Pheochromocytoma (PCC) is a rare catecholamine-producing tumor arising from the chromaffin cells in the adrenal medulla. The incidence is about 0.3–0.5 cases per 100,000 person-years (1, 2). Excessive secretion of catecholamines (CAs) (epinephrine, norepinephrine, and dopamine) may evoke typical manifestations such as sustained or episodic hypertension, headaches, palpitations, and perspiration. However, it is not an unusual phenomenon that pheochromocytomas were discovered as adrenal incidentalomas with the widespread use of cross-sectional imaging for unrelated disorders.

Since surgical removal of pheochromocytoma is the cornerstone of therapy, intraoperative hemodynamic instability (IHD), which could cause intraoperative and postoperative catecholamine-induced life-threatening complications, is the major concern of a multidisciplinary team. Despite a number of previous studies, the predictive risk factors associated with IHD during pheochromocytoma resection remain inconclusive (3–7). In the present study, the aim was to develop and validate a nomogram that incorporated multiple preoperative radiological and clinical parameters for individual preoperative prediction of hemodynamic instability during the surgery of pheochromocytoma.

Special considerations are required for IHD during resection of pheochromocytoma, a functional tumor, as blood-pressure spike and drop are associated with an increased risk of complications. Current evidence shows that age, preoperative blood pressure, orthostatic hypotension, BMI, body weight change, HCT, heart rate, higher catecholamine levels, tumor size, alpha-blockade type, hydration status, and procedure type may be associated with IHD during pheochromocytoma resection (3–7). However, CT, the most widely used and effective imaging modality for the diagnosis of PCC, provides excellent morphologic data but was seldomly used to predict IHD (11). Therefore, we aimed to develop a user-friendly tool that specially incorporates CT characteristics to predict the risk of encountering IHD.

This present study identified seven preoperative predictive factors for intraoperative hemodynamic instability during unilateral adrenalectomy, including age, tumor shape, Mayo Adhesive Probability score, laterality, necrosis, body mass index, and surgical technique. We utilized the seven predictive factors to create a nomogram that predicts the likelihood of the occurrence of IHD.

In our results, age >60 years was an effective predictor for IHD. We speculated that the observed characteristics might be the combined effect of diminished cardiac reserve and increased vascular resistances responding to intraoperative stimulations.

In our study, lobular type and irregular type were associated with IHD with regard to tumor shape. The present analyses showed that round type was frequently found in pheochromocytomas (9, 12). To the best of our knowledge, the shape of lesions was not adopted into reports on risk factors of IHD in patients with pheochromocytoma. Moreover, we speculated that lobular type and irregular type might be the impact of activated angiogenesis and prominent vascular network.

Another effective predictor for IHD was the MAP. Davidiuk et al. first sought to create an image-based scoring system predicting intraoperative adherent perinephric fat (APF) during robotic partial nephrectomy (8). A large body of evidence noted that APF, the so-called toxic fat, is a risk factor of surgical outcomes of partial nephrectomy (PN), such as operative time, blood loss, and rates of conversion, but not associated with postoperative complications (13–15). It is not an uncommon phenomenon that the encountered sticky fat renders the surgical resection of the pheochromocytoma more difficult, resulting in hypertensive episodes and/or tachycardia as well as temporary cessation of tumor manipulation.

Our analysis also implied that necrosis is a predictor for IHD in patients with pheochromocytoma. Studies investigating the relationship of necrotic changes on CT and IHD are scarce, and contemporary series were designed to evaluate CT features in the diagnosis and prognosis of pheochromocytomas. Andreoni et al. reported that patients with cystic pheochromocytomas have more chance of being asymptomatic and having negative biochemical evaluations (16). However, Motta-Ramirez et al. reported that none of radiologic parameters including necrosis were found to differentiate incidental and symptomatic pheochromocytomas (17). Besides, Bai et al. excluded tumor necrosis as a risk predictor for IHD (7). It has been suggested that larger lesions are usually heterogeneous because of tissue necrosis or internal hemorrhage (18, 19).

With respect to the association of BMI with morbidity, the population-based findings could not be applied in patients with pheochromocytoma. Khan et al. noted that higher BMI was associated with significantly increased risk of developing CVD as well as cardiovascular morbidity (20). In addition, a meta-analysis of Mendelian randomized studies confirmed the association of obesity measured using BMI with type 2 diabetes and coronary artery disease (21). However, previous studies found that low BMI served as an independent risk factor for cardiovascular morbidity as well as severer morbidity in patients after pheochromocytoma surgery (22). Besides, our study showed that low BMI was a significant predictor for IHD, confirming earlier reports (7).

For laterality, the right-sided pheochromocytomas were associated with a higher risk of IHD than the left-sided in our study. Amar et al. noted that right-sided tumors were more common and larger, excreted greater amounts of metanephrines, and presented more frequently as incidentalomas than the left-sided (23). In addition, the shorter course and more common variation of the right suprarenal vein may render the surgery for right-sided tumor more vulnerable to substantial hemodynamic perturbations (24).

Our study found that incidence of IHD was higher in open adrenalectomy compared to minimal invasive adrenalectomy including laparoscopic and robot-assisted surgeries. This was consistent with a recent published meta-analysis of 9 studies by Li et al. (25). Open resection for large pheochromocytomas was strongly recommended in the 2014 guidelines of the Endocrine Society (26). Laparoscopic adrenalectomy including the transperitoneal approach and retroperitoneal approach has become a safe and standard technique for treatment of benign adrenal neoplasms (26–30). To be noted, Shiraishi et al. reported that the retroperitoneal approach was superior to the transperitoneal approach for right-sided large pheochromocytomas in terms of operation time, pneumoperitoneum time, and estimated blood loss. The superior perioperative outcomes of the retroperitoneal approach over the transperitoneal approach for patients with PCC were suggested from a meta-analysis of four retrospective studies (31).

This nomogram comprised of both preoperative clinical and CT risk factors could contribute to optimize treatment strategies by quantifying the probability of IHD before pheochromocytoma surgery. Once identified as a group with high risk of IHD based on the nomogram, patients should refer to a tertiary-care hospital and receive treatment from the experienced surgical team; besides, admission to intensive care unit after operation may be necessary in order to reduce the risk of postoperative complications.

Our study had several limitations in addition to those inherent in the retrospective design. Firstly, the sample size of this study is relatively small partly because we excluded a number of patients with only unenhanced CT scans. Secondly, due to a decade interval, methods of detecting catecholamines and metanephrines were not constant. Thirdly, this nomogram was developed from the cohort at a single center without external validation and adopted relatively simple parameters. Based on the uniform and complete radiological data of pheochromocytomas, further research on radiomics is needed.

In conclusion, our nomogram based on clinical and CT parameters could facilitate the treatment strategy according to assessment of the risk of IHD in patients with pheochromocytoma. In addition, this nomogram needs external validation in a larger cohort.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Institutional Review Board at the First Affiliated Hospital, Sun Yat-sen University (Guangdong, China). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

Conceptualization: FZ and YY. Data collection: ZZ, JY. Methodology: CL. CT analysis: WP, YG. Formal analysis and investigation: ZZ, CL, JY. Resources: SL, FZ. Writing—original draft preparation: ZZ. Writing—review and editing: FZ, YY. Visualization, CL, SJ. Supervision: FZ, YY. Project administration: FZ. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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