18F-FDG PET/CT in a Patient With Malignant Pheochromocytoma Recurrence and Bone Metastasis After Operation—Case Report and Review of the Literature

Introduction: Bone metastasis of malignant pheochromocytoma is a rare disease. We report a patient with a 10-year history who underwent 18F-FDG PET/CT to detect bone metastasis and receive radiotherapy and chemotherapy with complete response for bilateral iliac pain. Case presentation: A 48-year-old male patient complained of dizziness, hypertension, and bilateral iliac pain for 2 months. The patient had a history of resection of bilateral malignant adrenal pheochromocytoma 10 years earlier, and all complaints were relieved immediately after operation. 18F-FDGPET/CT showed abdominal lymph node uptake and multiple bone uptake, as well as multiple brown fat uptake. A biopsy of the left ilium confirms the metastasis of malignant pheochromocytoma. Discussion: In our literature review, we discuss the metastasis of pheochromocytoma reported by some scholars, and the role of radionuclides such as 18F-FDG PET/CT, 18F-DOPA PET/CT, I-123MIBG, and 68Ga-DOTATATE PET, in the diagnosis of malignant pheochromocytoma. The patient above is a good case for clinicians in the diagnosis and treatment of metastatic pheochromocytoma, especially in some hospitals with only 18F-FDG imaging agents. Conclusion: A review of this case and similar rare cases in the literature illustrates the importance of 18F-FDG PET/CT in the diagnosis of malignant pheochromocytoma.


INTRODUCTION
According to the classification of tumors of the World Health Organization, 3-13% of patients with adrenal pheochromocytoma are diagnosed as malignant lesions (1). The 5-year survival rate was 34-60%, depending on the site of tumor metastasis. Patients with liver and lung metastasis were shown shorten survival time, while those with only bone metastasis showed the best prognosis (2). Unfortunately, it is extremely rare that the pheochromocytoma metastasizes to the bone.
Currently, the commonly used imaging for detecting bone metastasis is CT, MRI, PET/CT, and SPECT/CT. Among them, PET/CT or SPECT/CT is a "one-stop" examination, which displays not only morphological but also metabolic information of the whole body by one test. 18F-FDG is the analog of glucose, which reflects the metabolism of glycolysis inside the tumors. 18F-FDG PET/CT has been widely used in the detection, staging, prognosis, and therapeutic assessment of various kinds of tumors. Besides the primary lesions, all metastatic lesions can be shown, including osteogenic and osteolytic bone destructions (3). Pacak et al. (4) found that 18F-FDG PET/CT imaging is helpful for the localization and diagnosis of pheochromocytoma with high sensitivity and specificity.
Here, we report a rare case of 10-year postoperative bone metastasis of malignant pheochromocytoma detected by 18F-FDG PET/CT. The patient has provided a written informed consent form and agreed to publish this manuscript and any identifiable images or data.

CASE PRESENTATION
We report a 48-year-old male patient with dizziness, hypertension, bilateral iliac pain, and elevated blood pressure for 2 months. Bilateral adrenalectomy and splenectomy were performed in 2009. Postoperative pathology confirmed bilateral adrenal pheochromocytoma. All the symptoms were completely relieved, and the blood pressure returns to a normal level after operation. No antitumor and antihypertension therapy were needed. In April 2020, the patient visited the hospital and complained bone pain in the left hip, accompanied by palpitation, shortness of breath, and dizziness. The highest blood pressure was 200/120 mmHg, cortisol 4PM was 6.54 µg/dl (3.44-16.76), cortisol 8PM was 13.64 µg/dl (5.27-22.45), and serum corticotropin was 167.9 pg/ml (7.20-63.30). Chest X-ray showed no abnormality, UCG: left ventricular diastolic function decreased (Grade I), aortic sinus widened. T3, T4, TSH, CEA, CA125, CA199, PSA, HCG, NSE, CY-FRA21-1, and other tumor-related markers were normal. Urapidil sustained-release tablets were not effective, and the blood pressure control was not satisfied. The bone pain was obviously aggravated in nearly half a month.
In order to further find out the cause of bone pain, the patient underwent 18F-FDG PET/CT examination in our hospital. After fasting for more than 4 h, 7.91 mCi was injected intravenously, and 18F-FDG PET/CT brain body tomography was performed after 60-min rest.
The patients received cyclophosphamide, vincristine, and dacarbazine (CVD) chemotherapy for three cycles. Then, bilateral iliac metastatic lesions were treated with high-dose-rate interstitial brachytherapy (54Gy/3Gy/18f). Finally, the pain in the ilium of the patient was completely relieved after radiotherapy and chemotherapy.

DISCUSSION
Pheochromocytoma is a benign tumor derived from chromaffin tissue adjacent to adrenal medulla or sympathetic ganglion (5). About 10% of the tumors are bilateral, 10% are non-functional, and 10% are malignant (6). The metastasis has occurred when the malignant pheochromocytoma was found. The only diagnostic criterion for malignant pheochromocytoma is the detection of tumor metastasis (7). Metastases can be isolated or multifocal, commonly in bone, and rarely metastatic to lymph, lung, and liver. The order of involvement was long bone, pelvis, skull, vertebral body and ribs, mostly osteolytic destruction (8).
Studies show that the 5-year survival rate of patients with pheochromocytoma without metastasis can reach 89.3% (9). However, the prognosis of patients with distant metastasis is very poor, with a 5-year survival rate of about 40% and a low longterm survival rate (10). Press et al. (11) believed that recurrence was difficult to treat, especially if diagnosis was not in time or disease had metastatic spread. Therefore, early diagnosis of patients with pheochromocytoma, with malignant potential and careful evaluation of the location and extent of the tumor, is of great significance for the cure of the tumor and the prolongation of survival of the patients.
We searched PubMed with the words "pheochromocytoma" and "osseousmetastasis, " and a total of 35 cases have been reported. McCarthy et al. (12) reported a case of pheochromocytoma metastatic to the left femur, which was detected by X-ray in 1977. They suggested surgical treatment was a nice method for patients with isolated bone metastasis. In 18F-FDG PET/CT scans, the incidence of brown adipose tissue uptake is 1.44-6.7% for physiological reasons (15). The most common location of brown adipose tissue detected by adult 18F-FDG PET/CT is the blue area in Figure 2A. In this case, there is brown fat uptake in the intercostal muscle, suggesting a recurrence of pheochromocytoma. On the other hand, in recent years, 18F-FDGPET/CT has confirmed the existence of metabolically active brown fat under pathological conditions (16). The increase of brown adipose tissue in patients with pheochromocytoma is associated with high levels of serum catecholamine secretion (17).
More and more new molecular probes or agents were introduced to modality imaging techniques, especially PET/CT. Besides FDG, there are many new probes in  radiopharmaceuticals were reported, which played an important and promising role in the diagnosis and therapeutic assessment of metastatic malignant pheochromocytoma.
A SPECT radionuclide tracer, 123I-MIBG, has high specificity in the localization and diagnosis of pheochromocytoma, and is of great significance in ectopic pheochromocytoma, postoperative reexamination, and multiple diseases (18). In addition, Grassi et al. (19) reported a patient with malignant pheochromocytoma who underwent 18F-DOPA PET/CT, I-123MIBG, and 68Ga-DOTATATE PET examinations. The results show that I-123MIBG imaging has traditionally been used to detect pheochromocytoma, but recent studies have shown that some pheochromocytoma imaging may be false negative. Therefore, in order to better display pheochromocytoma, we can consider using new imaging agents, such as 18F-DOPA PET/CT and 68Ga-DOTATATE PET. In addition, Yanagi et al. (20) reported a primary lesion of the right adrenal, illustrating low uptake due to wide centric necrosis, and metastatic lesions of liver, lumber vertebrae, ribs, and sacroiliac joint showed high uptake on the I-131 MIBG scintigraphy. 131I-MIBG can be selectively absorbed by pheochromocytoma and stored in catecholamine granules of tumor cells to release β-rays in particles and act on tumor cells to achieve therapeutic effect. 131I-MIBG palliative treatment has a certain effect (21). A recent study using FDG-PET, 18F-fluorodopamine PET, MIBG, 111In-pentetreotode, and 99mTc-methylene diphosphate scintigraphy indicated that FDG-PET was the preferable functional imaging modality for the localization of metastatic paraganglioma (22). Jaiswal et al. (23) studies show that 177Lu-DOTATATE is a safe and effective method for the treatment of metastatic pheochromocytoma. Win et al. (24) retrospectively reviewed five patients with malignant phaeochromocytoma who underwent imaging with CT and 123I-MIBG and compared the results with those of PET imaging using 68Ga-DOTATATE. The results showed that, compared with 123I-MIBG, 68Ga-DOTATATE showed more lesions, a higher uptake rate, and better resolution.
The patient above is a good case for clinicians in the assessment of metastatic pheochromocytoma, especially in some hospitals with only 18F-FDG imaging agents.

CONCLUDING REMARKS
Bone metastasis of malignant pheochromocytoma is a rare disease with poor prognosis. For patients with the potential for malignant recurrence, it is necessary to screen valuable predictors of recurrence, strengthen follow-up, and find recurrent diseases.
This will help to completely cure and improve the prognosis of patients. Our case shows that 18F-FDG PET/CT has a good value in the localization diagnosis and clinical staging of malignant chromaffin bone metastasis. In addition, brown fat imaging can evaluate the level of catecholamine secretion in diseased blood and very helpful for clinical diagnosis of recurrent malignant pheochromocytoma.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

ETHICS STATEMENT
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

AUTHOR CONTRIBUTIONS
BF and MC initiated the idea for case reporting and prepared the final copy of the manuscript. YH and YJ took responsibility for collecting patient's data. QZ took responsibility for reviewing the CT and FDG PET/CT. All authors have read and approved the final manuscript.