PHEOs and PGLs have the same cellular origin. They are generally slow-growing but all have potentials of recurrence and metastasis, according to the last WHO classification (2017 version) on endocrine tumors, which eliminated benign versus malignant discrimination [1, 3]. In the clinical practice, the patients of PPGL are usually latent until huge massing effect and/or metastasis has occurred. Previous researches identified some factors associated with higher risk of metastasis, including the primary tumor site and size, age at diagnosis and some specific genotypes [1, 3–7, 23]. The bone is one of the most common metastatic sites (72%), and the spinal involvement is one of the most deadly situation [24, 25]. Metastatic spinal PPGLs can significantly impair patients’ activity of daily living and quality of life, due to the emergence of devastating skeletal-related events, such as pathological fracture and severe local pain and paraplegia . Literature regarding this entity is lacking, so few references are currently availed about the clinical features and treatment outcomes of the spinal metastasis. In this report, we described and analyzed a cohort of 18 patients with metastatic spinal PPGLs, hoping to provide references for the future clinical practice in this field.
This study found that the spinal PPGL was mostly seen in mid-aged patients (Table 1), and that 94.4% (17/18) cases were younger than 60 years. The study noted gender variation with a predominance of males (2.6/1). The time between the prior surgery of primary site and the spinal metastasis varied in a wide range, from one to 27 years. The clinical symptoms of the cohort were not pathognomonic. Local pain and neurological dysfunction were related to bony erosion and pathological fractures. As the primary PPGLs, metastatic lesions can also be functional, which are capable to secrete catecholamines (Table 2). Typical catecholamine-arousing symptoms include headache, palpitation, fatigue, flushing, sweating and/or paroxysmal hypertension [1, 4, 24].In our case series, there were six patients (33.3%, 6/18) having secondary hypertension, which were presumably related to the metastases. Malignant hypertension may cause a series of hemodynamic disorders and vascular events [1, 25]. As previously reported, we prepared these patients with α-adrenergic receptor antagonists, in avoidance of perioperative hypertension crisis and lethal vascular events [1, 4, 6, 25].
In this study, all cases had different extents of pathological fractures, from cortical destruction to severe vertebral collapse. The thoracic spine was the most susceptible metastatic sites, as a percentage of 55.6%. The imaging manifestations of metastatic PPGLs were consistent with other osteolytic lesions. CT and MRI scans are the modalities of choice to identify the involved vertebral segments. On CT films, the lesions usually a homogenously osteolytic mass within the vertebral body, with paraspinal soft tissue mass in some cases. Different from the inflections and metabolic bone diseases, the surrounding cancellous bone is normal and no existence of sclerotic girdle. On MRI scans, the lesion is a mass with hypointensive signal on T1-weighted images and hyperintense signal on T2-weighted images (Fig. 1). Sometimes, we could find the signs of vascular flow void on T2 sequences, due to the heavy vascularity in some cases [16, 18].
The treatment strategies of the case series were schemed by our institutional MDT team in a concerted way. As for spinal metastases, a holistic set of treatment modalities are emphasized, including surgery, radiotherapy, chemotherapy and/or other anti-tumor therapies [4, 7, 11, 16, 25]. Preoperative evaluation was carried out by our MDT team. Especially, the patients’ physical condition (KPS), the spinal instability neoplastic score (SINS), Tokuhashi and Tomita staging systems were evaluated, to facilitate the scheming of surgical strategies. Surgical resection is the most effective way to reduce the tumor burden, and it is recognized as the treatment of choice for spinal PPGLs, especially for those with intractable local pain and neurological impairment [4, 16, 25–28]. Preoperative hemodynamic reconditioning is essential to the safety of the operation. Preoperatively, adrenergic blockade is typically accomplished with either a nonselective or a selective α-adrenergic receptor antagonist (e.g., phenoxybenzamine, and doxazosin), usually started at least one week before surgery [7, 15, 27].The βadrenergic antagonist should be administered to control tachycardia after αadrenergic blockade has been effective in normalizing blood pressure. Another precaution needs to be taken into account in the surgical planning of metastatic spinal PPGLs: the vascularity of the tumor. This spinal metastasis tends to be hypervascular, which can lead to significant blood loss intraoperatively. Our case series had an over 1100 ml of blood loss averagely. It has been suggested that preoperative embolization of the supplying arteries 24h-48 h before surgery can minimize blood loss .
Palliative surgeries, including separation surgeries, neurological decompression and vertebral augmentation procedures, are the mainstay of treatment choice, for the patients with multiple metastases, recurrent spinal lesions, acute neurological deterioration and intractable local pain. In our case series, 17 patients underwent palliative surgeries, and the main surgical goals were to restore the spinal stability with or without decompress the neurological elements. In recent years, separation surgery has gained wide acceptance for metastatic spinal tumors. In our series, the surgeries of 13 patients were performed under the principles of separation surgeries. Within the operation, two therapeutic goals were achieved, namely sufficient neurological decompression and sparing a safe distance for radiotherapy. Percutaneous vertebral augmentation procedure was proven to be an effective method to control the local pain for the patients with no symptoms of neurological impairment (case #1).
For the patients with solitary spinal metastasis, total resection shall be attempted. PPGLs have a high recurrent rate when partially resected. Richter et al.  reported that total en-bloc spondylectomy complemented with radiotherapy led to tumor-free survival at the 10-year follow-up in their patient. Yin et al.  shared a series of 18 patients with spinal PGLs and 15 of them received total tumor resection. The surgical outcomes were encouraging, with a relapse-free period over 40 months. However, given the intricate growth pattern and encasement of neural tissue by spinal metastases, intrusion to the spinal cord and paraspinal vital structures, and heavy bleeding during the surgery, total resection is not always feasible. Therefore, we should make a reasonable choice, based on the balance of the safety and efficacy of tumor resection for each surgical option. In recent years, the advances in the surgical tools and instruments, such as 3D printing prosthetic vertebra and ultrasonic bone scalpel, facilitate the challenging procedure of tumor resection [29, 30]. Even in the procedures of PR, maximal tumor mass resection should be attempted, to reduce the tumor load and spare more space in avoidance of relapse of neurological compression.
Locoregional recurrence or progression is a big concern for patients with spinal tumors. When removal of the entire tumor is not possible, radiation treatment is recommended [1, 16, 24]. The doses delivered to our cases ranged 35 Gy to 45Gy. The dose was referred to studies performed on giant cell tumors and chordomas. Overall, among the patients treated with radiotherapy in our study, four patients survived more than two years and one died five months after the indexed surgery. For the past several decades, systemic therapies for PPGLs have been mainly referred to 131I-MIBG. Current knowledge of systemic therapies relies on the results of a few mainly retrospective studies . Up to 70% of metastatic PPGLs do not respond to the treatment . Overall, six patients in our study were treated with 131I-MIBG, while three patients died ten to 14 months after the therapy, one died 38 months later and the other two patients enjoyed a long survival. The outcomes suggest that the use and efficacy of 131I-MIBG therapy in spinal PPGLs needs further exploration and verification.
The use of chemotherapy is controversial. The chemotherapeutic drugs are various for metastatic PPGLs, including almost all currently available agents. The single or combined use of chemotherapeutic drugs is practically experience based given the rarity of the diseases. CVD regimen (cyclophosphamide, vincristine and dacarbazine) is recommended as the best protocol. Ayala-Pamirez et al.  reported that 5-year OS rate of PPGLs patients who received CVD regimen was 51%. A meta-analysis found that only 37% of malignant PPGLs showed response to the regimen .U-King-Im et al  reported successful therapeutic use of octreotide in a patient with carotid body PGL that metastasized to multiple vertebrae. Mertens et al.  demonstrated the successful regression and palliation of metastases of PGL with chemotherapy, particularly with the CVD regimen. However, the application and efficacy of chemotherapy after the surgeries were not well established and in need of support from high-quality, large-scale clinical trials. Radiotherapy is a valuable adjuvant therapy for spinal tumors after the operation, to provide a better locoregional control for the cases with residual tumor mass. In our cohort, five out of 13 patients who underwent separation surgeries received radiotherapy after the operation, among whom one patient died five after the therapy and the other four patients manifested a satisfying local control after more than 2 years of follow-up.
The present study has several limitations. Firstly, it is a retrospective study with a small sample size. Thus, the results of this study need further examination and references with caution.. Secondly, the primary tumors were operated many years ago in other hospitals, so access to information related to surgical margin status, the size of the primary tumor, and treatment after primary tumor resection was limited. Thirdly, it was difficult to obtain the continuity, regularity, periodicity and dose of radiotherapy and chemotherapy after the indexed surgeries for spinal PPGLs, because some of adjuvant therapies were not implemented in our hospital.