68Ga-DOTAGA-IAC PET/CT for Imaging Metastatic and Recurrent Adrenocortical Carcinoma A Case Series
Somit Pandey, PhD Scholar,* Rama Walia, MD,f Rajender Kumar, MD,* Sejal Chopra, PhD Scholar,*
Nivedita Rana, PhD,* Debajyoti Chatterjee, MD, DM,¿ Stanley Satz, PhD,§
Bhagwant Rai Mittal, MD, DNB,* and Jaya Shukla, PhD*
Abstract: Adrenocortical carcinoma (ACC) is a rare malignancy with a
prevalence of 1 to 2 cases/million/year. The diagnosis depends upon endo-
crine workup followed by imaging with CT, MRI, and 18F-FDG PET/CT.
The treatment includes surgical resection, debulking surgery, chemotherapy,
and radiotherapy. However, patients do not respond well to any of the avail-
able therapies. We present noninvasive imaging of histopathology-proven
ACC patients using 68Ga-DOTAGA-IAC PET/CT, specific for integrin
avB3. 68Ga-DOTAGA-IAC PET/CT 45 minutes after IV injection showed
a decent tumor-to-background ratio and could be used as a promising radio-
tracer for metastatic and recurrent ACC.
Received for publication June 8, 2022; revision accepted October 13, 2022.
From the *Department of Nuclear Medicine, Postgraduate Institute of Medical
Education and Research, Chandigarh, India; ¡ Department of Endocrinology,
Postgraduate Institute of Medical Education and Research, Chandigarh,
India; įDepartment of Histopathology, Postgraduate Institute of Medical Ed-
ucation and Research, Chandigarh, India; and §Advanced Innovative Part-
ners, Inc, Miami, FL.
Conflicts of interest and sources of funding: none declared.
This study was funded by the Advanced Innovative Partners, Inc, USA.
Correspondence to: Jaya Shukla, PhD, Department of Nuclear Medicine, Postgraduate
Institute of Medical Education and Research, Chandigarh 160012, India. E-mail:
shuklajaya@gmail.com.
Copyright C 2023 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0363-9762/23/4802-0e95
DOI: 10.1097/RLU.0000000000004497
REFERENCES
1. Fassnacht M, Dekkers OM, Else T, et al. European Society of Endocrinology
Clinical Practice Guidelines on the management of adrenocortical carcinoma
in adults, in collaboration with the European network for the study of adrenal
tumors. Eur J Endocrinol. 2018;179:G1-G46.
3. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med.
1971;285:1182-1186.
4. Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications
and therapeutic opportunities. Nat Rev Cancer. 2010;10:9-22.
5. Nussenbaum F, Herman IM. Tumor angiogenesis: insights and innovations.
J Oncol. 2010;2010:132641.
6. Weismann D, Briese J, Niemann J, et al. Osteopontin stimulates invasion of
NCI-h295 cells but is not associated with survival in adrenocortical carci-
noma. J Pathol. 2009;218:232-240.
7. Jang BS, Lim E, Hee Park S, et al. Radiolabeled high affinity peptidomimetic
antagonist selectively targets alpha(v)beta(3) receptor-positive tumor in mice.
Nucl Med Biol. 2007;34:363-370.
8. Kim YS, Nwe K, Milenic DE, et al. Synthesis and characterization of xxvß3-
targeting peptidomimetic chelate conjugates for PET and SPECT imaging.
Bioorg Med Chem Lett. 2012;22:5517-5522.
9. Baum RP, Kulkarni HR, Müller D, et al. First-in-human study demonstrating
tumor-angiogenesis by PET/CT imaging with (68)Ga-NODAGA-THERANOST,
a high-affinity peptidomimetic for avß3 integrin receptor targeting. Cancer
Biother Radiopharm. 2015;30:152-159.
FIGURE 1. A 55-year-old woman (patient 1) presented with metastatic ACC after right adrenalectomy in 2011 with hepatic lesions. She received 6 cycles of chemotherapy. 18F-FDG PET/CT revealed complete resolution of liver lesions. However, on follow-up, recurrent FDG-avid hepatic (segment VI) and thyroid (right lobe) lesions were noted. Post second-line chemotherapy, FDG-avid omental deposits, liver, and left second intercostal lesion suggested disease progression. Further, 68Ga-DOTAGA-IAC (79.92 MBq) PET/CT images were acquired with low-dose CT (120 keV, 40 mA). The MIP image of 68Ga-DOTAGA-IAC PET/CT showed physiological uptake in the lungs, liver, spleen, and excretion via kidneys (A). Transaxial PET (B), CT (C), and fused PET/CT (D) demonstrated tracer avidity in the right lobe of the thyroid (SUVmax, 5.2), upper panel; nodule in the posterior segment of the right lung upper lobe (SUVmax, 4.4), middle panel; and faintly tracer-avid liver lesion (segment Il; SUVmax, 5.5), lower panel.
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FIGURE 2. A 64-year-old man (patient 2) with a known case of left ACC. 18F-FDG revealed a large heterogeneously enhancing lobulated mass in the left suprarenal region with multiple liver metastases. The MIP of 68Ga-DOTAGA-IAC (129.5 MBq) PET/CT (A) transaxial PET (B), CT (C), and fused PET/CT (D) images demonstrated the increased tracer localization in multiple discrete and coalescing hypodense lesions in both lobes of the liver with most avid lesion showing an SUVmax of 17.6 in segment III (solid arrow). Increased tracer uptake was also noted in the periphery of heterogeneously enhancing soft tissue mass in the left suprarenal location (SUVmax, 6.8; dashed arrow).
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FIGURE 3. A 39-year-old woman (patient 3) of right ACC and undergone right adrenalectomy in 2017. Immunohistochemistry of resected tissue showed positivity for vimentin and cytokeratin. The patient was lost to follow-up and now presented with amenorrhea, hirsutism, clitoromegaly, weight gain, striae, and moon facies. CECT abdomen revealed bilateral metastatic lung lesions. 18F-FDG PET/CT for metastatic workup revealed tracer-avid soft tissue lesions in bilateral lung fields and aortocaval lymph nodes suggestive of metastases. The MIP image of 68Ga-DOTAGA-IAC (94.6 MBq) PET/CT showed physiological uptake as above and renal excretion (A). Transaxial PET (B), CT (C), and fused PET/CT (D) showed localized tracer avidity in the bilateral lung lesions (SUVmax, 4.0).
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FIGURE 4. Immunohistopathology of patient 1 shows a highly cellular tumor arranged in sheets with the presence of many large, bizarre cells (hematoxylin-eosin, x400) (A). Immunohistopathology of patient 3 shows a cellular tumor arranged in trabeculae with areas of necrosis (hematoxylin-eosin, x100) (B). ACC is a highly aggressive dedifferentiated malignancy and the most common cause of Cushing syndrome in children less than 5 years, and the second peak occurs in the fifth decade. Usually, 70% of the tumor already spreads beyond the adrenal when diagnosed. Five-year survival of stage 4 disease is less than 20%. However, there is inhomogeneity and even high-grade tumors may not metastasize, whereas patients with a small tumor with almost complete resection may later present with metastasis. There is a lack of effective therapies for patients with ACC. ,2 As per reports, the invasiveness of ACC is related to the overexpression of integrin avB3, a key promoter of cancer angiogenesis. 3-6 IAC (integrin antagonist carbamate derivative) is a peptidomimetic molecule and has been explored as a diagnostic PET/CT tracer to image the integrin avß3 overexpression.7-9 Here we report the effectiveness of 68Ga-DOTAGA-IAC to detect adrenocortical carcinomas. The DOTAGA-IAC may have a theranostic potential if 177 Lu or 225 Ac may be used in lieu of 68Ga. It may give a ray of hope for patients with metastatic and recurrent ACC.