Benign Pathologies and Variants with 68Ga-Dotatate Uptake in PET/CT Studies

Original

Benign Pathologies and Variants with 68ga-Dotatate Uptake in PET/CT Studies

L. Servente, C. Bianco, V. Gigiret and O. Alonso

Centro Uruguayo de Imagenología Molecular, CUDIM, Montevideo, Uruguay

Abstract Purpose: To evaluate the physiological, anatomical variants and benign lesions in positron emission computed tomography (PET/CT) studies with 68Ga-DOTATATE. Materials and methods: We retrospectively reviewed reports of 68Ga-DOTATATE PET/CT scans and selected those that contained words in the report related to anatomical, physiological variants and benign tumors. The degree of 68Ga-DOTATATE uptake was qualitatively and quantitatively evaluated by measuring the standardized uptake max value (SUVmax value). The anatomical location, SUVmax value and morphological computed tomography (CT) image findings were recorded. All cases had a clinical and imaging follow-up. Results: From a total of 772 PET/CT reports, we obtained 28 patients with 33 benign variants or tumors, 14 females and 14 males with a median age of 63 years. Uptake patterns were classified into four groups: anatomic and physiological variants (n = 15), dependent on osteoblastic activity (n=4), dependent on inflammatory activity (n=10) and non-neuroendocrine benign tumors (n=4). Discussion: Somatostatin receptors are overexpressed not only in the neuroendocrine system but also in other tissues. Physiological, anatomical variants and benign tumors expressing these receptors may be misleading. Conclusion: Physiological variants and benign lesions (tumor and inflammatory lesions) can accumulate 68Ga-DOT- ATATE since their tissues can express somatostatin receptors. The semiological analysis of the tomographic component of this hybrid imaging method enhances the diagnostic efficacy, optimizing PET/CT study performance. © 2017 Sociedad Argentina de Radiología. Published by Elsevier Spain, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Keywords: 68-Gallium DOTATATE; Positron emission tomography/computed tomography; Somatostatin receptors; Hy- brid imaging

Introduction The biodistribution of this tracer shows the highest uptake in the spleen, followed by adrenal glands, the pituitary gland Positron emission tomography combined with computer to- and the kidney. In decreasing order of uptake intensity, these mography (PET/CT) using 68 Gallium (68Ga)-DOTATATE, a are followed by the liver, salivary glands and the thyroid6,7. radioactively labeled somatostatin (SST) analog, is a first-line The uptake in the stomach, small and large bowel is variable hybrid imaging method for the evaluation of patients with because of neuroendocrine cell hyperplasia. In the pancreas, well-differentiated neuroendocrine tumors (NET) for local- the presence of a larger number of cells expressing soma- izing the primary tumor, staging-restaging tumors and se- tostatin receptors has been reported, mainly in the pancreatic lecting patients for radionuclide therapy1-4. This method has head and in the uncinate process6,8,9. also been used in the imaging of granulomatous and auto- As there is an overlap in uptake intensity between benign and immune conditions as well as of other non-neuroendocrine malignant lesions, it is essential to know the anatomic, physi- tumors, although in these cases it cannot be considered as ologic variants and benign entities that most frequently occur the first-choice functional imaging modality3,5. as findings unrelated to the underlying tumor. Somatostatin receptors are distributed in the whole body. The aim of this study is to consider the physiologic, anatomic Normal tissues and benign diseases (benign tumors or in- variants and benign lesions in PET/CT scans with 68Ga-DOT- flammatory conditions) can also express these receptors and ATATE that may constitute potential sources of diagnostic error. therefore can also show increased uptake of this tracer.

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Materials and methods droma, inflammatory, uncinate, accessory spleen, splenosis, prostatitis, fracture, accessory, reactive, dysplasia, fibrous. Patients gave their written informed consent authorizing the use of their scans and clinical data for scientific purposes; Image acquisition data were anonymized. Because of its retrospective design, 68Ga-DOTATATE was injected at a dose of 2.5 MBq/kg of the study was not submitted to the Ethics Committee. weight. At 30 minutes post-injection, 3D images were ac- quired by PET/CT with and without tomography attenuation Selection of scans correction on 16- and 64-slice General Electric (GE) hybrid We retrospectively reviewed a total of 772 reports of 68Ga- scanners (Discovery STE and 690 Discovery, respectively). DOTATATE PET/TC scans performed to 639 patients between Images were recorded from the skull to the middle third of June 2011 and June 2016. A search was performed in the site the femoral shaft for 120 seconds/bed for the STE Discovery database for the following keywords mentioned in reports: scanner and for 90 seconds/bed for the 690 Discovery scan- hemangioma, angioma, schwannoma, meningioma, enchon- ner. Computed tomography (CT) was performed with 80-180

Table 1: Description of indication, gender, age, SUVmax and findings.

Patient # FINDING SUV 1 SUV 2,3 AGE GENDER INDICATION

1 Paget 6.4 79 M Prostate cancer 2 Fracture 6.7 34 M Oncogenic osteomalacia 3 Echondroma 3.8 53 F NETUP 4 Accessory spleen 18.8 65 F Gastrointestinal NET 5 Accessory spleen 14 60 M NETUP 6 Accessory spleen 17.4 13 M Gastrointestinal NET 7 Splenosis 21 70 F Pancreatic NET 8 Splenosis 10 56 F Pancreatic NET 9 Duodenum variant 10 44 M Adrenal carcinoma 10 Pancreas variant 12.5 21 M Multicenter ganglioneuroma, MEN syndrome 11 Pancreas variant 9.6 70 F Gastrointestinal NET 12 Pancreas variant/accessory spleen 8.3 13.1 56 F Insulinoma 13 Uterine uptake 4.4 63 F Gastrointestinal NET 14 Uterine uptake 5.7 44 F NETUP 15 Uterine uptake 4.6 76 F Pancreatic NET 16 Uterine uptake/ degenerative disc disease 9.1 6.7 54 F NETUP 17 Bone hemangioma 7.9 51 M Gastrointestinal NET 18 Bone hemangioma 6.6 57 M Prostate cancer 19 Hemangioma/fracture/inflammatory 3.9 4.3/4.1 74 F Medullary thyroid carcinoma 20 Lymph node chronic inflammation 5.5 41 M Mediastinal adenopathies 21 Lymph node chronic inflammation 3.7 24 M Mediastinal adenopathies 22 Postoperative chronic inflammation 7.1 66 M Gastrointestinal NET 23 Degenerative disc disease/accessory spleen 6.1 22 65 F Invasive thymoma / insulinoma 24 Prostatitis 5.9 63 M Gastrointestinal NET 25 Cerebral falx meningioma 5.1 69 F Breast cancer, dural lesion 26 CPA meningioma 3.1 64 M NETUP 27 Cerebral falx meningioma 5.2 72 M Pulmonary NET 28 Left C4 schwannoma 8.8 69 F Gastrointestinal NET

Patient # 1 to 3: findings dependent on osteoblastic activity. Patients # 4 to 16: anatomic and physiological variants. Patients # 17 to 24: chronic inflammation. Patients # 25 to 28: non-neuroendocrine tumors. Ca: cancer; MEN 1: multiple endocrine neoplasia syndrome 1, NETUP: neuroendocrine tumor of unknown primary, NET: neuroendocrine tumor.

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mA, 120 kV (noise index, 20) and 3.75-mm slice thickness, experience in hybrid imaging. pitch 1,375 and table movement 27.5 mm per rotation for Data were recorded on uptake location, SUVmax value, the STE Discovery scanner and 17.5 mm per rotation for the oth- CT morphological image, age, gender, the reason for per- er scanner. Emission data were processed by iterative recon- forming the PET scan, the use of radiological contrast and struction (OSEM). All patients received an oral contrast agent follow-up. An electronic datasheet was prepared. and the intravenous (IV) contrast only when indicated by the Histological confirmatory tests were performed in two pa- imaging specialist. No late phase imaging was performed. tients: CT-guided aspiration in one patient and laparotomy in the other. In all other patients benign findings were con- Evaluation of images firmed by their clinical course and an imaging follow-up (CT, Axial, coronal and sagittal images as well as maximum-in- MRI or PET/CT) between 6 months and 6 years, with an aver- tensity projection (MIP) images were evaluated. The degree age follow-up of 1 year. of 68Ga-DOTATATE uptake was evaluated by a qualitative and quantitative visual analysis, with the latter being done by maximum standardized uptake value (SUVmax) measure- Results ment. Images were analyzed on GE Advantage workstations, versions 4.5 and 4.6. The scans were reviewed jointly by two Out of 772 reports performed during a 5-year period (corre- physicians: a nuclear medicine specialist and a radiology spe- sponding to 639 patients), 101 contained the keywords listed cialist, both certified and with 5 years’ experience in conven- above. Reports in which the keyword was unrelated to the tional nuclear medicine and radiology and at least 2 years’ aim of our study were excluded.

Figure 1 Patient # 10. Male, 21 years old. Left adrenal multicentric ganglioneuroma resection. Multiple endocrine neoplasia syndrome. Physiological variant of the uncinate process. (a) MIP PET image shows abdominal focal uptake (arrow), (b) Axial PET image and (c) fused PET/CT image with IV contrast: focal uptake in uncinate process (arrow) SUVmax 12.5.

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Figure 2 Patient # 8. Female, 56 years old, caudal pancreatectomy and splenectomy for NET of the pancreatic tail. PET/CT scan for restaging. Splenosis. (a) Axial fused PET/CT image shows focal uptake in splenosis (arrow). SUVmax 10, (B) MIP PET image shows focal uptake (arrow).

Figure 3 Patient # 3. Female, 53 years old. Carotid adenopathy resection. Pathology examination reported neuroendocrine metastasis. PET/CT for localization of the primary tumor. Finding: enchondroma. (a) Coronal CT: left femoral intertrochanteric lesion. (b) Axial CT, (c) Axial fused PET/CT scan, (d) axial PET image showing focal uptake (arrow).

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Figure 4 Patient # 24. Male, 63 years old. Diagnosis of NET of gastrointestinal origin stage IV at onset (liver, bone and multiple lymph node). Treatment with octeotride. Prostatitis. (a) Sagittal fused PET/CT image, (b) Sagittal PET image, (c) Axial fused PET/ CT image and (d) Axial PET image showing diffuse prostatic uptake (arrow) SUVmax 5.9.

As a result, 28 patients were included with 33 benign find- disease (n = 2), mediastinal adenopathy (n = 2), vertebral ings: 14 females and 14 males with an age range between 13 hemangioma (n = 3) and prostatitis. Finally, in fourth group, and 79 years old and a mean age of 63. which included benign non-neuroendocrine tumors (11%) Among the scans with benign findings (n=28), indications with high levels of somatostatin receptors, we found menin- were: initial staging and restaging in gastrointestinal NET gioma (n = 3) and schwannoma. (n=8), NET of unknown primary site (n=5), pancreatic NET All results are summarized in table 1 and some of the scans (n=5), patients with prostate cancer resistant to hormone of the series are shown in figs 1-5. therapy (n = 2) and others (n = 8): adrenal carcinoma, medullary thyroid carcinoma, multicentric ganglioneuroma, oncogenic osteomalacia, pulmonary NET and breast cancer. Discussion Among a total of 639 patients, 33 findings were detected, which accounts for a 5.1% rate of benign uptakes in scans We used Hofman’s classification 3 to group 68Ga-DOTATATE with this radiotracer. These findings can be classified into four uptakes unrelated to NET. The proposed classification groups groups; the first group shows anatomic and physiologic vari- these uptakes first as anatomic or physiologic variants: such ants (45%) including: accessory spleen (n = 5), splenosis (n as the uncinate process of the pancreas and the accessory = 2), uncinate and duodenum variants (n = 4) and uterine spleen, with or without a main spleen. Secondly, as depen- uptake (n = 4). The second group shows osteoblastic activity dent on osteoblastic activity: degenerative bone and joint dis- (11%): fractures (n = 2), enchondroma and Paget’s disease. ease, fracture repair, some bone tumors and growth plates. The third group shows inflammatory activity (33%): postop- Thirdly, as dependent on inflammatory activity: reactive lymph erative and post-radiation changes (n=2), degenerative disc nodes, prostatitis, post-radiation and postoperative changes

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and vertebral hemagioma10. Finally, as non-neuroendocrine tumors with high levels of somatostatin receptors: schwannoma, meningioma and mesenchymal tumor causing oncogenic osteomalacia11. Somatostatin is a peptide hormone present in the brain and peripheral organs, with a broad range of actions, mainly in- hibitory in nature. Somatostatin modulates neurotransmission in the central nervous system, regulates the release of growth hormone (GH), thyroid-stimulating hormone (TSH), adreno- corticotropic hormone (ACTH) and renin; regulates pancreatic endocrine and exocrine secretion, intestinal absorption, gastrointestinal motility, cell growth and activated immune cells function. These various actions are mediated by specific cell- surface receptors (SSTRs), of which 5 subtypes are known: SSTR 1, SSTR 2, SSTR 3, SSTR 4 and SSTR 5 with different tis- sue distribution. SSTRs subtypes 1 and 4 are more common in central nervous system, colon, liver, pancreas, lung, breast and skin tumors. SSTRs subtype 2 occur in NETs. SSTRs subtype 5 predominate in the pituitary, the smooth muscle, the gastrointestinal tract and medullary thyroid cancer3. The expression of these receptors, mainly SSTR 2, is increased in neuroendocrine cells. 6 These cells are derived from the neural crest and endoderm; they share common features with neuronal cells and are characterized by the produc- tion of neuropeptide hormones, neuromodulators and neu- rotransmitters, the presence of secretory granules and the absence of axons and synapses. Neuroendocrine cells are organized into glands (pituitary, parathyroid, adrenal medulla and paraganglion) or diffusely in the pancreas, intestinal and respiratory tracts, bile ducts, urogenital tract, thymus, thyroid (c cells) and skin. 68Ga-DOTATATE binds to receptors expressed in the cell membrane of SSTRs subtypes 2 and 57,12. The intensity of radiotracer uptake overlaps in benign and malignant lesions. In tissues such as bone and lymph nodes non-tributary to tumors, the standardized uptake value of malignant lesions overlaps with that of non-neoplastic lesions and benign tumors. Conversely, this does not occur in the liver parenchyma, the peritoneum and lymph nodes tributary to the primary tumor. In these tissues, SUVmax may more strongly contribute to differentiate benign from malignant lesions6,7. Knowledge of this group of findings with radiotracer uptake and of their morphological appearance with specific or Figure 5 Patient # 25. Female, 69 years old. Bilateral breast guiding features in the CT component enables differential cancer. Axilla (+), bone scan (+) in cranial vault. CT scan diagnosis. As a hybrid method, the PET/CT scan has a func- showed extra-axial lesions. MRI showed a left expansive ex- tional component, which for this tracer corresponds to the tra-axial parasagittal process in relation to the cerebral falx, presence of SST receptors, and a morphological component 15 mm in size with gadolinium enhancement. Differential di- based on CT imaging. For any radiotracer, this basic principle agnosis metastasis/meningioma. The lesion was interpreted is of paramount importance to avoid diagnostic errors, false as meningioma. (a) Sagittal fused PET/CT image, (b) Sagittal PET image: focal uptake (arrow) with SUVmax 5.1 and (c) positives or false negatives. Sagittal CT; the arrow points to the meningioma. In the literature, a detection of up to 14% of benign lesions

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has been reported in studies with 68Ga-DOTATATE6, while Conflicts of interest in our study this percentage was 5.1%. We think that the The authors declare no conflicts of interest, except for Dr. lower percentage of benign lesions found in our study may Alonso who declares as a potential conflict of interest being be due to biases and limitations inherent to the study design: coauthor of cited reference number 2. reports were reviewed but images were not reevaluated, the keyword may not exactly match that used in the report and, References finally, benign findings may only be reported when differen- 1. Ambrosini V, Nanni C, Fanti S. The use of gallium-68 labeled somatostatin receptors in PET/CT imaging. PET Clin. 2014;9:323---9. tial diagnosis is clinically relevant. 2. Alonso O, Rodríguez-Taroco M, Savio E, Bentancourt C, Gambini JP, En- gler H. (68)Ga-DOTATATE PET/CT in the evaluation of patients with neuroendocrine metastatic carcinoma of unknown origin. Ann Nucl Med. 2014;28:638---45. Conclusion 3. Hofman MS, Lau WF, Hicks RJ. Somatostatin receptor imaging with 68Ga DOTATATE PET/CT: clinical utility, normal patterns, pearls, and pitfalls in interpretation. Radiographics. 2015;35:500---16. Benign lesions (physiological, tumor and inflammatory le- 4. Haug AR, Cindea-Drimus R, Auernhammer CJ, Reincke M, Wängler B, sions) can accumulate 68Ga-DOTATATE because their tissues Uebleis C, et al. The role of 68Ga-DOTATATE PET/CT in suspected neuroendocrine tumors. J Nucl Med. 2012;53:1686---92. can express somatostatin receptors. 5. Sollini M, Erba PA, Fraternali A, Casali M, Di Paolo ML, Froio A, et al. PET In this study, we found 5.1% of benign lesions as findings and PET/CT with 68gallium-labeled somatostatin analogues in Non GEP- unrelated to the underlying disease. The semiological analysis NETs Tumors. ScientificWorldJournal. 2014;13:191---242. 6. Kuyumcu S, Özkan ZG, Sanli Y, Yilmaz E, Mudun A, Adalet I, et al. Physi- of the CT component of this hybrid technique provides diag- ological and tumoral uptake of (68) Ga-DOTATATE: standardized uptake nostic guidance, optimizing PET/CT scan performance. values and challenges in interpretation. Ann Nucl Med. 2013;27:538---45. 7. Moradi F, Jamali M, Barkhodari A, Schneider B, Chin F, Quon A, et al. Spectrum of 68Ga-DOTA TATE Uptake in Patients With Neuroendocrine Ethical responsibilities Tumors. Clin Nucl Med. 2016;41:281---7. 8. Castellucci P, Pou Ucha J, Fuccio C, Rubello D, Ambrosini V, Montini GC, et al. Incidence of increased 68Ga-DOTANOC uptake in the pancreatic head Protection of human subjects and animals. The authors in a large series of extrapancreatic NET patients studied with sequential declare that no experiments were performed on humans or PET/CT. J Nucl Med. 2011;52:886---90. 9. Kunikowska J, Królicki L, Pawlak D, Zerizer I, Mikołajczak R. Semiquan- animals for this investigation. titative Analysis and Characterization of Physiological Biodistribution of 68Ga-DOTATATE PET/CT. Clin Nucl Med. 2012;37:1052---7. 10. Brogsitter C1, Hofmockel T, Kotzerke J. (68) Ga DOTATATE uptake in ver- Confidentiality of data.The authors declare that they have tebral hemangioma. Clin Nucl Med. 2014;39:462---3. followed the protocols of their work center on the publica- 11. Agrawal K1, Bhadada S, Mittal BR, Shukla J, Sood A, Bhattacharya A, et tion of patient data. al. Comparison of 18F-FDG and 68Ga DOTATATE PET/CT in localization of tumor causing oncogenic osteomalacia. Clin Nucl Med. 2015;40:e6---10. 12. Wong KK, Waterfield RT, Marzola MC, Scarsbrook AF, Chowdhury FU, Right to privacy and informed consent. The authors de- Gross MD, et al. Contemporary nuclear medicine imaging of neuroendocrine tumours. Clin Radiol. 2012;67:1035---50. clare that no patient data appear in this article.

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