The diagnostic criteria of ‘malignant’ pheochromocytoma remains a controversial topic. Nearly 10 to 20% of patients with PCC may develop metastasis, more commonly in patients with specific mutations [14, 15]. The 2022 WHO classification of endocrine tumors defines metastatic disease as “tumor identified at sites where normal paraganglia do not occur (i.e., histologically confirmed lymph node or bone).” [13]. Differentiating malignant tumors from benign ones is a challenging task as they may appear histologically and biochemically identical, and currently there are no markers either histological or molecular or predictive factors that can differentiate the two spectra of disease. However certain factors such as large tumor size, extra-adrenal location, increased dopamine secretion (> 3-fold increase), high Ki-67 index and presence of SDHB mutation (most important factor) to be associated with higher metastatic potential in PCCs [6, 16,17,18].

Risk-stratification scores using histological features such as the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) [19] and Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP) score [20] are commonly used in clinical practice to predict risk of malignancy aid decision-making. The various parameters used in the two scoring systems are shown in Table 3. Tumors with a PASS > 4 and GAPP > 3 are thought to have increased metastatic potential though with lower specificity [19, 21]. However, there remains no high-level evidence behind the use of any prognostication score. Apart from determining the malignant potential of a pheochromocytoma, the risk of recurrence is an important clinical consideration. The recurrence rate for PPGLs is estimated to be one per 100 person-years, with 40% being malignant recurrence.

The European Society of Endocrinology defines high risk patients as young patients < 20 years old, those with a genetic disease, tumor size > 1.5 cm, or a paraganglioma who should be offered annual follow-up with biochemical screening for the rest of their lives [18]. Similarly, in a recent retrospective study involving 242 patients, features such as genetic mutation, younger age, larger tumor size, and PASS value were associated with recurrence [17]. With little ability to determine the natural history of PCC, the European Society of Endocrinology recommends follow-up with annual biochemical screening for at least 10 years in patients who have been operated on, and for lifelong annual follow-up in high risk patient groups [18, 22]. In addition, in patients with high-risk histology (such as PASS > 4 or GAPP > 3), should be considered under the high-risk screening group (Fig. 5).

The standard treatment of pheochromocytoma is complete surgical resection following medical therapy (alpha blockade–selective or non-selective). Minimally invasive adrenalectomy is recommended for most pheochromocytomas, while an open approach is preferred for large tumors > 6 cm and where there is local invasion [6] Partial cortical-sparing adrenalectomy may be considered for a small group of patients, namely those with hereditary disease who have small tumors and have previously undergone contralateral complete adrenalectomy, to prevent subsequent adrenal insufficiency [13]. In patients with metastatic disease, open resection of both primary and secondary lesions is preferred, where possible, as in the case of our patient [23].

Metastasis to the various organs is dependent on mutational status [24] and occurs via hematogenous or lymphatic routes usually to the bones, lungs, lymph nodes and liver [15]. Poor survival is associated with metastases to the liver and lungs especially in those with SDHB mutations compared to sporadic disease [24, 25]. Local therapies like radiotherapy, nonsurgical ablative therapy, and trans-arterial chemoembolization (TACE) may be considered in the treatment of liver metastasis, where surgical resection in not possible [26, 27]. External beam radiation therapy (EBRT) at doses > 40 Gy has been shown to provide symptom and local tumor control for sites other than liver such as soft tissue and bones [27]. Local ablative therapies such as radiofrequency ablation, cryoablation, and ethanol ablation are generally used in tumors < 4 cm and have been demonstrated to have up to 85% efficacy for local control and 92% for symptomatic control, making them a safe and effective treatment modality [28], whereas TACE may be useful especially for patients with multiple liver metastases. All these procedures used in local ablation may induce catecholamine surge causing hypertensive crisis, may require premedication and therefore must be closely monitored during treatment [29].

Systemic therapies also play a role in the management of unresectable disease and metastases involving organs other than the liver. 131I-MBIG has been shown to alleviate symptoms and stabilize tumor growth, with a study showing a complete response in 10%, partial response in 20% and a 5-year survival of 64% [30]. Sixty percent of Iobenguane I-131 avid tumors respond to MIBG, and it has been suggested that MBIG may be used in patients who have (a) unresectable progressive pheochromocytoma/paraganglioma, (b) symptoms from disease not amenable to locoregional control, or (c) a high tumor burden and few bony metastases [31].

As PCCs have been shown to express somatostatin receptor types 2 (SSTR2) and 3 (SSTR3), analogs such as DOTATOC and DOTATOC labeled with indium (111In), gallium (68Ga), yttrium (90Y), and lutetium (177Lu) have been used in both detection and therapy [32]. Studies have shown that peptide receptor radioligand therapy (PRRT) using Yttrium-90-labeled DOTA0-Tyr3-octreotide and lutetium Lu-177 dotatate achieved disease control or a partial response between 71 and 90% in patients with progressive unresectable pheochromocytoma and has a disease control rate of 71% [32, 33]. Systemic chemotherapy using a combination of cyclophosphamide, vincristine, doxorubicin, and dacarbazine is also used for patients with unresectable and rapidly progressive pheochromocytoma, especially in patients with high tumor burden or many bony metastases [34], with a higher efficacy in patients with SHB mutation [35]. A combination of cyclophosphamide, vincristine, doxorubicin, and dacarbazine is typically used [28], though some suggest that tumors with SDH mutations respond to temozolomide either as a single agent or in combination with other chemotherapeutic drugs such as streptozotozin, cisplatin, and 5-fluorouracil [29].

Recent understanding of the molecular pathways especially with kinase signaling involving cluster 2 PCCs have been shown to be associated with PCCs. Cluster 2 mutations involve germline mutations of the rearranged-during-transfection (RET) oncogene associated with MEN 2A/2B disease, neurofibromin (NF1), transmembrane protein 127 (TMEM127), Myc-associated factor (MAX) and somatic mutations of HRAS and fibroblast growth factor receptor 1 (FGFR1) genes [12]. The risk of metastasis in association with the cluster 2 mutations range between 2-12 %[12]. Targeted therapies such as Sunitinib, a tyrosine kinase inhibitor, has shown promise in the treatment of metastatic pheochromocytoma. A recent phase 2 trial in patients with progressive PPGL demonstrated a disease control rate of 83% and a median progression-free survival of 13 months [36].