40042244

CXCR4-A Potential Novel Theranostic Target in Adrenocortical Carcinoma

Amir Nazar, MBBS, MD, ** Ashwini Kalshetty, MBBS, Diplomate NB, MNAMS, ** and Sandip Basu, MBBS, DRM, Diplomate NB, MNAMS **

Abstract: Adrenocortical carcinoma (ACC) is a highly aggressive malignancy with high recurrence rates and poor prognosis. There are only limited treatment options with poor response rates. ACCs are docu- mented to express chemokine receptor CXCR4, which can be visualized using 68Ga-pentixafor PET/CT. We herein present a case of ACC with local recurrence and peritoneal metastases, which was well visualized on FDG and pentixafor PET/CT. The high expression of CXCR4 offers the potential of theranostics and targeted endoradiotherapy in patients with metastatic ACC. We also observed thymic rebound to illustrate mild to moderate grade uptake of 68Ga-pentixafor in this patient.

Key Words: adrenocortical carcinoma, 68Ga-pentixafor, PET/CT, FDG PET/CT, metastasis, chemokine ligand 12 (CXCL12) (Clin Nucl Med 2025;50:e286-e287)

Received for publication July 29, 2024; accepted November 20, 2024.

From the *Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe, Mumbai, India; and ¡Homi Bhabha National Institute, Mumbai, India.

Conflicts of interest and sources of funding: none declared.

Correspondence to: Sandip Basu, Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe, Jerbai Wadia Rd, Parel, Mumbai 400012. E-mail: drsanb@yahoo.com.

Copyright @ 2024 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/RLU.0000000000005656

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3. Libé R. Adrenocortical carcinoma (ACC): diagnosis, prognosis, and treatment. Front Cell Dev Biol. 2015;3:45. Published 2015 Jul 3. doi:10.3389/fcell.2015.00045.

4. Chifu I, Heinze B, Fuss CT, et al. Impact of the chemokine receptors CXCR4 and CXCR7 on clinical outcome in adreno- cortical carcinoma. Front Endocrinol (Lausanne). 2020; 11:597878. Published 2020 Nov 13. doi:10.3389/fendo.2020. 597878.

5. Dreher N, Hahner S, Fuß CT, et al. CXCR4-directed PET/CT with [68 Ga]Ga-pentixafor in solid tumors-a comprehensive analysis of imaging findings and comparison with histopathol- ogy. Eur J Nucl Med Mol Imaging. 2024;51:1383-1394. doi:10. 1007/s00259-023-06547-z.

6. Buck AK, Haug A, Dreher N, et al. Imaging of C-X-C motif chemokine receptor 4 expression in 690 patients with solid or hematologic neoplasms using 68Ga-Pentixafor PET. J Nucl Med. 2022;63:1687-1692. doi:10.2967/jnumed.121.263693.

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FIGURE 1. A 29-year-old woman with left adrenal cortical carcinoma (ACC) initially presented with hypercortisolism with baseline urine cortisol of 6100 µg/24 h. The patient defaulted after left adrenalectomy and 18 months later presented with disease recurrence. She presented with pain in surgical site, and USG showed multiple ill-defined heterogenous predominantly hypoechoic lesions in left suprarenal region suggestive of recurrence. 18F-FDG PET/CT MIP (first pane) and transaxial fused images (second pane) show highly metabolically active multiple soft tissue deposits at postoperative site (SUVmax: 17.23, yellow arrow) and peritoneum (SUVmax: 7.16, green and red arrows). 68Ga-CXCR4 PET/CT MIP (fifth pane) and fused transaxial images (fourth pane) show high CXCR4 expression in almost all the lesions (postoperative site [SUVmax: 23.38, yellow arrow] and peritoneum [SUVmax: 10.87 green arrow]) except for a peritoneal lesion (red arrow). A note is also made on enlarged thymus (blue arrow), which showed increased metabolic activity (SUVmax: 5.19) as well as CXCR4 expression (SUVmax: 10.60). Binding of chemokine receptor 4 (CXCR4) with chemokine ligand 12 (CXCL12) plays an important role in tumor growth, metastases, and resistance to therapies.1 Higher CXCR4 expression is associated with reduced overall survival.2 ACC is notorious for recurrence and resistance to conventional therapies with 5-year survival < 50% in stage III and IV disease.3 CXCR4 is one of the most highly expressed chemokine receptors in ACC,4 and ACC is one among the solid tumors that show highest 68Ga-pentixafor uptake.5,6 The high expression of CXCR4 offers the potential of targeted endoradiotherapy in patients with metastatic ACC. We also observed postadrenalectomy thymic rebound in this patient. In patients with hypercortisolism, there can be depletion of thymic lymphocytes mediated by high cortisol levels leading to rebound hyperplasia once the cortisol levels come down. The fall in cortisol levels can also mimic recovery from stressful condition causing rebound thymic hyperplasia.7

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