Paraganglioma (PGL), also known as ectopic pheochromocytoma (PHEO), is a kind of neuroendocrine tumour derived from neural crest cells. Approximately 90% of PGLs can secrete catecholamine. Excessive secretion can cause paroxysmal or persistent hypertension, palpitations, hyperhidrosis, gastrointestinal dysfunction and other catecholamine syndromes, as well as serious heart, brain and kidney complications.[1, 2] PGL is mostly benign and less malignant. PGL can occur in all ages and in many parts of the body but is mainly distributed in the head, neck, mediastinum, retroperitoneum and other parts with paraganglion aggregation. Without a specific location, PGL is difficult to diagnose by ordinary CT. According to the clinical manifestations, PGL can be divided into functional, subclinical and non-functional types. The clinical manifestations of functional PGL are paroxysmal or persistent hypertension and accelerated heart rate and are often accompanied by headache, dizziness, palpitations, sweating, anxiety and other symptoms. The classic clinical manifestations are paroxysmal hypertension with headache, sweating, and palpitations. Subclinical PGL is characterized by insufficient secretion of catecholamine, which produces clinical symptoms. There are usually no clinical manifestations of subclinical PGL. However, operation traction and compression can induce increases in BP, resulting in sharp fluctuations in blood pressure values that cannot be predicted before the operation, thereby increasing the difficulty of the operation and the risk to the patient. Non-functional PGL lacks typical symptoms and is only found when the tumour volume increases or a physical examination is performed. The patient in this study had a history of hypertension for many years, no history of regular oral antihypertensive drugs, and good blood pressure control. The patient had no obvious hypertension before the operation, but her blood pressure fluctuated during the operation due to the stimulation of the tumour body; thus, she was diagnosed with subclinical retroperitoneal PGL.
The secretion of large amounts of catecholamine can also increase blood glucose levels, but PGL with abnormal glucose metabolism as the main manifestation is rare. The possible mechanism is that catecholamine secreted by the tumour can reduce insulin secretion, promote glucagon secretion, promote glycogen decomposition in the liver and muscle tissue and effect glucose absorption in the intestine. Recently, scientists from Japan used hyperglycaemic glucose clamp and hyperinsulinaemic normal glucose clamp technology to study PGL and found that the decrease in glucose tolerance caused by catecholamine section is mainly caused by altered insulin secretion, especially in the early stage of the insulin secretion response. In this case, the patient had a history of diabetes for 13 years, and showed persistent increased blood glucose. The application of multiple hypoglycaemic drugs to control the patient’s blood glucose was ineffective, and no effect of high-dose insulin was observed. Therefore, her increased blood glucose levels may have been related to the inhibition of insulin secretion by catecholamine released from the PGL.
Retroperitoneal PGL should be differentiated from schwannoma, neurofibroma, ganglioneuroma, solid pseudopapilloma of the pancreas, retroperitoneal sarcoma and giant lymphadenopathy. The initial diagnosis mainly depends on the imaging examination. Ultrasound, CT and MRI can be used as imaging examination modalities at the initial diagnosis. No specific manifestations are observed on ultrasound and this imaging modality is generally used as a means of postoperative follow-up. Contrast-enhanced CT can show the location, size, shape, blood supply and relationship with the adjacent tissues of the tumour. The sensitivity of the localization diagnosis of retroperitoneal PGL is 90%, although the sensitivity of MRI is better than that of CT. MRI shows a similar round or irregular mass. CT and MRI have advantages in the localization diagnosis of PGL, with accuracies of 80–95%, but the specificity is poor.[5, 6]Most PGLs secrete excessive catecholamine levels. The detection of catecholamine levels in plasma or urine and its metabolite, urovanillic mandelic acid, can provide the main basis for the qualitative diagnosis of PGL.However, the levels of angiotensinII, aldosterone, renin and VMA in the urine were not increased in this case, and some of them were decreased, suggesting that even if the above results are negative, PGL cannot be completely ruled out.
It has been reported that patients with hyperglycaemia may account for more than 50% of PHEO/PGL patients. If the primary cause cannot be eliminated, the high levels of blood glucose will be difficult to control. Surgical resection of the tumour is the most effective method for treating refractory hyperglycaemia, and this condition should be actively treated. Because PGL has a complete capsule and abundant blood supply, it is necessary to carefully separate the tissues and blood vessels around the tumour during the operation to ensure the tumour is completely removed, avoid massive haemorrhage and reverse the flow of vasoactive substances into the blood. Meanwhile, it is necessary to gently operate in these cases to reduce pulling and squeezing of the tumour and avoid the risk of hypertension caused by the release of catecholamine from the tumour. For functional tumours, preoperative hypotension, dilatation and correction of arrhythmias can reduce perioperative mortality. After the operation, changes in blood glucose should be noted, and hypoglycaemic drugs should be adjusted in time to avoid the occurrence of serious hypoglycaemia. In this case, the patient’s blood glucose levels were significantly improved after the tumour was removed. Hypoglycaemia occurred at her original treatment dose of insulin, indicating that the endocrine function of the tumour had a significant impact on the increased blood glucose levels. Hyperglycaemia caused by PGL is rarely seen in the clinic; therefore, it is necessary to pay attention to the relevant blood glucose indexes during the preoperative examination and diagnosis process to improve the examination process and further assist in the preoperative diagnosis of PGL. The diagnosis of PGLis based on pathological and immunohistochemical examinations. The combined application of CgA and Syn provides a reliable basis for the diagnosis of PGL. However, it is impossible to distinguish benign and malignant tumours using pathology and histology alone. The diagnosis of PGL should be based on the clinical biological behaviour of the tumour. LowKi-67 expression, a cell proliferation marker, is related to benign tumours and suggests that the prognosis of the patient is good.[8, 9]PGL may also be malignant. At present, the only conclusive evidence for the diagnosis of malignant PGL is metastasis.[10, 11] Therefore, long-term follow-up should be carried out to confirm whether the tumour is benign and malignant. PGL is not sensitive to radiotherapy and chemotherapy. Radiotherapy and chemotherapy are only used as analgesic treatment for metastatic tumours or to eliminate the residual tumour after operation. Operation is the only effective treatment for PGL. Patients should be followed up for life to monitor the recurrence of the tumour. If there is recurrence, the tumour should be resected again. Based on the theory that PGL involves multiple gene mutations, targeted therapy has become a new research hotspot. Some studies have shown that Hif-2α inhibitors, Everolimus, Sunitinib and other drugs, can be used for the effective treatment of the disease.[12–14]
In this study, the patient had hyperglycaemia in the early stage of the course of the disease, and she was resultantly misdiagnosed with type 2 diabetes mellitus. The clinician used a variety of hypoglycaemic drugs to try to control the patient’s blood glucose level, but these drugs were unsuccessful. Additionally, there was no effect of high dose insulin on the control of the patient’s blood glucose levels; however, neither PHEO nor PGL was suspected. PHEO and PGL patients often have a history of hypertension, and the conventional use of antihypertensive drugs often has poor efficacy. The patient in this study had a 4-year history of hypertension, and using a single antihypertensive drug or not taking antihypertensive drugs allowed her to control her blood pressure within the ideal range; thus, there was no doubt that the patient had PHEO or PGL. The diagnosis of PGL was not confirmed until the abdominal CT examination, which showed a lesion occupying the retroperitoneal space. An operation was performed, and PGL was confirmed by pathology after the operation. The misdiagnosis of PGL is based on the following: clinicians’ lack of experience, lack of knowledge about atypical PGL, and narrow diagnostic thinking.