Granulocyte Colony-stimulating Factor-associated Aortitis on Gallium Scintigraphy

Abstract

Aortitis is a rare adverse event associated with granulocyte colony-stimulating factor (G-CSF). Contrast-enhanced computed tomography (CECT) is widely used to diagnose G-CSF-associated aortitis. However, the usefulness of gallium scintigraphy for the diagnosis of G-CSF-associated aortitis is unknown. We herein report a set of pre- and post-treatment gallium scintigrams of a patient with G-CSF-associated aortitis. During the diagnosis, gallium scintigraphy revealed hot spots on the arterial walls that appeared inflamed on CECT. Both the CECT and gallium scintigraphy findings disappeared. Gallium scintigraphy can be a supportive diagnostic tool for G-CSF-associated aortitis, especially in patients with an impaired renal function or allergy to iodine contrast.

Introduction

Granulocyte colony-stimulating factor (G-CSF) is widely used in various types of cancers to prevent febrile neutropenia, which is a serious complication of chemotherapy. G-CSF-associated aortitis is a rare adverse event, first described in 2004 by Darie et al. (1). The prognosis of G-CSF-associated aortitis is generally good; however, serious complications, such as aortic dissection and aneurysm, have been reported (2,3). Thus, an accurate diagnosis and treatment are required. Because of its novelty and rarity, no diagnostic criteria for G-CSF-associated aortitis have been established, and the diagnosis is based on the exclusion of other possible causes.

Contrast-enhanced computed tomography (CECT) is the most commonly used imaging modality for diagnosing G-CSF-associated aortitis, followed by magnetic resonance imaging (MRI), positron emission tomography (PET), and ultrasound sonography (US) (4). However, limited information is available regarding the findings of G-CSF-associated aortitis on gallium scintigraphy.

We herein report a set of pre- and post-treatment gallium scintigrams of a patient with G-CSF-associated aortitis.

Case Report

A 66-year-old man with hypertension and diabetes mellitus was diagnosed with prostate cancer with bone metastasis. After seven years of treatment with a growth hormone-releasing hormone agonist and multiple anti-androgenic agents, the patient started chemotherapy with docetaxel and oral dexamethasone (1 mg/day). Due to severe neutropenia, he received pegfilgrastim on day 3 of the 9th and 10th cycles of docetaxel.

Eight days after administering pegfilgrastim on the 10th cycle, the patient developed a fever and pain in the left neck, prompting consultation at our hospital 4 days later. At presentation, he had difficulty swallowing due to neck pain but denied chills, headache, chest or abdominal pain, arthralgia, changes in vision, or any sick contacts. The patient was hemodynamically stable without desaturation. Point tenderness on the left side of the neck was noted; however, other physical examination results were unremarkable, without any rash or joint tenderness.

Laboratory tests revealed an elevated white blood cell count (15,800 /μL), C-reactive protein level (23.99 mg/dL), and erythrocyte sedimentation rate (>110 mm/h), as well as a decreased immunoglobulin G level. Laboratory tests revealed no significant autoimmune antibodies, such as antinuclear antibodies, rheumatoid factor, antineutrophilic cytoplasmic antibodies, and anti-glomerular basement membrane antibodies. Blood and sputum cultures were negative, and no serological findings of syphilis or hepatitis B or C were observed. Ultrasound cardiography did not detect any signs of infectious endocarditis, such as vegetation or valvular diseases. CECT showed thickened walls of the left common carotid and subclavian arteries, brachiocephalic artery, and aortic arch (Fig. 1a, 2a). Most lesions of prostate cancer had shrunk compared with two months earlier. The patient was diagnosed with G-CSF-associated aortitis.

Figure 1.

Transitional findings of the left common carotid artery on contrast-enhanced computed tomography (CECT) and gallium scintigraphy (GS). (a, b) CECT at the diagnosis showed enhanced soft tissue around the left common carotid artery (arrow), where GS had shown a hot spot (arrow). (c) The coronal view of GS at the diagnosis revealed a hot spot extending along the left common carotid artery (arrow). (d-f) Improvement of the enhancement on post-treatment CECT and the concurrent disappearance of the hot spots on GS were observed.

Figure 2.

Transitional findings of the brachiocephalic artery on CECT and GS. (a, b) CECT at the diagnosis showed a thickened wall of the brachiocephalic artery (a, arrow), where GS showed a hot spot (b, arrow). (c, d) Resolution of the thickened wall on post-treatment CECT and the concurrent disappearance of the hot spots on GS were seen.

We therefore explored the extent of inflammation using gallium scintigraphy, which has been suggested to be useful in diagnosing other arterial diseases (5-7). The gallium scan revealed hot spots at the same sites where CECT showed thickening of the arterial walls (Fig. 1b, c, 2b).

As the patient's neck pain and dysphagia resolved spontaneously three days after hospitalization, and his inflammatory markers were continuously decreasing, he was monitored carefully without additional corticosteroids. After confirming no extension of the inflammatory area on carotid ultrasound compared with the findings on CECT at the diagnosis, the patient was discharged on day 10 of hospitalization.

Two weeks after the diagnosis, follow-up CECT showed improvement in arteritis (Fig. 1d, 2c), which was consistent with the levels of inflammatory markers returning to within normal ranges, as determined by laboratory tests. The hot spots identified on previous gallium scintigraphy were undetectable (Fig. 1e, f, 2d).

Discussion

G-CSF-associated aortitis is a rare complication, occurring in 0.3-0.47% of patients receiving G-CSF (8,9). In a systematic review, 75.5% of the cases were reported in Asian countries (10). The mean age was 60.1 years old, and 91.8% of the patients were women. Pegfilgrastim was the most commonly administered G-CSF agent in documented cases (69.4%). The median time to the onset of aortitis after G-CSF administration was 8.0 days. A fever was the most common symptom, while other symptoms included pain in the back, chest, abdomen, and neck. CT was utilized as a diagnostic imaging modality in most cases (89.8%) (10). Some patients were diagnosed via MRI, PET, or US.

G-CSF-associated aortitis is often treated with corticosteroids, while cases that resolve spontaneously without corticosteroids have also been reported (10). The prognosis is generally considered good, but some serious potential complications, such as aortic dissection and iliac aneurysm, should be noted. The pathogenesis of G-CSF-associated aortitis is not well understood, but inflammatory cytokines released by neutrophils upon activation with G-CSF may be related to arteritis.

Our patient had a typical clinical course of G-CSF-associated aortitis, developing a fever and neck pain eight days after the second administration of pegfilgrastim, and the aortic arch and adjacent arteries appeared inflamed on CECT. Inflammation of the aorta and its branches, as in our case, is classified as large-vessel vasculitis (LVV) (5). The two dominant causes of LVV are Takayasu's arteritis and giant cell arteritis. Other minor causes of LVV include bacterial and viral infections, autoimmune diseases, paraneoplastic aortitis, and drug-induced vasculitis such as G-CSF-associated aortitis. As our patient was an elderly man, the clinical picture was quite different from that of Takayasu's arteritis, which typically affects young women. Giant cell arteritis was also unlikely, as no inflammation was detected around the temporal arteries. In addition to negative cultures, the spontaneous resolution of inflammation without antibiotics or antivirals made infectious etiologies less likely. The possibility of autoimmune diseases was also low because the patient had no abnormal physical findings other than tenderness in the left neck. As the patient showed regression of prostate cancer at the occurrence of aortitis, the diagnosis of paraneoplastic aortitis was not reasonable. Thus, the patient was diagnosed with G-CSF-associated aortitis.

The present case suggests the usefulness of gallium scintigraphy for the diagnosis of G-CSF-associated aortitis. Gallium scintigraphy at the diagnosis revealed hot spots in the same locations where CECT had shown thickening of the arterial walls. Subsequently, both aortitis on CECT and the hot spots on the previous gallium scintigraphy disappeared. To our knowledge, no reports have discussed the usefulness of gallium scintigraphy in diagnosing G-CSF-associated aortitis. However, some reports have suggested its utility in the diagnosis of Takayasu's arteritis or giant cell arteritis, although it is not widely used to diagnose these diseases (5-7). Various imaging modalities, such as CT, MRI, US, and PET, are frequently used to diagnose LVV. Among them, PET, unlike other modalities, can evaluate inflammation qualitatively. Gallium scintigraphy uses Gallium-67-citrate, the radiopharmaceutical that accumulates in inflammatory lesions, enabling the qualitative evaluation of inflammation (11). PET has a higher diagnostic ability than gallium scintigraphy, with greater spatial resolution and sensitivity to inflammation. However, limited access to PET and its relatively high cost can be an obstacle to the accurate diagnosis of G-CSF-associated aortitis (12). In addition, the Japanese medical insurance system serves as a limitation as well, as it only covers PET for assessing the inflammatory activity and not for diagnosing aortitis. Gallium scintigraphy, by contrast, can be performed for diagnostic purposes.

Although the usefulness of gallium scintigraphy requires a further evaluation, it can be an alternative to CECT for diagnosing G-CSF-associated aortitis in patients ineligible for iodine contrast due to an impaired renal function or iodine allergy.

The authors state that they have no Conflict of Interest (COI).