Discussion
In this paper, we report the case of recurrent phaeochromocytoma in a middle-aged male patient with atypical clinical presentations that could be well controlled with medication. The patient had already received two adrenalectomies before his admission. According to the pathological reports provided, all of the removed tumors underwent immunohistochemistry analysis, and suggested a positive expression of neuroendocrine markers (Syn and CgA). Ki-67 index was no more than 2%, indicating a low proliferation capacity, and was consistent with the slow progression of the disease. Laboratory results did not reveal any endocrine abnormalities. However, there was always a local recurrence following surgery and distant lesions appeared as disease developed. Although we didn’t perform a biopsy of extra-adrenal lesions, PET/CT showed catecholamine hypermetabolism in right adrenal gland and several intra-abdominal nodules, indicating the possibility of malignant phaeochromocytoma.
Currently, the World Health Organization (WHO) has replaced the previous concept of ‘malignant PPGL’ with ‘metastatic PPGL’, and proposes that all PPGL should have malignant potential.3 A definite diagnosis of malignancy can only be validated by the presence of metastasis in non-chromaffin tissues (such as brain, lung, liver, bones or lymph nodes). There have already been several methods to predict metastasis of PPGL. Some scoring systems, like PASS and GAPP, are primarily based on histopathological features. Both systems have been proved to be highly sensitive to metastatic potential, but lack specificity.4, 5 Metastatic and non-metastatic PPGLs are similar histologically and hard to distinguish from each other. It may be more convincing to rule out the possibility of malignancy when scores are low, rather than to make a metastatic prediction with high scores. Analogously, it is also difficult to determine the metastatic potential of PPGL by a single biomarker. Ki-67 is a proliferative marker that has been shown to be predictive of metastases in PPGL. But some studies indicate that Ki-67 index has a low sensitivity, and correlates with progression-free survival rather than the occurrence of metastasis. The recommended thresholds are also disputed. Another system, the COPPS score, integrates clinic-pathological features and immunohistochemical markers (PS100 losses, SDHB immunostaining) for risk assessment of metastasis, and exhibits an excellent reproducibility (AUROC = 0.981).6 However, in our case, slides of primary tumor were not available and immunohistochemical results were incomplete, which limited the application of COPPS. Taking clinical features into account, the primary tumor was large, and showed a strong tendency to recurrence, but presented no rapid invasion with a biochemical silent phenotype. It might be judged as a slowly progressing metastatic PPGL.
The preferred treatment for metastatic PPGL is tumor resection. Conservative treatments include the following methods. Chemotherapy is mainly used for rapid progressing metastatic PPGL. The common chemotherapy regimen is CVD regimen, a combination of cyclophosphamide, vincristine and dacarbazine. It is reported that the complete remission rate of CVD regimen is 4%, while partial remission rate is 37%, and the rate of stabilization is 14%, as assessed by tumor volume reductions. 7However, it may cause severe adverse reactions, such as marrow suppression and hypertensive crisis. Nuclide therapy, including metaiodobenzylguanidine (MIBG) therapy and peptide receptor radionuclide therapy (PRRT), needs to evaluate the nuclide uptake in tumor cells before treatment. The conventional MIBG preparations has been shown to prolong survival with an increased 5-year survival rate of 45%-68% and achieve stabilization in 73%-79% of patients. However, the preparations contain large doses of unlabeled MIBG that disrupt the norepinephrine-reuptake mechanism, leading to very low specific activity and life-threatening side effects. In comparison, high-specific-activity MIBG shows improved efficacy and tolerability in vivo. 8So far, the new preparations haven’t been available domestically. PRRT is considered as a viable alternative to chemotherapy and MIBG therapy. Meta-analyses reported PRRT remission rate and disease control rate of 25% and 84%, respectively. 9MIBG treatment and PRRT are usually applied to advanced systemic PPGL. Radiofrequency ablation and embolization perform well in local control. Kohlenberg, J et ml. reported an ablative efficacy of 86% local control on imaging, ang 92% symptomatic remission with a low incidence of serious complications.10 Targeted therapeutic agents, for instance, tyrosine kinase inhibitors, also show potential efficacy, especially in patients bearing SDHB gene mutations. Relevant clinical trials are ongoing and there is still a lot to be done in this area.11
In this case, due to multiorgan involvement, and intra-abdominal adhesions caused by previous operations, surgery became risky. We turned to conservative options for a safer solution. Chemotherapy could act on the whole body and was usually used in the treatment of advanced PPGL. However, chemotherapy-induced myelosuppression, and severe infection and intracranial hemorrhage that may occur afterwards, might be fatal. It was not a priority to take the hazard for a slow-progressing PPGL with mild symptoms. Considering the life-threatening side effects of conventional MIBG preparations, MIBG therapy was not preferred as well. Furthermore, targeted therapy was costly and we had to take into account the patient’s financial burden. Radiofrequency ablation and embolization might be useful, but were rarely performed in PPGL in our hospital. The efficacy was uncertain. We decided to wait and see under the close observation of the multidisciplinary team.
PPGL is of great heterogeneity, progression and metastasis may occur even 10 years after diagnosis. All PPGL patients need long-term assessment, basically containing endocrine workup and imaging examinations. MRI is preferred to reduce radiation. Genetic testing should be completed early if possible, especially in patients with large primary tumors (≥5-6cm), extra-adrenal tumors, positive family history, recurrence, or young onset. For cost saving, screening for RET, VHL and SDHx genes may be recommended. Ma, X et ml. reported a genetic profile in Chinese PPGL patients in a single center study: SDHB mutation is the most frequent, accounting for 20%, followed by RET (3.8%), VHL (3.8%), SDHD (2.5%), SDHA (2.2%).12 Based on genetic results, extra screening should be added. VHL patients have to pay attention to VHL-associated tumors, and receive careful ophthalmic examinations and MRI scans of the head and abdomen. At-risk relatives should also undergo comprehensive screening and molecular genetic testing early. 2For biochemical silent PPGLs, apart from regular checkup, target organ management is also necessary, to avoid complications. In our case, the patient underwent cardiovascular and renal function screening, glucose level and lipid profile checkup every 12 months. Interestingly, we observed no significant vascular benefits with the use of α-adrenoceptor blocker. Given that the tumors were non-functional, there was a probability that α-adrenoceptor blocker application had a limited effect. Significant improvement occurred after the initiation of overall target organ management.
In conclusion, some advanced phaeochromocytomas and paragangliomas are unresectable. Therapeutic strategies are recommended to be selected under the coordination of a multidisciplinary team according to concrete situations. Watch and wait may become a choice when PPGL is inoperable but slow-progressing. Symptom control and effective management of target organ damage contribute to better clinical outcomes. Long-term benefits still need to be confirmed. As the observation continues, we may learn more.