire cohort of patients with MTC (N = 30). Our findings indicate that 68Ga PET/CT was superior to bone scan in detecting bone metastatic lesions and similar to chest CT in detecting mediastinal LNs. Regarding other sites commonly involved by MTC, 68Ga PET/CT was less accurate than recommended imaging studies. Table 3. Sensitivity and Specificity of Ga68-DOTATATE PET/CT for Each Disease Site for the Entire Cohort of Patients With MTC (N = 30) Disease Site Sensitivity, % Specificity, % Reference Standard Best Image Study Cervical LNs 63 93 Cytology or pathology or negative ultrasound Ultrasound Mediastinal LNs 100 100 CT Ga68 PET/CT = CT Liver 9 100 CT or MRI CT or MRI Lung 63 100 CT CT Bone 100 95 Bone scan/MRI Ga68 PET/CT bone scan (sensitivity, 50%; specificity, 90%) Disease Site Sensitivity, % Specificity, % Reference Standard Best Image Study Cervical LNs 63 93 Cytology or pathology or negative ultrasound Ultrasound Mediastinal LNs 100 100 CT Ga68 PET/CT = CT Liver 9 100 CT or MRI CT or MRI Lung 63 100 CT CT Bone 100 95 Bone scan/MRI Ga68 PET/CT bone scan (sensitivity, 50%; specificity, 90%) View Large Table 3. Sensitivity and Specificity of Ga68-DOTATATE PET/CT for Each Disease Site for the Entire Cohort of Patients With MTC (N = 30) Disease Site Sensitivity, % Specificity, % Reference Standard Best Image Study Cervical LNs 63 93 Cytology or pathology or negative ultrasound Ultrasound Mediastinal LNs 100 100 CT Ga68 PET/CT = CT Liver 9 100 CT or MRI CT or MRI Lung 63 100 CT CT Bone 100 95 Bone scan/MRI Ga68 PET/CT bone scan (sensitivity, 50%; specificity, 90%) Disease Site Sensitivity, % Specificity, % Reference Standard Best Image Study Cervical LNs 63 93 Cytology or pathology or negative ultrasound Ultrasound Mediastinal LNs 100 100 CT Ga68 PET/CT = CT Liver 9 100 CT or MRI CT or MRI Lung 63 100 CT CT Bone 100 95 Bone scan/MRI Ga68 PET/CT bone scan (sensitivity, 50%; specificity, 90%) View Large The analysis of the 68Ga-DOTATATE uptake in each metastatic lesion detected by 68Ga PET/CT showed that the median SUV max for all the true-positives lesions was 6.4 (range, 1.1 to 22.6), varying according to metastatic sites [5.5 (range, 1.8 to 22.6) for LNs, 10.3 (range, 2.3 to 19.2) for bone, 1.6 (range, 1.1 to 2.1) for lung, and 11.9 in the only liver metastasis]. For LNs, the median SUV max of true-positive lesions was significantly greater than the SUV max of false-positive lesions [5.5 (range, 1.8 to 22.6) vs 1.9 (range, 1.3 to 2.5), P = 0.0001]. The LN SUV max threshold of 3.1 was found to optimize sensibility (78%) and specificity (100%), and all lesions with the LN SUV max lower than 1.8 were negative for disease (sensitivity, 100%; specificity, 58.3%). The 68Ga PET/CT results led to a change of management in 1 of the 16 patients (6.25%) in group 1 and 5 (35.7%) of the 14 patients in group 2. All patients from group 2 had a bone lesion detected by 68Ga PET/CT that was missed by a bone scan. The change of management was defined as initiation of treatments such as bone antiresorptives, radiation therapy, or a change of radiological workup during follow-up. Table 4 demonstrates the SSTR and Ki-67 immunohistochemical analysis of the available tumors (primary thyroid tumor and metastases) of 5 patients from group 1 and 11 patients from group 2. In nine patients, immunohistochemical analysis of primary or metastatic tumor did not show expression of SSTR2, SSTR3, and SSTR5; seven (78%) of these patients presented with disease detected by 68Ga PET/CT. From seven patients with expression of SSTRs, five patients demonstrated 68Ga PET/CT uptake (71.4%). Expression of SSTR2 was observed in five patients, weak expression in primary tumor in three patients (one patient with bone uptake in 68Ga PET/CT, one with no uptake and no disease identified by other studies, and one with no uptake in 68Ga PET/CT but with metastatic disease involving lung, liver, and cervical LNs), and moderate SSTR2 immunoreactivity (IR) in one patient with 68Ga PET/CT uptake in a cervical LN. The fifth patient had SSTR 2 expression in an adrenal tumor (pheochromocytoma), for which 68Ga PET/CT showed uptake in bone and adrenal lesions. Interestingly, this same patient had liver metastases not detected by 68Ga PET/CT, and biopsy of one of the liver lesions was negative for SSTR2 but had strong expression for SSTR5. Three patients had tumor samples with IR for SSTR3; two of these patients had disease detected by 68Ga PET/CT, and one patient had no disease detected by any imaging studies. Two patients had tumor samples with IR for SSTR5: one patient with strong IR in a liver metastasis with no uptake by 68Ga PET/CT and one with weak IR in a cervical LN with uptake in 68Ga PET/CT but that also showed IR for SSTR2. Ki-67 staining inversely correlated with 68Ga-DOTATATE PET/CT findings; mean Ki-67 index in tumor samples with 68Ga-DOTATATE uptake was 3.5% compared with 42% in tumors with no uptake. Table 4. SSRT and Ki-67 Immunohistochemical Analysis of Available Tumors Patient No. Group Tumor Ki-67, % SSTR2a SSTR3a SSTR5a 68Ga PET/CT Uptake Sites of Confirmed Disease 1 2 Thyroid 3 0 0 0 Liver, bone Liver, bone 2 2 Thyroid 80 0 0 0 — Liver 5 2 Thyroid 0.6 0 0 0 Neck LN, mediastinal LN, bone Lung, neck LN, mediastinal LNs, bone Tibia metastasis 1.6 0 0 0 Breast metastasis 3.6 0 0 0 6 2 Bone metastasis 1.2 0 0 0 Bone Liver, neck LN, bone 7 2 Thyroid 2.4 1 0 0 — Lung, liver, neck LN Neck LN 16.4 1 0 0 Liver metastasis 12 0 0 0 Pheo 0.6 0 0 0 8 2 Liver metastasis 30 0 0 3 Pheo, bone Lung, liver, pheo, bone Right pheo 0.8 2 0 0 Left pheo 1.8 1 0 0 9 2 Neck LNs 4.3 0 0 0 Lung, neck LN, mediastinal LN, bone Lung, liver, neck LN, mediastinal LN, bone 10 2 Thyroid 6 1 0 0 Bone Liver, bone 11 2 Thyroid 10 0 0 0 Lung, neck LN, mediastinal LN Lung, neck LN, mediastinal LN 12 2 Neck LN 0.75 0 0 0 Lung, neck LN, mediastinal LN, bone Lung, liver, pancreas, neck LN, mediastinal LN, bone 13 2 Thyroid 7.3 0 1 0 Lung, neck LN, mediastinal LN, bone Lung, liver, kidney, pancreas mediastinal LN, bone Mediastinal LN 8 0 0 0 19 1 Thyroid 2.8 1 2 0 — — 21 1 Neck LN 1.4 0 0 1 Neck LN Neck LN (cell block) 0 2 0 0 Neck LN 23 1 Thyroid 0.8 0 0 0 Neck LN Neck LN 25 1 Neck LN 1.8 0 0 0 — — 30 1 Thyroid 0.4 0 1 0 Bone Bone Patient No. Group Tumor Ki-67, % SSTR2a SSTR3a SSTR5a 68Ga PET/CT Uptake Sites of Confirmed Disease 1 2 Thyroid 3 0 0 0 Liver, bone Liver, bone 2 2 Thyroid 80 0 0 0 — Liver 5 2 Thyroid 0.6 0 0 0 Neck LN, mediastinal LN, bone Lung, neck LN, mediastinal LNs, bone Tibia metastasis 1.6 0 0 0 Breast metastasis 3.6 0 0 0 6 2 Bone metastasis 1.2 0 0 0 Bone Liver, neck LN, bone 7 2 Thyroid 2.4 1 0 0 — Lung, liver, neck LN Neck LN 16.4 1 0 0 Liver metastasis 12 0 0 0 Pheo 0.6 0 0 0 8 2 Liver metastasis 30 0 0 3 Pheo, bone Lung, liver, pheo, bone Right pheo 0.8 2 0 0 Left pheo 1.8 1 0 0 9 2 Neck LNs 4.3 0 0 0 Lung, neck LN, mediastinal LN, bone Lung, liver, neck LN, mediastinal LN, bone 10 2 Thyroid 6 1 0 0 Bone Liver, bone 11 2 Thyroid 10 0 0 0 Lung, neck LN, mediastinal LN Lung, neck LN, mediastinal LN 12 2 Neck LN 0.75 0 0 0 Lung, neck LN, mediastinal LN, bone Lung, liver, pancreas, neck LN, mediastinal LN, bone 13 2 Thyroid 7.3 0 1 0 Lung, neck LN, mediastinal LN, bone Lung, liver, kidney, pancreas mediastinal LN, bone Mediastinal LN 8 0 0 0 19 1 Thyroid 2.8 1 2 0 — — 21 1 Neck LN 1.4 0 0 1 Neck LN Neck LN (cell block) 0 2 0 0 Neck LN 23 1 Thyroid 0.8 0 0 0 Neck LN Neck LN 25 1 Neck LN 1.8 0 0 0 — — 30 1 Thyroid 0.4 0 1 0 Bone Bone Abbreviation: pheo, pheochromocytoma. a Stained slides examined according to criteria defined by the Clinical and Laboratory Standards Institute (25): score 0 (cases that did not express the marker in question were considered negative in any cell of interest), score 1 (weak positive/borderline cases showed weak staining in <10% of the cells of interest), score 2 (cases with moderate to strong staining between 10% and 50% of the cells of interest were considered positive), and score 3 (cases with moderate to strong staining were considered positive in >50% of the cells of interest). View Large Table 4. SSRT and Ki-67 Immunohistochemical Analysis of Available Tumors Patient No. Group Tumor Ki-67, % SSTR2a SSTR3a SSTR5a 68Ga PET/CT Uptake Sites of Confirmed Disease 1 2 Thyroid 3 0 0 0 Liver, bone Liver, bone 2 2 Thyroid 80 0 0 0 — Liver 5 2 Thyroid 0.6 0 0 0 Neck LN, mediastinal LN, bone Lung, neck LN, mediastinal LNs, bone Tibia metastasis 1.6 0 0 0 Breast metastasis 3.6 0 0 0 6 2 Bone metastasis 1.2 0 0 0 Bone Liver, neck LN, bone 7 2 Thyroid 2.4 1 0 0 — Lung, liver, neck LN Neck LN 16.4 1 0 0 Liver metastasis 12 0 0 0 Pheo 0.6 0 0 0 8 2 Liver metastasis 30 0 0 3 Pheo, bone Lung, liver, pheo, bone Right pheo 0.8 2 0 0 Left pheo 1.8 1 0 0 9 2 Neck LNs 4.3 0 0 0 Lung, neck LN, mediastinal LN, bone Lung, liver, neck LN, mediastinal LN, bone 10 2 Thyroid 6 1 0 0 Bone Liver, bone 11 2 Thyroid 10 0 0 0 Lung, neck LN, mediastinal LN Lung, neck LN, mediastinal LN 12 2 Neck LN 0.75 0 0 0 Lung, neck LN, mediastinal LN, bone Lung, liver, pancreas, neck LN, mediastinal LN, bone 13 2 Thyroid 7.3 0 1 0 Lung, neck LN, mediastinal LN, bone Lung, liver, kidney, pancreas mediastinal LN, bone Mediastinal LN 8 0 0 0 19 1 Thyroid 2.8 1 2 0 — — 21 1 Neck LN 1.4 0 0 1 Neck LN Neck LN (cell block) 0 2 0 0 Neck LN 23 1 Thyroid 0.8 0 0 0 Neck LN Neck LN 25 1 Neck LN 1.8 0 0 0 — — 30 1 Thyroid 0.4 0 1 0 Bone Bone Patient No. Group Tumor Ki-67, % SSTR2a SSTR3a SSTR5a 68Ga PET/CT Uptake Sites of Confirmed Disease 1 2 Thyroid 3 0 0 0 Liver, bone Liver, bone 2 2 Thyroid 80 0 0 0 — Liver 5 2 Thyroid 0.6 0 0 0 Neck LN, mediastinal LN, bone Lung, neck LN, mediastinal LNs, bone Tibia metastasis 1.6 0 0 0 Breast metastasis 3.6 0 0 0 6 2 Bone metastasis 1.2 0 0 0 Bone Liver, neck LN, bone 7 2 Thyroid 2.4 1 0 0 — Lung, liver, neck LN Neck LN 16.4 1 0 0 Liver metastasis 12 0 0 0 Pheo 0.6 0 0 0 8 2 Liver metastasis 30 0 0 3 Pheo, bone Lung, liver, pheo, bone Right pheo 0.8 2 0 0 Left pheo 1.8 1 0 0 9 2 Neck LNs 4.3 0 0 0 Lung, neck LN, mediastinal LN, bone Lung, liver, neck LN, mediastinal LN, bone 10 2 Thyroid 6 1 0 0 Bone Liver, bone 11 2 Thyroid 10 0 0 0 Lung, neck LN, mediastinal LN Lung, neck LN, mediastinal LN 12 2 Neck LN 0.75 0 0 0 Lung, neck LN, mediastinal LN, bone Lung, liver, pancreas, neck LN, mediastinal LN, bone 13 2 Thyroid 7.3 0 1 0 Lung, neck LN, mediastinal LN, bone Lung, liver, kidney, pancreas mediastinal LN, bone Mediastinal LN 8 0 0 0 19 1 Thyroid 2.8 1 2 0 — — 21 1 Neck LN 1.4 0 0 1 Neck LN Neck LN (cell block) 0 2 0 0 Neck LN 23 1 Thyroid 0.8 0 0 0 Neck LN Neck LN 25 1 Neck LN 1.8 0 0 0 — — 30 1 Thyroid 0.4 0 1 0 Bone Bone Abbreviation: pheo, pheochromocytoma. a Stained slides examined according to criteria defined by the Clinical and Laboratory Standards Institute (25): score 0 (cases that did not express the marker in question were considered negative in any cell of interest), score 1 (weak positive/borderline cases showed weak staining in <10% of the cells of interest), score 2 (cases with moderate to strong staining between 10% and 50% of the cells of interest were considered positive), and score 3 (cases with moderate to strong staining were considered positive in >50% of the cells of interest). View Large Discussion Despite optimal surgical treatment, residual and recurrent disease is frequent in MTC. During postoperative follow-up, patients with serum Ctn levels <150 pg/mL have disease almost always confined to LNs in the neck; therefore, the recommendation from the American Thyroid Association is to follow these patients with a neck ultrasound (2). Patients with serum Ctn >150 pg/mL have a higher risk for distant metastatic disease, and radiological evaluation should also include contrast-enhanced chest CT for detection of lung and mediastinal LN metastases, three-phase contrast-enhanced multidetector liver CT or contrast-enhanced MRI to detect liver metastases, bone scintigraphy, and axial MRI to detect bone metastases (2, 4, 5). A more sensitive test that detects lesions in patients with biochemical disease or a test that includes evaluation of all disease sites in patients with metastatic MTC would be ideal for those who require lifelong radiological surveillance. 18F-FDG PET/CT is useful in patients with aggressive disease; however, most patients with MTC, even with metastatic disease, tend to have an indolent course (7, 8). As MTC is a neuroendocrine tumor that expresses SSTR and as 68Ga PET/CT has been shown to be extremely useful in other neuroendocrine tumors (28), several studies have investigated the role of 68Ga PET/CT in MTC with promising results. However, most of these studies were retrospective and did not include a systematic comparison with current recommended imaging studies at each disease site (13–18). In the study by Conry et al. (15) with 18 patients with sporadic MTC (6 with occult disease and 12 with metastatic disease), 68Ga PET/CT showed at least one site of metastatic disease in 13 of the 18 patients, and the reported overall sensitivity was 72.2% (95% CI, 46.4% to 89.3%). Recently, Yamaga et al. (18) compared prospectively the detection rate of 68Ga PET/CT with 11In-octreotide single photon emission CT/CT and conventional imaging in 15 patients with MTC (1 with occult disease and 14 with metastatic disease). The sensitivity and accuracy of 68Ga PET/CT reported was 100% and 93%, respectively, similar to the conventional images, and 68Ga PET/CT was superior to bone scan and bone MRI in the identification of bone lesions. However, the conventional images besides chest CT and neck ultrasound or CT were done only if clinically indicated; abdominal evaluation with CT or MRI was performed in only 53.3% of the patients and bone MRI in 40% of the patients. As most of the studies were retrospective and did not uniformly include all recommended imaging modalities to evaluate each disease site, it is unclear whether a negative 68Ga PET/CT finding was also negative by the recommended imaging study for each site (13–18). In this study, the primary objective was to investigate the sensitivity and specificity of 68Ga PET/CT in detecting disease in patients with no localization of disease prior to study entry (biochemical disease) and to analyze whether 68Ga PET/CT would be a better modality to evaluate extent of disease in metastatic patients, to eventually substitute the conventional imaging studies for a unique whole-body imaging modality. A second objective was to analyze the SSTR expression in the thyroid tumor or metastases by immunohistochemistry and to correlate it with the 68Ga PET/CT findings. We included 16 patients with biochemical disease and 14 patients with metastatic MTC and performed 68Ga PET/CT in addition to other recommended imaging studies. In the cohort of patients with biochemical disease, eight patients had localization of the disease site: six patients had cervical LN metastases (all detected by ultrasound and three by 68Ga PET/CT), one patient had a hilar LN detected by chest CT and 68Ga PET/CT, and one patient had a right humerus lesion detected by bone scan and 68Ga PET/CT, which was confirmed by MRI. Further analysis of these patients according to Ctn levels demonstrated that all patients with Ctn <50 pg/mL had no detectable disease, whereas disease was detected in four of five patients (80%) with Ctn between 50 and 150 pg/mL (three patients with cervical LNs and one bone lesion) and four of seven patients (57%) with Ctn >150 pg/mL (three patients with cervical LN and one hilar LN). In accordance with the American Thyroid Association recommendations, ultrasound of the neck, especially when performed by an experienced physician, is the most sensitive and useful imaging in patients with biochemical disease. At the same time, our study showed that despite an extensive imaging workup, 43% of patients with Ctn >150 pg/mL had occult disease. In the group with metastatic disease, 68Ga PET/CT was clearly superior to bone scan in detecting bone lesions; it identified lesions in 9 of 14 patients (all confirmed by MRI), whereas bone scan identified lesions in 4 of 14 patients (sensitivity, 68Ga PET/CT 100% vs bone scan 44.4%). The Ctn and CEA level cutoff associated with detection of bone lesions only by 68Ga PET/CT was 30,902 pg/mL and 242 ng/mL, respectively, suggesting that patients with extensive disease would benefit from undergoing 68Ga PET/CT instead of bone scan to optimize disease detection. This finding could have an impact on disease management as bone lesions that are frequently associated with skeletal events and impairment of quality of life could be detected and treated earlier if indicated. For the other disease sites, 68Ga PET/CT was similar to chest CT in detecting mediastinal LNs and inferior to ultrasound, chest CT, and CT/MRI of the abdomen for detection of neck LNs, lung metastases, and liver metastases, respectively. The low sensitivity in detecting liver lesions was striking and different from what was observed in patients with other neuroendocrine tumors, specifically gastroenteropancreatic tumors (28); this may be related to a high basal radiopharmaceutical uptake in the liver, which could impair the detection of lesions or could be related to differences in the biology of the tumor with a lower expression of the SSTR. In fact, the two samples of liver metastases analyzed for SSTR expression identified one with absent IR for SSTR2, SSTR3, and SSTR5 and the other with IR only for SSTR5, which is a possible reason for not being detected by 68Ga-DOTATATE. Similarly, sensitivity was low in detecting lung nodules; one explanation would be the lower sensitivity in detecting lesions <1 cm (Fig. 3). Alternatively, it could be related to expression of SSTR and the profile of affinity of the somatostatin analogue used in our study (DOTATATE), which has affinity to SSTR2. Most of the studies investigating the role of 68Ga somatostatin analogue PET/CT in MTC used DOTATATE and therefore are comparable, except for the study by Treglia et al. (13), which used DOTATOC in 4 patients and DOTANOC in 14 patients. Despite a wider SSTR affinity of DOTATOC (SSTR2 and SSTR5) and DOTANOC (SSTR2, SSTR3, and SSTR5), the sensitivity of 68Ga PET/CT was 33% vs 72% with 18F-DOPA PET/CT. Up to now, 18F-DOPA PET/CT seemed to be the most useful functional imaging method for detection of locoregional and distant metastatic MTC. Several studies have compared 18F-DOPA PET/CT with 18F-FDG PET/CT in MTC, showing greater sensitivity of 18F-DOPA PET/CT (10, 12). The better sensitivity for 18F-DOPA PET/CT was also observed in the study by Treglia et al. (13) that compared 18F-DOPA PET/CT, 68Ga PET/CT, and 18F-FDG PET (72%, 33%, and 17%, respectively. Expression of SSTR, performed by immunohistochemical analysis of SSTR2, SSTR3, and SSTR5, was observed in 44% of analyzed tumor samples. This analysis was not particularly useful to identify which patients would have a positive 68Ga PET/CT study as 68Ga-DOTATATE uptake was observed in patients with and without SSTR expression. From the 16 patients with tumor samples (primary thyroid tumor and/or metastases) available for analysis, 9 patients had tumors with absent IR for SSTR2, SSTR3, and SSTR5 (56%) and 7 patients had tumor samples expressing SSTR2 (5/7), SSTR3 (3/7), and SSTR5 (2/7). 68Ga-DOTATATE uptake was observed in seven of nine (78%) patients with absent IR and in 62.5% of patients with SSTR2, SSTR3, and SSTR5 IR. On the other hand, Ki-67 staining was inversely correlated with 68Ga-DOTATATE uptake, suggesting that 68Ga PET/CT has better sensitivity in low proliferative tumors. In this study, the analysis of SUV max was useful in distinguishing benign from malignant LN lesions. An SUV max >3.1 was associated with metastatic disease (specificity of 100%), whereas all LNs with an SUV max <1.8 were not. These results suggest that FNAB could be spared in LNs with low 68Ga-DOTATATE uptake and no ultrasound suspicious findings. In summary, this study provided a systematic analysis of the efficacy of 68Ga PET/CT in detecting disease at commonly involved sites by MTC, demonstrating that it is inferior to neck ultrasound, chest CT, and CT/MRI of the abdomen but superior to bone scan in detecting bone metastases. Conclusion 68Ga-DOTATATE PET/CT does not provide optimal whole-body imaging as a single procedure in patients with biochemical or metastatic MTC. The low sensitivity of detection in cervical LNs, lung metastases, and liver metastases requires additional imaging modalities for these common metastatic MTC sites. However, it was superior to bone scan and equivalent to MRI in identifying bone lesions, suggesting that it could be a substitute for bone scan and MRI. Abbreviations: Abbreviations: 18F-DOPA 6-fluoro-(18F)-L-3,4-dihydroxyphenylalanine 18F-FDG deoxy-glucose radiolabeled with fluorine-18 68Ga gallium-68 CEA carcinoembryonic antigen Ctn calcitonin FNAB fine-needle aspiration biopsy IR immunoreactivity LN lymph node MTC medullary thyroid cancer PET positron emission tomography SSTR somatostatin receptor SUV max maximum standardized uptake Acknowledgments Financial Support: Supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (2013/03876-4, to A.O.H.). Disclosure Summary: The authors have nothing to disclose. References 1. Pelizzo MR , Boschin IM , Bernante P , Toniato A , Piotto A , Pagetta C , Nibale O , Rampin L , Muzzio PC , Rubello D . Natural history, diagnosis, treatment and outcome of medullary thyroid cancer: 37 years experience on 157 patients . Eur J Surg Oncol . 2007 ; 33 ( 4 ): 493 – 497 . Google Scholar Crossref Search ADS PubMed 2. 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Am J Surg Pathol . 2012 ; 36 ( 12 ): 1761 – 1770 . Google Scholar Crossref Search ADS PubMed 28. Sadowski SM , Neychev V , Millo C , Shih J , Nilubol N , Herscovitch P , Pacak K , Marx SJ , Kebebew E . Prospective Study of 68Ga-DOTATATE positron emission tomography/computed tomography for detecting gastro-entero-pancreatic neuroendocrine tumors and unknown primary sites . J Clin Oncol . 2016 ; 34 ( 6 ): 588 – 596 . Google Scholar Crossref Search ADS PubMed Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

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Oxford University Press
Copyright
Copyright © 2018 Endocrine Society
ISSN
0021-972X
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1945-7197
D.O.I.
10.1210/jc.2018-00193
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Abstract

Abstract Context Persistent disease after surgery is common in medullary thyroid cancer (MTC), requiring lifelong radiological surveillance. Staging workup includes imaging of neck, chest, abdomen, and bones. A study integrating all sites would be ideal. Despite the established use of gallium-68 (68Ga) positron emission tomography (PET)/CT with somatostatin analogues in most neuroendocrine tumors, its efficacy is controversial in MTC. Objective Evaluate the efficacy of 68Ga PET/CT in detecting MTC lesions and evaluate tumor expression of somatostatin receptors (SSTRs) associated with 68Ga PET/CT findings. Methods Prospective study evaluating 30 patients with MTC [group 1 (n = 16), biochemical disease; group 2 (n = 14), metastatic disease]. Patients underwent 68Ga PET/CT, bone scan, CT and ultrasound of the neck, CT of the chest, CT/MRI of the abdomen, and MRI of the spine. 68Ga PET/CT findings were analyzed by disease site as positive or negative and as concordant or discordant with conventional studies. Sensitivity and specificity were calculated using pathological or cytological analysis or unequivocal identification by standard imaging studies. Immunohistochemical analysis of SSTRs was compared with 68Ga PET/CT findings. Results In both groups, 68Ga PET/CT was inferior to currently used imaging studies except for bone scan. In group 2, 68Ga PET/CT sensitivities were 56%, 57%, and 9% for detecting neck lymph nodes, lung metastases, and liver metastases, respectively, and 100% for bone metastases, superior to the bone scan (44%). Expression of SSTRs, observed in 44% of tumors, was not associated with 68Ga-DOTATATE uptake. Conclusions 68Ga PET/CT does not provide optimal whole-body imaging as a single procedure in patients with MTC. However, it is highly sensitive in detecting bone lesions and could be a substitute for a bone scan and MRI. Medullary thyroid cancer (MTC) is a rare neuroendocrine tumor that arises from the parafollicular cells of the thyroid and secretes calcitonin (Ctn) and carcinoembryonic antigen (CEA), which are used as tumor markers. MTC occurs either as a sporadic form or, in 20% to 30% of the cases, as part of an autosomal dominant inherited syndrome called multiple endocrine neoplasia, which is caused by a germline mutation of the rearranged during transfection (RET) proto-oncogene. A substantial percentage (38% to 90%) of patients remains with persistent disease after surgical treatment and will need lifelong radiological surveillance in addition to Ctn and CEA measurements (1–3). Several studies have indicated the best imaging modalities for the radiological surveillance of these patients. With the knowledge that MTC metastatic sites involve cervical lymph nodes (LNs), lung, mediastinal LNs, liver, and bone, the currently recommended studies include neck ultrasound, contrast-enhanced neck and chest CT, three-phase contrast-enhanced multidetector abdominal CT, or contrast-enhanced MRI of the abdomen and spine and bone scan (2, 4, 5). As metastatic disease frequently involves multiple organs, a single whole-body imaging technique in MTC would be ideal for time saving and comfort of patients. High-resolution positron emission tomography (PET)/CT with deoxy-glucose radiolabeled with fluorine-18 (18F-FDG PET/CT) is useful for tumors with aggressive behavior and high glucose consumption. The studies investigating the role of 18F-FDG PET/CT in neuroendocrine tumors have demonstrated high sensitivity only with high-grade tumors, correlating with a worse prognosis (6). However, most neuroendocrine tumors have an indolent behavior (7–9), and other radiolabeled peptides may be more sensitive. For example, 6-fluoro-(18F)-L-3,4-dihydroxyphenylalanine (18F-DOPA) PET has been shown to be superior to 18F-FDG PET/CT in MTC lesions and is probably the most sensitive PET technique in patients with MTC (10–13). New promising gallium-68 (68Ga) radiolabeled somatostatin analogue peptides (DOTATATE, DOTATOC, and DOTANOC) in PET/CT imaging have improved the detection and localization of neuroendocrine tumors. Based on the knowledge that MTC is a neuroendocrine tumor that expresses somatostatin receptors (SSTRs), few studies, mostly case series, have evaluated the role of 68Ga-DOTATATE PET/CT (68Ga PET/CT) in MTC (13–18) with variable results, showing 68Ga PET/CT sensitivity between 33% and 100%, with variability likely related to the production and half-life of 68Ga. We conducted a prospective study aimed at the evaluation of the sensitivity and specificity of 68Ga PET/CT in detecting metastatic MTC lesions identified by the best recommended conventional imaging modalities in different sites. The secondary objective was to analyze the immunoexpression of the SSTRs and Ki-67 in available MTC tumors and compare these findings with detection by 68Ga PET/CT. Patients and Methods Imaging studies Thirty patients with MTC and elevated Ctn were prospectively included between May 2013 and January 2016 at the Instituto do Câncer do Estado de São Paulo, Brazil. The study was approved by the local research ethics committee. Informed consent was obtained from all patients before imaging. The patients were classified in two groups: group 1 included patients with biochemical disease (Ctn >10 pg/mL with no evidence of disease by previous imaging studies), and group 2 included patients with previously known metastatic disease. Patients were evaluated by imaging studies that included 68Ga PET/CT, bone scan, ultrasound of the neck, contrast-enhanced CT of the neck and chest, and three-phase CT or MRI of the abdomen. MRI of spine and/or long bones was performed in case of bone uptake by bone scan or 68Ga PET/CT. An immunochemiluminescence assay (Immulite 2000; Siemens Diagnostics, Malvern, PA) measured Ctn (normal range <5 pg/mL for females and <8.4 pg/mL for males) and CEA (normal range <5 ng/mL). PET/CT studies were obtained after intravenous injection of 185 MBq radiolabeled 68Ga-DOTATATE in an automated system (Modular LabPharmTracer; Eckert-Ziegler, Berlin, Germany) with 68Ga eluate from a 68Ga generator (Obninsk, Kaluga Oblast, Russia) and complexation with DOTATATE (piCHEM, Graz, Styria, Austria). PET images were acquired on a Discovery 690 PET/CT scanner (GE Healthcare, Waukesha, WI) using three-dimensional time-of-flight mode, with 2 minutes per bed position with 15 cm per bed along 3 cm of overlap between beds with the patients lying supine on the scanner bed with the arms along the body. Acquisition matrix was 192 × 192 pixels with an in-slice pixel size of 3.27 mm and a transaxial slice thickness of 3.27 mm, correcting images for attenuation, scatter, random radiation decays, dead time, and decay. A three-dimensional ordered-subset expectation maximization iterative reconstruction algorithm was used to reconstruct images, using two iterations and 28 subsets as reconstruction settings. CT protocol used an automatic exposure control, a 10- to 400-mAs range, 120 kVp, a 0.5-second rotation time, and 1.37 pitch. Images had an axial slice thickness of 3.27 mm and a resolution of 512 × 512 pixels. A semiquantitative analysis was performed by the median of maximum standardized uptake (SUV max) obtained by manually placing a volume of interest over the whole abnormal lesion, avoiding undesired adjacent areas. In each patient, all scans were taken within a median of 31 (4 to 111) days. 68Ga PET/CT findings were classified as positive or negative on visual interpretation by blinded board-certified nuclear medicine physicians and as concordant or discordant with the conventional imaging studies. Two radiologists (R.M.C.F. and E.F.) and two nuclear physicians (G.C.F. and C.A.B.) who were unaware of clinical data and each other’s results independently evaluated the imaging findings. The interobserver variation was 7.3% and 4.6% for nuclear medicine and radiology, respectively. After a consensus, the interobserver agreement was 0.98 for nuclear medicine and 0.99 for radiology. The 68Ga PET/CT and conventional images results were analyzed by comparing the same lesions on a per-organ and per-patient basis, and an analysis of influence of additional information provided by 68Ga PET/CT on the patient’s management was evaluated. Immunohistochemistry A total of 98 paraffin-embedded samples were obtained from the department of pathology of the Instituto do Câncer do Estado de São Paulo and Hospital das Clínicas da Faculdade Medicina da Universidade de São Paulo. All cases were reviewed prior to further analysis regarding the state of conservation and quality and quantity of the material; diagnostic review and morphological classification were performed according to the classification of the World Health Organization (19, 20). Representative samples of tumors of the primary site and/or metastatic sites for LNs and/or visceral organs and bone were selected. Exclusion criteria for the immunohistochemical and molecular analysis were lack of biologic samples recovered from the file and insufficient tumor. Paraffin sections of 3 μm thickness were deparaffinized in xylol and ethanol in decreasing degrees to hydration. Antigen retrieval was performed in 0.01 M sodium citrate buffer (pH 6.0) in a stainless steel pressure cooker. After antigen retrieval, endogenous peroxidase blocking was performed with 6% hydrogen peroxide. Slides were washed in tap and distilled water and PBS. Histological sections were incubated overnight at 4°C with SSTR2 (rabbit monoclonal, UMB1 clone, product code ab134152, titration 1:400; Abcam), SSTR3 (rabbit polyclonal, product code ab28680, titration 1:500; Abcam), SSTR5 (rabbit polyclonal, product code ab28618, titration 1:1000; Abcam), and Ki-67 (MIB-1 clone, product code M7240, titration 1:500 in PBS containing 1% bovine serum albumin; DAKO, Glostrup, Denmark). Antigen-antibody binding was amplified with Post Primary Block (NovoLink Max Polymer Detection System RE7140-K, Newcastle upon Tyne, UK). Slides were washed between steps with PBS three times for 5 minutes each. Sections were developed with diaminobenzidine substrate (D5637; Sigma, St. Louis, MO) and counterstained with Harris’s hematoxylin. Nuclear and/or cytoplasmic golden brown was considered positive. Positive controls consisted of a specimen from pancreas (SSTR2 and SSTR5), brain (SSTR3), and tonsil (Ki-67). Negative control was performed by omission of the antibody, based on protocols validated by the literature and the product label (21–24). A board-certified pathologist (R.S.) examined all stained slides according to criteria defined by the Clinical and Laboratory Standards Institute (25): score 0 (cases that did not express the marker in question were considered negative in any cell of interest), score 1 (weak positive/borderline cases showed weak staining in <10% of the cells of interest), score 2 (cases with moderate to strong staining between 10% and 50% of the cells of interest were considered positive), and score 3 (cases with moderate to strong staining were considered positive in >50% of the cells of interest). The immunohistochemical evaluation for the Ki-67 marker was performed quantitatively by counting the absolute number of neoplastic cells with nuclear expression, selecting the areas with the highest expression (hot spots), and the result was expressed as a percentage by the ratio of the number of positive cells and the total number of cells evaluated. At least 2000 cells per sample or 50 large-scale fields were evaluated (26, 27). Statistical analysis Descriptive statistics were calculated for categorical (frequencies and percentages) and continuous variables (mean, median, and minimum and maximum values). The definition of a true-positive lesion and analysis of sensitivity and specificity in each site were based on (1) cytological or pathological analysis or by unequivocal identification by established gold-standard imaging studies defined as neck ultrasound and CT for neck lesions, (2) chest CT with contrast for pulmonary nodules and mediastinal LNs, (3) three-phase contrast-enhanced CT or MRI abdomen for liver lesions, and (4) MRI for bone lesions (MRI of spine or from specific sites identified by bone scan or by 68Ga PET/CT), which are considered reference standards (2). Radiological follow-up indicating progression of a lesion was also used to confirm a true-positive lesion. For ethical and practical reasons, not every lesion interpreted as positive underwent a biopsy. Wilcoxon test, logistic regression, and receiver operating characteristic curves were performed to analyze the association between SUV max of LNs and positivity for metastatic disease, using the software JMP version 11 (SAS Institute, Inc., Cary, NC). Results From a total of 30 patients, 16 were classified as having biochemical disease (group 1) and 14 with established metastatic disease (group 2) prior to entering the study. Table 1 demonstrates demographic and clinical data. In group 1, there were 14 women and 2 men with a median age of 52 years (range, 24 to 78 years), median Ctn level was 133 pg/mL (range, 11 to 1162 pg/mL), and median CEA level was 4.85 ng/mL (range, 0.6 to 140 ng/mL) with a median duration of disease of 11 years (range, 1 to 31 years). In group 2, there were 3 women and 11 men with a median age of 44 years (range, 19 to 72 years), median Ctn was 8323 pg/mL (range, 564 to 101,083 pg/mL), median CEA was 245 ng/mL (range, 9.4 to 3287 ng/mL), and median duration of disease was 7 years (range, 0.25 to 19 years). Except for one patient in group 2, all patients underwent total thyroidectomy with LN dissection; in addition, patients from group 2 underwent other treatments, including external beam radiotherapy to the neck and bone and systemic treatment with conventional chemotherapy and/or tyrosine kinase inhibitors. Table 1. Clinical Characteristics Characteristic Occult MTC (n = 16) Metastatic MTC (n = 14) Age, median (range), y 52 (24–78) 44 (19–72) Sex, n (%)  Female 14 (87.5) 3 (21.4)  Male 2 (12.5) 11 (78.5) Hereditary MTC, n (%) 7 (43.7) 7 (50) RET mutationsa Cys634Thyr (2), Val804Met, Cys611Trp, Cys634Arg (2), Cys620Arg Cys634Thyr/Y791F (2), Cys609Thyr, Val804Met, Met918T (3) Time from diagnosis, median (range), y 11 (1–31) 7 (0.25–19) Time of metastatic disease, median (range), y — 3 (0.25–10) Ctn, median (range), pg/mL 133 (12–1162) 8323 (564–101,083) DT Ctn, median (range), mo — 23 (1.86–106) CEA, median (range), ng/mL 4.85 (0.6–140) 245 (9.4–3287) DT CEA, median (range), mo — 29 (7–167) Characteristic Occult MTC (n = 16) Metastatic MTC (n = 14) Age, median (range), y 52 (24–78) 44 (19–72) Sex, n (%)  Female 14 (87.5) 3 (21.4)  Male 2 (12.5) 11 (78.5) Hereditary MTC, n (%) 7 (43.7) 7 (50) RET mutationsa Cys634Thyr (2), Val804Met, Cys611Trp, Cys634Arg (2), Cys620Arg Cys634Thyr/Y791F (2), Cys609Thyr, Val804Met, Met918T (3) Time from diagnosis, median (range), y 11 (1–31) 7 (0.25–19) Time of metastatic disease, median (range), y — 3 (0.25–10) Ctn, median (range), pg/mL 133 (12–1162) 8323 (564–101,083) DT Ctn, median (range), mo — 23 (1.86–106) CEA, median (range), ng/mL 4.85 (0.6–140) 245 (9.4–3287) DT CEA, median (range), mo — 29 (7–167) Abbreviation: DT, doubling time. a Numbers in parentheses indicate the number of patients with the RET mutation. View Large Table 1. Clinical Characteristics Characteristic Occult MTC (n = 16) Metastatic MTC (n = 14) Age, median (range), y 52 (24–78) 44 (19–72) Sex, n (%)  Female 14 (87.5) 3 (21.4)  Male 2 (12.5) 11 (78.5) Hereditary MTC, n (%) 7 (43.7) 7 (50) RET mutationsa Cys634Thyr (2), Val804Met, Cys611Trp, Cys634Arg (2), Cys620Arg Cys634Thyr/Y791F (2), Cys609Thyr, Val804Met, Met918T (3) Time from diagnosis, median (range), y 11 (1–31) 7 (0.25–19) Time of metastatic disease, median (range), y — 3 (0.25–10) Ctn, median (range), pg/mL 133 (12–1162) 8323 (564–101,083) DT Ctn, median (range), mo — 23 (1.86–106) CEA, median (range), ng/mL 4.85 (0.6–140) 245 (9.4–3287) DT CEA, median (range), mo — 29 (7–167) Characteristic Occult MTC (n = 16) Metastatic MTC (n = 14) Age, median (range), y 52 (24–78) 44 (19–72) Sex, n (%)  Female 14 (87.5) 3 (21.4)  Male 2 (12.5) 11 (78.5) Hereditary MTC, n (%) 7 (43.7) 7 (50) RET mutationsa Cys634Thyr (2), Val804Met, Cys611Trp, Cys634Arg (2), Cys620Arg Cys634Thyr/Y791F (2), Cys609Thyr, Val804Met, Met918T (3) Time from diagnosis, median (range), y 11 (1–31) 7 (0.25–19) Time of metastatic disease, median (range), y — 3 (0.25–10) Ctn, median (range), pg/mL 133 (12–1162) 8323 (564–101,083) DT Ctn, median (range), mo — 23 (1.86–106) CEA, median (range), ng/mL 4.85 (0.6–140) 245 (9.4–3287) DT CEA, median (range), mo — 29 (7–167) Abbreviation: DT, doubling time. a Numbers in parentheses indicate the number of patients with the RET mutation. View Large All patients were evaluated by imaging studies, including 68Ga PET/CT, neck ultrasound, neck and chest CT, three-phase abdominal CT or MRI, and bone scan. MRI of the spine and of a specific site was done to confirm metastatic disease based on bone scan and 68Ga PET/CT findings. Analysis of imaging studies was performed according to site of disease, and 68Ga PET/CT findings were compared with the gold or reference standard methods for each site. In group 1 (n = 16), ultrasound identified suspicious cervical LNs in eight patients and 68Ga PET/CT in three patients (also detected by ultrasound). All of these patients underwent fine-needle aspiration biopsy (FNAB), and cytology confirmed MTC in six patients with LNs detected by ultrasound and in three patients with LNs detected by 68Ga PET/CT. Therefore, the rate of detection of neck disease in this group of patients, initially defined as having biochemical disease, was 37.5% with ultrasound and 18.7% with 68Ga PET/CT. Considering the association of ultrasound and FNAB as the gold standard, the sensitivity of 68Ga PET/CT in detecting neck disease was 50% and specificity was 100% in group 1 patients. In this same group, two patients were found to have distant metastatic disease, one patient had a hilar LN detected by chest CT and 68Ga PET/CT, and another patient had a bone lesion (right humerus) identified by MRI and 68Ga PET/CT. In bone scan, this lesion was considered indeterminate. In addition, three patients had uptake in bone, two with bone scan and one with 68Ga PET/CT, that was not confirmed by MRI and considered false-positive results. Table 2 demonstrates all the imaging findings for each patient from group 2. In this group (n = 14), ultrasound detected suspicious cervical LNs in 10 patients and 68Ga PET/CT in 6 patients. The cytology confirmed MTC in 9 of 10 patients (ultrasound) and in 5 of 6 patients (68Ga PET/CT). The detection rate of metastatic LNs was 64.3% for ultrasound and 35.7% for 68Ga PET/CT. The sensitivity of 68Ga PET/CT in detecting neck disease in this group of patients was 56.6%, and specificity was 80% (Fig. 1). Table 2. Findings of Ga68-DOTATATE PET/CT and Conventional Studies in Patients With Metastatic MTC (Group 2) Patient No. Ctn (pg/mL) CEA (ng/mL) Ga68 PET/CT Neck Ultrasound CT Chest CT/MRI Abdomen Bone Scan MRI Bone Altered Plan 1 8683 248 Liver + − Liver − + Yes Bone FNAB − 2 895 65 Pancreas − − Liver − − No Endoscopic ultrasound W FNA − 3 2763 152 Neck LN − − Liver − ND No FNAB − 4 12,376 242 Neck LN + MD LN Liver + + No MD LN FNAB + Bone 5 4652 340 Neck LN + MD LN lung − − + Yes MD LN FNAB + Bone 6 50,948 3287 Bone + − Liver − + Yes FNAB + 7 4359 22.5 − + Lung Liver − ND No FNAB + 8a 7962 618 Thyroid 6.5-cm thyroid nodule Lung Liver − + Yes Adrenal Adrenal Bone 9 31,092 1939 MD LN + MD LN lung Liver + + No Lung FNAB + Bone 10 101,083 2203 Bone − − Spleen − + Yes Liver 11 14,256 188 MD LN + MD LN − − ND No Lung FNAB + Lung 12 59,979 650 Neck LN + MD LN Pancreas + + No MD LN FNAB + Lung Liver Lung Kidney Bone 13 795 16 Neck LN + MD LN Pancreas + + No MD LN FNAB + Lung Kidney Lung Liver Bone 14 564 9.4 Neck LN + − − − ND No FNAB + Patient No. Ctn (pg/mL) CEA (ng/mL) Ga68 PET/CT Neck Ultrasound CT Chest CT/MRI Abdomen Bone Scan MRI Bone Altered Plan 1 8683 248 Liver + − Liver − + Yes Bone FNAB − 2 895 65 Pancreas − − Liver − − No Endoscopic ultrasound W FNA − 3 2763 152 Neck LN − − Liver − ND No FNAB − 4 12,376 242 Neck LN + MD LN Liver + + No MD LN FNAB + Bone 5 4652 340 Neck LN + MD LN lung − − + Yes MD LN FNAB + Bone 6 50,948 3287 Bone + − Liver − + Yes FNAB + 7 4359 22.5 − + Lung Liver − ND No FNAB + 8a 7962 618 Thyroid 6.5-cm thyroid nodule Lung Liver − + Yes Adrenal Adrenal Bone 9 31,092 1939 MD LN + MD LN lung Liver + + No Lung FNAB + Bone 10 101,083 2203 Bone − − Spleen − + Yes Liver 11 14,256 188 MD LN + MD LN − − ND No Lung FNAB + Lung 12 59,979 650 Neck LN + MD LN Pancreas + + No MD LN FNAB + Lung Liver Lung Kidney Bone 13 795 16 Neck LN + MD LN Pancreas + + No MD LN FNAB + Lung Kidney Lung Liver Bone 14 564 9.4 Neck LN + − − − ND No FNAB + Altered plan: detection of a new metastatic site of disease, resulting in modification in follow-up interval, examinations, or treatment. Abbreviations: −, negative; + positive; MD, mediastinal; ND, not done; W FNA, with fine needle aspiration. a Patient included at diagnosis of medullary thyroid carcinoma. View Large Table 2. Findings of Ga68-DOTATATE PET/CT and Conventional Studies in Patients With Metastatic MTC (Group 2) Patient No. Ctn (pg/mL) CEA (ng/mL) Ga68 PET/CT Neck Ultrasound CT Chest CT/MRI Abdomen Bone Scan MRI Bone Altered Plan 1 8683 248 Liver + − Liver − + Yes Bone FNAB − 2 895 65 Pancreas − − Liver − − No Endoscopic ultrasound W FNA − 3 2763 152 Neck LN − − Liver − ND No FNAB − 4 12,376 242 Neck LN + MD LN Liver + + No MD LN FNAB + Bone 5 4652 340 Neck LN + MD LN lung − − + Yes MD LN FNAB + Bone 6 50,948 3287 Bone + − Liver − + Yes FNAB + 7 4359 22.5 − + Lung Liver − ND No FNAB + 8a 7962 618 Thyroid 6.5-cm thyroid nodule Lung Liver − + Yes Adrenal Adrenal Bone 9 31,092 1939 MD LN + MD LN lung Liver + + No Lung FNAB + Bone 10 101,083 2203 Bone − − Spleen − + Yes Liver 11 14,256 188 MD LN + MD LN − − ND No Lung FNAB + Lung 12 59,979 650 Neck LN + MD LN Pancreas + + No MD LN FNAB + Lung Liver Lung Kidney Bone 13 795 16 Neck LN + MD LN Pancreas + + No MD LN FNAB + Lung Kidney Lung Liver Bone 14 564 9.4 Neck LN + − − − ND No FNAB + Patient No. Ctn (pg/mL) CEA (ng/mL) Ga68 PET/CT Neck Ultrasound CT Chest CT/MRI Abdomen Bone Scan MRI Bone Altered Plan 1 8683 248 Liver + − Liver − + Yes Bone FNAB − 2 895 65 Pancreas − − Liver − − No Endoscopic ultrasound W FNA − 3 2763 152 Neck LN − − Liver − ND No FNAB − 4 12,376 242 Neck LN + MD LN Liver + + No MD LN FNAB + Bone 5 4652 340 Neck LN + MD LN lung − − + Yes MD LN FNAB + Bone 6 50,948 3287 Bone + − Liver − + Yes FNAB + 7 4359 22.5 − + Lung Liver − ND No FNAB + 8a 7962 618 Thyroid 6.5-cm thyroid nodule Lung Liver − + Yes Adrenal Adrenal Bone 9 31,092 1939 MD LN + MD LN lung Liver + + No Lung FNAB + Bone 10 101,083 2203 Bone − − Spleen − + Yes Liver 11 14,256 188 MD LN + MD LN − − ND No Lung FNAB + Lung 12 59,979 650 Neck LN + MD LN Pancreas + + No MD LN FNAB + Lung Liver Lung Kidney Bone 13 795 16 Neck LN + MD LN Pancreas + + No MD LN FNAB + Lung Kidney Lung Liver Bone 14 564 9.4 Neck LN + − − − ND No FNAB + Altered plan: detection of a new metastatic site of disease, resulting in modification in follow-up interval, examinations, or treatment. Abbreviations: −, negative; + positive; MD, mediastinal; ND, not done; W FNA, with fine needle aspiration. a Patient included at diagnosis of medullary thyroid carcinoma. View Large Figure 1. View largeDownload slide (a) Patient with LNs in 68Ga PET/CT (arrows) and ultrasound, in which fine-needle aspiration biopsy confirmed disease. (b) A true-positive result for 68Ga PET/CT. (c) Patient with positive 68Ga PET/CT (arrow) and negative ultrasound. (d) A false-positive result for 68Ga PET/CT. (e) Patient with negative 68Ga PET/CT and positive neck ultrasound (f) and FNAB; a false-negative 68Ga PET/CT result. Figure 1. View largeDownload slide (a) Patient with LNs in 68Ga PET/CT (arrows) and ultrasound, in which fine-needle aspiration biopsy confirmed disease. (b) A true-positive result for 68Ga PET/CT. (c) Patient with positive 68Ga PET/CT (arrow) and negative ultrasound. (d) A false-positive result for 68Ga PET/CT. (e) Patient with negative 68Ga PET/CT and positive neck ultrasound (f) and FNAB; a false-negative 68Ga PET/CT result. Analysis of liver lesions by three-phase contrast-enhanced CT or MRI of the abdomen and 68Ga PET/CT demonstrated disease in 11 of 14 patients by abdominal CT or MRI and in only 1 patient by 68Ga PET/CT. No false-positive lesions were identified by 68Ga PET/CT (Fig. 2). Analysis of lung lesions in this group of patients also revealed superiority of CT; seven patients had disease detected by chest CT and four patients by 68Ga PET/CT. Further analysis of these findings revealed that the size of the lesions may influence the 68Ga-DOTATATE uptake; all false-negative cases (true lesions in CT with no 68Ga-DOTATATE uptake) were in nodules <1 cm (Fig. 3). Detection of mediastinal LNs was similar by both 68Ga PET/CT and chest CT (6 of 14 patients). Regarding bone metastases, bone scan identified lesions in 4 of 14 patients and 68Ga PET/CT in 9 of 14 patients. All of these lesions were confirmed by MRI, and there were no lesions detected only by MRI (Fig. 4). In summary, in group 2, 68Ga PET/CT sensitivity was 56% to detect cervical metastases, 9% for liver metastasis, and 57% for lung metastasis. However, 68Ga PET/CT sensitivity was superior to bone scan in detecting bone lesions. Figure 2. View largeDownload slide Images demonstrate a variable pattern of 68Ga-DOTATATE uptake in hepatic lesions. (a, b) A lesion in CT [arrow in (a)] with mild uptake [arrow in (b)] presenting as a true positive. (c, d) A lesion in CT (c) without uptake shown by the arrow (d) presenting as a false negative. (e, f) A normal liver with normal radiopharmaceutical uptake, a true negative. No false-positive liver images of 68Ga-DOTATATE PET/CT were found in this study. Figure 2. View largeDownload slide Images demonstrate a variable pattern of 68Ga-DOTATATE uptake in hepatic lesions. (a, b) A lesion in CT [arrow in (a)] with mild uptake [arrow in (b)] presenting as a true positive. (c, d) A lesion in CT (c) without uptake shown by the arrow (d) presenting as a false negative. (e, f) A normal liver with normal radiopharmaceutical uptake, a true negative. No false-positive liver images of 68Ga-DOTATATE PET/CT were found in this study. Figure 3. View largeDownload slide Images demonstrate lung nodules with 68Ga-DOTATATE uptake: (a, b) a true-positive result and lung nodules in CT [arrows in (a)] with 68Ga-DOTATATE uptake [arrows in (b)]; (c, d) a micronodule in CT [arrow in (c)] with no 68Ga-DOTATATE uptake (d); a false-negative result. Note in images (a) and (b) that the larger nodules in the left lung present mild uptake, whereas the smaller nodule in the right lung presents a faint uptake. Figure 3. View largeDownload slide Images demonstrate lung nodules with 68Ga-DOTATATE uptake: (a, b) a true-positive result and lung nodules in CT [arrows in (a)] with 68Ga-DOTATATE uptake [arrows in (b)]; (c, d) a micronodule in CT [arrow in (c)] with no 68Ga-DOTATATE uptake (d); a false-negative result. Note in images (a) and (b) that the larger nodules in the left lung present mild uptake, whereas the smaller nodule in the right lung presents a faint uptake. Figure 4. View largeDownload slide Images demonstrate a positive bone lesion in the second left rib detected by both (a) bone scan and (b–d) 68Ga-DOTATATE PET/CT. Arrows indicate the same lesion in bone scan (a) and in 68Ga-DOTATATE PET/CT (b–d). In another patient, a positive bone lesion in the lumbar spine detected by (f–h) 68Ga-DOTATATE PET/CT but not seen in the (e) bone scan. Figure 4. View largeDownload slide Images demonstrate a positive bone lesion in the second left rib detected by both (a) bone scan and (b–d) 68Ga-DOTATATE PET/CT. Arrows indicate the same lesion in bone scan (a) and in 68Ga-DOTATATE PET/CT (b–d). In another patient, a positive bone lesion in the lumbar spine detected by (f–h) 68Ga-DOTATATE PET/CT but not seen in the (e) bone scan. Table 3 demonstrates the sensitivity and specificity of 68Ga PET/CT for each site of disease for the entire cohort of patients with MTC (N = 30). Our findings indicate that 68Ga PET/CT was superior to bone scan in detecting bone metastatic lesions and similar to chest CT in detecting mediastinal LNs. Regarding other sites commonly involved by MTC, 68Ga PET/CT was less accurate than recommended imaging studies. Table 3. Sensitivity and Specificity of Ga68-DOTATATE PET/CT for Each Disease Site for the Entire Cohort of Patients With MTC (N = 30) Disease Site Sensitivity, % Specificity, % Reference Standard Best Image Study Cervical LNs 63 93 Cytology or pathology or negative ultrasound Ultrasound Mediastinal LNs 100 100 CT Ga68 PET/CT = CT Liver 9 100 CT or MRI CT or MRI Lung 63 100 CT CT Bone 100 95 Bone scan/MRI Ga68 PET/CT bone scan (sensitivity, 50%; specificity, 90%) Disease Site Sensitivity, % Specificity, % Reference Standard Best Image Study Cervical LNs 63 93 Cytology or pathology or negative ultrasound Ultrasound Mediastinal LNs 100 100 CT Ga68 PET/CT = CT Liver 9 100 CT or MRI CT or MRI Lung 63 100 CT CT Bone 100 95 Bone scan/MRI Ga68 PET/CT bone scan (sensitivity, 50%; specificity, 90%) View Large Table 3. Sensitivity and Specificity of Ga68-DOTATATE PET/CT for Each Disease Site for the Entire Cohort of Patients With MTC (N = 30) Disease Site Sensitivity, % Specificity, % Reference Standard Best Image Study Cervical LNs 63 93 Cytology or pathology or negative ultrasound Ultrasound Mediastinal LNs 100 100 CT Ga68 PET/CT = CT Liver 9 100 CT or MRI CT or MRI Lung 63 100 CT CT Bone 100 95 Bone scan/MRI Ga68 PET/CT bone scan (sensitivity, 50%; specificity, 90%) Disease Site Sensitivity, % Specificity, % Reference Standard Best Image Study Cervical LNs 63 93 Cytology or pathology or negative ultrasound Ultrasound Mediastinal LNs 100 100 CT Ga68 PET/CT = CT Liver 9 100 CT or MRI CT or MRI Lung 63 100 CT CT Bone 100 95 Bone scan/MRI Ga68 PET/CT bone scan (sensitivity, 50%; specificity, 90%) View Large The analysis of the 68Ga-DOTATATE uptake in each metastatic lesion detected by 68Ga PET/CT showed that the median SUV max for all the true-positives lesions was 6.4 (range, 1.1 to 22.6), varying according to metastatic sites [5.5 (range, 1.8 to 22.6) for LNs, 10.3 (range, 2.3 to 19.2) for bone, 1.6 (range, 1.1 to 2.1) for lung, and 11.9 in the only liver metastasis]. For LNs, the median SUV max of true-positive lesions was significantly greater than the SUV max of false-positive lesions [5.5 (range, 1.8 to 22.6) vs 1.9 (range, 1.3 to 2.5), P = 0.0001]. The LN SUV max threshold of 3.1 was found to optimize sensibility (78%) and specificity (100%), and all lesions with the LN SUV max lower than 1.8 were negative for disease (sensitivity, 100%; specificity, 58.3%). The 68Ga PET/CT results led to a change of management in 1 of the 16 patients (6.25%) in group 1 and 5 (35.7%) of the 14 patients in group 2. All patients from group 2 had a bone lesion detected by 68Ga PET/CT that was missed by a bone scan. The change of management was defined as initiation of treatments such as bone antiresorptives, radiation therapy, or a change of radiological workup during follow-up. Table 4 demonstrates the SSTR and Ki-67 immunohistochemical analysis of the available tumors (primary thyroid tumor and metastases) of 5 patients from group 1 and 11 patients from group 2. In nine patients, immunohistochemical analysis of primary or metastatic tumor did not show expression of SSTR2, SSTR3, and SSTR5; seven (78%) of these patients presented with disease detected by 68Ga PET/CT. From seven patients with expression of SSTRs, five patients demonstrated 68Ga PET/CT uptake (71.4%). Expression of SSTR2 was observed in five patients, weak expression in primary tumor in three patients (one patient with bone uptake in 68Ga PET/CT, one with no uptake and no disease identified by other studies, and one with no uptake in 68Ga PET/CT but with metastatic disease involving lung, liver, and cervical LNs), and moderate SSTR2 immunoreactivity (IR) in one patient with 68Ga PET/CT uptake in a cervical LN. The fifth patient had SSTR 2 expression in an adrenal tumor (pheochromocytoma), for which 68Ga PET/CT showed uptake in bone and adrenal lesions. Interestingly, this same patient had liver metastases not detected by 68Ga PET/CT, and biopsy of one of the liver lesions was negative for SSTR2 but had strong expression for SSTR5. Three patients had tumor samples with IR for SSTR3; two of these patients had disease detected by 68Ga PET/CT, and one patient had no disease detected by any imaging studies. Two patients had tumor samples with IR for SSTR5: one patient with strong IR in a liver metastasis with no uptake by 68Ga PET/CT and one with weak IR in a cervical LN with uptake in 68Ga PET/CT but that also showed IR for SSTR2. Ki-67 staining inversely correlated with 68Ga-DOTATATE PET/CT findings; mean Ki-67 index in tumor samples with 68Ga-DOTATATE uptake was 3.5% compared with 42% in tumors with no uptake. Table 4. SSRT and Ki-67 Immunohistochemical Analysis of Available Tumors Patient No. Group Tumor Ki-67, % SSTR2a SSTR3a SSTR5a 68Ga PET/CT Uptake Sites of Confirmed Disease 1 2 Thyroid 3 0 0 0 Liver, bone Liver, bone 2 2 Thyroid 80 0 0 0 — Liver 5 2 Thyroid 0.6 0 0 0 Neck LN, mediastinal LN, bone Lung, neck LN, mediastinal LNs, bone Tibia metastasis 1.6 0 0 0 Breast metastasis 3.6 0 0 0 6 2 Bone metastasis 1.2 0 0 0 Bone Liver, neck LN, bone 7 2 Thyroid 2.4 1 0 0 — Lung, liver, neck LN Neck LN 16.4 1 0 0 Liver metastasis 12 0 0 0 Pheo 0.6 0 0 0 8 2 Liver metastasis 30 0 0 3 Pheo, bone Lung, liver, pheo, bone Right pheo 0.8 2 0 0 Left pheo 1.8 1 0 0 9 2 Neck LNs 4.3 0 0 0 Lung, neck LN, mediastinal LN, bone Lung, liver, neck LN, mediastinal LN, bone 10 2 Thyroid 6 1 0 0 Bone Liver, bone 11 2 Thyroid 10 0 0 0 Lung, neck LN, mediastinal LN Lung, neck LN, mediastinal LN 12 2 Neck LN 0.75 0 0 0 Lung, neck LN, mediastinal LN, bone Lung, liver, pancreas, neck LN, mediastinal LN, bone 13 2 Thyroid 7.3 0 1 0 Lung, neck LN, mediastinal LN, bone Lung, liver, kidney, pancreas mediastinal LN, bone Mediastinal LN 8 0 0 0 19 1 Thyroid 2.8 1 2 0 — — 21 1 Neck LN 1.4 0 0 1 Neck LN Neck LN (cell block) 0 2 0 0 Neck LN 23 1 Thyroid 0.8 0 0 0 Neck LN Neck LN 25 1 Neck LN 1.8 0 0 0 — — 30 1 Thyroid 0.4 0 1 0 Bone Bone Patient No. Group Tumor Ki-67, % SSTR2a SSTR3a SSTR5a 68Ga PET/CT Uptake Sites of Confirmed Disease 1 2 Thyroid 3 0 0 0 Liver, bone Liver, bone 2 2 Thyroid 80 0 0 0 — Liver 5 2 Thyroid 0.6 0 0 0 Neck LN, mediastinal LN, bone Lung, neck LN, mediastinal LNs, bone Tibia metastasis 1.6 0 0 0 Breast metastasis 3.6 0 0 0 6 2 Bone metastasis 1.2 0 0 0 Bone Liver, neck LN, bone 7 2 Thyroid 2.4 1 0 0 — Lung, liver, neck LN Neck LN 16.4 1 0 0 Liver metastasis 12 0 0 0 Pheo 0.6 0 0 0 8 2 Liver metastasis 30 0 0 3 Pheo, bone Lung, liver, pheo, bone Right pheo 0.8 2 0 0 Left pheo 1.8 1 0 0 9 2 Neck LNs 4.3 0 0 0 Lung, neck LN, mediastinal LN, bone Lung, liver, neck LN, mediastinal LN, bone 10 2 Thyroid 6 1 0 0 Bone Liver, bone 11 2 Thyroid 10 0 0 0 Lung, neck LN, mediastinal LN Lung, neck LN, mediastinal LN 12 2 Neck LN 0.75 0 0 0 Lung, neck LN, mediastinal LN, bone Lung, liver, pancreas, neck LN, mediastinal LN, bone 13 2 Thyroid 7.3 0 1 0 Lung, neck LN, mediastinal LN, bone Lung, liver, kidney, pancreas mediastinal LN, bone Mediastinal LN 8 0 0 0 19 1 Thyroid 2.8 1 2 0 — — 21 1 Neck LN 1.4 0 0 1 Neck LN Neck LN (cell block) 0 2 0 0 Neck LN 23 1 Thyroid 0.8 0 0 0 Neck LN Neck LN 25 1 Neck LN 1.8 0 0 0 — — 30 1 Thyroid 0.4 0 1 0 Bone Bone Abbreviation: pheo, pheochromocytoma. a Stained slides examined according to criteria defined by the Clinical and Laboratory Standards Institute (25): score 0 (cases that did not express the marker in question were considered negative in any cell of interest), score 1 (weak positive/borderline cases showed weak staining in <10% of the cells of interest), score 2 (cases with moderate to strong staining between 10% and 50% of the cells of interest were considered positive), and score 3 (cases with moderate to strong staining were considered positive in >50% of the cells of interest). View Large Table 4. SSRT and Ki-67 Immunohistochemical Analysis of Available Tumors Patient No. Group Tumor Ki-67, % SSTR2a SSTR3a SSTR5a 68Ga PET/CT Uptake Sites of Confirmed Disease 1 2 Thyroid 3 0 0 0 Liver, bone Liver, bone 2 2 Thyroid 80 0 0 0 — Liver 5 2 Thyroid 0.6 0 0 0 Neck LN, mediastinal LN, bone Lung, neck LN, mediastinal LNs, bone Tibia metastasis 1.6 0 0 0 Breast metastasis 3.6 0 0 0 6 2 Bone metastasis 1.2 0 0 0 Bone Liver, neck LN, bone 7 2 Thyroid 2.4 1 0 0 — Lung, liver, neck LN Neck LN 16.4 1 0 0 Liver metastasis 12 0 0 0 Pheo 0.6 0 0 0 8 2 Liver metastasis 30 0 0 3 Pheo, bone Lung, liver, pheo, bone Right pheo 0.8 2 0 0 Left pheo 1.8 1 0 0 9 2 Neck LNs 4.3 0 0 0 Lung, neck LN, mediastinal LN, bone Lung, liver, neck LN, mediastinal LN, bone 10 2 Thyroid 6 1 0 0 Bone Liver, bone 11 2 Thyroid 10 0 0 0 Lung, neck LN, mediastinal LN Lung, neck LN, mediastinal LN 12 2 Neck LN 0.75 0 0 0 Lung, neck LN, mediastinal LN, bone Lung, liver, pancreas, neck LN, mediastinal LN, bone 13 2 Thyroid 7.3 0 1 0 Lung, neck LN, mediastinal LN, bone Lung, liver, kidney, pancreas mediastinal LN, bone Mediastinal LN 8 0 0 0 19 1 Thyroid 2.8 1 2 0 — — 21 1 Neck LN 1.4 0 0 1 Neck LN Neck LN (cell block) 0 2 0 0 Neck LN 23 1 Thyroid 0.8 0 0 0 Neck LN Neck LN 25 1 Neck LN 1.8 0 0 0 — — 30 1 Thyroid 0.4 0 1 0 Bone Bone Patient No. Group Tumor Ki-67, % SSTR2a SSTR3a SSTR5a 68Ga PET/CT Uptake Sites of Confirmed Disease 1 2 Thyroid 3 0 0 0 Liver, bone Liver, bone 2 2 Thyroid 80 0 0 0 — Liver 5 2 Thyroid 0.6 0 0 0 Neck LN, mediastinal LN, bone Lung, neck LN, mediastinal LNs, bone Tibia metastasis 1.6 0 0 0 Breast metastasis 3.6 0 0 0 6 2 Bone metastasis 1.2 0 0 0 Bone Liver, neck LN, bone 7 2 Thyroid 2.4 1 0 0 — Lung, liver, neck LN Neck LN 16.4 1 0 0 Liver metastasis 12 0 0 0 Pheo 0.6 0 0 0 8 2 Liver metastasis 30 0 0 3 Pheo, bone Lung, liver, pheo, bone Right pheo 0.8 2 0 0 Left pheo 1.8 1 0 0 9 2 Neck LNs 4.3 0 0 0 Lung, neck LN, mediastinal LN, bone Lung, liver, neck LN, mediastinal LN, bone 10 2 Thyroid 6 1 0 0 Bone Liver, bone 11 2 Thyroid 10 0 0 0 Lung, neck LN, mediastinal LN Lung, neck LN, mediastinal LN 12 2 Neck LN 0.75 0 0 0 Lung, neck LN, mediastinal LN, bone Lung, liver, pancreas, neck LN, mediastinal LN, bone 13 2 Thyroid 7.3 0 1 0 Lung, neck LN, mediastinal LN, bone Lung, liver, kidney, pancreas mediastinal LN, bone Mediastinal LN 8 0 0 0 19 1 Thyroid 2.8 1 2 0 — — 21 1 Neck LN 1.4 0 0 1 Neck LN Neck LN (cell block) 0 2 0 0 Neck LN 23 1 Thyroid 0.8 0 0 0 Neck LN Neck LN 25 1 Neck LN 1.8 0 0 0 — — 30 1 Thyroid 0.4 0 1 0 Bone Bone Abbreviation: pheo, pheochromocytoma. a Stained slides examined according to criteria defined by the Clinical and Laboratory Standards Institute (25): score 0 (cases that did not express the marker in question were considered negative in any cell of interest), score 1 (weak positive/borderline cases showed weak staining in <10% of the cells of interest), score 2 (cases with moderate to strong staining between 10% and 50% of the cells of interest were considered positive), and score 3 (cases with moderate to strong staining were considered positive in >50% of the cells of interest). View Large Discussion Despite optimal surgical treatment, residual and recurrent disease is frequent in MTC. During postoperative follow-up, patients with serum Ctn levels <150 pg/mL have disease almost always confined to LNs in the neck; therefore, the recommendation from the American Thyroid Association is to follow these patients with a neck ultrasound (2). Patients with serum Ctn >150 pg/mL have a higher risk for distant metastatic disease, and radiological evaluation should also include contrast-enhanced chest CT for detection of lung and mediastinal LN metastases, three-phase contrast-enhanced multidetector liver CT or contrast-enhanced MRI to detect liver metastases, bone scintigraphy, and axial MRI to detect bone metastases (2, 4, 5). A more sensitive test that detects lesions in patients with biochemical disease or a test that includes evaluation of all disease sites in patients with metastatic MTC would be ideal for those who require lifelong radiological surveillance. 18F-FDG PET/CT is useful in patients with aggressive disease; however, most patients with MTC, even with metastatic disease, tend to have an indolent course (7, 8). As MTC is a neuroendocrine tumor that expresses SSTR and as 68Ga PET/CT has been shown to be extremely useful in other neuroendocrine tumors (28), several studies have investigated the role of 68Ga PET/CT in MTC with promising results. However, most of these studies were retrospective and did not include a systematic comparison with current recommended imaging studies at each disease site (13–18). In the study by Conry et al. (15) with 18 patients with sporadic MTC (6 with occult disease and 12 with metastatic disease), 68Ga PET/CT showed at least one site of metastatic disease in 13 of the 18 patients, and the reported overall sensitivity was 72.2% (95% CI, 46.4% to 89.3%). Recently, Yamaga et al. (18) compared prospectively the detection rate of 68Ga PET/CT with 11In-octreotide single photon emission CT/CT and conventional imaging in 15 patients with MTC (1 with occult disease and 14 with metastatic disease). The sensitivity and accuracy of 68Ga PET/CT reported was 100% and 93%, respectively, similar to the conventional images, and 68Ga PET/CT was superior to bone scan and bone MRI in the identification of bone lesions. However, the conventional images besides chest CT and neck ultrasound or CT were done only if clinically indicated; abdominal evaluation with CT or MRI was performed in only 53.3% of the patients and bone MRI in 40% of the patients. As most of the studies were retrospective and did not uniformly include all recommended imaging modalities to evaluate each disease site, it is unclear whether a negative 68Ga PET/CT finding was also negative by the recommended imaging study for each site (13–18). In this study, the primary objective was to investigate the sensitivity and specificity of 68Ga PET/CT in detecting disease in patients with no localization of disease prior to study entry (biochemical disease) and to analyze whether 68Ga PET/CT would be a better modality to evaluate extent of disease in metastatic patients, to eventually substitute the conventional imaging studies for a unique whole-body imaging modality. A second objective was to analyze the SSTR expression in the thyroid tumor or metastases by immunohistochemistry and to correlate it with the 68Ga PET/CT findings. We included 16 patients with biochemical disease and 14 patients with metastatic MTC and performed 68Ga PET/CT in addition to other recommended imaging studies. In the cohort of patients with biochemical disease, eight patients had localization of the disease site: six patients had cervical LN metastases (all detected by ultrasound and three by 68Ga PET/CT), one patient had a hilar LN detected by chest CT and 68Ga PET/CT, and one patient had a right humerus lesion detected by bone scan and 68Ga PET/CT, which was confirmed by MRI. Further analysis of these patients according to Ctn levels demonstrated that all patients with Ctn <50 pg/mL had no detectable disease, whereas disease was detected in four of five patients (80%) with Ctn between 50 and 150 pg/mL (three patients with cervical LNs and one bone lesion) and four of seven patients (57%) with Ctn >150 pg/mL (three patients with cervical LN and one hilar LN). In accordance with the American Thyroid Association recommendations, ultrasound of the neck, especially when performed by an experienced physician, is the most sensitive and useful imaging in patients with biochemical disease. At the same time, our study showed that despite an extensive imaging workup, 43% of patients with Ctn >150 pg/mL had occult disease. In the group with metastatic disease, 68Ga PET/CT was clearly superior to bone scan in detecting bone lesions; it identified lesions in 9 of 14 patients (all confirmed by MRI), whereas bone scan identified lesions in 4 of 14 patients (sensitivity, 68Ga PET/CT 100% vs bone scan 44.4%). The Ctn and CEA level cutoff associated with detection of bone lesions only by 68Ga PET/CT was 30,902 pg/mL and 242 ng/mL, respectively, suggesting that patients with extensive disease would benefit from undergoing 68Ga PET/CT instead of bone scan to optimize disease detection. This finding could have an impact on disease management as bone lesions that are frequently associated with skeletal events and impairment of quality of life could be detected and treated earlier if indicated. For the other disease sites, 68Ga PET/CT was similar to chest CT in detecting mediastinal LNs and inferior to ultrasound, chest CT, and CT/MRI of the abdomen for detection of neck LNs, lung metastases, and liver metastases, respectively. The low sensitivity in detecting liver lesions was striking and different from what was observed in patients with other neuroendocrine tumors, specifically gastroenteropancreatic tumors (28); this may be related to a high basal radiopharmaceutical uptake in the liver, which could impair the detection of lesions or could be related to differences in the biology of the tumor with a lower expression of the SSTR. In fact, the two samples of liver metastases analyzed for SSTR expression identified one with absent IR for SSTR2, SSTR3, and SSTR5 and the other with IR only for SSTR5, which is a possible reason for not being detected by 68Ga-DOTATATE. Similarly, sensitivity was low in detecting lung nodules; one explanation would be the lower sensitivity in detecting lesions <1 cm (Fig. 3). Alternatively, it could be related to expression of SSTR and the profile of affinity of the somatostatin analogue used in our study (DOTATATE), which has affinity to SSTR2. Most of the studies investigating the role of 68Ga somatostatin analogue PET/CT in MTC used DOTATATE and therefore are comparable, except for the study by Treglia et al. (13), which used DOTATOC in 4 patients and DOTANOC in 14 patients. Despite a wider SSTR affinity of DOTATOC (SSTR2 and SSTR5) and DOTANOC (SSTR2, SSTR3, and SSTR5), the sensitivity of 68Ga PET/CT was 33% vs 72% with 18F-DOPA PET/CT. Up to now, 18F-DOPA PET/CT seemed to be the most useful functional imaging method for detection of locoregional and distant metastatic MTC. Several studies have compared 18F-DOPA PET/CT with 18F-FDG PET/CT in MTC, showing greater sensitivity of 18F-DOPA PET/CT (10, 12). The better sensitivity for 18F-DOPA PET/CT was also observed in the study by Treglia et al. (13) that compared 18F-DOPA PET/CT, 68Ga PET/CT, and 18F-FDG PET (72%, 33%, and 17%, respectively. Expression of SSTR, performed by immunohistochemical analysis of SSTR2, SSTR3, and SSTR5, was observed in 44% of analyzed tumor samples. This analysis was not particularly useful to identify which patients would have a positive 68Ga PET/CT study as 68Ga-DOTATATE uptake was observed in patients with and without SSTR expression. From the 16 patients with tumor samples (primary thyroid tumor and/or metastases) available for analysis, 9 patients had tumors with absent IR for SSTR2, SSTR3, and SSTR5 (56%) and 7 patients had tumor samples expressing SSTR2 (5/7), SSTR3 (3/7), and SSTR5 (2/7). 68Ga-DOTATATE uptake was observed in seven of nine (78%) patients with absent IR and in 62.5% of patients with SSTR2, SSTR3, and SSTR5 IR. On the other hand, Ki-67 staining was inversely correlated with 68Ga-DOTATATE uptake, suggesting that 68Ga PET/CT has better sensitivity in low proliferative tumors. In this study, the analysis of SUV max was useful in distinguishing benign from malignant LN lesions. An SUV max >3.1 was associated with metastatic disease (specificity of 100%), whereas all LNs with an SUV max <1.8 were not. These results suggest that FNAB could be spared in LNs with low 68Ga-DOTATATE uptake and no ultrasound suspicious findings. In summary, this study provided a systematic analysis of the efficacy of 68Ga PET/CT in detecting disease at commonly involved sites by MTC, demonstrating that it is inferior to neck ultrasound, chest CT, and CT/MRI of the abdomen but superior to bone scan in detecting bone metastases. Conclusion 68Ga-DOTATATE PET/CT does not provide optimal whole-body imaging as a single procedure in patients with biochemical or metastatic MTC. The low sensitivity of detection in cervical LNs, lung metastases, and liver metastases requires additional imaging modalities for these common metastatic MTC sites. However, it was superior to bone scan and equivalent to MRI in identifying bone lesions, suggesting that it could be a substitute for bone scan and MRI. Abbreviations: Abbreviations: 18F-DOPA 6-fluoro-(18F)-L-3,4-dihydroxyphenylalanine 18F-FDG deoxy-glucose radiolabeled with fluorine-18 68Ga gallium-68 CEA carcinoembryonic antigen Ctn calcitonin FNAB fine-needle aspiration biopsy IR immunoreactivity LN lymph node MTC medullary thyroid cancer PET positron emission tomography SSTR somatostatin receptor SUV max maximum standardized uptake Acknowledgments Financial Support: Supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (2013/03876-4, to A.O.H.). Disclosure Summary: The authors have nothing to disclose. References 1. Pelizzo MR , Boschin IM , Bernante P , Toniato A , Piotto A , Pagetta C , Nibale O , Rampin L , Muzzio PC , Rubello D . Natural history, diagnosis, treatment and outcome of medullary thyroid cancer: 37 years experience on 157 patients . Eur J Surg Oncol . 2007 ; 33 ( 4 ): 493 – 497 . Google Scholar Crossref Search ADS PubMed 2. 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Journal

Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Sep 1, 2018

References

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